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J	Awi, NJ; Armon, S; Peh, KB; Peh, SC; Teow, SY				Awi, Noel Jacques; Armon, Subasri; Peh, Kaik-Boo; Peh, Suat-Cheng; Teow, Sin-Yeang			High expression of LC3A, LC3B, and p62/SQSTM1 autophagic proteins in human colonic ganglion cells	MALAYSIAN JOURNAL OF PATHOLOGY			English	Article						autophagy; colorectal cancer; colon; ganglion cells; LC3A; LC3B; p62/SQSTM1; immunohistochemistry		Introduction: Autophagy is a mechanism that degrades large damaged organelles and misfolded proteins to maintain the homeostasis in all cells. It plays double-faceted roles in tumourigenesis and prevention of various cancers. In our side observation of investigating the prognostic value of autophagy in colorectal cancer (CRC), we found high expression of autophagy proteins (LC3A, LC3B, and p62/SQSTM1) in the colonic ganglion cells. To our best understanding, this is the first paper reporting such finding. Materials and Methods: Formalin- ixed paraffin-embedded (FFPE) CRC tissues blocks were retrieved and confirmed by haematoxylin & eosin (H&E) staining. Immunohistochemistry (IHC) targeting autophagy proteins (LC3A, LC3B, and p62/SQSTM1) was then performed followed by pathological examination. Results: All three autophagy proteins were present in both normal and tumour tissues of CRC patients. Interestingly, high expression of autophagy proteins in colonic ganglion cells was consistently seen regardless of tissue type (normal or cancer) or tumour site (caecum, ascending, transverse, descending, sigmoid colon and rectum). Conclusions: This work highlights the high autophagic activities in human colonic ganglion cells.	[Awi, Noel Jacques; Peh, Suat-Cheng; Teow, Sin-Yeang] Sunway Univ, Sch Healthcare & Med Sci, Dept Med Sci, Jalan Univ, Subang Jaya 47500, Selangor Darul, Malaysia; [Armon, Subasri] Hosp Kuala Lumpur, Pathol Dept, Jalan Pahang, Kuala Lumpur 50586, Malaysia; [Peh, Kaik-Boo] Mahkota Med Ctr, Jalan Merdeka, Melaka 75000, Malaysia; [Peh, Suat-Cheng] Sunway Med Ctr, Jalan Lagoon Selatan, Subang Jaya 47500, Selangor Darul, Malaysia		Teow, SY (corresponding author), Sunway Univ, Subang Jaya 47500, Selangor Darul, Malaysia.	ronaldt@sunway.edu.my	Teow, Sin-Yeang/J-2253-2019	Teow, Sin-Yeang/0000-0002-3824-0224	Sunway University [INT-2019-SHMS-DMS-01]; National Cancer Council Malaysia (MAKNA) Cancer Research Award (CRA) 2016 [EXT-SIDS-SIHD-MAKNA-2017-01]; Sunway Medical Centre Research Funds [SRC/002/2017/FR, SRC/003/2017/FR]; Sunway University	This work was funded by Sunway University Internal Research Grant 2019 (INT-2019-SHMS-DMS-01), National Cancer Council Malaysia (MAKNA) Cancer Research Award (CRA) 2016 (EXT-SIDS-SIHD-MAKNA-2017-01), and Sunway Medical Centre Research Funds (SRC/002/2017/FR and SRC/003/2017/FR). Noel Jacques Awi is the recipient of Sunway University Postgraduate Degree by Research Scholarship.	Boya P, 2017, EYE, V31, P185, DOI 10.1038/eye.2016.278; Gil J, 2016, BIOMARK MED, V10, P1081, DOI 10.2217/bmm-2016-0083; Kim SH, 2008, J NEUROSCI RES, V86, P2943, DOI 10.1002/jnr.21738; Knoferle J, 2010, P NATL ACAD SCI USA, V107, P6064, DOI 10.1073/pnas.0909794107; Lee K, 2016, CURR EYE RES, V41, P1367, DOI 10.3109/02713683.2015.1119856; Li HY, 2019, CELL TRANSPLANT; Lin WJ, 2014, AUTOPHAGY, V10, P1692, DOI 10.4161/auto.36076; Mokarram P, 2017, AUTOPHAGY, V13, P781, DOI 10.1080/15548627.2017.1290751; Pang SW, 2018, CELL CULTURE, P75; Rodriguez-Muela N, 2012, AUTOPHAGY, V8, P286, DOI 10.4161/auto.8.2.18982; Rubinsztein DC, 2011, CELL, V146, P682, DOI 10.1016/j.cell.2011.07.030; Santana-Codina N, 2017, ANNU REV CANC BIOL, V1, P19, DOI 10.1146/annurev-cancerbio-041816-122338; Sivridis E, 2010, AM J PATHOL, V176, P2477, DOI 10.2353/ajpath.2010.090049; White E, 2015, J CLIN INVEST, V125, P42, DOI 10.1172/JCI73941	14	0	0	0	1	MALAYSIAN JOURNAL PATHOLOGY	KUALA LUMPUR	UNIV MALAYSIA, FAC MEDICINE, DEPT PATHOLOGY, KUALA LUMPUR, 59100, MALAYSIA	0126-8635			MALAYS J PATHOL	Malay. J. Pathol.	APR	2020	42	1					85	90					6	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	LI9ZW	WOS:000529835400011	32342935				2022-04-25	
J	Wu, WKK; Sung, JJY; Wu, YC; Li, HT; Yu, L; Li, ZJ; Cho, CH				Wu, William Ka Kei; Sung, Joseph Jao Yiu; Wu, Ya Chun; Li, Hai To; Yu, Le; Li, Zhi Jie; Cho, Chi Hin			Inhibition of cyclooxygenase-1 lowers proliferation and induces macroautophagy in colon cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Cyclooxygenase-1; Colon cancer; Proliferation; Cell cycle; Macroautophagy	FAMILIAL ADENOMATOUS POLYPOSIS; SELECTIVE INHIBITOR; CARCINOMA CELLS; RECTAL ADENOMAS; AUTOPHAGY; DEATH; SUPPRESSION; APOPTOSIS; CELECOXIB; MOFEZOLAC	Evolving evidence supports that cyclooxygenase-1 (COX-1) takes part in colon carcinogenesis. The effects of COX-1 inhibition on colon cancer cells, however, remains obscured. In this Study, we demonstrate that COX-1 inhibitor sc-560 inhibited colon cancer cell proliferation with concomitant G(0)/G(1)-phase cell cycle arrest. The anti-proliferative effect was associated with down-regulation of c-Fos, cyclin E-2 and E2F-1 and up-regulation of p21(Waf1/Cip1) and p27(Kip1). In addition, sc-560 induced macroautophagy, an emerging mechanism of tumor suppression, as evidenced by the formation of LC3(+) autophagic vacuoles, enhanced LC3 processing, and the accumulation of acidic vesicular organelles and autolysosomes. In this connection, 3-methyladenine, a Class III phosphoinositide 3-kinase inhibitor, significantly abolished the formation of LC3(+) autophagic vacuoles and the processing of LC3 induced by sc-560. To conclude, this study reveals the unreported relationship between COX-1 and proliferation/macroautophagy of colon cancer cells. (C) 2009 Elsevier Inc. All rights reserved.	[Wu, William Ka Kei; Sung, Joseph Jao Yiu; Yu, Le; Cho, Chi Hin] Chinese Univ Hong Kong, Inst Digest Dis, Fac Med, Hong Kong, Hong Kong, Peoples R China; [Wu, William Ka Kei; Sung, Joseph Jao Yiu] Chinese Univ Hong Kong, Dept Med & Therapeut, Fac Med, Hong Kong, Hong Kong, Peoples R China; [Wu, William Ka Kei; Wu, Ya Chun; Li, Hai To; Yu, Le; Li, Zhi Jie; Cho, Chi Hin] Chinese Univ Hong Kong, Dept Pharmacol, Shatin, Hong Kong, Peoples R China		Sung, JJY (corresponding author), Prince Wales Hosp, Dept Med & Therapeut, 9-F Clin Sci Bldg, Shatin, Hong Kong, Peoples R China.	wukakei@cuhk.edu.hk; joesung@cuhk.edu.hk; chcho@cuhk.edu.hk	Sung, Joseph J. Y./R-3203-2018; Wu, William K.K./A-3277-2009; Cho, Chi Hin/C-6543-2014	Sung, Joseph J. Y./0000-0003-3125-5199; Wu, William K.K./0000-0002-5662-5240; Cho, Chi Hin/0000-0002-7658-3260			Akasu T, 2002, HEPATO-GASTROENTEROL, V49, P1259; Arico S, 2002, J BIOL CHEM, V277, P27613, DOI 10.1074/jbc.M201119200; Backer JM, 2008, BIOCHEM J, V410, P1, DOI 10.1042/BJ20071427; Bialik S, 2008, ADV EXP MED BIOL, V615, P177, DOI 10.1007/978-1-4020-6554-5_9; Chen Q, 2008, BLOOD, V111, P4690, DOI 10.1182/blood-2007-09-112904; Chulada PC, 2000, CANCER RES, V60, P4705; Dolara P, 1999, SCAND J GASTROENTERO, V34, P1168; GIARDIELLO FM, 1993, NEW ENGL J MED, V328, P1313, DOI 10.1056/NEJM199305063281805; Ionov Y, 2004, ONCOGENE, V23, P639, DOI 10.1038/sj.onc.1207178; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kitamura T, 2002, CARCINOGENESIS, V23, P1463, DOI 10.1093/carcin/23.9.1463; Martin S, 2005, CANCER RES, V65, P11447, DOI 10.1158/0008-5472.CAN-05-1494; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Mizushima N, 2007, AUTOPHAGY, V3, P542, DOI 10.4161/auto.4600; Munafo DB, 2001, J CELL SCI, V114, P3619; Niho N, 2006, CANCER SCI, V97, P1011, DOI 10.1111/j.1349-7006.2006.00275.x; Paglin S, 2001, CANCER RES, V61, P439; Riehl TE, 2006, AM J PHYSIOL-GASTR L, V291, pG1062, DOI 10.1152/ajpgi.00129.2006; Rubinsztein DC, 2007, NAT REV DRUG DISCOV, V6, P304, DOI 10.1038/nrd2272; Steinbach G, 2000, NEW ENGL J MED, V342, P1946, DOI 10.1056/NEJM200006293422603; Wang M, 2008, J BIOL CHEM, V283, P18678, DOI 10.1074/jbc.M801855200; Wu WKK, 2008, BIOCHEM BIOPH RES CO, V374, P258, DOI 10.1016/j.bbrc.2008.07.031; Yazbeck VY, 2008, EXP HEMATOL, V36, P443, DOI 10.1016/j.exphem.2007.12.008; Zhang ZH, 2000, GASTROENTEROLOGY, V118, P1012, DOI 10.1016/S0016-5085(00)70352-0	24	9	9	0	3	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	APR 24	2009	382	1					79	84		10.1016/j.bbrc.2009.02.140			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	432HO	WOS:000265124300016	19258012				2022-04-25	
J	DiPrima, M; Wang, DR; Troster, A; Maric, D; Terrades-Garcia, N; Ha, T; Kwak, H; Sanchez-Martin, D; Kudlinzki, D; Schwalbe, H; Tosato, G				DiPrima, Michael; Wang, Dunrui; Troester, Alix; Maric, Dragan; Terrades-Garcia, Nekane; Ha, Taekyu; Kwak, Hyeongil; Sanchez-Martin, David; Kudlinzki, Denis; Schwalbe, Harald; Tosato, Giovanna			Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma	MOLECULAR ONCOLOGY			English	Article						cell death; colorectal cancer; Eph receptors; Ephrin ligand; tyrosine kinase signaling	STEM-CELLS; SMALL-INTESTINE; CANCER; EXPRESSION; COLON; PROLIFERATION; GENE; PROGRESSION; METASTASIS; PROMOTES	Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine-dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3-methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy-mediated cell death that follows inhibition of phosphotyrosine-dependent Eph signaling in colorectal cancer cells. A small-molecule inhibitor of the Eph kinase, NVP-BHG712 or its regioisomer NVP-Iso, reduces human colorectal cancer cell growth in vitro and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.	[DiPrima, Michael; Wang, Dunrui; Ha, Taekyu; Kwak, Hyeongil; Sanchez-Martin, David; Tosato, Giovanna] NCI, Lab Cellular Oncol, Ctr Canc Res, 37 Convent Dr,NIH Bethesda Campus,Bldg 37, Bethesda, MD 20892 USA; [Troester, Alix; Kudlinzki, Denis; Schwalbe, Harald] Goethe Univ Frankfurt, Ctr Biomol Magnet Resonance, Inst Organ Chem & Chem Biol, Frankfurt, Germany; [Maric, Dragan] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA; [Terrades-Garcia, Nekane] Univ Barcelona, Hosp Clin, Dept Autoimmune Dis, Vasculitis Res Unit, Barcelona, Spain		Tosato, G (corresponding author), NCI, Lab Cellular Oncol, Ctr Canc Res, 37 Convent Dr,NIH Bethesda Campus,Bldg 37, Bethesda, MD 20892 USA.	Tosatog@mail.nih.gov	Schwalbe, Harald/AAB-3143-2020; Schwalbe, Harald J/F-9023-2010; Sanchez Martin, David/C-9927-2013	Schwalbe, Harald/0000-0001-5693-7909; Schwalbe, Harald J/0000-0001-5693-7909; Tosato, Giovanna/0000-0003-1663-3227; DiPrima, Michael/0000-0001-9189-6049; Sanchez Martin, David/0000-0002-2712-4762	intramural research program of the CCR/NCI/NIH	We thank Dr Seth Steinberg, Biostatistics and Data Management Section, CCR, NCI for his assistance in the statistical analyses; Drs Alexey Nesvizhskii, Felipe Leprevost, and Hui-Yin Chang, Department of Computational Medicine & Bioinformatics, University of Michigan for MSfragger proteomics data analysis; Dr Douglas Lowy for intellectual input and review of the manuscript; Drs Lisa Jenkins, Hidetaka Ohnuki, Ombretta Salvucci, and Maria C. Cid for their help in various aspects of this work; the CCR animal facility personnel; Langston Lim for confocal imaging; Addgene for sharing pk-LC3 vector; and Dr Ira Daar for constructive suggestions. This work was supported by the intramural research program of the CCR/NCI/NIH.	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Oncol.	NOV	2019	13	11					2441	2459		10.1002/1878-0261.12576		OCT 2019	19	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JU0OO	WOS:000491574000001	31545551	Green Published, gold			2022-04-25	
J	Ellington, AA; Berhow, M; Singletary, KW				Ellington, AA; Berhow, M; Singletary, KW			Induction of macroautophagy in human colon cancer cells by soybean B-group triterpenoid saponins	CARCINOGENESIS			English	Article							CARCINOMA CELLS; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; DEATH; AUTOPHAGY; RISK; SOY; CONSUMPTION; DIVERSITY	The impact of triterpenoid saponins isolated from soybeans on suppression of colon cancer cell proliferation was evaluated. Experiments were conducted to determine the effects of a purified soybean B-group saponin extract on cell proliferation, cell-cycle distribution and programmed cell death in cultures of human HCT-15 colon adenocarcinoma cells. Treatment of cells with the soyasaponins at concentrations of 25-500 p.p.m. significantly reduced viable cell numbers after 24 and 48 h of exposure. Treatment of cells with 25 and 100 p.p.m. of saponins also resulted in a transient accumulation of cells in the S-phase of the cell cycle that was associated with a significant reduction of cyclin-dependant kinase-2 (CDK-2) activity. More striking was that, when examined by transmission electron microscopy, soyasaponin-treated cells exhibited an similar to4.5-fold increase in cell morphologies characteristic of Type II non-apoptotic programmed cell death (PCD) including numerous autophagic vacuoles, changes that collectively suggest autophagic cell death. In addition, the protein levels of microtubule-associated protein light chain 3 (LC-3), a specific marker of macroautophagy, increased substantially following soyasaponin treatment. Taken together these results thus indicate that soybean saponins, at physiologically relevant doses, can suppress HCT-15 colon cancer cell proliferation through S-phase cell-cycle delay, and can induce macroautophagy, the hallmark of Type II PCD. These findings suggest that B-group soyasaponins may be another colon-cancer suppressive component of soy that warrants further examination as a potential chemopreventive phytochemical.	Dept Food Sci & Human Nutr, 905 S Goodwin Ave,467 Bevier Hall, Urbana, IL 61801 USA; Natl Ctr Agr Res Serv, Peoria, IL USA		Singletary, KW (corresponding author), Dept Food Sci & Human Nutr, 905 S Goodwin Ave,467 Bevier Hall, Urbana, IL 61801 USA.	kws@uiuc.edu		Berhow, Mark/0000-0002-1278-4071			Bashir T, 2000, P NATL ACAD SCI USA, V97, P5522, DOI 10.1073/pnas.090485297; Bennink MR, 2001, ADV EXP MED BIOL, V492, P11; BERGMAN AS, 1994, BIOCHEM J, V298, P661, DOI 10.1042/bj2980661; Berhow MA, 2002, PHYTOCHEM ANALYSIS, V13, P343, DOI 10.1002/pca.664; BIEDERBICK A, 1995, EUR J CELL BIOL, V66, P3; Bursch W, 2001, CELL DEATH DIFFER, V8, P569, DOI 10.1038/sj.cdd.4400852; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; Butler R, 2000, CELL GROWTH DIFFER, V11, P49; Byers T, 2002, CA-CANCER J CLIN, V52, P92, DOI 10.3322/canjclin.52.2.92; Chiu BCH, 2003, CANCER EPIDEM BIOMAR, V12, P201; CLARKE PGH, 1990, ANAT EMBRYOL, V181, P195, DOI 10.1007/bf00174615; Coulonval K, 2003, J BIOL CHEM, V278, P52052, DOI 10.1074/jbc.M307012200; DANLOY S, 1994, PLANTA MED, V60, P45, DOI 10.1055/s-2006-959406; DOLL R, 1981, JNCI-J NATL CANCER I, V66, P1191, DOI 10.1093/jnci/66.6.1192; Edinger AL, 2003, CANCER CELL, V4, P422, DOI 10.1016/S1535-6108(03)00306-4; Franceschi S, 1997, INT J CANCER, V72, P56, DOI 10.1002/(SICI)1097-0215(19970703)72:1&lt;56::AID-IJC8&gt;3.0.CO;2-3; Fung T, 2003, ARCH INTERN MED, V163, P309, DOI 10.1001/archinte.163.3.309; GESTETNER B, 1968, J AGR FOOD CHEM, V16, P1031, DOI 10.1021/jf60160a025; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Greenwald P, 2001, EUR J CANCER, V37, P948, DOI 10.1016/S0959-8049(01)00070-3; Gurfinkel DM, 2003, NUTR CANCER, V47, P24, DOI 10.1207/s15327914nc4701_3; Hakkak R, 2001, CANCER LETT, V166, P27, DOI 10.1016/S0304-3835(01)00441-4; Hu J, 2004, J AGR FOOD CHEM, V52, P2689, DOI 10.1021/jf035290s; Hu J, 2004, J NUTR, V134, P1867, DOI 10.1093/jn/134.8.1867; Jemal A, 2003, CA-CANCER J CLIN, V53, P5, DOI 10.3322/canjclin.53.1.5; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kanzawa T, 2003, CANCER RES, V63, P2103; Komata T, 2003, BRIT J CANCER, V88, P1277, DOI 10.1038/sj.bjc.6600862; Koratkar R, 1997, NUTR CANCER, V27, P206, DOI 10.1080/01635589709514526; Larsen KE, 2002, HISTOL HISTOPATHOL, V17, P897, DOI 10.14670/HH-17.897; MILGATE J, 1995, NUTR RES, V15, P1223, DOI 10.1016/0271-5317(95)00081-S; Munafo DB, 2001, J CELL SCI, V114, P3619; Ogier-Denis E, 2003, BBA-REV CANCER, V1603, P113, DOI 10.1016/S0304-419X(03)00004-0; Oh YJ, 2001, NUTR CANCER, V39, P132, DOI 10.1207/S15327914nc391_18; Opipari AW, 2004, CANCER RES, V64, P696, DOI 10.1158/0008-5472.CAN-03-2404; Petiot A, 2002, CELL STRUCT FUNCT, V27, P431, DOI 10.1247/csf.27.431; Philipp-Staheli J, 2001, EXP CELL RES, V264, P148, DOI 10.1006/excr.2000.5143; Rao A V, 2000, Drug Metabol Drug Interact, V17, P211; Rowlands JC, 2002, FOOD CHEM TOXICOL, V40, P1767, DOI 10.1016/S0278-6915(02)00181-3; SchulteHermann R, 1997, TOXICOL PATHOL, V25, P89, DOI 10.1177/019262339702500117; SEGLEN PO, 1992, EXPERIENTIA, V48, P158, DOI 10.1007/BF01923509; Singh PN, 1998, AM J EPIDEMIOL, V148, P761, DOI 10.1093/oxfordjournals.aje.a009697; Spector D, 2003, NUTR CANCER, V47, P1, DOI 10.1207/s15327914nc4701_1; SUNG MK, 1995, FOOD CHEM TOXICOL, V33, P357, DOI 10.1016/0278-6915(95)00007-O; SUNG MK, 1995, NUTR CANCER, V23, P259, DOI 10.1080/01635589509514380; Thiagarajan DG, 1998, AM J CLIN NUTR, V68, p1394S, DOI 10.1093/ajcn/68.6.1394S; Yanamandra N, 2003, CLIN EXP METASTAS, V20, P375, DOI 10.1023/A:1024043104803; Yew PR, 2001, J CELL PHYSIOL, V187, P1, DOI 10.1002/1097-4652(2001)9999:9999<1::AID-JCP1049>3.0.CO;2-O; Yoshiki Y, 1998, BIOSCI BIOTECH BIOCH, V62, P2291, DOI 10.1271/bbb.62.2291; Zheng L, 2001, EXP CELL RES, V264, P2, DOI 10.1006/excr.2000.5129	50	138	152	2	14	OXFORD UNIV PRESS	OXFORD	GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND	0143-3334	1460-2180		CARCINOGENESIS	Carcinogenesis	JAN	2005	26	1					159	167		10.1093/carcin/bgh297			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	885WB	WOS:000226186800019	15471899	Green Published, Bronze			2022-04-25	
J	Knaevelsrud, H; Ahlquist, T; Merok, MA; Nesbakken, A; Stenmark, H; Lothe, RA; Simonsen, A				Knaevelsrud, Helene; Ahlquist, Terje; Merok, Marianne A.; Nesbakken, Arild; Stenmark, Harald; Lothe, Ragnhild A.; Simonsen, Anne			UVRAG mutations associated with microsatellite unstable colon cancer do not affect autophagy	AUTOPHAGY			English	Article						UVRAG; Vps34/PI3K complex; microsatellite instability; colorectal neoplasm; survival; autophagy; tumor suppressor; tumorigenesis; frameshift mutation	PHOSPHATIDYLINOSITOL 3-KINASE COMPLEXES; MISMATCH REPAIR; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; BECLIN 1; INSTABILITY; GENES; CELLS; TUMORIGENESIS; IDENTIFICATION	Reduced levels of autophagy correlate with tumorigenesis, and several inducers of autophagy have been found to be tumor suppressors. One such autophagic inducer is the Beclin 1 binding protein UVRAG, a positive regulator of the class III PI3K/Vps34 complex. UVRAG has been implicated in the formation and maturation of autophagosomes, as well as in endocytic trafficking and suppression of proliferation and in vivo tumorigenicity. In this study we show that approximately one-third of a large series of colon carcinomas with microsatellite instability (MSI) (n = 102) carry a monoallelic UVRAG mutation, leading to expression of a truncated protein, indicating that this event is involved in tumorigenesis. In order to investigate whether the high incidence of UVRAG mutation in MSI colorectal carcinomas is associated with dysfunctional autophagy we analyzed autophagy levels in several colon cancer cell lines that express wild-type or mutant UVRAG protein. No reduction in autophagy was detected in cell lines expressing mutant UVRAG. Consistent with this, depletion of UVRAG in HEK cells stably expressing GFP-LC3 did not inhibit autophagy, but did decrease epidermal growth factor receptor (EGFR) degradation. Overall our results show that there is no correlation between the presence of the monoallelic UVRAG mutation and inhibition of autophagy. Thus, our data indicate that mechanisms other than autophagy contribute to the tumorigenicity of microsatellite unstable colon carcinomas with monoallelic UVRAG mutation.	[Knaevelsrud, Helene; Simonsen, Anne] Univ Oslo, Inst Basic Med Sci, Oslo, Norway; [Knaevelsrud, Helene; Ahlquist, Terje; Merok, Marianne A.; Nesbakken, Arild; Stenmark, Harald; Lothe, Ragnhild A.] Univ Oslo, Ctr Canc Biomed, Oslo, Norway; [Merok, Marianne A.; Nesbakken, Arild; Stenmark, Harald; Lothe, Ragnhild A.] Univ Oslo, Fac Med, Oslo, Norway; [Knaevelsrud, Helene; Stenmark, Harald] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Biochem, Oslo, Norway; [Ahlquist, Terje; Merok, Marianne A.; Lothe, Ragnhild A.] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Canc Prevent, Oslo, Norway; [Merok, Marianne A.; Nesbakken, Arild] Oslo Univ Hosp Aker, Dept Surg, Oslo, Norway		Simonsen, A (corresponding author), Univ Oslo, Inst Basic Med Sci, Oslo, Norway.	anne.simonsen@medisin.uio.no	Knævelsrud, Helene/G-9302-2016; Stenmark, Harald/B-8868-2008; Knævelsrud, Helene/E-5279-2010	Knævelsrud, Helene/0000-0001-8848-8829; Lothe, Ragnhild/0000-0002-1693-1032; Simonsen, Anne/0000-0003-4711-7057	EMBIO, University of Oslo; Norwegian Cancer SocietyNorwegian Cancer Society; Research Council of NorwayResearch Council of Norway	We thank Sharon Tooze for the gift of the HEK CFP-LC3 cells. H.K. is supported by grants from EMBIO, University of Oslo. A.S. is supported by grants from the Norwegian Cancer Society and the Research Council of Norway.	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J	Sun, YZ; Mironova, V; Chen, Y; Lundh, EPF; Zhang, Q; Cai, YP; Vasiliou, V; Zhang, YW; Garcia-Milian, R; Khan, SA; Johnson, CH				Sun, Yazhi; Mironova, Varvara; Chen, Ying; Lundh, Elliott P. F.; Zhang, Qian; Cai, Yuping; Vasiliou, Vasilis; Zhang, Yawei; Garcia-Milian, Rolando; Khan, Sajid A.; Johnson, Caroline H.			Molecular Pathway Analysis Indicates a Distinct Metabolic Phenotype in Women With Right-Sided Colon Cancer	TRANSLATIONAL ONCOLOGY			English	Article							COLORECTAL-CANCER; DENDRITIC CELLS; TUMOR REJECTION; EXPRESSION; EPIDEMIOLOGY; VACCINATION; AUTOPHAGY; SATB2; LEADS	Colon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided colon cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men, but have a higher propensity for RCC. The reason for this difference is not known; however, identification of sex-specific differences in gene expression by tumor anatomical location in the colon could provide further insight. Moreover, it could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancers using four publicly available annotated data sets housed in the National Center for Biotechnology Information's Gene Expression Omnibus. We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared with women with LCC. Specifically, we showed the downregulation of 5' AMP-activated protein kinase alpha subunit (AMPK alpha) and anti-tumor immune responses in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.	[Sun, Yazhi; Mironova, Varvara; Chen, Ying; Lundh, Elliott P. F.; Zhang, Qian; Cai, Yuping; Vasiliou, Vasilis; Zhang, Yawei; Garcia-Milian, Rolando; Johnson, Caroline H.] Yale Univ, Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA; [Mironova, Varvara; Khan, Sajid A.] Yale Univ, Sch Med, Dept Surg, Sect Surg Oncol, New Haven, CT 06510 USA; [Zhang, Qian] Harbin Med Univ, Affiliated Hosp 2, Dept Colorectal Surg, Harbin, Heilongjiang, Peoples R China; [Zhang, Yawei] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA; [Garcia-Milian, Rolando] Yale Sch Med, Cushing Whitney Med Lib, Bioinformat Support Program, New Haven, CT USA		Johnson, CH (corresponding author), Yale Univ, Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA.	caroline.johnson@yale.edu		Garcia-Milian, Rolando/0000-0003-1557-566X; Johnson, Caroline/0000-0002-5298-1299	Women's Health Research at Yale; Yale Cancer Center; National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R21CA223686-01, 5R24AA022057-08, 5R01AA021724-05, 5K01AA025093-04]; National Center for Advancing Translational Science (NCATS), components of the NIH [UL1 TR001863]	The authors would like to thank Women's Health Research at Yale, and the Yale Cancer Center for funding this project (C.J., S.K., Y.Z.). They would also like to acknowledge funding from the National Institutes of Health (NIH); 1R21CA223686-01 (CJ, SJ), 5R24AA022057-08 (VV), 5R01AA021724-05 (VV) and 5K01AA025093-04 (YC). This publication was also made possible by CTSA Grant Number UL1 TR001863 from the National Center for Advancing Translational Science (NCATS), components of the NIH, and NIH roadmap for Medical Research (SK). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.	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Oncol.	JAN	2020	13	1					42	56		10.1016/j.tranon.2019.09.004			15	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JW1MD	WOS:000502822300006	31760268	Green Published, gold, Green Submitted			2022-04-25	
J	Wu, Q; Deng, JJ; Fan, DD; Duan, ZG; Zhu, CH; Fu, RZ; Wang, SS				Wu, Qian; Deng, Jianjun; Fan, Daidi; Duan, Zhiguang; Zhu, Chenhui; Fu, Rongzhan; Wang, Shanshan			Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells	BIOCHEMICAL PHARMACOLOGY			English	Article						Apoptosis; Autophagic cell death; Colorectal cancer; Ginsenoside Rh4; ROS/JNK/p53 pathway	CARCINOMA CELLS; DOWN-REGULATION; CYCLE; INDUCTION; SUPPRESSION; INHIBITION; EXPRESSION; CROSSTALK; ANTITUMOR; ROLES	The use of ginsenosides in cancer therapy has been intensively investigated. The ginsenoside Rh4 (Rh4), a rare saponin obtained from Panax notoginseng, dissolves in water more readily than total saponins, making this compound easier to use in anti-cancer pharmaceutics. Here, we investigated the antiproliferative activity and mechanisms of Rh4 in colorectal cancer, both in vivo and in vitro. A colorectal cancer xenograft model showed that Rh4 significantly inhibited tumor growth with few side effects. CCK-8 assays, flow cytometric analysis, Western blotting and immunohistochemistry revealed that Rh4 effectively suppressed colorectal cancer cell proliferation via inducing G(0)/G(1) phase arrest, caspase-dependent apoptosis and autophagic cell death but was not significantly cytotoxic to normal colon epithelial cells. Furthermore, apoptosis played a dominant role in Rh4-induced cell death, as the pan-caspase inhibitor Z-VAD-FMK blocked cell death to a greater extent than the autophagy inhibitor 3-methyladenine. Moreover, Rh4 increased reactive oxygen species (ROS) accumulation and subsequently activated the JNK-p53 pathway. An ROS scavenger and JNK and p53 inhibitors significantly attenuated Rh4-induced apoptosis and autophagy. Thus, the present study is the first to illustrate that Rh4 triggers apoptosis and autophagy via activating the ROS/JNK/p53 pathway in colorectal cancer cells, providing basic scientific evidence that Rh4 shows great potential as an anti-cancer agent. (C) 2017 Elsevier Inc. All rights reserved.	[Wu, Qian; Deng, Jianjun; Fan, Daidi; Duan, Zhiguang; Zhu, Chenhui; Fu, Rongzhan; Wang, Shanshan] Northwest Univ Xian, Sch Chem Engn, Shaanxi Key Lab Degradable Biomed Mat, 229 North Taibai Rd, Xian 710069, Shaanxi, Peoples R China; [Wu, Qian; Deng, Jianjun; Fan, Daidi; Duan, Zhiguang; Zhu, Chenhui; Fu, Rongzhan; Wang, Shanshan] Northwest Univ Xian, Sch Chem Engn, Shaanxi R&D Ctr Biomat & Fermentat Engn, 229 North Taibai Rd, Xian 710069, Shaanxi, Peoples R China		Fan, DD (corresponding author), Northwest Univ Xian, Sch Chem Engn, Shaanxi Key Lab Degradable Biomed Mat, 229 North Taibai Rd, Xian 710069, Shaanxi, Peoples R China.	fandaidi@nwu.edu.cn	Jianjun, Deng/U-5306-2019	Jianjun, Deng/0000-0002-3057-6997	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21476182, 21776227, 21776228, 21506171]; Shaanxi Key Laboratory of Degradable Biomedical Materials Program [2014SZS07-K04, 2014SZS07-P05, 14JS104]; Shaanxi R&D Center of Biomaterials and Fermentation Engineering Program [2015HBGC-04]	The present study was financially supported by Grants from the National Natural Science Foundation of China (21476182, 21776227, 21776228, and 21506171), the Shaanxi Key Laboratory of Degradable Biomedical Materials Program (2014SZS07-K04, 2014SZS07-P05, and 14JS104), and the Shaanxi R&D Center of Biomaterials and Fermentation Engineering Program (2015HBGC-04).	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Pharmacol.	FEB	2018	148						64	74		10.1016/j.bcp.2017.12.004			11	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	FX5SZ	WOS:000426141200006	29225132				2022-04-25	
J	Xie, CM; Chan, WY; Yu, S; Zhao, J; Cheng, CHK				Xie, Chuan-Ming; Chan, Wood Yee; Yu, Sidney; Zhao, Jun; Cheng, Christopher H. K.			Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygen species generation and JNK activation	FREE RADICAL BIOLOGY AND MEDICINE			English	Article						Bufalin; Colon cancer; ROS; JNK; LC3; Apoptosis; Autophagy; Cell death; Cancer therapy	LEUKEMIA U937 CELLS; HEPATOCELLULAR-CARCINOMA; INDUCED APOPTOSIS; SIGNALING PATHWAYS; ARSENIC TRIOXIDE; UP-REGULATION; GLIOMA-CELLS; INHIBITION; PROTEIN; LC3	Colorectal cancer is the second most common cause of cancer death in the world and about half of the patients with colorectal cancer require adjuvant therapy after surgical resection. Therefore, the eradication of cancer cells via chemotherapy constitutes a viable approach to treating patients with colorectal cancer. In this study, the effects of bufalin isolated from a traditional Chinese medicine were evaluated and characterized in HT-29 and Caco-2 human colon cancer cells. Contrary to its well-documented apoptosis-promoting activity in other cancer cells, bufalin did not cause caspase-dependent cell death in colon cancer cells, as indicated by the absence of significant early apoptosis as well as poly(ADP-ribose) polymerase and caspase-3 cleavage. Instead, bufalin activated an autophagy pathway, as characterized by the accumulation of LC3-II and the stimulation of autophagic flux. The induction of autophagy by bufalin was linked to the generation of reactive oxygen species (ROS). ROS activated autophagy via the c-Jun NH(2)-terminal kinase (JNK). JNK activation increased expression of ATG5 and Beclin-1. ROS antioxidants (N-acetylcysteine and vitamin C), the JNK-specific inhibitor SP600125, and JNK2 siRNA attenuated bufalin-induced autophagy. Our findings unveil a novel mechanism of drug action by bufalin in colon cancer cells and open up the possibility of treating colorectal cancer through a ROS-dependent autophagy pathway. (C) 2011 Elsevier Inc. All rights reserved.	[Xie, Chuan-Ming; Chan, Wood Yee; Yu, Sidney; Cheng, Christopher H. K.] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China; [Zhao, Jun] Shanghai Normal Univ, Coll Life & Environm Sci, Shanghai 200234, Peoples R China; [Cheng, Christopher H. K.] Chinese Univ Hong Kong, Ctr Novel Funct Mol, Shatin, Hong Kong, Peoples R China		Cheng, CHK (corresponding author), Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China.	chkcheng@cuhk.edu.hk	CHENG, Ki Christopher/R-9641-2018; Bin Sidney Yu, Siu/R-4936-2018; Chan, Wood Yee/R-6692-2018; Xie, Chuan-Ming/AAT-9557-2021	CHENG, Ki Christopher/0000-0001-8970-9048; Bin Sidney Yu, Siu/0000-0001-9643-2729; Chan, Wood Yee/0000-0002-7114-1463; Xie, Chuan-Ming/0000-0003-4362-6612	Chinese University of Hong KongChinese University of Hong Kong	This work was supported by a Strategic Investments Scheme from the Chinese University of Hong Kong. The authors thank the Chinese University of Hong Kong for the provision of Direct Grants and graduate studentships. The authors also thank Jean Lai-Sin Kung and Cathy Yui Hung for their valuable technical assistance in transmission electron microscopy.	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Biol. Med.	OCT 1	2011	51	7					1365	1375		10.1016/j.freeradbiomed.2011.06.016			11	Biochemistry & Molecular Biology; Endocrinology & Metabolism	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Endocrinology & Metabolism	818GV	WOS:000294740700009	21763418				2022-04-25	
J	Li, SG; Wang, XW; Wang, G; Shi, PY; Lin, SL; Xu, DF; Chen, B; Liu, AL; Huang, LY; Lin, XH; Yao, H				Li, Shaoguang; Wang, Xuewen; Wang, Gang; Shi, Peiying; Lin, Shilan; Xu, Dafen; Chen, Bing; Liu, Ailin; Huang, Liying; Lin, Xinhua; Yao, Hong			Ethyl Acetate Extract of Selaginella doederleinii Hieron Induces Cell Autophagic Death and Apoptosis in Colorectal Cancer via PI3K-Akt-mTOR and AMPK alpha-Signaling Pathways	FRONTIERS IN PHARMACOLOGY			English	Article						colorectal carcinoma; autophagy; apoptosis; Selaginella doederleinii Hieron ethyl acetate; antitumor mechanism	KAPPA-B ACTIVATION; LUNG-CANCER; CYCLE ARREST; AMENTOFLAVONE; A549; GROWTH; SUPPRESSION; INHIBITION; BIFLAVONES; FLAVONES	Colorectal cancer is one type of cancer with high incidence rate and high mortality worldwide. Thus, developing new chemotherapeutic drugs is important. The Selaginella doederleinii Hieron ethyl acetate (SDEA) extract showed good anti-colon cancer effect in vitro and in vivo, but its mechanism is unclear. This study aimed to further reveal the anti-colon cancer effect of SDEA and its possible mechanism. The effects on cell viability, apoptosis, autophagy, and cell cycle in colorectal cells (HT29 and HCT116) were studied using MTT assay, fluorescence microscopy, transmission electron microscopy, and flow cytometry. The mechanisms were further studied using cell transfection, Western blot, and real-time quantitative polymerase chain reaction assay. The effect of xenotransplantation in vivo was observed using immunohistochemistry. Results showed that SDEA inhibited cell proliferation and induced cell morphological changes, cell cycle arrest, autophagy, and apoptosis. It also induced loss of mitochondrial membrane potential, increased the autophagic flux, raised the ratio of Bax/Bcl-2, activated caspases, and inhibited PI3K-Akt-mTOR signaling pathways. Furthermore, SDEA inhibited the growth of xenograft tumors in a dose-dependent manner. Immunohistochemistry analysis confirmed the alteration of autophagy- and apoptosis-related proteins and immunohistochemical microvascular density in xenografts, which were consistent with the results in vitro. Therefore, SDEA is important for developing candidate drugs against colorectal cancers.	[Li, Shaoguang; Wang, Xuewen; Wang, Gang; Lin, Shilan; Xu, Dafen; Chen, Bing; Liu, Ailin; Huang, Liying; Lin, Xinhua; Yao, Hong] Fujian Med Univ, Sch Pharm, Dept Pharmaceut Anal, Fuzhou, Peoples R China; [Li, Shaoguang; Wang, Xuewen; Wang, Gang; Lin, Shilan; Xu, Dafen; Chen, Bing; Liu, Ailin; Lin, Xinhua; Yao, Hong] Fujian Med Univ, Higher Educ Key Lab Nano Biomed Technol Fujian Pr, Fuzhou, Peoples R China; [Li, Shaoguang; Wang, Xuewen; Wang, Gang; Lin, Shilan; Xu, Dafen; Chen, Bing; Liu, Ailin; Lin, Xinhua; Yao, Hong] Fujian Med Univ, Nano Med Technol Res Inst, Fuzhou, Peoples R China; [Shi, Peiying] Fujian Agr & Forestry Univ, Dept Tradit Chinese Med Resource & Bee Prod, Bee Sci Coll, Fuzhou, Peoples R China; [Yao, Hong] Fujian Med Univ, Fujian Key Lab Drug Target Discovery & Struct & F, Fuzhou, Peoples R China		Lin, XH; Yao, H (corresponding author), Fujian Med Univ, Sch Pharm, Dept Pharmaceut Anal, Fuzhou, Peoples R China.; Lin, XH; Yao, H (corresponding author), Fujian Med Univ, Higher Educ Key Lab Nano Biomed Technol Fujian Pr, Fuzhou, Peoples R China.; Lin, XH; Yao, H (corresponding author), Fujian Med Univ, Nano Med Technol Res Inst, Fuzhou, Peoples R China.; Yao, H (corresponding author), Fujian Med Univ, Fujian Key Lab Drug Target Discovery & Struct & F, Fuzhou, Peoples R China.	xhlin1963@sina.com; yauhung@126.com		Chen, Bing/0000-0002-0026-1249	National Nature Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21775023, 81303298, 81973558]; Joint Funds for the Innovation of Science and Technology, Fujian Province [2017Y9118, 2017Y9123, 2017Y9124]; Fujian Provincial Natural Science Foundation [2018J01596]	The authors gratefully acknowledge the financial supports of the National Nature Science Foundation of China (grant numbers 21775023, 81303298, and 81973558), the Joint Funds for the Innovation of Science and Technology, Fujian Province (grant numbers 2017Y9118, 2017Y9123, and 2017Y9124), and the Fujian Provincial Natural Science Foundation (grant numbers 2018J01596).	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Pharmacol.	OCT 19	2020	11								565090	10.3389/fphar.2020.565090			17	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	OI5II	WOS:000583311600001	33192508	gold, Green Published			2022-04-25	
J	Peng, JQ; Han, SM; Chen, ZH; Yang, J; Pei, YQ; Bao, C; Qiao, L; Chen, WQ; Liu, B				Peng, Jie-qiong; Han, Shu-mei; Chen, Ze-hao; Yang, Jing; Pei, Yan-qing; Bao, Cong; Qiao, Lei; Chen, Wen-qiang; Liu, Bo			Chaperone-mediated autophagy regulates apoptosis and the proliferation of colon carcinoma cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Colorectal cancer; Chaperone-mediated autophagy; Apoptosis; Proliferation	TUMOR-SUPPRESSOR; DEGRADATION; CANCER; TUMORIGENESIS; PROTEINS; UNIQUE	Chaperone-mediated autophagy (CMA) is one of the three types of autophagy. In recent years, CMA has been shown to be associated with the pathogenesis of several types of cancer. However, whether CMA is involved in the pathogenesis of colorectal cancer (CRC) remains unclear. In this study, we investigated CMA activity in tissue specimens from CRC patients and mouse models of colitis-associated CRC (induced by administration of AOM plus DSS). In addition, we down-regulated CMA in CT26 colon carcinoma cells stably transfected with a vector expressing a siRNA targeting LAMP-2A, the limiting component in the CMA pathway, to explore the role of CMA in these cells. Apoptosis was detected using TUNEL assay, and the apoptosis-related proteins were detected using western blotting. Cell proliferation was assessed using MTT assay, Ki-67 labelling and western blotting for PCNA. We found that LAMP-2A expression was significantly increased in CRC patients and mouse models and varied according to the stage of the disease. Inhibition of CMA in CT26 cells facilitated apoptosis, as evidenced by increased TUNEL immunolabeling, increased expression of Bax and Bnip3, and decreased expression of Bcl-2. Cell proliferation assays showed that inhibition of CMA impeded the proliferation of CT26 cells. These data support the hypothesis that CMA is up-regulated in CRC, and inhibition of CMA may be a new therapeutic strategy for CRC patients. (C) 2019 Elsevier Inc. All rights reserved.	[Peng, Jie-qiong] Univ Jinan, Sch Med & Life Sci, Shandong Acad Med Sci, Jinan, Peoples R China; [Peng, Jie-qiong; Han, Shu-mei; Yang, Jing; Pei, Yan-qing; Liu, Bo] Shandong First Med Univ & Shandong Acad Med Sci, Shandong Canc Hosp & Inst, Dept Oncol, Jinan, Peoples R China; [Qiao, Lei; Chen, Wen-qiang] Shandong Univ, Qilu Hosp, Key Lab Cardiovasc Remodeling & Funct Res, Chinese Minist Educ,Chinese Natl Hlth Commiss, 107 Wenhuaxi Rd, Jinan 250012, Peoples R China; [Qiao, Lei; Chen, Wen-qiang] Shandong Univ, Qilu Hosp, Chinese Acad Med Sci, State & Shandong Prov Joint Key Lab Translat Card, 107 Wenhuaxi Rd, Jinan 250012, Peoples R China; [Bao, Cong] Pingyi Cty Peoples Hosp, Dept Pathol, Linyi 273300, Shandong, Peoples R China; [Chen, Ze-hao] Shandong First Med Univ, Tai An, Shandong, Peoples R China		Chen, WQ (corresponding author), Shandong Univ, Qilu Hosp, Key Lab Cardiovasc Remodeling & Funct Res, Chinese Minist Educ, 107 Wen Hua Xi Rd, Jinan 250012, Shandong, Peoples R China.; Chen, WQ (corresponding author), Shandong Univ, Qilu Hosp, Chinese Minist Hlth,Dept Cardiol, State & Shandong Prov Joint Key Lab Translat Card, 107 Wen Hua Xi Rd, Jinan 250012, Shandong, Peoples R China.; Liu, B (corresponding author), Shandong First Med Univ & Shandong Acad Med Sci, Shandong Canc Hosp & Inst, 440 Jiyan Rd, Jinan 250117, Peoples R China.	199262000802@sdu.edu.cn; 15553115688@163.com		Pei, Yanqing/0000-0003-0936-4049	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81770436]; National Key Project of Chronic Non-Communicable Diseases of China [2016 YFC1300403]	This work was supported by grants from the National Natural Science Foundation of China (81770436). This reserach was also supported by the National Key Project of Chronic Non-Communicable Diseases of China (No. 2016 YFC1300403).	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J	Ellington, AA; Berhow, MA; Singletary, KW				Ellington, AA; Berhow, MA; Singletary, KW			Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells	CARCINOGENESIS			English	Article							ALPHA-INTERACTING PROTEIN; SOYBEAN SAPONINS; CARCINOMA CELLS; COLORECTAL-CANCER; GROWTH-FACTOR; AMINO-ACIDS; KINASE-B; AUTOPHAGY; DEATH; RISK	Triterpenoid B-group soyasaponins have been found to induce macroautophagy in human colon cancer cells at concentrations obtainable through consumption of legume foodstuffs. In the present studies the mechanism(s) for this autophagy-inducing action of soyasaponins was evaluated by measuring changes in signal transduction pathways associated with autophagy. Specifically, inhibition of the Akt signaling pathway and enhanced activity of ERK1/2 have previously been implicated in controlling induction of macroautophagy in mammalian cancer cells. Here we show that these pathways are also involved in B-group soyasaponin-induced macroautophagy, as changes in enzyme activities preceded significant increases in autophagic activity. The autophagic capacity of HCT-15 cells was significantly increased by 6 h post-saponin exposure, which led us to measure alterations in signaling events that preceded this time point. We determined that exposure to B-group soyasaponins suppressed Akt activity maximally by 50%, which was associated with a reduction in the activating phosphorylation of the Akt-serine(473) residue. In addition, ERK1/2 activity was significantly increased by 60%, and was determined to be necessary for B-group soyasaponin-induced autophagy. The raf-1 kinase has been identified as a potential point of cross-talk between the Akt and ERK1/2 signaling cascades. Following B-group soyasaponin treatment activity of raf-1 was significantly increased by a maximal 200%, suggesting that this enzyme in part modulates the enhanced ERK1/2 activity. These results provide new insights into the signaling events that control induction of autophagy by B-group soyasaponins in human colon cancer cells and suggest that soyasaponins warrant further study as potential colon cancer chemopreventive agents.	Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA; Natl Ctr Agr Res Serv, Peoria, IL 61601 USA		Ellington, AA (corresponding author), Univ Illinois, Dept Food Sci & Human Nutr, 905 S Goodwin Ave,Bevier Hall, Urbana, IL 61801 USA.	kws@uiuc.edu		Berhow, Mark/0000-0002-1278-4071			Arico S, 2001, J BIOL CHEM, V276, P35243, DOI 10.1074/jbc.C100319200; Bauvy C, 2001, EXP CELL RES, V268, P139, DOI 10.1006/excr.2001.5285; Bennink MR, 2001, ADV EXP MED BIOL, V492, P11; BIEDERBICK A, 1995, EUR J CELL BIOL, V66, P3; Bondzi C, 2000, ONCOGENE, V19, P5030, DOI 10.1038/sj.onc.1203862; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; Byers T, 2002, CA-CANCER J CLIN, V52, P92, DOI 10.3322/canjclin.52.2.92; Chiang Gary G, 2004, Methods Mol Biol, V281, P125; Clark GJ, 2000, CANC DRUG DISC DEV, V5, P213; CLARKE PGH, 1990, ANAT EMBRYOL, V181, P195, DOI 10.1007/bf00174615; DUNN WA, 1990, J CELL BIOL, V110, P1923, DOI 10.1083/jcb.110.6.1923; DUNN WA, 1990, J CELL BIOL, V110, P1935, DOI 10.1083/jcb.110.6.1935; Ellington AA, 2005, CARCINOGENESIS, V26, P159, DOI 10.1093/carcin/bgh297; Franceschi S, 1997, INT J CANCER, V72, P56, DOI 10.1002/(SICI)1097-0215(19970703)72:1&lt;56::AID-IJC8&gt;3.0.CO;2-3; Franke TF, 2003, ONCOGENE, V22, P8983, DOI 10.1038/sj.onc.1207115; Fung T, 2003, ARCH INTERN MED, V163, P309, DOI 10.1001/archinte.163.3.309; GESTETNER B, 1968, J AGR FOOD CHEM, V16, P1031, DOI 10.1021/jf60160a025; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Greenwald P, 2001, EUR J CANCER, V37, P948, DOI 10.1016/S0959-8049(01)00070-3; Gurfinkel DM, 2003, NUTR CANCER, V47, P24, DOI 10.1207/s15327914nc4701_3; Hakkak R, 2001, CANCER LETT, V166, P27, DOI 10.1016/S0304-3835(01)00441-4; Hanada M, 2004, BBA-PROTEINS PROTEOM, V1697, P3, DOI 10.1016/j.bbapap.2003.11.009; Hay N, 2004, GENE DEV, V18, P1926, DOI 10.1101/gad.1212704; Hu J, 2004, J AGR FOOD CHEM, V52, P2689, DOI 10.1021/jf035290s; Jemal A, 2005, CA-CANCER J CLIN, V55, P10, DOI 10.3322/canjclin.55.1.10; Kanazawa T, 2004, J BIOL CHEM, V279, P8452, DOI 10.1074/jbc.M306337200; Kanzawa T, 2003, CANCER RES, V63, P2103; Kim HY, 2004, CANCER LETT, V210, P1, DOI 10.1016/j.canlet.2004.01.009; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Koratkar R, 1997, NUTR CANCER, V27, P206, DOI 10.1080/01635589709514526; Manning BD, 2002, MOL CELL, V10, P151, DOI 10.1016/S1097-2765(02)00568-3; Manning BD, 2003, TRENDS BIOCHEM SCI, V28, P573, DOI 10.1016/j.tibs.2003.09.003; Martin TFJ, 1998, ANNU REV CELL DEV BI, V14, P231, DOI 10.1146/annurev.cellbio.14.1.231; Meijer AJ, 2004, INT J BIOCHEM CELL B, V36, P2445, DOI 10.1016/j.biocel.2004.02.002; Mochizuki T, 2002, J BIOL CHEM, V277, P2790, DOI 10.1074/jbc.M106361200; Mordier S, 2000, J BIOL CHEM, V275, P29900, DOI 10.1074/jbc.M003633200; Munafo DB, 2001, J CELL SCI, V114, P3619; Murillo G, 2004, ANTICANCER RES, V24, P3049; Ogier-Denis E, 2003, BBA-REV CANCER, V1603, P113, DOI 10.1016/S0304-419X(03)00004-0; Ogier-Denis E, 2000, J BIOL CHEM, V275, P39090, DOI 10.1074/jbc.M006198200; OGIERDENIS E, 1995, J BIOL CHEM, V270, P13, DOI 10.1074/jbc.270.1.13; Oh YJ, 2001, NUTR CANCER, V39, P132, DOI 10.1207/S15327914nc391_18; Opipari AW, 2004, CANCER RES, V64, P696, DOI 10.1158/0008-5472.CAN-03-2404; Pattingre S, 2004, METHOD ENZYMOL, V390, P17; Pattingre S, 2003, J BIOL CHEM, V278, P16667, DOI 10.1074/jbc.M210998200; Pearl LH, 2002, CURR OPIN STRUC BIOL, V12, P761, DOI 10.1016/S0959-440X(02)00386-X; Petiot A, 1999, BIOCHEM J, V337, P289, DOI 10.1042/0264-6021:3370289; Rao A V, 2000, Drug Metabol Drug Interact, V17, P211; Saeki K, 2003, J LEUKOCYTE BIOL, V74, P1108, DOI 10.1189/jlb.0503211; Scarlatti F, 2004, J BIOL CHEM, V279, P18384, DOI 10.1074/jbc.M313561200; SchulteHermann R, 1997, TOXICOL PATHOL, V25, P89, DOI 10.1177/019262339702500117; Singh PN, 1998, AM J EPIDEMIOL, V148, P761, DOI 10.1093/oxfordjournals.aje.a009697; Spector D, 2003, NUTR CANCER, V47, P1, DOI 10.1207/s15327914nc4701_1; SUNG MK, 1995, FOOD CHEM TOXICOL, V33, P357, DOI 10.1016/0278-6915(95)00007-O; SUNG MK, 1995, NUTR CANCER, V23, P259, DOI 10.1080/01635589509514380; Takeuchi H, 2004, BRIT J CANCER, V90, P1069, DOI 10.1038/sj.bjc.6601605; Tee AR, 2003, J BIOL CHEM, V278, P37288, DOI 10.1074/jbc.M303257200; Thiagarajan DG, 1998, AM J CLIN NUTR, V68, p1394S, DOI 10.1093/ajcn/68.6.1394S; VARA J, 2001, CANC TREAT REV, V30, P193; Yao KC, 2003, J NEUROSURG, V98, P378, DOI 10.3171/jns.2003.98.2.0378; Yoshiki Y, 1998, BIOSCI BIOTECH BIOCH, V62, P2291, DOI 10.1271/bbb.62.2291; Zimmermann S, 1999, SCIENCE, V286, P1741, DOI 10.1126/science.286.5445.1741	62	179	190	2	20	OXFORD UNIV PRESS	OXFORD	GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND	0143-3334	1460-2180		CARCINOGENESIS	Carcinogenesis	FEB	2006	27	2					298	306		10.1093/carcin/bgi214			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	004UU	WOS:000234778700015	16113053	Bronze			2022-04-25	
J	Elamin, KM; Yamashita, Y; Motoyama, K; Higashi, T; Arima, H				Elamin, Khaled M.; Yamashita, Yuki; Motoyama, Keiichi; Higashi, Taishi; Arima, Hidetoshi			Involvement of mitophagy-mediated cell death in colon cancer cells by folate-appended methyl-beta-cyclodextrin	JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY			English	Article						Folate receptor; Methyl-beta-cyclodextrin; Colon cancer; Autophagy; Targeting	COLORECTAL-CANCER; DRUG-DELIVERY; MECHANISMS; AUTOPHAGY; PROGRESSION; PATHWAYS; SYSTEMS	In recent years, colorectal cancer has gained great attention among various types of cancers. We previously synthesized folate-appended methyl-beta-cyclodextrin (FA-M-beta-CyD) as a novel autophagic antitumor agent. In this study, to further elucidate the impact of FA-M-beta-CyD as an antitumor agent, we evaluated cytotoxic activity and the antiproliferative effect in colon cancer cells and colorectal cancer model mice, respectively. As a result, FA-M-beta-CyD showed potent cytotoxic activity in HCT116 cells, a human colon cancer cell line, through folate receptor-alpha (FR-alpha)-mediated cellular uptake. In addition, FA-M-beta-CyD elicited autophagosome formation and induced mitophagy in HCT116 cells. Importantly, FA-M-beta-CyD drastically reduced the number of tumor polyps in colorectal cancer model mice induced by azoxymethane/dextran sodium sulfate after intravenous injections once a week for 4 weeks. These results suggest that FA-M-beta-CyD has the antiproliferative effect in the colorectal cancer, due to the FR-alpha-mediated endocytosis and mitophagy induction.	[Elamin, Khaled M.; Yamashita, Yuki; Motoyama, Keiichi; Higashi, Taishi; Arima, Hidetoshi] Kumamoto Univ, Grad Sch Pharmaceut Sci, Dept Phys Pharmaceut, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan; [Yamashita, Yuki; Arima, Hidetoshi] Kumamoto Univ, Program Leading Grad Sch, HIGO Hlth Life Sci Interdisciplinary & Glocal Ori, Kumamoto, Japan		Arima, H (corresponding author), Kumamoto Univ, Grad Sch Pharmaceut Sci, Dept Phys Pharmaceut, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan.; Arima, H (corresponding author), Kumamoto Univ, Program Leading Grad Sch, HIGO Hlth Life Sci Interdisciplinary & Glocal Ori, Kumamoto, Japan.	arimah@gpo.kumamoto-u.ac.jp			Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [16K08198]; Center for Clinical and Translational Research of Kyushu University; Ministry of Health, Labor, and WelfareMinistry of Health, Labour and Welfare, Japan [24100701]	This work was partially supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (16K08198), Center for Clinical and Translational Research of Kyushu University, and a Ministry of Health, Labor, and Welfare Grant-in-Aid for Third Term Comprehensive Control Research for Cancer program (24100701).	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Incl. Phenom. Macrocycl. Chem.	DEC	2017	89	3-4					333	342		10.1007/s10847-017-0757-x			10	Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry	FM0YL	WOS:000414694500011					2022-04-25	
J	Yang, KZ; Niu, T; Luo, MY; Tang, LH; Kang, L				Yang Kaizhen; Niu Ting; Luo Mengyu; Tang Lihua; Kang Ling			Enhanced cytotoxicity and apoptosis through inhibiting autophagy in metastatic potential colon cancer SW620 cells treated with Chlorin e6 photodynamic therapy	PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY			English	Article						Autophagy; Apoptosis; Photodynamic therapy; Chlorin e6; Colorectal cancer	DEATH; PHOTOSENSITIZER; STATISTICS; PATHWAYS; ACTIVATION; GUIDELINES; PROTEINS; STRESS; FAMILY; ASSAYS	Photodynamic therapy (PDT) is a novel and non-invasive treatment that induces apoptosis and autophagy. Autophagy could play a pro-survival role, thus inhibiting autophagic activity might be a promising method to enhance the effectiveness of PDT for tumors. In the present study, photosensitizer Chlorin e6 (Ce6) was found to mainly locate in endoplasmic reticulum, and to a lesser extent in mitochondria and lysosome. Chlorin e6 photodynamic therapy (Ce6-PDT) could kill human colon cancer SW620 cells by inducing apoptotic cell death, and autophagy also induced by Ce6-PDT in colon cancer cells. More importantly, autophagy played a pro-survival role. Its inhibition enhanced Ce6-PDT-associated apoptotic cell death because cells pretreated with the typical autophagy inhibitor 3-methyladenine exhibited higher cytotoxicity and apoptotic cell death.	[Yang Kaizhen; Tang Lihua] First Peoples Hosp Urumqi, Teaching & Res Dept, 1 Jiankang Rd, Urumqi, Xinjiang Uygur, Peoples R China; [Niu Ting; Luo Mengyu; Kang Ling] Xinjiang Med Univ, Sch Publ Hlth, 393 Xinyi Rd, Urumqi, Xinjiang Uygur, Peoples R China		Kang, L (corresponding author), Xinjiang Med Univ, Sch Publ Hlth, 393 Xinyi Rd, Urumqi, Xinjiang Uygur, Peoples R China.	lingkang1220@sina.com			Xinjiang Uygur Autonomous Region Natural Science Foundation [2014211C003]	This study was supported by the Xinjiang Uygur Autonomous Region Natural Science Foundation (No. 2014211C003).	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J	John, S; Mls, J; Cervinka, M; Rudolf, E				John, Stanislav; Mls, Jan; Cervinka, Miroslav; Rudolf, Emil			The Role of Autophagic Cell Death and Apoptosis in Irinotecan-treated p53 Null Colon Cancer Cells	ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY			English	Article						Irinotecan; Colon cancer; Autophagy; p53; Chemotherapy; Autophagic cell death; Apoptosis; Bax; Lysosomes; Mitochondria	LYSOSOMAL MEMBRANE PERMEABILIZATION; COLORECTAL-CANCER; INVOLVEMENT; THERAPY	The roles of autophagic cell death and apoptosis induced by topoisomerase inhibitor irinotecan in colon cancer cells with deleted p53 were investigated during 48 h. We report that irinotecan-dependent cytotoxicity and proapoptotic activity were reduced in the present model while autophagy levels significantly increased. Upon p53 transfection, cell demise rates increased, with cells bearing the features of apoptosis and autophagic cell death. The subsequent studies into mechanisms of cell death process revealed the important role of Bax in mediating mitochondrial and lysosomal leakage which might serve as leading signals for both apoptosis and autophagic cell death. These results suggest that different modes of cell death in p53 null colon cancer cells treated with cytostatics (irinotecan) may be activated simultaneously. Moreover, their interactions possibly occur at several stages and aren't mutually exclusive. This might thus lead to a potential synergism with interesting therapeutic ramifications.	[John, Stanislav; Mls, Jan; Cervinka, Miroslav; Rudolf, Emil] Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Hradec Kralove 50038, Czech Republic		Rudolf, E (corresponding author), Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Simkova 870, Hradec Kralove 50038, Czech Republic.	rudolf@lfhk.cuni.cz	Cervinka, Miroslav/R-7387-2016; Rudolf, Emil/B-5956-2017	Cervinka, Miroslav/0000-0001-8602-4756; Rudolf, Emil/0000-0002-9526-3174	program PRVOUK [P37/01]	This work was supported by the program PRVOUK P37/01.	Bitomsky N, 2009, FEBS J, V276, P6074, DOI 10.1111/j.1742-4658.2009.07331.x; Boya P, 2008, ONCOGENE, V27, P6434, DOI 10.1038/onc.2008.310; Bunz F, 1998, SCIENCE, V282, P1497, DOI 10.1126/science.282.5393.1497; Das G., 2012, COLD SPRING HARB PER, V4, P25; Gagne JF, 2002, MOL PHARMACOL, V62, P608, DOI 10.1124/mol.62.3.608; Gross A, 1999, GENE DEV, V13, P1899, DOI 10.1101/gad.13.15.1899; Humerickhouse R, 2000, CANCER RES, V60, P1189; Kagedal K, 2005, INT J EXP PATHOL, V86, P309, DOI 10.1111/j.0959-9673.2005.00442.x; Ko LJ, 1996, GENE DEV, V10, P1054, DOI 10.1101/gad.10.9.1054; Kroemer G, 2005, NAT REV CANCER, V5, P886, DOI 10.1038/nrc1738; Kroemer G, 2010, MOL CELL, V40, P280, DOI 10.1016/j.molcel.2010.09.023; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Li H, 2011, CANCER RES, V71, P3625, DOI 10.1158/0008-5472.CAN-10-4475; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038/nrm2239; Maiuri MC, 2010, CURR OPIN CELL BIOL, V22, P181, DOI 10.1016/j.ceb.2009.12.001; Morselli E, 2008, CELL CYCLE, V7, P3056, DOI 10.4161/cc.7.19.6751; Nakatomi K, 2001, BIOCHEM BIOPH RES CO, V288, P827, DOI 10.1006/bbrc.2001.5850; Ng G, 2005, MOL CARCINOGEN, V43, P183, DOI 10.1002/mc.20097; O'Connell MJ, 2009, J CLIN ONCOL, V27, P3082, DOI 10.1200/JCO.2009.22.2919; Pommier Y, 2006, NAT REV CANCER, V6, P789, DOI 10.1038/nrc1977; Potter JD, 1999, JNCI-J NATL CANCER I, V91, P916, DOI 10.1093/jnci/91.11.916; Pourahmad J, 2001, FREE RADICAL BIO MED, V30, P89, DOI 10.1016/S0891-5849(00)00450-0; Roos WP, 2006, TRENDS MOL MED, V12, P440, DOI 10.1016/j.molmed.2006.07.007; Rufini A, 2011, BIOCHEM BIOPH RES CO, V414, P445, DOI 10.1016/j.bbrc.2011.09.110; Weekes J, 2009, WORLD J GASTROENTERO, V15, P3597, DOI 10.3748/wjg.15.3597; Werneburg NW, 2007, J BIOL CHEM, V282, P28960, DOI 10.1074/jbc.M705671200; White E, 2009, CLIN CANCER RES, V15, P5308, DOI 10.1158/1078-0432.CCR-07-5023; Worthley DL, 2007, WORLD J GASTROENTERO, V13, P3784	29	4	5	0	21	BENTHAM SCIENCE PUBL LTD	SHARJAH	EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES	1871-5206	1875-5992		ANTI-CANCER AGENT ME	Anti-Cancer Agents Med. Chem.	JUN	2013	13	5					811	820		10.2174/1871520611313050015			10	Oncology; Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	147TP	WOS:000319190500015	22721392				2022-04-25	
J	Shafabakhsh, R; Arianfar, F; Vosough, M; Mirzaei, HR; Mahjoubin-Tehran, M; Khanbabaei, H; Kowsari, H; Shojaie, L; Azar, MEF; Hamblin, MR; Mirzaei, H				Shafabakhsh, Rana; Arianfar, Farzaneh; Vosough, Massoud; Mirzaei, Hamid Reza; Mahjoubin-Tehran, Maryam; Khanbabaei, Hashem; Kowsari, Hamed; Shojaie, Layla; Azar, Maryam Ebadi Fard; Hamblin, Michael R.; Mirzaei, Hamed			Autophagy and gastrointestinal cancers: the behind the scenes role of long non-coding RNAs in initiation, progression, and treatment resistance	CANCER GENE THERAPY			English	Review							PROMOTES CELL-PROLIFERATION; COMPETING ENDOGENOUS RNA; HEPATOCELLULAR-CARCINOMA PROGRESSION; HNF1A-AS1 REGULATES PROLIFERATION; EPITHELIAL-MESENCHYMAL TRANSITION; ANTERIOR GRADIENT 2; GASTRIC-CANCER; COLORECTAL-CANCER; PANCREATIC-CANCER; POOR-PROGNOSIS	Gastrointestinal (GI) cancers comprise a heterogeneous group of complex disorders that affect different organs, including esophagus, stomach, gallbladder, liver, biliary tract, pancreas, small intestine, colon, rectum, and anus. Recently, an explosion in nucleic acid-based technologies has led to the discovery of long non-coding RNAs (lncRNAs) that have been found to possess unique regulatory functions. This class of RNAs is >200 nucleotides in length, and is characterized by their lack of protein coding. LncRNAs exert regulatory effects in GI cancer development by affecting different functions such as the proliferation and metastasis of cancer cells, apoptosis, glycolysis and angiogenesis. Over the past few decades, considerable evidence has revealed the important role of autophagy in both GI cancer progression and suppression. In addition, recent studies have confirmed a significant correlation between lncRNAs and the regulation of autophagy. In this review, we summarize how lncRNAs play a behind the scenes role in the pathogenesis of GI cancers through regulation of autophagy.	[Shafabakhsh, Rana; Kowsari, Hamed; Mirzaei, Hamed] Kashan Univ Med Sci, Inst Basic Sci, Res Ctr Biochem & Nutr Metab Dis, Kashan, Iran; [Arianfar, Farzaneh] Shiraz Univ Med Sci, Sch Med, Dept Biochem, Shiraz, Iran; [Vosough, Massoud] ACECR, Royan Inst Stem Cell Biol & Technol, Cell Sci Res Ctr, Dept Stem Cells & Dev Biol, Tehran 1665659911, Iran; [Mirzaei, Hamid Reza] Univ Tehran Med Sci, Sch Med, Dept Med Immunol, Tehran, Iran; [Mahjoubin-Tehran, Maryam] Mashhad Univ Med Sci, Student Res Comm, Mashhad, Razavi Khorasan, Iran; [Mahjoubin-Tehran, Maryam] Mashhad Univ Med Sci, Fac Med, Dept Med Biotechnol, Mashhad, Razavi Khorasan, Iran; [Khanbabaei, Hashem] Ahvaz Jundishapur Univ Med Sci, Sch Med, Med Phys Dept, Ahvaz, Iran; [Shojaie, Layla] Univ Southern Calif, Keck Sch Med, Dept Med, Res Ctr Liver Dis, Los Angeles, CA 90007 USA; [Azar, Maryam Ebadi Fard] Iran Univ Med Sci, Student Res Comm, Tehran, Iran; [Hamblin, Michael R.] Univ Johannesburg, Fac Hlth Sci, Laser Res Ctr, ZA-2028 Doornfontein, South Africa		Mirzaei, H (corresponding author), Kashan Univ Med Sci, Inst Basic Sci, Res Ctr Biochem & Nutr Metab Dis, Kashan, Iran.; 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DEC	2021	28	12					1229	1255		10.1038/s41417-020-00272-7		JAN 2021	27	Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine	XG6LD	WOS:000607045900001	33432087	hybrid	Y	N	2022-04-25	
J	Zhang, SL; Hu, B; You, Y; Yang, ZW; Liu, LX; Tang, HH; Bao, WL; Guan, YY; Shen, XY				Zhang, Sulin; Hu, Bin; You, Yan; Yang, Zhiwen; Liu, Lixin; Tang, Huanhuan; Bao, Weilian; Guan, Yunyun; Shen, Xiaoyan			Sorting nexin 10 acts as a tumor suppressor in tumorigenesis and progression of colorectal cancer through regulating chaperone mediated autophagy degradation of p21(Cip1/WAF1)	CANCER LETTERS			English	Article						SNX10; Chaperone-mediated autophagy; Colorectal cancer; p21(Cip1/WAF1)	COLON-CANCER; LYSOSOME; CELLS; CARCINOGENESIS; INFLAMMATION; PREVENTION; PROTEINS; RECEPTOR; COLITIS; DISEASE	Chaperone-mediated autophagy (CMA) characterized by the selective degradation of target proteins has been linked with tumorigenesis in recent years. Here, we explored the function of sorting nexin 10 (SNX10), a protein involved in maintaining endosome/lysosome homeostasis, in mediating CMA activity and its impact on the progression of mouse inflammation-driven colorectal cancer. Our results revealed that SNX10 deficiency increased the activation of CMA by preventing the degradation of lysosomal LAMP-2A. In SNX10 KO cells, we disclosed that p21(Cip1/WAF1). a master effector in various tumor suppressor pathways, is a substrate of CMA, and decrease of p21(Cip1/WAF1) caused by SNX10-mediated CMA activation contributes to HCT116 cell proliferation and survival. Moreover, we found that SNX10 KO promoted tumorigenesis in the mouse colorectum which could be restored by SNX10 over-expression. Furthermore, SNX10 was remarkably down-regulated in. human CRC tissues which showed the increased activity of CMA and decreased expression of p21(Cip1/lWAF1). These findings suggest that SNX10 acts as a tumor suppressor in the mouse colorectum and drives inflammation-associated colorectal cancer by a chaperone-mediated autophagy mechanism. (C) 2018 Elsevier B.V. All rights reserved.	[Zhang, Sulin; Hu, Bin; You, Yan; Liu, Lixin; Tang, Huanhuan; Bao, Weilian; Guan, Yunyun; Shen, Xiaoyan] Fudan Univ, Sch Pharm, Dept Pharmacol, 826 Zhangheng Rd, Shanghai 201203, Peoples R China; [Yang, Zhiwen] Shanghai Jiao Tong Univ, Affiliated Shanghai Peoples Hosp 1, Songjiang Hosp, Dept Pharm, Shanghai, Peoples R China		Shen, XY (corresponding author), Fudan Univ, Sch Pharm, Dept Pharmacol, 826 Zhangheng Rd, Shanghai 201203, Peoples R China.	shxiaoy@fudan.edu.cn	Bao, Weilian/AAU-5822-2021		National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773744, 81573441, 81371923, 81173056]	This study was supported by the National Natural Science Foundation of China (No. 81773744, 81573441, 81371923, and 81173056).	Abbas T, 2009, NAT REV CANCER, V9, P400, DOI 10.1038/nrc2657; Abdulamir A. 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J	Yang, F; Sun, SY; Yang, F				Yang, Fan; Sun, Siyu; Yang, Fei			Prognostic and Predicted Significance of FENDRR in Colon and Rectum Adenocarcinoma	FRONTIERS IN ONCOLOGY			English	Article						colon and rectum adenocarcinoma; LncRNA; FENDRR; TCGA database; biomarker	COLORECTAL-CANCER; LNCRNA	Background The role of fetal-lethal non-coding developmental regulatory RNA (FENDRR) has been explored in various cancers; however, its relationship with colon adenocarcinoma/rectum adenocarcinoma (COAD/READ) remains unclear. The objectives of this study were to identify and assess any associations between FENDRR and COAD/READ using The Cancer Genome Atlas (TCGA) database and the Genetic Data Commons (GDC) Data Portal. Methods The records of patients with COAD/READ were collected from the GDC Data Portal. After comparing the expression level of FENDRR in COAD/READ and healthy tissues, we evaluated the association of FENDRR with clinicopathological characters and the survival rate, the impact of FENDRR on prognosis, the biological function of FENDRR, and the relative abundance of tumor-infiltrating immune cells in patients with COAD/READ. Moreover, we aimed to construct a protein-protein interaction (PPI) network for selecting genes and a ceRNA network for presenting mRNA-miRNA-lncRNA interactions. Results In patients with COAD/READ, FENDRR expression could differentiate tumor tissues from the adjacent healthy tissues since it was significantly lower in the former than in the latter. High FENDRR expression was correlated with poorer survival and higher tumor stage, current tumor stage, and metastasis stage, and also exhibited high scores for apoptosis, autophagy, and senescence. Immune cell infiltration analysis showed that the high expression group had significantly lower immune and stromal scores. Low FENDRR expression was correlated with poor overall survival (OS), and thus, it could serve as an independent risk factor. The prognostic models constructed in the study performed well for the prediction of OS and disease-specific survival (DFS) using FENDRR expression. Gene set enrichment analysis revealed that vascular smooth muscle contraction, melanogenesis, basal cell carcinoma, and Hedgehog signaling pathways were significantly enriched in patients with high FENDRR expression. Eight hub genes, namely, PKM, ALDOA, PFKP, ALDOC, PYGL, CTNNB1, PSMA5, and WNT5A, were selected from the PPI network, and a ceRNA network was constructed based on the differentially expressed mRNAs, miRNAs, and lncRNAs to illustrate their regulatory relationships. Conclusion FENDRR may serve as a potential biomarker for the diagnosis and prognosis of COAD/READ.	[Yang, Fan; Sun, Siyu; Yang, Fei] China Med Univ, Dept Gastroenterol, Sheng Jing Hosp, Shenyang, Peoples R China		Sun, SY (corresponding author), China Med Univ, Dept Gastroenterol, Sheng Jing Hosp, Shenyang, Peoples R China.	sunsy@sj-hospital.org			China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2020M670101ZX]; Doctoral Scientific Research Foundation of Liaoning Province [2019-BS276]; Science and Technology Program of Shenyang [19-112-4-103]; Youth Support Foundation of China Medical University [QGZ2018058]; Scientific Fund of Shengjing Hospital [201801]; 345 Talent Project of Shengjing Hospital [52-30C]	This study was supported by the China Postdoctoral Science Foundation (Grant No. 2020M670101ZX), Doctoral Scientific Research Foundation of Liaoning Province (Grant No. 2019-BS276), Science and Technology Program of Shenyang (Grant No. 19-112-4-103), Youth Support Foundation of China Medical University (Grant No. QGZ2018058), Scientific Fund of Shengjing Hospital (Grant No. 201801), and 345 Talent Project of Shengjing Hospital (Grant No. 52-30C).	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Oncol.	SEP 21	2021	11								668595	10.3389/fonc.2021.668595			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	WB3IT	WOS:000703470000001	34621665	Green Published, gold			2022-04-25	
J	Sakitani, K; Hirata, Y; Hikiba, Y; Hayakawa, Y; Ihara, S; Suzuki, H; Suzuki, N; Serizawa, T; Kinoshita, H; Sakamoto, K; Nakagawa, H; Tateishi, K; Maeda, S; Ikenoue, T; Kawazu, S; Koike, K				Sakitani, Kosuke; Hirata, Yoshihiro; Hikiba, Yohko; Hayakawa, Yoku; Ihara, Sozaburo; Suzuki, Hirobumi; Suzuki, Nobumi; Serizawa, Takako; Kinoshita, Hiroto; Sakamoto, Kei; Nakagawa, Hayato; Tateishi, Keisuke; Maeda, Shin; Ikenoue, Tsuneo; Kawazu, Shoji; Koike, Kazuhiko			Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress	BMC CANCER			English	Article						Autophagy; Colon cancer; Apoptosis	ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; GENOME-WIDE ASSOCIATION; CROHN-DISEASE; EXPRESSION; MOUSE; CELLS; 5-FLUOROURACIL; INFLAMMATION; INVOLVEMENT	Background: Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer. Methods: We crossed K19(CreERT) and Atg5(flox/flox) mice to generate Atg5(flox/flox)/K19(CreERT) mice. Atg5(flox/flox)/K19(CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins. Results: Colon tumors in Atg5(flox/flox)/K19(CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5(flox/flox)/K19(CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5(flox/flox)/K19(CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells. Conclusions: Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition.	[Sakitani, Kosuke; Hikiba, Yohko; Sakamoto, Kei; Kawazu, Shoji] Asahi Life Fdn, Inst Adult Dis, Chuo Ku, Tokyo 1138655, Japan; [Sakitani, Kosuke; Hirata, Yoshihiro; Hayakawa, Yoku; Ihara, Sozaburo; Suzuki, Hirobumi; Suzuki, Nobumi; Serizawa, Takako; Kinoshita, Hiroto; Nakagawa, Hayato; Tateishi, Keisuke; Koike, Kazuhiko] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo, Japan; [Maeda, Shin] Yokohama City Univ, Grad Sch Med, Gastroenterol Div, Yokohama, Kanagawa 232, Japan; [Ikenoue, Tsuneo] Univ Tokyo, Inst Med Sci, Div Clin Genome Res, Tokyo, Japan		Sakitani, K (corresponding author), Asahi Life Fdn, Inst Adult Dis, Chuo Ku, 2-2-6 Bakuro Cho, Tokyo 1138655, Japan.	sakitani-tky@umin.ac.jp	Nakagawa, Hayato/I-2837-2012; Hayakawa, Yoku/AAI-8581-2020; Ihara, Sozaburo/ABF-5268-2021	Nakagawa, Hayato/0000-0002-6973-5094; Hayakawa, Yoku/0000-0002-3988-2499; Sakitani, Kosuke/0000-0002-4537-6023	JSPS KAKENHIMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) [26860538]; Life Science Foundation of JapanLife Science Foundation of Japan; Kato Memorial Bioscience Foundation	This study was supported by grants from JSPS KAKENHI (Grant Number 26860538), the Life Science Foundation of Japan, and the Kato Memorial Bioscience Foundation to K. Sakitani. The authors are grateful to Dr. Noboru Mizushima (The University of Tokyo) and Dr. Guoqiang Gu (Vanderbilt University) for providing the mice.	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J	Zhu, J; Zhao, BX; Xiong, PG; Wang, CY; Zhang, JJ; Tian, XH; Huang, YH				Zhu, Jing; Zhao, Bangxia; Xiong, Pingan; Wang, Chaoyun; Zhang, Juanjuan; Tian, Xiaohua; Huang, Yinghui			Curcumin Induces Autophagy via Inhibition of Yes-Associated Protein (YAP) in Human Colon Cancer Cells	MEDICAL SCIENCE MONITOR			English	Article						Autophagy; Colonic Neoplasms; Curcumin	PROLIFERATION; DEGRADATION; ENCODES; KINASE	Background: Colon cancer is one of the most common cancers and it is the fourth leading cause of cancer-related deaths worldwide. YAP can promote cell proliferation and inhibit apoptosis, leading to loss of cell contact inhibition and promoting malignant cell transformation. Material/Methods: In this study we analyzed the effects of different curcumin concentrations on the proliferation of colon cancer cells using MTT and colony formation assays. Western blot detection was performed to confirm the YAP,LC3-II, and P62 expression. Results: Curcumin inhibited proliferation and promoted colon cancer cell autophagy. In addition, Western blot results indicated that curcumin suppressed YAP expression in colon cancer cells. To assess the mechanism, we treated the cell lines with curcumin and assessed YAP overexpression and YAP knockdown. The results revealed that curcumin inhibits the proliferation and promotes autophagy of these cell lines. Western blot results showed that curcumin reversed the effect of YAP in colon cancer cells. Conclusions: Our results suggest that YAP has great promise for treatment of colon cancer and that it might be a potential diagnostic marker for colon cancer.	[Zhu, Jing; Huang, Yinghui] Beijing Univ Technol, Coll Life Sci & Bioengn, Lab Canc, Beijing, Peoples R China; [Zhu, Jing] Hubei Univ Med, Inst Basic Med Sci, Shiyan, Hubei, Peoples R China; [Zhao, Bangxia; Xiong, Pingan; Wang, Chaoyun; Zhang, Juanjuan; Tian, Xiaohua] Hubei Univ Med, Taihe Hosp, Reprod Med Ctr, Shiyan, Hubei, Peoples R China		Zhu, J; Huang, YH (corresponding author), Beijing Univ Technol, Coll Life Sci & Bioengn, Lab Canc, Beijing, Peoples R China.; Zhu, J (corresponding author), Hubei Univ Med, Inst Basic Med Sci, Shiyan, Hubei, Peoples R China.	Jing_Zhu0719@163.com; yhuang@bjut.edu.en		Zhu, Jing/0000-0002-2860-3685	National Natural Technology Foundation of China [81428016]; Key Program for Science and Technology Development of Beijing [Z151100003915073]	This study was supported by the National Natural Technology Foundation of China (No. 81428016) and the Key Program for Science and Technology Development of Beijing (No. Z151100003915073)	Boehmer U, 2014, BMJ OPEN, V4, DOI 10.1136/bmjopen-2013-004461; Carvalho C, 2017, LANCET ONCOL, V18, pE354, DOI 10.1016/S1470-2045(17)30346-7; Commandeur JNM, 1996, XENOBIOTICA, V26, P667, DOI 10.3109/00498259609046741; Gao Y, 2014, INT J MOL SCI, V15, P15173, DOI 10.3390/ijms150915173; Hewlings SJ, 2017, FOODS, V6, DOI 10.3390/foods6100092; Huang F, 2017, AM J TRANSL RES, V9, P5538; Jalili-Nik M, 2018, J CELL PHYSIOL, V233, P6337, DOI 10.1002/jcp.26368; Jia YL, 2009, J ASIAN NAT PROD RES, V11, P918, DOI 10.1080/10286020903264077; JUSTICE RW, 1995, GENE DEV, V9, P534, DOI 10.1101/gad.9.5.534; Liu XW, 2017, ONCOL REP, V38, P271, DOI 10.3892/or.2017.5648; Liu ZM, 2017, AM J TRANSL RES, V9, P3212; Moroishi T, 2015, NAT REV CANCER, V15, P73, DOI 10.1038/nrc3876; Petherick KJ, 2013, EMBO J, V32, P1903, DOI 10.1038/emboj.2013.123; SUDOL M, 1994, ONCOGENE, V9, P2145; Torre LA, 2016, CANCER EPIDEM BIOMAR, V25, P16, DOI 10.1158/1055-9965.EPI-15-0578; Wang SP, 2016, OPEN BIOL, V6, DOI 10.1098/rsob.160119; Wang YP, 2015, INT J CLIN EXP MED, V8, P1080; XU TA, 1995, DEVELOPMENT, V121, P1053; Zhou DW, 2011, P NATL ACAD SCI USA, V108, pE1312, DOI 10.1073/pnas.1110428108; Zhou XX, 2016, ONCOTARGET, V7, P79062, DOI 10.18632/oncotarget.12596; Zhuang WZ, 2012, CANCER SCI, V103, P684, DOI 10.1111/j.1349-7006.2011.02198.x	21	26	26	0	25	INT SCIENTIFIC LITERATURE, INC	MELVILLE	150 BROADHOLLOW RD, STE 114, MELVILLE, NY 11747 USA	1643-3750			MED SCI MONITOR	Med. Sci. Monitor	OCT 3	2018	24						7035	7042		10.12659/MSM.910650			8	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	GV5WK	WOS:000446175800003	30281585	Green Published, Green Submitted			2022-04-25	
J	Yuk, JM; Shin, DM; Song, KS; Lim, K; Kim, KH; Lee, SH; Kim, JM; Lee, JS; Paik, TH; Kim, JS; Jo, EK				Yuk, Jae-Min; Shin, Dong-Min; Song, Kyoung-Sub; Lim, Kyu; Kim, Ki-Hye; Lee, Sang-Hee; Kim, Jin-Man; Lee, Ji-Sook; Paik, Tae-Hyun; Kim, Jun-Sang; Jo, Eun-Kyeong			Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy	AUTOPHAGY			English	Article						BCG cell wall skeleton; autophagy; radiosensitization; reactive oxygen species; JNK; toll-like receptor	RECTAL-CANCER; RADIATION-THERAPY; IMMUNE-RESPONSES; DENDRITIC CELLS; LUNG-CANCER; II TRIAL; SKELETON; DEATH; IMMUNOTHERAPY; ACTIVATION	The cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guerin (BCG/CWS) is an effective antitumor immunotherapy agent. Here, we demonstrate that BCG/CWS has a radiosensitizing effect on colon cancer cells through the induction of autophagic cell death. Exposure of HCT116 colon cancer cells to BCG/CWS before ionizing radiation (IR) resulted in increased cell death in a caspase-independent manner. Treatment with BCG/CWS plus IR resulted in the induction of autophagy in colon cancer cells. Either the autophagy inhibitor 3-methyladenine or knockdown of beclin 1 or Atg7 significantly reduced tumor cell death induced by BCG/CWS plus IR, whereas the caspase inhibitor z-VAD-fmk failed to do so. BCG/CWS plus IR-mediated autophagy and cell death was mediated predominantly by the generation of reactive oxygen species (ROS). The c-Jun NH2-terminal kinase pathway functioned upstream of ROS generation in the induction of autophagy and cell death in HCT116 cells after co-treatment with BCG/CWS and IR. Furthermore, toll-like receptor (TLR) 2, and in part, TLR4, were responsible for BCG/CWS-induced radiosensitization. In vivo studies revealed that BCG/ CWS-mediated radiosensitization of HCT116 xenograft growth is accompanied predominantly by autophagy. Our data suggest that BCG/CWS in combination with IR is a promising therapeutic strategy for enhancing radiation therapy in colon cancer cells through the induction of autophagy.	[Kim, Jun-Sang] Chungnam Natl Univ Hosp, Taejon, South Korea; [Yuk, Jae-Min; Shin, Dong-Min; Kim, Ki-Hye; Jo, Eun-Kyeong] Chungnam Natl Univ, Coll Med, Dept Microbiol, Taejon, South Korea; [Song, Kyoung-Sub; Lim, Kyu] Chungnam Natl Univ, Coll Med, Dept Biochem, Taejon, South Korea; [Yuk, Jae-Min; Shin, Dong-Min; Lim, Kyu; Kim, Ki-Hye; Kim, Jin-Man; Lee, Ji-Sook; Paik, Tae-Hyun; Jo, Eun-Kyeong] Chungnam Natl Univ, Coll Med, Infect Signaling Network Res Ctr, Taejon, South Korea; [Kim, Jin-Man] Chungnam Natl Univ, Coll Med, Dept Pathol, Taejon, South Korea; [Lim, Kyu; Kim, Jin-Man; Kim, Jun-Sang] Chungnam Natl Univ, Canc Res Inst, Dept Pathol, Taejon, South Korea; [Jo, Eun-Kyeong] Chungnam Natl Univ, Res Inst Med Sci, Dept Pathol, Taejon, South Korea; [Lee, Sang-Hee] Korea Adv Inst Sci & Technol, Mol Genom Lab, Dept Biol Sci, Taejon 305701, South Korea		Kim, JS (corresponding author), Chungnam Natl Univ Hosp, Taejon, South Korea.	k423j@cnu.ac.kr; hayoungj@cnu.ac.kr		KIM, JUN-SANG/0000-0002-5329-6605; Eun-Kyeong, Jo/0000-0001-7191-0587; Yuk, Jae-Min/0000-0002-0630-9194; KIM, JIN MAN/0000-0003-0905-9730	Korea Science & Engineering Foundation through the Infection Signaling Network Research CenterKorea Science and Engineering Foundation [R13-2007-020-01000-0]	We thank B. Vogelstein and J. W. Son for reagents; T. H. Paik for invaluable discussion and reagents; and H. H. Choi for technical support. This work was supported by the Korea Science & Engineering Foundation through the Infection Signaling Network Research Center (R13-2007-020-01000-0) at Chungnam National University. The authors have no financial conflict of interests.	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S	Naji, M; Soroudi, S; Akaberi, M; Sahebkar, A; Emami, SA		Barreto, GE; Sahebkar, A		Naji, Melika; Soroudi, Setareh; Akaberi, Maryam; Sahebkar, Amirhossein; Emami, Seyed Ahmad			Updated Review on the Role of Curcumin in Gastrointestinal Cancers	PHARMACOLOGICAL PROPERTIES OF PLANT-DERIVED NATURAL PRODUCTS AND IMPLICATIONS FOR HUMAN HEALTH	Advances in Experimental Medicine and Biology		English	Review; Book Chapter						Gastrointestinal; Cancer; Curcumin; Esophagus; Colon; Oral cavity	HUMAN COLORECTAL-CANCER; HUMAN COLON-CANCER; EPITHELIAL-MESENCHYMAL TRANSITION; SQUAMOUS-CELL CARCINOMA; GASTRIC-CANCER; ESOPHAGEAL CANCER; DOWN-REGULATION; ORAL-CANCER; SUPPRESSES PROLIFERATION; POLYMERIC NANOPARTICLES	Malignant conditions of the gastrointestinal tract and accessory organs of digestion, including the oral cavity, esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus, are referred to as gastrointestinal cancers. Curcumin is a natural compound derived from turmeric with a wide range of biological activities. Several in vitro and in vivo studies have investigated the effects of curcumin on gastrointestinal cancers. In the current review, we aimed to provide an updated summary on the recent findings regarding the beneficial effects of curcumin on different gastrointestinal cancers in the recent decade. For this purpose, ScienceDirect," "Google Scholar," "PubMed," "ISI Web of Knowledge," and "Wiley Online Library" databases were searched using "curcumin", "cancer", and "gastrointestinal organs" as keywords. In vitro studies performed on different gastrointestinal cancerous cell lines have shown that curcumin can inhibit cell growth through cycle arrest at the G2/M and G1 phases, as well as stimulated apoptosis and autophagy by interacting with multiple molecular targets. In vivo studies performed in various animal models have confirmed mainly the chemopreventive effects of curcumin. Several nano-formulations have been proposed to improve the bioavailability of curcumin and increase its absorption. Moreover, curcumin has been used in combinations with many anti-tumor drugs to increase their anticarcinogenic properties. Taken together, curcumin falls within the category of plant-derived substances capable of preventing or treating gastrointestinal cancers. Further studies, particularly clinical trials, on the efficacy and safety of curcumin are suggested in this regard.	[Naji, Melika; Soroudi, Setareh; Akaberi, Maryam] Mashhad Univ Med Sci, Sch Pharm, Dept Pharmacognosy, Mashhad, Razavi Khorasan, Iran; [Sahebkar, Amirhossein] Mashhad Univ Med Sci, Appl Biomed Res Ctr, Mashhad, Razavi Khorasan, Iran; [Sahebkar, Amirhossein] Mashhad Univ Med Sci, Pharmaceut Technol Inst, Biotechnol Res Ctr, Mashhad, Razavi Khorasan, Iran; [Sahebkar, Amirhossein] Mashhad Univ Med Sci, Sch Pharm, Mashhad, Razavi Khorasan, Iran; [Sahebkar, Amirhossein] Polish Mothers Mem Hosp Res Inst PMMHRI, Lodz, Poland; [Emami, Seyed Ahmad] Mashhad Univ Med Sci, Sch Pharm, Dept Tradit Pharm, Mashhad, Razavi Khorasan, Iran		Sahebkar, A (corresponding author), Mashhad Univ Med Sci, Appl Biomed Res Ctr, Mashhad, Razavi Khorasan, Iran.; Sahebkar, A (corresponding author), Mashhad Univ Med Sci, Pharmaceut Technol Inst, Biotechnol Res Ctr, Mashhad, Razavi Khorasan, Iran.; Sahebkar, A (corresponding author), Mashhad Univ Med Sci, Sch Pharm, Mashhad, Razavi Khorasan, Iran.; Sahebkar, A (corresponding author), Polish Mothers Mem Hosp Res Inst PMMHRI, Lodz, Poland.; Emami, SA (corresponding author), Mashhad Univ Med Sci, Sch Pharm, Dept Tradit Pharm, Mashhad, Razavi Khorasan, Iran.	sahebkara@mums.ac.ir; emamia@mums.ac.ir			Mashhad University of Medical Sciences (MUMS)	The authors are grateful to Mashhad University of Medical Sciences (MUMS) for the help and support.	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J	Efe, EY; Mazumder, A; Lee, JY; Gaigneaux, A; Radogna, F; Nasim, MJ; Christov, C; Jacob, C; Kim, KW; Dicato, M; Chaimbault, P; Cerella, C; Diederich, M				Efe, Esma Yagdi; Mazumder, Aloran; Lee, Jin-Young; Gaigneaux, Anthoula; Radogna, Flavia; Nasim, Muhammad Jawad; Christov, Christo; Jacob, Claus; Kim, Kyu-Won; Dicato, Mario; Chaimbault, Patrick; Cerella, Claudia; Diederich, Marc			Tubulin-binding anticancer polysulfides induce cell death via mitotic arrest and autophagic interference in colorectal cancer	CANCER LETTERS			English	Article						Diallyl sulfide; Mitotic arrest; Cell death; Autophagic flux; Zebrafish xenografts	HUMAN COLON; CARCINOMA CELLS; P-GLYCOPROTEIN; CYCLE ARREST; IN-VITRO; P62; APOPTOSIS; SURVIVAL; PROTEIN; PROLIFERATION	Polysulfanes show chemopreventive effects against gastrointestinal tumors. We identified diallyl tetra-sulfide and its derivative, dibenzyl tetrasulfide (DBTTS), to be mitotic inhibitors and apoptosis inducers. Here, we translate their application in colorectal cancer (CRC). MALDI-TOF-MS analysis identified both compounds as reversible tubulin binders, validated by in cellulo alpha-tubulin degradation. BRAF(V600E)mutated HT-29 cells were resistant to DBTTS, as evidenced by mitotic arrest for 48 h prior to apoptosis induction compared to KRAS(G12V)-mutated SW480/620 cells, which committed to death earlier. The prolonged mitotic block correlated with autophagy impairment and p62 protein accumulation in HT-29 but not in SW480/620 cells, whereas siRNA-mediated p62 inhibition sensitized HT 29 cells to death. In silico analysis with 484 colorectal cancer patients associated higher p62 expression and reduced autophagic flux with greater overall survival. Accordingly, we hypothesized that DB1TS targets CRC survival/death through autophagy interference in cell types with differential autophagic capacities. We confirmed the therapeutic potential of DBTTS by the inhibition of spheroid and colony formation capacities in CRC cells, as well as in HT-29 zebrafish xenografts in vivo. (C) 2017 Elsevier B.V. All rights reserved.	[Efe, Esma Yagdi; Gaigneaux, Anthoula; Radogna, Flavia; Dicato, Mario; Cerella, Claudia] Hop Kirchberg, Lab Biol Mol & Cellulaire Canc, 9 Rue Edward Steichen, L-2540 Luxembourg, Luxembourg; [Mazumder, Aloran; Lee, Jin-Young; Kim, Kyu-Won; Diederich, Marc] Seoul Natl Univ, Coll Pharm, Seoul 08826, South Korea; [Nasim, Muhammad Jawad; Jacob, Claus] Univ Saarland, Sch Pharm, Div Bioorgan Chem, Campus B 2-1, D-66123 Saarbrucken, Germany; [Christov, Christo] Univ Lorraine, Serv Commun Microscopie, Nancy, France; [Chaimbault, Patrick] Univ Lorraine, SRSMC, UMR7565, Metz, France		Diederich, M (corresponding author), Seoul Natl Univ, Dept Pharm, Coll Pharm, Bldg 29 Room 233,1 Gwanak Ro, Seoul 08826, South Korea.	marcdiederich@snu.ac.kr	Radogna, Flavia/AAL-5698-2020; Diederich, Marc/O-7335-2015; Kim, Kyu Won/AAJ-7213-2020	Diederich, Marc/0000-0003-0115-4725; Cerella, Claudia/0000-0001-9308-8176; Radogna, Flavia/0000-0003-0385-3335; CHAIMBAULT, Patrick/0000-0001-7588-8751	Televie Luxembourg fellowship; "Recherche Cancer et Sang" Foundation; "Recherches Scientifiques Luxembourg" Association; "Een Faerz fir kriibskrank Kanner" Association; Action LIONS "Vaincre le Cancer" Association; NRF; MEST of KoreaMinistry of Education, Science and Technology, Republic of Korea [GCRC 2012-0001184]; Brain Korea (BK21) PLUS program; Televie Luxembourg	EY, CC, AG, and FR are recipients of a Televie Luxembourg fellowship. This work was supported by the "Recherche Cancer et Sang" Foundation, the "Recherches Scientifiques Luxembourg" Association, the "Een Faerz fir kriibskrank Kanner" Association, the Action LIONS "Vaincre le Cancer" Association, and by Televie Luxembourg. AM, JYL, and MD are supported by the NRF, the MEST of Korea for Tumor Microenvironment GCRC 2012-0001184 grant, and by Brain Korea (BK21) PLUS program.	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Team, 2016, LANG ENV STAT COMP; Ritchie ME, 2015, NUCLEIC ACIDS RES, V43, DOI 10.1093/nar/gkv007; Schnekenburger M, 2011, BIOCHEM PHARMACOL, V81, P364, DOI 10.1016/j.bcp.2010.10.013; Sean D, 2007, BIOINFORMATICS, V23, P1846, DOI 10.1093/bioinformatics/btm254; Sparreboom A, 1997, P NATL ACAD SCI USA, V94, P2031, DOI 10.1073/pnas.94.5.2031; Spitzner M, 2010, INT J RADIAT ONCOL, V78, P1184, DOI 10.1016/j.ijrobp.2010.06.023; Therneau T.M., 2000, STAT BIOL HEALTH; Therneau TM, 2015, A Package for Survival Analysis in S.; Wei HJ, 2014, GENE DEV, V28, P1204, DOI 10.1101/gad.237354.113; Yagdi E, 2016, FOOD CHEM TOXICOL, V95, P219, DOI 10.1016/j.fct.2016.07.016; Zeng RX, 2014, CELL BIOL INT, V38, P1221, DOI 10.1002/cbin.10311	45	9	9	1	29	ELSEVIER IRELAND LTD	CLARE	ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND	0304-3835	1872-7980		CANCER LETT	Cancer Lett.	DEC 1	2017	410						139	157		10.1016/j.canlet.2017.09.011			19	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FN1VB	WOS:000415778200014	28943451				2022-04-25	
J	Wei, Y; Huang, C; Wu, HY; Huang, J				Wei, Yong; Huang, Can; Wu, Haoyu; Huang, Jian			Estrogen Receptor Beta (ER beta) Mediated-CyclinD1 Degradation via Autophagy Plays an Anti-Proliferation Role in Colon Cells	INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES			English	Article						ER beta; autophagy; colorectal cancer; mTOR; BNIP3; CyclinD1	COLORECTAL-CANCER; CYCLIN D1; DOWN-REGULATION; EXPRESSION; DEATH; ARREST; PROLIFERATION; PROGRESSION; ACTIVATION; PREVENTION	Dysfunction of autophagic degradation machinery causes tumorigenesis, including colorectal cancer (CRC). Overexpression of CyclinD1 in CRC has been reported. Recent evidence also suggests that ER beta deficiency is related to the pathogenesis of CRC. Very little is known, however, about the detailed molecular mechanisms underlying the relationship among ER beta, autophagy, and CyclinD1 in CRC. Here, results showed that ER beta played an anti-proliferation role in HCT116 through impairing cell cycle but not apoptosis. Additionally, CyclinD1 accumulation was increased in response to chloroquine (CQ) or in MEF Atg7 knockout cells. Further, ER beta could inhibit the mammalian target of rapamycin (mTOR) or activate Bcl-2/adenovirus E1 B 19-kDa-interacting protein 3 (BNIP3) to promote autophagy in HCT116. In summary, these results indicate that ER beta-mediated CyclinD1 degradation can inhibit colon cancer cell growth via autophagy.	[Wei, Yong; Wu, Haoyu; Huang, Jian] Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan, Hubei, Peoples R China; [Huang, Can] Wuhan Agr Inspect Ctr, Wuhan, Hubei, Peoples R China		Huang, J (corresponding author), Wuhan Univ, Coll Life Sci, Room 5105, Wuhan 430072, Hubei, Peoples R China.	jianhuang@whu.edu.cn		Wei, Yong/0000-0002-3506-7921	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31870786, 31371331]; National Basic Research Program of China (973 Program)National Basic Research Program of China [2012CB720600]	We are grateful to Professor Michael Mancini, Professor LongPing Wen, Professor Xiaochun Bai and Professor Wei Ding for generously providing plasmids. We also thank Dr. Du and Dr. Li for providing the support of TEM (The Core Facility and Technical Support, Wuhan Institute of Virology). This study was supported by the National Natural Science Foundation of China (NO. 31870786 and 31371331) and The National Basic Research Program of China (973 Program, 2012CB720600). We thank Mr. Ryan Tames and Dr. Yujun Hou (National Institutes of Health) for critical reading of the manuscript.	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J. Biol. Sci.		2019	15	5					942	952		10.7150/ijbs.30930			11	Biochemistry & Molecular Biology; Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics	HX9PE	WOS:000467739600004	31182915	Green Submitted, Green Published, gold			2022-04-25	
J	Lin, SC; Yang, LY; Shi, HY; Du, WP; Qi, YX; Qiu, C; Liang, X; Shi, WB; Liu, JW				Lin, Shengchao; Yang, Liyan; Shi, Haiyang; Du, Wenpei; Qi, Yingxue; Qiu, Cen; Liang, Xin; Shi, Weibin; Liu, Jianwen			Endoplasmic reticulum-targeting photosensitizer Hypericin confers chemosensitization towards oxaliplatin through inducing pro-death autophagy	INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY			English	Article						Endoplasmic reticulum (ER); Photodynamic therapy (PDT); Autophagic cell death; Chemo-sensitization	MEDIATED PHOTODYNAMIC THERAPY; CELL-DEATH; CANCER-CELLS; ER STRESS; COLORECTAL-CANCER; CARCINOMA CELLS; BREAST-CANCER; GLIOMA-CELLS; ACTIVATION; PATHWAY	Hypericin is an endoplasmic reticulum (ER)-located photosensitizer, which causes oxidative damage to ER during photodynamic therapy (PDT). Hypericin-mediated PDT (HY-PDT) has been confirmed to enhance chemosensitivity of oxaliplatin (L-OHP) in colon cancer cells. The present study reveals that autophagy plays a key role in chemosensitization during HY-PDT. We proved pro-death autophagy was required for sensitization and HY-PDT/L-OHP antitumor synergism. High dosage of HY-PDT induced autophagic cell death; while low dose of HY-PDT predominantly triggered protective autophagy and promoted cell proliferation. Low dose of HY-PDT reduced the cytotoxicity of L-OHP in oxaliplatin-resistant colon cancer cells. Different level of autophagy therefore contributed to the opposite effect of HY-PDT on cell fate and chemo-sensitivity. Furthermore, we revealed the role of CHOP as a regulator connecting pro-survival and pro-death autophagy under ER damage. High dose of HY-PDT induced massive ROS generation and severe ER stress, which then led to induction of CHOP. CHOP thereby activated CHOP/TRIB3/Akt/mTOR cascade and triggered autophagic cell death. Additionally, when apoptotic pathway was blocked, cells treated with high dose of HY-PDT preferentially underwent death through autophagic pathway. On the other hand, suppression of autophagy made cells more vulnerable to apoptosis under low dose of HY-PDT. These results provided new evidences for the clinical application of ER-targeting PDT in modifying chemosensitivity of colorectal cancer therapy.	[Lin, Shengchao; Yang, Liyan; Shi, Haiyang; Du, Wenpei; Qi, Yingxue; Qiu, Cen; Liang, Xin; Liu, Jianwen] East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Sch Pharm, POB 268,130 Meilong Rd, Shanghai 200237, Peoples R China; [Lin, Shengchao; Yang, Liyan; Shi, Haiyang; Du, Wenpei; Qi, Yingxue; Qiu, Cen; Liang, Xin; Liu, Jianwen] East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, POB 268,130 Meilong Rd, Shanghai 200237, Peoples R China; [Shi, Weibin] Shanghai Jiao Tong Univ, Dept Gen Surg, Xinhua Hosp, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China		Liang, X; Liu, JW (corresponding author), East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Sch Pharm, POB 268,130 Meilong Rd, Shanghai 200237, Peoples R China.; Liang, X; Liu, JW (corresponding author), East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, POB 268,130 Meilong Rd, Shanghai 200237, Peoples R China.; Shi, WB (corresponding author), Shanghai Jiao Tong Univ, Dept Gen Surg, Xinhua Hosp, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China.	xin.liang@ecust.edu.cn; weibindr@aliyun.com; liujian@ecust.edu.cn			Shanghai Committee of Science and TechnologyShanghai Science & Technology Committee [11DZ2260600]; Shanghai Health and Family Planning Commission [201440495]	We are grateful to Prof. Feng Qian (Fudan University, Shanghai China) for providing the pCDNA3.1-GFP-LC3 plasmid. This work was supported by Shanghai Committee of Science and Technology [grant 11DZ2260600] and Program of Shanghai Health and Family Planning Commission (201440495).	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J. Biochem. Cell Biol.	JUN	2017	87						54	68		10.1016/j.biocel.2017.04.001			15	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	EX8VN	WOS:000403528400008	28392376				2022-04-25	
J	Mokarram, P; Albokashy, M; Zarghooni, M; Moosavi, MA; Sepehri, Z; Chen, QM; Hudecki, A; Sargazi, A; Alizadeh, J; Moghadam, AR; Hashemi, M; Movassagh, H; Klonisch, T; Owji, AA; Los, MJ; Ghavami, S				Mokarram, Pooneh; Albokashy, Mohammed; Zarghooni, Maryam; Moosavi, Mohammad Amin; Sepehri, Zahra; Chen, Qi Min; Hudecki, Andrzej; Sargazi, Aliyeh; Alizadeh, Javad; Moghadam, Adel Rezaei; Hashemi, Mohammad; Movassagh, Hesam; Klonisch, Thomas; Owji, Ali Akbar; Los, Marek J.; Ghavami, Saeid			New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets	AUTOPHAGY			English	Review						autophagy; Beclin 1; cancer therapy; colorectal cancer; ER-stress; GRP78; unfolded protein response	ENDOPLASMIC-RETICULUM-STRESS; CHAPERONE-MEDIATED AUTOPHAGY; GENE COPY NUMBER; RANDOMIZED CONTROLLED-TRIAL; GENOME-WIDE ASSOCIATION; INDUCED COLON-CANCER; STEM-LIKE CELLS; GROWTH IN-VIVO; DENDRITIC CELLS; THYMIDYLATE SYNTHASE	Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.	[Mokarram, Pooneh] Shiraz Univ Med Sci, Colorectal Res Ctr, Shiraz, Iran; [Mokarram, Pooneh] Shiraz Univ Med Sci, Dept Biochem, Sch Med, Shiraz, Iran; [Albokashy, Mohammed; Chen, Qi Min; Alizadeh, Javad; Moghadam, Adel Rezaei; Klonisch, Thomas; Ghavami, Saeid] Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada; [Zarghooni, Maryam; Sepehri, Zahra; Sargazi, Aliyeh] Zabol Univ Med Sci, Zabol, Iran; [Zarghooni, Maryam] Univ Toronto Alumni, Toronto, ON, Canada; [Moosavi, Mohammad Amin] Natl Inst Genet Engn & Biotechnol, Inst Med Biotechnol, Dept Mol Med, Tehran, Iran; [Hudecki, Andrzej] Inst Nonferrous Met, Gliwice, Poland; [Hashemi, Mohammad] Zahedan Univ Med Sci, Sch Med, Dept Clin Biochem, Zahedan, Iran; [Movassagh, Hesam] Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Dept Immunol, Winnipeg, MB, Canada; [Owji, Ali Akbar] Shiraz Med Univ, Sch Med, Dept Clin Biochem, Shiraz, Iran; [Los, Marek J.] Jagiellonian Univ, Malopolska Ctr Biotechnol, Krakow, Poland; [Ghavami, Saeid] LinkoCare Life Sci AB, Mjardevi Sci Pk,Teknikringen 10,Floor 3, Linkoping, Sweden; [Ghavami, Saeid] Shiraz Univ Med Sci, Hlth Policy Res Ctr, Shiraz, Iran		Los, MJ (corresponding author), LinkoCare Life Sci AB, Mjardevi Sci Pk,Teknikringen 10,Floor 3, Linkoping, Sweden.; Ghavami, S (corresponding author), Univ Manitoba, Coll Med, Fac Hlth Sci, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada.	bioappl@gmail.com; saied.ghavami@umanitoba.ca	Klonisch, Thomas/W-9923-2019; Hashemi, Mohammad/H-2446-2016; Alizadeh, Javad/AAR-4824-2020; Moosavi, Mohammad Amin/AAK-3240-2020; Mokarram, Pooneh/E-1613-2012	Hashemi, Mohammad/0000-0002-6074-7101; Alizadeh, Javad/0000-0001-9082-3083; Mokarram, Pooneh/0000-0002-9717-0473; Ghavami, Saeid/0000-0001-5948-508X; ALBOKASHY, MOHAMMED/0000-0002-0933-9110; Sargazi, Aliyeh/0000-0002-9037-6639; Klonisch, Thomas/0000-0003-0448-6741	University of Manitoba; National Institute for Genetic Engineering and Biotechnology; Natural Sciences and Engineering Council of Canada (NSERC)Natural Sciences and Engineering Research Council of Canada (NSERC); MITACS; NCN [2016/21/B/NZ1/02812]; Manitoba Medical Service Foundation	SG acknowledges Manitoba Medical Service Foundation, and University of Manitoba Research Grant Program. AM acknowledges National Institute for Genetic Engineering and Biotechnology Research Grants. TK extends his gratitude to the Natural Sciences and Engineering Council of Canada (NSERC) for funding. MA was supported by MITACS Globalink award. MJL and AH kindly acknowledges the support from NCN grant #: 2016/21/B/NZ1/02812.	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J	Kantara, C; O'Connell, M; Sarkar, S; Moya, S; Ullrich, R; Singh, P				Kantara, Carla; O'Connell, Malaney; Sarkar, Shubhashish; Moya, Stephanie; Ullrich, Robert; Singh, Pomila			Curcumin Promotes Autophagic Survival of a Subset of Colon Cancer Stem Cells, Which Are Ablated by DCLK1-siRNA	CANCER RESEARCH			English	Article							NF-KAPPA-B; SIGNALING PATHWAYS; BETA-CATENIN; PROGASTRIN; APOPTOSIS; GROWTH; DOUBLECORTIN; RADIATION; MICE; DIFFERENTIATION	Curcumin is known to induce apoptosis of cancer cells by different mechanisms, but its effects on cancer stem cells (CSC) have been less investigated. Here, we report that curcumin promotes the survival of DCLK1-positive colon CSCs, potentially confounding application of its anticancer properties. At optimal concentrations, curcumin greatly reduced expression levels of stem cell markers (DCLK1/CD44/ALDHA1/Lgr5/Nanog) in three-dimensional spheroid cultures and tumor xenografts derived from colon cancer cells. However, curcumin unexpectedly induced proliferation and autophagic survival of a subset of DCLK1-positive CSCs. Spheroid cultures were disintegrated by curcumin in vitro but regrew within 30 to 40 days of treatment, suggesting a survival benefit from autophagy, permitting long-term persistence of colorectal cancer. Notably, RNA interference-mediated silencing of DCLK1 triggered apoptotic cell death of colon cancer cells in vitro and in vivo, and abolished colorectal cancer survival in response to curcumin; combination of DCLK1-siRNA and curcumin dramatically reversed CSC phenotype, contributing to attenuation of the growth of spheroid cultures and tumor xenografts. Taken together, our findings confirm a role of DCLK1 in colon CSCs and highlight DCLK1 as a target to enhance antitumor properties of curcumin.	[Kantara, Carla; O'Connell, Malaney; Sarkar, Shubhashish; Moya, Stephanie; Singh, Pomila] Univ Texas Med Branch, Dept Cell Biol & Neurosci, Galveston, TX 77555 USA; [Kantara, Carla; Ullrich, Robert; Singh, Pomila] Univ Texas Med Branch Hlth, Sealy Canc Ctr, Galveston, TX 77555 USA		Singh, P (corresponding author), Univ Texas Med Branch, Dept Cell Biol & Neurosci, 10-104 Med Res Bldg,301 Univ Blvd,Route 1043, Galveston, TX 77555 USA.	posingh@utmb.edu			NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA97959, CA114264]; NASANational Aeronautics & Space Administration (NASA) [NNX09AM08G, NNJ04HD83G]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA114264, R01CA097959] Funding Source: NIH RePORTER	This work was supported by NIH grants CA97959 and CA114264 to P. Singh and NASA grants NNX09AM08G and NNJ04HD83G to R. Ullrich.	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MAY 1	2014	74	9					2487	2498		10.1158/0008-5472.CAN-13-3536			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AH1ZH	WOS:000335920000012	24626093	Green Accepted			2022-04-25	
J	Lee, KTW; Islam, F; Vider, J; Martin, J; Chruscik, A; Lu, CT; Gopalan, V; Lam, AKY				Lee, Katherine Ting-Wei; Islam, Farhadul; Vider, Jelena; Martin, Jeremy; Chruscik, Anna; Lu, Cu-Tai; Gopalan, Vinod; King-Yin Lam, Alfred			Overexpression of family with sequence similarity 134, member B (FAM134B) in colon cancers and its tumor suppressive properties in vitro	CANCER BIOLOGY & THERAPY			English	Article						FAM134B; MIF; p53; mitochondrial function; colorectal; colon; cancer	MIGRATION-INHIBITORY-FACTOR; EXPRESSION; MUTATIONS; STRESS; JK1; MITOCHONDRIA; CROSSTALK; AUTOPHAGY; PROTEIN; UPR	This study aims to investigate the overexpression-induced properties of tumor suppressorFAM134B(family with sequence similarity 134, member B) in colon cancer, examine the potential gene regulators ofFAM134Bexpression and its impact on mitochondrial function.FAM134Bwas overexpressed in colon cancer and non-neoplastic colonic epithelial cells. Various cell-based assays including apoptosis, cell cycle, cell proliferation, clonogenic, extracellular flux and wound healing assays were performed. Western blot analysis was used to confirm and identify potential interacting partners ofFAM134B in vitro. Immunohistochemistry and qPCR were employed to determine the expressions of MIF andFAM134B, respectively, on 63 patients with colorectal carcinoma. Results showed thatFAM134Bis involved in the cell cycle and mitochondrial function of colon cancer. Overexpression ofFAM134Bwas coupled with increased expression levels of APC, p53, and MIF. Increased expression of both APC and p53 further validates the potential role of tumor suppressorFAM134Bin regulating cancer progression through the WNT/ss-catenin signaling pathway. In approximately 70% of the patients with colorectal cancer,FAM134Bdownregulation was correlated with MIF protein overexpression while the remaining 30% showed concurrent expression ofFAM134Band MIF (P= .045). High expression of MIF coupled with low expression ofFAM134Bis associated with microsatellite instability status in colorectal carcinomas (P= .049).FAM134Bmay exert its tumor suppressive function through affecting cell cycle, mitochondrial function via potentially interacting with MIF and p53.	[Lee, Katherine Ting-Wei; Islam, Farhadul; Martin, Jeremy; Chruscik, Anna; Gopalan, Vinod; King-Yin Lam, Alfred] Griffith Univ, Sch Med, Canc Mol Pathol, Gold Coast, Qld, Australia; [Islam, Farhadul] Univ Rajshahi, Dept Biochem & Mol Biol, Rajshahi, Bangladesh; [Vider, Jelena] Griffith Univ, Sch Med Sci, Gold Coast, Qld, Australia; [Lu, Cu-Tai] Gold Coast Univ Hosp, Dept Surg, Gold Coast, Qld, Australia		Lam, AKY (corresponding author), Griffith Univ, Sch Med, Pathol, Gold Coast, Qld 4222, Australia.	a.lam@griffith.edu.au	Vider, Jelena/B-9663-2011; Lam, Alfred/C-1652-2008; Chruścik, Anna/ABB-1328-2021	Vider, Jelena/0000-0003-1696-9812; Lam, Alfred/0000-0003-2771-564X; Chruścik, Anna/0000-0003-4147-9022; Lee, Katherine Ting-Wei/0000-0003-2068-7762; Lu, Cu Tai/0000-0001-9565-3749	HDR scholarship from Griffith University; Menzies Health Institute Queensland; Asian Foundation for Tropical Medicine; Griffith UniversityGriffith University; School of Medicine, Griffith University	The project was supported by the HDR scholarship from Griffith University and funding from Menzies Health Institute Queensland and Asian Foundation for Tropical Medicine. In addition, we would like to acknowledge the paper completion assistance from the School of Medical Science, Griffith University, HDR scholarship from Griffith University, research funding to support early career researcher from School of Medicine, Griffith University in 2019.	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Ther.	OCT 2	2020	21	10					954	962		10.1080/15384047.2020.1810535		AUG 2020	9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	OD5HV	WOS:000564161300001	32857678	Green Accepted, Bronze, Green Published			2022-04-25	
J	Li, YC; Li, CF; Li, DD; Yang, L; Jin, JP; Zhang, B				Li, Yongchao; Li, Changfeng; Li, Dandan; Yang, Lei; Jin, Jingpeng; Zhang, Bin			lncRNA KCNQ1OT1 enhances the chemoresistance of oxaliplatin in colon cancer by targeting the miR-34a/ATG4B pathway	ONCOTARGETS AND THERAPY			English	Article						KCNQ1OT1; colorectal cancer; protective autophagy; miR-34a; Atg4B; chemoresistance	COLORECTAL-CANCER; MOLECULAR-MECHANISMS; AUTOPHAGY; STATISTICS; RESISTANCE	Purpose: The chemoresistance of colon cancer to oxaliplatin (L-OHP) indicates poor prognosis. Long non-coding RNA (lncRNA) KCNQ1OT1 (KCNQ1 opposite strand/antisense transcript 1) has been shown to participate in the tumorigenesis of several types of cancers. However, little is known about the role of KCNQ1OT1 in the chemoresistance and prognosis of colon cancer. Materials and methods: Quantitative-PCR and Western blot were used to measure the expression profiles of KCNQ1OT1, miR-34a, and Atg4B in colon cancer tissues and cells. Cell viability assay and flow cytometry were used to examine their effects on cell proliferation and death. Cleavage of LC3 and GFP-LC3 plasmid transfection were used to detect autophagic activity. Double luciferase reporter assay was used to verify the interactions between miRNA and lncRNA or mRNA. Xenograft tumor model was used to verify the effects of KCNQ1OT1 in vivo. Results: In this study, it is shown that the expression level of KCNQ1OT1 was increased in tumor, which indicated poor prognosis in colon cancer patients. Using colon cancer cell lines HCT116 and SW480, it was demonstrated that knockdown of KCNQ1OT1 decreased the cell viability and increased the apoptosis rates upon L-OHP treatment. Further studies indicated that Atg4B upregulation was partially responsible for KCNQ1OT1-induced protective autophagy and chemoresistance. Moreover, miR-34a functioned as a bridge between KCNQ1OT1 and Atg4B, which could be sponged by KCNQ1OT1, while it could also bind to the 3'-UTR of Atg4B and downregulate its expressions. Finally, we show that the KCNQ1OT1/miR-34a/Atg4B axis regulated the chemoresistance of colon cancer cells in vitro and in vivo. Conclusion: lncRNA KCNQ1OT1 promoted the chemoresistance of colon cancer by sponging miR-34a, thus upregulating the expressions of Atg4B and enhancing protective autophagy. KCNQ1OT1 might become a promising target for colon cancer therapeutics.	[Li, Yongchao] Jilin Univ, China Japan Union Hosp, Dept Gastrointestinal Surg, Changchun 130033, Jilin, Peoples R China; [Li, Changfeng; Li, Dandan; Yang, Lei; Jin, Jingpeng; Zhang, Bin] Jilin Univ, China Japan Union Hosp, Dept Endoscopy Ctr, 126 Xiantai St, Changchun 130033, Jilin, Peoples R China		Li, CF (corresponding author), Jilin Univ, China Japan Union Hosp, Dept Endoscopy Ctr, 126 Xiantai St, Changchun 130033, Jilin, Peoples R China.	changfengli1975@163.com					Agostini M, 2014, ONCOTARGET, V5, P872, DOI 10.18632/oncotarget.1825; Akao Y, 2011, CANCER LETT, V300, P197, DOI 10.1016/j.canlet.2010.10.006; Beg MS, 2017, INVEST NEW DRUG, V35, P180, DOI 10.1007/s10637-016-0407-y; Bortnik S, 2016, ONCOTARGET, V7, P66970, DOI 10.18632/oncotarget.11408; Chen WQ, 2016, CA-CANCER J CLIN, V66, P115, DOI 10.3322/caac.21338; Farooqi AA, 2017, INT J MOL SCI, V18, DOI 10.3390/ijms18102089; Gao J, 2015, ONCOGENE, V34, P4142, DOI 10.1038/onc.2014.348; Ghandadi M, 2016, CURR PHARM DESIGN, V22, P933, DOI 10.2174/1381612822666151209153729; Hemelaar J, 2003, J BIOL CHEM, V278, P51841, DOI 10.1074/jbc.M308762200; Higashimoto K, 2006, CYTOGENET GENOME RES, V113, P306, DOI 10.1159/000090846; Hiyoshi Y, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0124899; Kallen AN, 2013, MOL CELL, V52, P101, DOI 10.1016/j.molcel.2013.08.027; Kastl L, 2012, BREAST CANCER RES TR, V131, P445, DOI 10.1007/s10549-011-1424-3; Kelland L, 2007, NAT REV CANCER, V7, P573, DOI 10.1038/nrc2167; Korostowski L, 2012, PLOS GENET, V8, DOI 10.1371/journal.pgen.1002956; Kumar A, 2015, FUTURE MED CHEM, V7, P1535, DOI 10.4155/fmc.15.88; Lai MG, 2015, MOL MED REP, V11, P3301, DOI 10.3892/mmr.2015.3182; Li CF, 2018, DEV CELL, V46, P441, DOI 10.1016/j.devcel.2018.07.012; Li CF, 2017, BIOCHEM BIOPH RES CO, V491, P552, DOI 10.1016/j.bbrc.2017.03.042; Li CY, 2018, WISEC'18: PROCEEDINGS OF THE 11TH ACM CONFERENCE ON SECURITY & PRIVACY IN WIRELESS AND MOBILE NETWORKS, P1, DOI 10.1145/3212480.3212496; Li XJ, 2014, CELL DEATH DIS, V5, DOI 10.1038/cddis.2014.270; Li Y, 2018, J IMMUNOL RES, V2018, DOI [10.1155/2018/7198514, 10.1155/2018/7498514]; Liao HQ, 2016, ONCOL REP, V35, P64, DOI 10.3892/or.2015.4331; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038/nrm2239; Martinez-Balibrea E, 2015, MOL CANCER THER, V14, P1767, DOI 10.1158/1535-7163.MCT-14-0636; Misso G, 2014, MOL THER-NUCL ACIDS, V3, DOI 10.1038/mtna.2014.47; Nagano T, 2011, CELL, V145, P178, DOI 10.1016/j.cell.2011.03.014; Ni ZH, 2018, AUTOPHAGY, V14, P685, DOI 10.1080/15548627.2017.1407887; Ogawa T, 2012, CANCER SCI, V103, P1737, DOI 10.1111/j.1349-7006.2012.02338.x; Pandey RR, 2008, MOL CELL, V32, P232, DOI 10.1016/j.molcel.2008.08.022; Paraskevopoulou MD, 2016, NUCLEIC ACIDS RES, V44, pD231, DOI 10.1093/nar/gkv1270; Quinn JJ, 2016, NAT REV GENET, V17, P47, DOI 10.1038/nrg.2015.10; Rafiee A, 2018, BIOTECHNOL GENET ENG, V34, P153, DOI 10.1080/02648725.2018.1471566; Rapti SM, 2017, CLIN BIOCHEM, V50, P918, DOI 10.1016/j.clinbiochem.2017.06.004; Ren FH, 2015, INT J CLIN EXP MED, V8, P17377; Ren KM, 2017, CANCER CHEMOTH PHARM, V80, P243, DOI 10.1007/s00280-017-3356-z; Satoo K, 2009, EMBO J, V28, P1341, DOI 10.1038/emboj.2009.80; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Sugawara K, 2005, J BIOL CHEM, V280, P40058, DOI 10.1074/jbc.M509158200; Thomson DW, 2016, NAT REV GENET, V17, P272, DOI 10.1038/nrg.2016.20; Wang J, 2015, ONCOTARGETS THER, V8, P2709, DOI 10.2147/OTT.S84043; Workman P, 2010, BRIT J CANCER, V102, P1555, DOI 10.1038/sj.bjc.6605642; Wu QB, 2018, MOL CLIN ONCOL, V8, P523, DOI 10.3892/mco.2018.1578; Wu SF, 2016, TUMOR BIOL, V37, P6943, DOI 10.1007/s13277-015-4587-4; Wu YR, 2016, AUTOPHAGY, V12, P1105, DOI 10.1080/15548627.2016.1173798; Yang ZF, 2015, J BIOL CHEM, V290, P26549, DOI 10.1074/jbc.M115.658088; Yang ZF, 2010, NAT CELL BIOL, V12, P814, DOI 10.1038/ncb0910-814; Zhang SY, 2018, CELL DEATH DIS, V9, DOI 10.1038/s41419-018-0793-5; Zhang Y, 2017, ONCOTARGET, V8, DOI 10.18632/oncotarget.20883	49	69	71	4	11	DOVE MEDICAL PRESS LTD	ALBANY	PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND	1178-6930			ONCOTARGETS THER	OncoTargets Ther.		2019	12						2649	2660		10.2147/OTT.S188054			12	Biotechnology & Applied Microbiology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Oncology	HS4VH	WOS:000463866800001	31040703	Green Published, gold, Green Submitted			2022-04-25	
J	Mao, LP; Yang, JX; Yue, JX; Chen, Y; Zhou, HR; Fan, DD; Zhang, QH; Buraschi, S; Iozzo, RV; Bi, XL				Mao, Liping; Yang, Jinxue; Yue, Jiaxin; Chen, Yang; Zhou, Hongrui; Fan, Dongdong; Zhang, Qiuhua; Buraschi, Simone; Iozzo, Renato V.; Bi, Xiuli			Decorin deficiency promotes epithelial-mesenchymal transition and colon cancer metastasis	MATRIX BIOLOGY			English	Article						Decorin; Tumor microenvironment; EMT; AOM/DS; Colorectal cancer; Celecoxib	LEUCINE-RICH PROTEOGLYCANS; GROWTH-FACTOR RECEPTOR; COLORECTAL-CANCER; GENE-EXPRESSION; IN-VIVO; TUMOR MICROENVIRONMENT; EXTRACELLULAR-MATRIX; DOWN-REGULATION; VII COLLAGEN; AUTOPHAGY	The tumor microenvironment encompasses a complex cellular network that includes cancer-associated fibroblasts, inflammatory cells, neo-vessels, and an extracellular matrix enriched in angiogenic growth factors. Decorin is one of the main components of the tumor stroma, but it is not expressed by cancer cells. Lack of this proteoglycan correlates with down-regulation of E-cadherin and induction of beta-catenin signaling. In this study, we investigated the role of a decorin-deficient tumor microenvironment in colon carcinoma progression and metastasis. We utilized an established model of colitis-associated cancer by administering Azoxymethane/Dextran sodium sulfate to adult wild-type and Dcn(-/-) mice. We discovered that after 12 weeks, all the animals developed intestinal tumors independently of their genotype. However, the number of intestinal neoplasms was significantly higher in the Dcn(-/-) microenvironment vis-a-vis wild-type mice. Mechanistically, we found that under unchallenged basal conditions, the intestinal epithelium of the Dcn(-/-) mice showed a significant increase in the protein levels of epithelial-mesenchymal transition associated factors including Snail, Slug, Twist, and MMP2. In comparison, in the colitis-associated cancer evoked in the Dcn(-/-) mice, we found that intercellular adhesion molecule 1 (ICAM-1) was also significantly increased, in parallel with epithelial-mesenchymal transition signaling pathway-related factors. Furthermore, a combined Celecoxib/decorin treatment revealed a promising therapeutic efficacy in treating human colorectal cancer cells, in decorin-deficient animals. Collectively, our results shed light on colorectal cancer progression and provide a protein-based therapy, i.e., treatment using recombinant decorin, to target the tumor microenvironment. (C) 2020 Elsevier B.V. All rights reserved.	[Mao, Liping; Yang, Jinxue; Yue, Jiaxin; Chen, Yang; Zhou, Hongrui; Fan, Dongdong; Bi, Xiuli] Liaoning Univ, Coll Life Sci, Shenyang 110036, Peoples R China; [Zhang, Qiuhua] Liaoning Univ Tradit Chinese Med, Dept Pharmacol, Shenyang 110036, Peoples R China; [Buraschi, Simone; Iozzo, Renato V.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA; [Buraschi, Simone; Iozzo, Renato V.] Thomas Jefferson Univ, Canc Cell Biol & Signaling Program, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA		Bi, XL (corresponding author), Liaoning Univ, Coll Life Sci, Shenyang 110036, Peoples R China.; Iozzo, RV (corresponding author), Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA.; Iozzo, RV (corresponding author), Thomas Jefferson Univ, Canc Cell Biol & Signaling Program, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA.	renato.iozzo@jefferson.edu; xiulibi@lnu.edu.cn		Buraschi, Simone/0000-0002-4233-7627	National Nature Science foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472821]; LiaoNing Revitalization Talents Program [XLYC 1807058]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA39481]; Key Grant of Education department of Liaoning Province [LZD201904]	We thank Thomas Neill for critically reading of the manuscript. This study was funded by National Nature Science foundation of China (Grants#: 81472821) LiaoNing Revitalization Talents Program (#XLYC 1807058), in part by National Institutes of Health grant CA39481 (to RVI), and partially supported by Key Grant of Education department of Liaoning Province (LZD201904).	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JAN	2021	95						1	14		10.1016/j.matbio.2020.10.001		FEB 2021	14	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	QG7WR	WOS:000617794300001	33065248	Green Accepted			2022-04-25	
J	Horng, CT; Wu, YJ; Chen, PN; Chu, SC; Tsai, CM; Hsieh, YS				Horng, Chi-Ting; Wu, Yueh-Jung; Chen, Pei-Ni; Chu, Shu-Chen; Tsai, Chun-Miao; Hsieh, Yih-Shou			Koelreuteria Formosana Extract Induces Growth Inhibition and Cell Death in Human Colon Carcinoma Cells via G2/M Arrest and LC3-II Activation-Dependent Autophagy	NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL			English	Article							CANCER CELLS; IN-VITRO; KINASE INHIBITORS; CYCLE ARREST; APOPTOSIS; BERBERINE; INDUCTION; PROTEIN; VIVO	Autophagy is a self-destructive process that degrades cytoplasmic constituents. In our previous study, Koelreuteria formosana ethanolic extract (KFEE), which is obtained from natural plants endemic to Taiwan, has inhibited cell metastasis in renal carcinoma cells. However, the anticancer effects of KFEE on colon cancer remain unclear. In this study, KFEE exerted a strong cytotoxic effect on DLD-1 and COLO 205 human colorectal cancer cell lines. KFEE effectively inhibited cancer cell proliferation, induced G2/M-phase arrest associated with downregulaton of cyclin E, cyclin B and cdc25C and upregulation of p21, and induced cell death by activating autophagy but did not cause apoptotic cell death. Exposed KFEE cells showed increased levels of acridine orange, autophagic vacuoles, and LC3-II proteins, which are specific autophagic markers. Bcl-2, p-Akt, and p-mTOR levels, which have been implicated in autophagic downregulation, were decreased after KFEE treatment. Autophagy inhibitor 3-methyladenosine and bafilomycin-A1 and genetic silencing of LC3 attenuated KFEE-induced growth inhibition. These findings suggested that KFEE causes cytostatic effect through autophagy. In xenograft studies, oral administration of KFEE had significantly inhibited the tumor growth in nude mice that had received subcutaneous injection of DLD-1 cells. KFEE is a promising candidate in phytochemical-based, mechanistic, and pathway-targeted cancer prevention strategies.	[Horng, Chi-Ting] Kaohsiung Armed Forces Gen Hosp, Med Educ Ctr, Kaohsiung, Taiwan; [Horng, Chi-Ting; Chen, Pei-Ni; Tsai, Chun-Miao; Hsieh, Yih-Shou] Chung Shang Med Univ, Inst Biochem Microbiol & Immunol, 110,Sect 1,Jianguo N Rd, Taichung 402, Taiwan; [Wu, Yueh-Jung] Kaohsiung Armed Forces Gen Hosp, Dept Colorectal Surg, Kaohsiung, Taiwan; [Chu, Shu-Chen] Cent Taiwan Univ Sci & Technol, Inst & Dept Food Sci, Taichung, Taiwan; [Hsieh, Yih-Shou] Chung Shan Med Univ Hosp, Clin Lab, Taichung, Taiwan			csmcysh@csmu.edu.tw			Kaohsiung Armed Forces General Hospital [104-15]	This study was supported by grants of Kaohsiung Armed Forces General Hospital [104-15].	Abal M, 2004, ONCOGENE, V23, P1737, DOI 10.1038/sj.onc.1207299; ABOUSHOER M, 1993, J NAT PROD, V56, P967, DOI 10.1021/np50096a027; Chang CJ, 1996, IN VIVO, V10, P185; Chen CH, 2009, MOLECULES, V14, P2947, DOI 10.3390/molecules14082947; Chen PN, 2005, NUTR CANCER, V53, P232, DOI 10.1207/s15327914nc5302_12; Chen PN, 2011, J AGR FOOD CHEM, V59, P3836, DOI 10.1021/jf1049408; Chu SC, 2014, MOL PHARMACOL, V86, P609, DOI 10.1124/mol.114.094037; Chu SC, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0101579; Chu SC, 2014, INTEGR CANCER THER, V13, P259, DOI 10.1177/1534735413510559; ELLEDGE SJ, 1994, CURR OPIN CELL BIOL, V6, P847, DOI 10.1016/0955-0674(94)90055-8; Gao P, 2013, BMC CANCER, V13, DOI 10.1186/1471-2407-13-123; Gewirtz DA, 2013, AUTOPHAGY, V9, P1263, DOI 10.4161/auto.25233; GRANA X, 1995, ONCOGENE, V11, P211; Ho YS, 2001, INT J CANCER, V91, P393, DOI 10.1002/1097-0215(200002)9999:9999&lt;::AID-IJC1070&gt;3.0.CO;2-#; Hsin IL, 2011, AUTOPHAGY, V7, P873, DOI 10.4161/auto.7.8.15698; Hu FW, 2012, MOL NUTR FOOD RES, V56, P1247, DOI 10.1002/mnfr.201200150; Huang AC, 2013, INT J ONCOL, V43, P485, DOI 10.3892/ijo.2013.1952; Lin CY, 2014, MOL MED REP, V10, P3334, DOI 10.3892/mmr.2014.2587; Lin CY, 2014, FOOD CHEM, V146, P299, DOI 10.1016/j.foodchem.2013.09.018; Liu N, 2013, ONCOL REP, V30, P2677, DOI 10.3892/or.2013.2771; Mantena SK, 2006, MOL CANCER THER, V5, P296, DOI 10.1158/1535-7163.MCT-05-0448; Mohammadzadeh M, 2013, INTEGR CANCER THER, V12, P496, DOI 10.1177/1534735413485417; Park SH, 2012, TOXICOL LETT, V212, P252, DOI 10.1016/j.toxlet.2012.06.007; Raghavan D, 1997, EUR J CANCER, V33, P566, DOI 10.1016/S0959-8049(96)00510-2; Speirs CK, 2011, AM J CANCER RES, V1, P43; Swanton C, 2004, LANCET ONCOL, V5, P27, DOI 10.1016/S1470-2045(03)01321-4; Tacar O, 2013, J PHARM PHARMACOL, V65, P1577, DOI 10.1111/jphp.12144	27	4	5	0	9	ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD	ABINGDON	2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND	0163-5581	1532-7914		NUTR CANCER	Nutr. Cancer		2017	69	1					44	55		10.1080/01635581.2017.1247889			12	Oncology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Nutrition & Dietetics	EI6QD	WOS:000392619700005	27880045				2022-04-25	
J	Chen, MC; Lee, NH; Hsu, HH; Ho, TJ; Tu, CC; Hsieh, DJY; Lin, YM; Chen, LM; Kuo, WW; Huang, CY				Chen, Ming-Cheng; Lee, Nien-Hung; Hsu, Hsi-Hsien; Ho, Tsung-Jung; Tu, Chuan-Chou; Hsieh, Dennis Jine-Yuan; Lin, Yueh-Min; Chen, Li-Mien; Kuo, Wei-Wen; Huang, Chih-Yang			Thymoquinone Induces Caspase-Independent, Autophagic Cell Death in CPT-11-Resistant LoVo Colon Cancer via Mitochondrial Dysfunction and Activation of JNK and p38	JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY			English	Article						apoptosis; autophagy; caspase-independent; CPT-11-R LoVo colon cancer cells; thymoquinone	NF-KAPPA-B; CHEMORESISTANCE; MECHANISMS; DRUG; CHEMOTHERAPY; METASTASIS; INHIBITION; PREVENTION; RESISTANCE; THERAPIES	Chemotherapy causes unwanted side effects and chemoresistance, limiting its effectiveness. Therefore, phytochemicals are now used as alternative treatments. Thymoquinone (TQ) is used to treat different cancers, including colon cancer. The irinotecan-resistant (CPT-11-R) LoVo colon cancer cell line was previously constructed by stepwise CPT-11 challenges to untreated parental LoVo cells. TQ dose-dependently increased the total cell death index and activated apoptosis at 2 mu M, which then diminished at increasing doses. The possibility of autophagic cell death was then investigated. TQ caused mitochondrial outer membrane permeability (MOMP) and activated autophagic cell death. JNK and p38 inhibitors (SP600125 and SB203580, respectively) reversed TQ autophagic cell death. TQ was also found to activate apoptosis before autophagy, and the direction of cell death was switched toward autophagic cell death at initiation of autophagosome formation. Therefore, TQ resulted in caspase-independent, autophagic cell death via MOMP and activation of JNK and p38 in CPT-11-R LoVo colon cancer cells.	[Chen, Ming-Cheng; Lee, Nien-Hung; Huang, Chih-Yang] China Med Univ, Grad Inst Basic Med Sci, Taichung 404, Taiwan; [Chen, Ming-Cheng] Taichung Vet Gen Hosp, Puli Branch, Nantou 545, Taiwan; [Hsu, Hsi-Hsien] Mackay Mem Hosp, Div Colorectal Surg, Taipei 104, Taiwan; [Hsu, Hsi-Hsien] Nursing & Management Coll, Mackay Med, Taipei 112, Taiwan; [Ho, Tsung-Jung] China Med Univ, Beigang Hosp, Chinese Med Dept, Yunlin 651, Taiwan; [Tu, Chuan-Chou; Chen, Li-Mien] Armed Force Taichung Gen Hosp, Div Chest Med, Dept Internal Med, Taichung 411, Taiwan; [Hsieh, Dennis Jine-Yuan] Chung Shan Med Univ, Sch Med Lab & Biotechnol, Taichung 402, Taiwan; [Hsieh, Dennis Jine-Yuan] Chung Shan Med Univ Hosp, Dept Clin Lab, Taichung 402, Taiwan; [Lin, Yueh-Min] Changhua Christian Hosp, Dept Pathol, Changhua 505, Taiwan; [Kuo, Wei-Wen] China Med Univ, Dept Biol Sci & Technol, Taichung 404, Taiwan; [Huang, Chih-Yang] China Med Univ, Grad Inst Chinese Med Sci, Taichung 404, Taiwan; [Huang, Chih-Yang] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 413, Taiwan		Huang, CY (corresponding author), China Med Univ, Grad Inst Basic Med Sci, Taichung 404, Taiwan.	cyhuang@mail.cmu.edu.tw	Yuang, Chih-Yang/O-5111-2015	Lee, Nien-Hung/0000-0001-5423-8880	Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence [MOHW104-TDU-B-212-113002]	This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002).	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Agric. Food Chem.	FEB 11	2015	63	5					1540	1546		10.1021/jf5054063			7	Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Agriculture; Chemistry; Food Science & Technology	CB4CW	WOS:000349576800025	25611974				2022-04-25	
J	Wu, TY; Cho, TY; Lu, CK; Liou, JP; Chen, MC				Wu, Tung-Yun; Cho, Ting-Yu; Lu, Chung-Kuang; Liou, Jing-Ping; Chen, Mei-Chuan			Identification of 7-(4 '-Cyanophenyl)indoline-1-benzenesulfonamide as a mitotic inhibitor to induce apoptotic cell death and inhibit autophagy in human colorectal cancer cells	SCIENTIFIC REPORTS			English	Article							MICROTUBULE-STABILIZING AGENT; 3-KINASE/MAMMALIAN TARGET; ANTICANCER ACTIVITY; PHOSPHORYLATION; CYCLE; NVP-BEZ235; RESISTANCE; MECHANISM; RADIATION; SURVIVAL	Targeting cellular mitosis in tumor cells is an attractive cancer treatment strategy. Here, we report that B220, a synthetic benzenesulfonamide compound, could represent a new mitotic inhibitor for the treatment of colorectal cancer. We examined the action mechanism of B220 in the colorectal carcinoma HCT116 cell line, and found that treatment of cells with B220 caused cells to accumulate in G2/M phase, with a concomitant induction of the mitotic phase markers, MPM2 and cyclin B1. After 48 h of B220 treatment, cells underwent apoptotic cell death via caspase-3 activation and poly(ADP ribose) polymerase (PARP) cleavage. In addition, B220 inhibits autophagy by blocking conversion of microtubule-associated protein 1 light chain 3 (LC3-I) to LC3-II and inhibiting autophagic flux. Notably, blockade of autophagy by pharmacological inhibition or using an Atg5-targeting shRNA reduced B220-induced cytotoxicity. Conversely, the autophagy inducer NVP-BEZ235 shows a synergistic interaction with B220 in HCT116 cells, indicating autophagy was required for the observed cell death. In summary, these results indicate B220 combined with the induction of autophagy using the dual PI3K/mTOR inhibitor, NVP-BEZ235, might be an attractive strategy for cancer therapy, and provides a framework for further development of B220 as a new therapeutic agent for colon cancer treatment.	[Wu, Tung-Yun; Chen, Mei-Chuan] Taipei Med Univ, Coll Pharm, PhD Program Clin Drug Discovery Bot Herbs, Taipei, Taiwan; [Cho, Ting-Yu; Chen, Mei-Chuan] Taipei Med Univ, Coll Pharm, Grad Inst Pharmacognosy, Taipei, Taiwan; [Lu, Chung-Kuang] Minist Hlth & Welf, Natl Res Inst Chinese Med, Taipei, Taiwan; [Liou, Jing-Ping] Taipei Med Univ, Coll Pharm, Sch Pharm, Taipei, Taiwan		Chen, MC (corresponding author), Taipei Med Univ, Coll Pharm, PhD Program Clin Drug Discovery Bot Herbs, Taipei, Taiwan.; Chen, MC (corresponding author), Taipei Med Univ, Coll Pharm, Grad Inst Pharmacognosy, Taipei, Taiwan.	mcchen1250@tmu.edu.tw			Ministry of Science and Technology of the Republic of ChinaMinistry of Science and Technology, China [MOST-103-2320-B-038-030-MY3]; Taipei Medical University [TMU102-AE1-B43]	We thank Core Facility Center of Taipei Medical University for the supports of deconvolution microscope. This research was supported by the Ministry of Science and Technology of the Republic of China (grant no. MOST-103-2320-B-038-030-MY3), and TMU102-AE1-B43 by Taipei Medical University.	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J	Linares, JF; Zhang, X; Martinez-Ordonez, A; Duran, A; Kinoshita, H; Kasashima, H; Nakanishi, N; Nakanishi, Y; Carelli, R; Cappelli, L; Arias, E; Yashiro, M; Ohira, M; Patel, S; Inghirami, G; Loda, M; Cuervo, AM; Diaz-Meco, MT; Moscat, J				Linares, Juan F.; Zhang, Xiao; Martinez-Ordonez, Anxo; Duran, Angeles; Kinoshita, Hiroto; Kasashima, Hiroaki; Nakanishi, Naoko; Nakanishi, Yuki; Carelli, Ryan; Cappelli, Luca; Arias, Esperanza; Yashiro, Masakazu; Ohira, Masaichi; Patel, Sanjay; Inghirami, Giorgio; Loda, Massimo; Cuervo, Ana Maria; Diaz-Meco, Maria T.; Moscat, Jorge			PKC lambda/iota inhibition activates an ULK2-mediated interferon response to repress tumorigenesis	MOLECULAR CELL			English	Article							GMP-AMP SYNTHASE; DNA SENSOR; IMMUNE CELLS; COLON-CANCER; AUTOPHAGY; INFLAMMATION; EXPRESSION; TUMORS; RESISTANCE; ADAPTER	The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKC lambda/iota inactivation results in the hyper stimulation of the IFN cascade and the enhanced recruitment of CD8(+) T cells that impaired the growth of intestinal tumors. PKC lambda/iota directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKC lambda/iota results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKC lambda/iota inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKC lambda/iota is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKC lambda/iota levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.	[Linares, Juan F.; Zhang, Xiao; Martinez-Ordonez, Anxo; Duran, Angeles; Kinoshita, Hiroto; Carelli, Ryan; Cappelli, Luca; Patel, Sanjay; Inghirami, Giorgio; Loda, Massimo; Diaz-Meco, Maria T.; Moscat, Jorge] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA; [Linares, Juan F.; Zhang, Xiao; Martinez-Ordonez, Anxo; Duran, Angeles; Kinoshita, Hiroto; Carelli, Ryan; Cappelli, Luca; Patel, Sanjay; Inghirami, Giorgio; Loda, Massimo; Diaz-Meco, Maria T.; Moscat, Jorge] Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY 10065 USA; [Kasashima, Hiroaki; Yashiro, Masakazu; Ohira, Masaichi] Osaka City Univ, Dept Gastroenterol Surg, Grad Sch Med, Abeno Ku, 1-4-3 Asahimachi, Osaka 5458585, Japan; [Nakanishi, Naoko] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Endocrinol & Metab, Kyoto, Japan; [Nakanishi, Yuki] Kyoto Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Kyoto, Japan; [Arias, Esperanza; Cuervo, Ana Maria] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA; [Arias, Esperanza; Cuervo, Ana Maria] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA; [Arias, Esperanza; Cuervo, Ana Maria] Albert Einstein Coll Med, Inst Aging Studies, Bronx, NY 10461 USA		Diaz-Meco, MT; Moscat, J (corresponding author), Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA.; Diaz-Meco, MT; Moscat, J (corresponding author), Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY 10065 USA.	mtd4001@med.cornell.edu; jom4010@med.cornell.edu	; Zhang, Xiao/L-6674-2013	KASASHIMA, HIROAKI/0000-0001-5234-4030; Zhang, Xiao/0000-0002-8213-6686; Nakanishi, Yuki/0000-0001-5493-6312; Arias, Esperanza/0000-0002-7836-5072; Cappelli, Luca Vincenzo/0000-0001-8090-3880	NCI of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA207177, R01CA250025, R01CA218254, P50CA211024]; Center for Translational Pathology and the Multiparametric In Situ Imaging Laboratory in the Department of Pathology and Laboratory Medicine, Weill Cornell Medicine	Research was supported by grants by NCI of the National Institutes of Health under awards R01CA207177 and R01CA250025 to J.M.; R01CA218254 to M.T.D.-M.; and P50CA211024 to M.L. Project support for this research was provided in part by the Center for Translational Pathology and the Multipara-metric In Situ Imaging Laboratory in the Department of Pathology and Labora-tory Medicine, Weill Cornell Medicine. We thank Dr. Eduard Batlle (IRB Barce-lona, Spain) for generously providing MTO organoids. We thank Tavonna Bryant and Tararin Nikomborirak for technical assistance. J.M. and M.T.D.-M. are Homer T. Hirst III Professors of Oncology in Pathology.	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J	Wiersma, VR; de Bruyn, M; Wei, YW; van Ginkel, RJ; Hirashima, M; Niki, T; Nishi, N; Zhou, J; Pouwels, SD; Samplonius, DF; Nijman, HW; Eggleton, P; Helfrich, W; Bremer, E				Wiersma, Valerie R.; de Bruyn, Marco; Wei, Yunwei; van Ginkel, Robert J.; Hirashima, Mitsuomi; Niki, Toshiro; Nishi, Nozomu; Zhou, Jin; Pouwels, Simon D.; Samplonius, Douwe F.; Nijman, Hans W.; Eggleton, Paul; Helfrich, Wijnand; Bremer, Edwin			The epithelial polarity regulator LGALS9/galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux	AUTOPHAGY			English	Article						autophagy; colon cancer; galectin-9; KRAS mutation; lysosomes	COLORECTAL-CANCER; CELL-DEATH; K-RAS; B-RAF; PROGNOSTIC-FACTOR; BREAST-CANCER; IN-VITRO; C-RAF; GALECTIN-9; RESISTANCE	Oncogenic mutation of KRAS (Kirsten rat sarcoma viral oncogene homolog) in colorectal cancer (CRC) confers resistance to both chemotherapy and EGFR (epidermal growth factor receptor)-targeted therapy. We uncovered that KRAS mutant (KRAS(mut)) CRC is uniquely sensitive to treatment with recombinant LGALS9/Galectin-9 (rLGALS9), a recently established regulator of epithelial polarity. Upon treatment of CRC cells, rLGALS9 rapidly internalizes via early- and late-endosomes and accumulates in the lysosomal compartment. Treatment with rLGALS9 is accompanied by induction of frustrated autophagy in KRAS(mut) CRC, but not in CRC with BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations (BRAF(mut)). In KRAS(mut) CRC, rLGALS9 acts as a lysosomal inhibitor that inhibits autophagosome-lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death. This antitumor activity of rLGALS9 directly correlates with elevated basal autophagic flux in KRAS(mut) cancer cells. Thus, rLGALS9 has potent antitumor activity toward refractory KRAS(mut) CRC cells that may be exploitable for therapeutic use.	[Wiersma, Valerie R.; Wei, Yunwei; van Ginkel, Robert J.; Samplonius, Douwe F.; Helfrich, Wijnand; Bremer, Edwin] Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Translat Surg Oncol, Groningen, Netherlands; [de Bruyn, Marco; Nijman, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Obstet & Gynecol, Groningen, Netherlands; [Wei, Yunwei] Harbin Med Univ, Affiliated Hosp 1, Oncol & Endoscop Surg Dept, Harbin, Peoples R China; [Hirashima, Mitsuomi; Niki, Toshiro] Kagawa Univ, Fac Med, Dept Immunol & Immunopathol, Takamatsu, Kagawa 760, Japan; [Hirashima, Mitsuomi; Niki, Toshiro] GalPharma Co Ltd, Takamatsu, Kagawa, Japan; [Nishi, Nozomu] Kagawa Univ, Life Sci Res Ctr, Div Res Instrument & Equipment, Takamatsu, Kagawa 760, Japan; [Zhou, Jin; Helfrich, Wijnand] Harbin Med Univ, Affiliated Hosp 1, Dept Hematol,Key Lab Cell Transplantat, Heilongjiang Inst Hematol & Oncol,Minist Hlth, Harbin, Peoples R China; [Pouwels, Simon D.] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pathol & Med Biol,Expt Pulmonol & Inflammat, Groningen, Netherlands; [Eggleton, Paul; Bremer, Edwin] Univ Exeter, Sch Med, Exeter EX4 4QJ, Devon, England		Bremer, E (corresponding author), Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Translat Surg Oncol, Groningen, Netherlands.	e.bremer@umcg.nl	Bremer, Edwin S/B-7508-2016	Bremer, Edwin S/0000-0002-0325-7376; Helfrich, Wijnand/0000-0001-7004-3995; Eggleton, Paul/0000-0001-8244-2125; de Bruyn, Marco/0000-0001-9819-9131; Wiersma, Valerie/0000-0001-8012-0376; Nishi, Nozomu/0000-0001-7050-3226; Pouwels, Simon/0000-0001-7345-8061	Dutch Cancer Society grantKWF Kankerbestrijding [RUG2009-4355, RUG2009-4542, RUG2011-5206, RUG2012-5541, RUG2013-6209]; Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO); Melanoma Research Alliance; Alexander von Humboldt FoundationAlexander von Humboldt Foundation	This work was supported by Dutch Cancer Society grants RUG2009-4355 (E.B.), RUG2009-4542, RUG2011-5206, RUG2012-5541, RUG2013-6209 (to E.B./W.H.), the Netherlands Organization for Scientific Research (E.B.), the Melanoma Research Alliance (E.B.), and the Alexander von Humboldt Foundation (E.B/M.B.).	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J	Saffari-Chaleshtori, J; Asadi-Samani, M; Rasouli, M; Shafiee, SM				Saffari-Chaleshtori, Javad; Asadi-Samani, Majid; Rasouli, Maryam; Shafiee, Sayed Mohammad			Autophagy and Ubiquitination as Two Major Players in Colorectal Cancer: A Review on Recent Patents	RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY			English	Review						Apoptosis; autophagy; cell proliferation; colon cancer; cell survival; ubiquitin-proteasome system	PROTEASOME INHIBITOR; ENDOPLASMIC-RETICULUM; TUMOR SUPPRESSION; PROGRESSION; INDUCTION; APOPTOSIS; EXPRESSION; CROSSTALK; MEMBRANES; CACHEXIA	Background: As one of the most commonly diagnosed cancers among men and women, Colorectal Cancer (CRC) leads to high rates of morbidity and mortality across the globe. Recent anti-CRC therapies are now targeting specific signaling pathways involved in colorectal carcinogenesis. Ubiquitin Proteasome System (UPS) and autophagy are two main protein quality control systems, which play major roles in the carcinogenesis of colorectal cancer. A balanced function of these two pathways is necessary for the regulation of cell proliferation and cell death. Objective: In this systematic review, we discuss the available evidence regarding the roles of autophagy and ubiquitination in progression and inhibition of CRC. Methods: The search terms "colorectal cancer" or "colon cancer" or "colorectal carcinoma" or "colon carcinoma" in combination with "ubiquitin proteasome" and "autophagy" were searched in PubMed, Web of Science, and Scopus databases, and also Google Patents (https://patents.google.com ) from January 2000 to Feb 2020. Results: The most important factors involved in UPS and autophagy have been investigated. There are many important factors involved in UPS and autophagy but this systematic review shows the studies that have mostly focused on the role of ATG, 20s proteasome and mTOR in CRC, and the more important factors such as ATG8, FIP200, and TIGAR factors that are effective in the regulation of autophagy in CRC cells have not been yet investigated. Conclusion: The most important factors involved in UPS and autophagy such as ATG, 20s proteasome and mTOR, ATG8, FIP200, and TIGAR can be considered in drug therapy for controlling or activating autophagy.	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Drug Discov.		2020	15	2					143	153		10.2174/1574892815666200630103626			11	Oncology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	OD6HK	WOS:000579952400004	32603286				2022-04-25	
J	Al-Emam, A; Al-Shraim, M; Eid, R; Alfaifi, M; Al-Shehri, M; Moustafa, MF; Radad, K				Al-Emam, Ahmed; Al-Shraim, Mubarak; Eid, Refaat; Alfaifi, Mohamed; Al-Shehri, Mohamed; Moustafa, Mahmoud Fawzy; Radad, Khaled			Ultrastructural changes induced by Solanum incanum aqueous extract on HCT 116 colon cancer cells	ULTRASTRUCTURAL PATHOLOGY			English	Article						Colon cancer; HCT 116 cells; herbs; Solanum incanum; ultrastructure	COLORECTAL-CANCER; METAANALYSIS; AUTOPHAGY; CYTOTOXICITY; AUTOSCHIZIS; APOPTOSIS; GROWTH; DEATH; RISK	Medicinal plants have recently gained increasing scientific interest as an important source of molecules with different therapeutic potentials. Accordingly, the present study was carried out to investigate ultrastructural changes induced by the aqueous extract of Solanum incanum (SI) fruit on human colorectal carcinoma cell line (HCT 116 cells). Examination of SI-treated HCT 116 cells with transmission electron microscopy (TEM) demonstrated numerous ultrastructural changes in the form of loss of the surface microvilli, mitochondrial damage and dilatation of cristae, and formation of autophagic vacuoles and increasing numbers of lipid droplets. Also, majority of the treated cells showed nuclear shrinkage with chromatin condensation and nucleolar changes. Moreover, some cells showed focal areas of cytoplasmic degeneration associating with formation of myelin figures and fatty globules. In conclusion, TEM was able to verify cytotoxicity of SI aqueous extract against HCT 116 colon cancer cells.	[Al-Emam, Ahmed; Al-Shraim, Mubarak; Eid, Refaat; Radad, Khaled] King Khalid Univ, Coll Med, Dept Pathol, Abha, Saudi Arabia; [Al-Emam, Ahmed] Mansoura Univ, Dept Forens Med & Clin Toxicol, Fac Med, Mansoura, Egypt; [Alfaifi, Mohamed; Al-Shehri, Mohamed; Moustafa, Mahmoud Fawzy] King Khalid Univ, Coll Sci, Dept Biol, Abha, Saudi Arabia; [Moustafa, Mahmoud Fawzy] South Vally Univ, Fac Sci, Dept Bot, Qena, Egypt		Radad, K (corresponding author), King Khalid Univ, Coll Med, Dept Pathol, Abha, Saudi Arabia.	khaledradad@hotmail.com		Alemam, Ahmed/0000-0002-5415-8992; Radad, Khaled/0000-0002-7620-8591			Almansour M, 2016, ULTRASTRUCT PATHOL, V40, P92, DOI 10.3109/01913123.2016.1150377; Batista APC, 2014, MICRON, V59, P17, DOI 10.1016/j.micron.2013.12.003; Bussmann RW, 2006, J ETHNOBIOL ETHNOMED, V2, DOI 10.1186/1746-4269-2-22; Chan DSM, 2011, PLOS ONE, V6, DOI [10.1371/journal.pone.0020456, 10.1371/journal.pone.0027218]; Chauhan AK, 2017, ANTI-CANCER AGENT ME, V17, P1942, DOI 10.2174/1871520617666170327121228; Cheng DL, 2015, WSPOLCZESNA ONKOL, V19, P36, DOI 10.5114/wo.2015.50011; Dold AP, 2000, S AFR J SCI, V96, P467; Fedirko V, 2011, ANN ONCOL, V22, P1958, DOI 10.1093/annonc/mdq653; Ferlay J, 2010, INT J CANCER, V127, P2893, DOI 10.1002/ijc.25516; Gbelcova H, 2013, LIPIDS HEALTH DIS, V12, DOI 10.1186/1476-511X-12-126; Gilloteaux J, 2001, ULTRASTRUCT PATHOL, V25, P183, DOI 10.1080/019131201300343810; Gilloteaux J, 1998, SCANNING, V20, P564; Gomes LC, 2011, AUTOPHAGY, V7, P1251, DOI 10.4161/auto.7.10.16771; Jess T, 2012, CLIN GASTROENTEROL H, V10, P639, DOI 10.1016/j.cgh.2012.01.010; Jin XB, 2013, BIOL PHARM BULL, V36, P938, DOI 10.1248/bpb.b12-00935; Liang PS, 2009, INT J CANCER, V124, P2406, DOI 10.1002/ijc.24191; Ma YL, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0053916; Mosieniak G, 2012, MECH AGEING DEV, V133, P444, DOI 10.1016/j.mad.2012.05.004; Mwonjoria J. K., 2014, INT J PHARM TOXICOLO, V2, P17, DOI DOI 10.14419/ijpt.v2i2.1454; REN J, 1990, JPN J CANCER RES, V81, P920, DOI 10.1111/j.1349-7006.1990.tb02668.x; Ricciardiello L, 2011, NAT REV GASTRO HEPAT, V8, P592, DOI 10.1038/nrgastro.2011.149; Santos CR, 2012, FEBS J, V279, P2610, DOI 10.1111/j.1742-4658.2012.08644.x; Shakibaei M, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0057218; Shin DY, 2009, INT J ONCOL, V35, P1499, DOI 10.3892/ijo_00000469; Tirinato L, 2015, STEM CELLS, V33, P35, DOI 10.1002/stem.1837; Vichai V, 2006, NAT PROTOC, V1, P1112, DOI 10.1038/nprot.2006.179; Wang GH, 2012, BIOCHEM J, V446, P415, DOI 10.1042/BJ20112050; Wen SJ, 2013, FUTURE MED CHEM, V5, P53, DOI 10.4155/fmc.12.190; Wong RSY, 2011, J EXP CLIN CANC RES, V30, DOI 10.1186/1756-9966-30-87; Xie XD, 2015, ONCOL LETT, V10, P168, DOI 10.3892/ol.2015.3194; Yamamuro S, 2015, INT J ONCOL, V47, P91, DOI 10.3892/ijo.2015.2992; Ye LH, 2012, ANAT REC, V295, P417, DOI 10.1002/ar.21528	32	3	3	0	3	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	0191-3123	1521-0758		ULTRASTRUCT PATHOL	Ultrastruct. Pathol.		2018	42	3					255	261		10.1080/01913123.2018.1447623			7	Microscopy; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Microscopy; Pathology	GH9SE	WOS:000434008700006	29565703				2022-04-25	
J	Alves, S; Castro, L; Fernandes, MS; Francisco, R; Castro, P; Priault, M; Chaves, SR; Moyer, MP; Oliveira, C; Seruca, R; Corte-Real, M; Sousa, MJ; Preto, A				Alves, Sara; Castro, Lisandra; Fernandes, Maria Sofia; Francisco, Rita; Castro, Paula; Priault, Muriel; Chaves, Susana Rodrigues; Moyer, Mary Pat; Oliveira, Carla; Seruca, Raquel; Corte-Real, Manuela; Sousa, Maria Joao; Preto, Ana			Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy	ONCOTARGET			English	Article						autophagy; KRAS mutations; colorectal cancer; humanized yeast; non-cancer colon cells	ADVANCED SOLID TUMORS; PHASE-I TRIAL; TARGETED THERAPIES; RAS ONCOGENES; MUTATIONS; HYDROXYCHLOROQUINE; INHIBITION; SURVIVAL; YEAST; MACROAUTOPHAGY	The recent interest to modulate autophagy in cancer therapy has been hampered by the dual roles of this conserved catabolic process in cancer, highlighting the need for tailored approaches. Since RAS isoforms have been implicated in autophagy regulation and mutation of the KRAS oncogene is highly frequent in colorectal cancer (CRC), we questioned whether/how mutant KRAS alleles regulate autophagy in CRC and its implications. We established two original models, KRAS-humanized yeast and KRAS-non-cancer colon cells and showed that expression of mutated KRAS up-regulates starvation-induced autophagy in both. Accordingly, KRAS down-regulation inhibited autophagy in CRC-derived cells harboring KRAS mutations. We further show that KRAS-induced autophagy proceeds via up-regulation of the MEK/ERK pathway in both colon models and that KRAS and autophagy contribute to CRC cell survival during starvation. Since KRAS inhibitors have proven difficult to develop, our results suggest using autophagy inhibitors as a combined/alternative therapeutic approach in CRCs with mutant KRAS.	[Alves, Sara; Castro, Lisandra; Francisco, Rita; Castro, Paula; Chaves, Susana Rodrigues; Corte-Real, Manuela; Sousa, Maria Joao; Preto, Ana] Univ Minho, Dept Biol, CBMA Ctr Mol & Environm Biol, P-4710057 Braga, Portugal; [Priault, Muriel] Univ Bordeaux 2, CNRS, UMR5095, F-33076 Bordeaux, France; [Fernandes, Maria Sofia; Oliveira, Carla; Seruca, Raquel] Univ Porto, Inst Invest & Inovacao Saude, IPATIMUP Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal; [Moyer, Mary Pat] INCELL Corp, San Antonio, TX USA		Preto, A (corresponding author), Univ Minho, Dept Biol, CBMA Ctr Mol & Environm Biol, Campus Gualtar, P-4710057 Braga, Portugal.	apreto@bio.uminho.pt	Fernandes, Sofia/J-5712-2013; Alves, Sara/U-5006-2019; Corte-Real, Manuela/B-6328-2013; Oliveira, Carla/F-8188-2011; Chaves, Susana R/H-8786-2013; Sousa, Maria João/H-8775-2013; Preto, Ana/H-8112-2012	Fernandes, Sofia/0000-0002-5021-3253; Corte-Real, Manuela/0000-0002-1423-1331; Oliveira, Carla/0000-0001-8340-2264; Chaves, Susana R/0000-0002-6004-9872; Sousa, Maria João/0000-0001-9424-4150; Preto, Ana/0000-0002-7302-0630; Castro, Lisandra/0000-0003-3048-933X; Francisco, Rita/0000-0002-4398-3401; Seruca, Raquel/0000-0002-8851-4166; Alves, Sara/0000-0003-0404-5954; Priault, Muriel/0000-0001-8193-0389	FCT/MEC through Portuguese funds (PIDDAC) [PEst-OE/BIA/UI4050/2014]; FCT I.P. through the strategic funding [UID/BIA/04050/2013]; FCTPortuguese Foundation for Science and TechnologyEuropean Commission [PTDC/BIA-BCM/69448/2006, FCT-ANR/BEX-BCM/0175/2012, SFRH/BD/64695/2009, SFRH/BPD/89980/2012]	This work was supported by FCT/MEC through Portuguese funds (PIDDAC) - PEst-OE/BIA/UI4050/2014 and FCT I.P. through the strategic funding UID/BIA/04050/2013 as well as by FCT through projects PTDC/BIA-BCM/69448/2006 and FCT-ANR/BEX-BCM/0175/2012, as well as fellowships to S.A. (SFRH/BD/64695/2009) and S.R.C. (SFRH/BPD/89980/2012).	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J	Xie, QQ; Liu, Y; Li, XF				Xie, Qingqiang; Liu, Yuan; Li, Xuefeng			The interaction mechanism between autophagy and apoptosis in colon cancer	TRANSLATIONAL ONCOLOGY			English	Review						Colorectal carcinoma (CRC); Autophagy; Apoptosis; Interaction; Balance	LONG NONCODING RNA; CELECOXIB-INDUCED APOPTOSIS; SELECTIVE AUTOPHAGY; CARCINOMA CELLS; PATHWAY; PROLIFERATION; MITOCHONDRIA; ACTIVATION; INHIBITION; DEATH	Autophagy and apoptosis play crucial roles in tumorigenesis. Recent studies have shown that autophagy and apoptosis have a cross-talk relationship in anti-tumor therapy. It is well established that apoptosis is one of the main pathways of tumor cell death. While autophagy can occurs in tumors with opposite function: protective autophagy and lethal autophagy. Protective autophagy can inhibit tumor apoptosis induced by anticancer drugs, while lethal autophagy can induce tumor cell apoptosis in cooperation with anticancer drugs. Hence, autophagy and apoptosis have synergistic and antagonistic effects in tumor. Colorectal cancer is a common malignant tumor with high morbidity and mortality. In recent years, colorectal carcinoma has achieved improved clinical efficacy with drug treatment. Nonetheless, increasing drug-resistance limit the treatment efficacy, highlighting the urgency of exploring the molecular events that drive drug resistance. Researchers have found that autophagy is one of the major factors leading to drug resistance in colon cancer. Therefore, elucidating the interaction between autophagy and apoptosis is helpful to improve the efficacy of anticancer drugs in clinical treatment of colorectal cancer. This review attaches great importance to the relationship between autophagy and apoptosis and related factors in colorectal cancer.	[Xie, Qingqiang; Liu, Yuan; Li, Xuefeng] Guangzhou Med Univ, Affiliated Hosp 6, Qingyuan Peoples Hosp, Guangzhou 511436, Peoples R China; [Xie, Qingqiang; Liu, Yuan; Li, Xuefeng] Guangzhou Med Univ, State Key Lab Resp Dis, Sino French Hoffmann Inst, Sch Basic Med Sci, Guangzhou 511436, Peoples R China; [Li, Xuefeng] Shenzhen Univ, Affiliated Hosp 3, Shenzhen Luohu Peoples Hosp, Shenzhen 518001, Peoples R China; [Li, Xuefeng] Chinese Acad Sci, South China Inst Stem Cell Biol & Regenerat Med, Guangzhou Inst Biomed & Hlth,Key Lab Regenerat Bi, Guangdong Prov Key Lab Stem Cell & Regenerat Med, Guangzhou 510530, Peoples R China		Li, XF (corresponding author), Guangzhou Med Univ, Affiliated Hosp 6, Qingyuan Peoples Hosp, Guangzhou 511436, Peoples R China.; Li, XF (corresponding author), Guangzhou Med Univ, State Key Lab Resp Dis, Sino French Hoffmann Inst, Sch Basic Med Sci, Guangzhou 511436, Peoples R China.	xuefengli@gzhmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81972204, 81702327]; Natural Science Foundation of Guangdong ProvinceNational Natural Science Foundation of Guangdong Province [2019A1515011097]; Innovation Program of Shenzhen [JCYJ20180508165208399]; Science and Technology Planning Project of Guangzhou [201904010089]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2018M640834, 2019T120756]; State Key Lab of Respiratory Disease, Guangzhou Medical University [SKLRD-Z202002]; 111 Project from the Ministry of Education of ChinaMinistry of Education, China - 111 Project [D18010]	This work was supported by National Natural Science Foundation of China (81972204 and 81702327), Natural Science Foundation of Guangdong Province (2019A1515011097), Innovation Program of Shenzhen (Grant No. JCYJ20180508165208399), Science and Technology Planning Project of Guangzhou (201904010089), China Postdoctoral Science Foundation (2018M640834 and 2019T120756), the grant from the State Key Lab of Respiratory Disease, Guangzhou Medical University (SKLRD-Z202002), and the 111 Project (D18010) from the Ministry of Education of China.	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Oncol.	DEC	2020	13	12							100871	10.1016/j.tranon.2020.100871			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	OA0VT	WOS:000577515200020	32950931	Green Published, gold			2022-04-25	
J	Wang, CX; Shi, ZS; Hong, ZS; Pan, JP; Chen, ZC; Qiu, CZ; Zhuang, HB; Zheng, XC				Wang, Chunxiao; Shi, Zesheng; Hong, Zhongshi; Pan, Jianpeng; Chen, Zhichuan; Qiu, Chengzhi; Zhuang, Haibin; Zheng, Xuecong			MicroRNA-1276 Promotes Colon Cancer Cell Proliferation by Negatively Regulating LACTB	CANCER MANAGEMENT AND RESEARCH			English	Article						microRNA; colonic neoplasms; cell proliferation; LACTB; miR-1276	METABOLISM; EXPRESSION; PROGNOSIS; PROTEIN	Purpose: LACTB, regulated by a variety of microRNAs (miRNAs), is proven to be a tumor suppressor. However, there are few reports that LACTB in colon cancer cells is regulated by miRNA. Therefore, the aim of this study was to explore the miRNAs that regulate LACTB in colon cancer. Patients and Methods: Data from TCGA were analyzed in starBase and GEPIA2, and Western blot and quantitative PCR (qPCR) were used to detect the expression of LACTB in colon cancer cell lines. MiRNAs targeting LACTB were predicted by MicroT-CDS, starBase, miRDB, mirDIP, and DIANA. The relationship between LACTB and miRNA was explored by dual-luciferase assay. MTT, propidium iodide (PI), Western blot, Annexin V-FITC/PI Kit, qPCR and transwell assay were used to detect the changes in cell proliferation, cell cycle, autophagy, apoptosis, epithelial-to-mesenchymal transition (EMT), cell migration, and invasiveness in colon cancer cells that overexpressed miR-1276 and/or LACTB. Results: The results showed that the LACTB mRNA level was lower and the miR-1276 level was higher in colon cancer than in normal tissue. MiR-1276 inhibited the expression of LACTB. Furthermore, overexpression of miR-1276 in colon cancer cells increased proliferation, migration, invasiveness and EMT, and decreased autophagy and apoptosis. Supplementing LACTB suppressed these effects of miR-1276. Conclusion: In conclusion, miR-1276, which may be a potential therapy for colon cancer, inhibits cell growth and promotes apoptosis by targeting LACTB in colon cancer cells.	[Wang, Chunxiao; Shi, Zesheng; Hong, Zhongshi; Pan, Jianpeng; Chen, Zhichuan; Qiu, Chengzhi; Zhuang, Haibin; Zheng, Xuecong] Fujian Med Univ, Affiliated Hosp 2, Dept Gen Surg, 34 Zhongshan North Rd, Quanzhou 362000, Fujian, Peoples R China		Hong, ZS (corresponding author), Fujian Med Univ, Affiliated Hosp 2, Dept Gen Surg, 34 Zhongshan North Rd, Quanzhou 362000, Fujian, Peoples R China.	hongzhongshi@163.com		Hong, Zhong-shi/0000-0003-1190-6839	Science and Technology Project of Quanzhou [2018Z127]; Educational Research Project for Young and Middle-aged Teachers of Fujian Educational Committee [JAT190216]; Startup Fund for scientific research of Fujian Medical University [2019QH1119]	Thank you for the financial support from the Science and Technology Project of Quanzhou (grant number 2018Z127), the Educational Research Project for Young and Middle-aged Teachers of Fujian Educational Committee (grant number JAT190216) and Startup Fund for scientific research of Fujian Medical University (grant number 2019QH1119).	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Res.		2020	12						12185	12195		10.2147/CMAR.S278566			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	PA2RQ	WOS:000595481400007	33273855	Green Published, gold			2022-04-25	
J	Shen, PW; Chou, YM; Li, CL; Liao, EC; Huang, HS; Yin, CH; Chen, CL; Yu, SJ				Shen, Pei-Wen; Chou, Yu-Mei; Li, Chia-Ling; Liao, En-Chih; Huang, Hung-Sen; Yin, Chun-Hao; Chen, Chien-Liang; Yu, Sheng-Jie			Itraconazole improves survival outcomes in patients with colon cancer by inducing autophagic cell death and inhibiting transketolase expression	ONCOLOGY LETTERS			English	Article						colon cancer; autophagy; apoptosis; itraconazole; transketolase	TUMORIGENESIS; THERAPY; HEALTH	The incidence of colon cancer continues to increase annually, and it is the leading cause of cancer-associated mortality worldwide. Altering cell metabolism and inducing autophagic cell death have recently emerged as novel strategies in preventing tumor growth. Autophagy plays an essential role in energy production by degrading damaged cellular components and is also associated with tumor proliferation suppression. Itraconazole is an FDA-approved drug used as an antifungal medication and has been reported to induce autophagic cell death in breast cancer. However, the effects of itraconazole on cell metabolism and induction of apoptosis in colon cancer remain unclear. The present study analyzed extensive data from patients diagnosed with colon cancer using itraconazole between January 2011 and December 2015, from the Taiwanese National Health Insurance Research Database. The underlying molecular mechanisms of itraconazole in autophagy-induced cell death were also investigated. The results demonstrated that the 5-year survival rate was significantly higher in patients with colon cancer who received itraconazole treatment. In addition, itraconazole decreased the viability and cell colony formation, and induced cleaved caspase-3 expression and G(1) cell cycle arrest of COLO 205 and HCT 116 cells. Notably, itraconazole induced autophagy by enhancing LC3B and p62 expression. Following LC3 knockdown, the viability of itraconazole-treated COLO 205 and HCT 116 cells notably improved. Taken together, the results of the present study suggest that itraconazole may have a beneficial effect on patients with colon cancer, and its underlying molecular mechanisms may be associated with the induction of autophagic cell death.	[Shen, Pei-Wen; Chou, Yu-Mei] Kaohsiung Vet Gen Hosp, Dept Anesthesiol, Kaohsiung 813, Taiwan; [Li, Chia-Ling] Taichung Vet Gen Hosp, Childrens Med Ctr, Taichung 407, Taiwan; [Liao, En-Chih] MacKay Med Coll, Dept Med, New Taipei 252, Taiwan; [Liao, En-Chih] MacKay Med Coll, Inst Biomed Sci, New Taipei 252, Taiwan; [Huang, Hung-Sen; Yin, Chun-Hao; Chen, Chien-Liang; Yu, Sheng-Jie] Kaohsiung Vet Gen Hosp, Dept Med Educ & Res, 386 Dazhong 1st Rd, Kaohsiung 813, Taiwan; [Chen, Chien-Liang] Kaohsiung Vet Gen Hosp, Div Nephrol, Kaohsiung 813, Taiwan		Yu, SJ (corresponding author), Kaohsiung Vet Gen Hosp, Dept Med Educ & Res, 386 Dazhong 1st Rd, Kaohsiung 813, Taiwan.	sjyu@vghks.gov.tw			Kaohsiung Veterans General Hospital [VGHKS109-D04-1, VGHKS109-180]	The present study was partly supported by the Kaohsiung Veterans General Hospital (grant nos. VGHKS109-D04-1 and VGHKS109-180).	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Lett.	NOV	2021	22	5							768	10.3892/ol.2021.13029			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	UT5TY	WOS:000698180500001	34589147	Green Published, gold			2022-04-25	
J	Xu, ZY; Jiang, H; Zhu, YH; Wang, HF; Jiang, J; Chen, L; Xu, WK; Hu, T; Cho, CH				Xu, Zhenyu; Jiang, Hui; Zhu, Yanhong; Wang, Huifang; Jiang, Jia; Chen, Lu; Xu, Wenke; Hu, Tao; Cho, Chi Hin			Cryptotanshinone induces ROS-dependent autophagy in multidrug-resistant colon cancer cells	CHEMICO-BIOLOGICAL INTERACTIONS			English	Article						Cryptotanshinone; Autophagy; Reactive oxygen species; Multidrug resistance; Colon cancer	SALVIA-MILTIORRHIZA; MOLECULAR DOCKING; INDUCED APOPTOSIS; P-GP; PATHWAY; DEATH; DIHYDROTANSHINONE; TANSHINONES; MECHANISMS; INDUCTION	The development of novel chemotherapeutic agents is highly desired for colon cancer treatment, in particular for the multidrug-resistant cancer types. Cryptotanshinone (CTS), an active quinoid diterpene isolated from Salvia miltiorrhiza Bunge, was previously reported to induce autophagy in various colon cancer cell lines. However, its mechanisms of action have not been fully understood. The current study aims to explore the mechanisms by which CTS induces autophagy in a multidrug-resistant human colon cancer cell line SW620 Ad300. Using MTT assay, CTS at 10 mu M exhibited no significant cytotoxicity on human normal colon fibroblasts CCD-18Co, but induced 45.67% and 48.35% cell death in SW620 and SW620 Ad300 cells, respectively. Further studies revealed that CTS induced weak apoptosis ( 9.37%) and significant caspase-independent cell death in SW620 Ad300 cells. In the same cell line, CTS also induced significant autophagy, which was found to promote cell death and to mediate the cytotoxicity of CTS in these multidrug-resistant cells. Moreover, activation of ROS-p38 MAPK-NF-kappa B signaling pathway was involved in autophagic cell death induced by CTS in SW620 Ad300 cells. Interestingly, our results also demonstrated a complementary relationship between CTS-induced apoptosis and autophagic cell death in SW620 Ad300 cells. Taken together, CTS induces autophagic cell death in SW620 Ad300 cells via the ROS-p38 MAPK-NF-kB signaling pathway, and it might be a potential candidate as a chemotherapeutic agent for the treatment of multidrug-resistant colon cancer. (C) 2017 Elsevier B.V. All rights reserved.	[Xu, Zhenyu; Jiang, Hui; Zhu, Yanhong; Wang, Huifang; Jiang, Jia; Chen, Lu; Xu, Wenke] Wannan Med Coll, Yijishan Affiliated Hosp, Dept Pharm, Wuhu, Anhui, Peoples R China; [Hu, Tao; Cho, Chi Hin] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China; [Cho, Chi Hin] Southwest Med Univ, Sch Pharm, Dept Pharmacol, Lab Mol Pharmacol, Luzhou, Sichuan, Peoples R China		Xu, WK (corresponding author), Wannan Med Coll, Yijishan Affiliated Hosp, Dept Pharm, Wuhu, Anhui, Peoples R China.; Hu, T (corresponding author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China.	1447486817@qq.com; taohu1985@hotmail.com	Hu, Tao/O-2570-2014	Hu, Tao/0000-0002-0601-3078			Biomed, 2016, PHARMACOTHERAPY, V82, P319; Chen WX, 2012, CANCER PREV RES, V5, P778, DOI 10.1158/1940-6207.CAPR-11-0551; Elmore S, 2007, TOXICOL PATHOL, V35, P495, DOI 10.1080/01926230701320337; Fulda S, 2010, PLANTA MED, V76, P1075, DOI 10.1055/s-0030-1249961; Hao WH, 2016, ANTI-CANCER AGENT ME, V16, P593, DOI 10.2174/1871520615666150907093036; Hu T, 2013, J BIOMOL RES THER, V2, P110, DOI [10.4172/21677956.1000110, DOI 10.4172/21677956.1000110]; Hu T, 2016, WORLD J GASTROENTERO, V22, P6876, DOI 10.3748/wjg.v22.i30.6876; Hu T, 2015, CURR PHARM DESIGN, V21, P2960, DOI 10.2174/1381612821666150514104244; Hu T, 2015, PHYTOMEDICINE, V22, P536, DOI 10.1016/j.phymed.2015.03.010; Hu T, 2015, CHEM-BIOL INTERACT, V230, P1, DOI 10.1016/j.cbi.2015.02.006; Hu T, 2014, PHYTOMEDICINE, V21, P1264, DOI 10.1016/j.phymed.2014.06.013; Huang M, 2013, MOL CANCER THER, V12, P184, DOI 10.1158/1535-7163.MCT-12-0425; Hui KF, 2016, ONCOTARGET, V7, P4454, DOI 10.18632/oncotarget.6601; Lefranc F, 2007, ONCOLOGIST, V12, P1395, DOI 10.1634/theoncologist.12-12-1395; Li LF, 2014, INT J MOL MED, V34, P372, DOI 10.3892/ijmm.2014.1786; Li XQ, 2015, EUR J MED CHEM, V101, P560, DOI 10.1016/j.ejmech.2015.06.049; Liang YJ, 2013, CELL BIOSCI, V3, DOI 10.1186/2045-3701-3-9; Liu B, 2008, FREE RADICAL BIO MED, V44, P1529, DOI 10.1016/j.freeradbiomed.2008.01.011; Mizushima N, 2007, GENE DEV, V21, P2861, DOI 10.1101/gad.1599207; Mukhtar E, 2012, CURR DRUG TARGETS, V13, P1831, DOI 10.2174/138945012804545489; Nahata A, 2013, INTEGR CANCER THER, V12, P236, DOI 10.1177/1534735412451997; Park EJ, 2007, FOOD CHEM TOXICOL, V45, P1891, DOI 10.1016/j.fct.2007.04.005; Park IJ, 2014, APOPTOSIS, V19, P615, DOI 10.1007/s10495-013-0929-0; Tang S, 2011, INFLAMMATION, V34, P111, DOI 10.1007/s10753-010-9214-3; THOMPSON CB, 1995, SCIENCE, V267, P1456, DOI 10.1126/science.7878464; Wang L, 2013, LIFE SCI, V93, P344, DOI 10.1016/j.lfs.2013.07.007; Wang L, 2016, LIFE SCI, V151, P224, DOI 10.1016/j.lfs.2016.02.083; Wang L, 2015, PHYTOMEDICINE, V22, P1079, DOI 10.1016/j.phymed.2015.08.009; Ye TH, 2016, BIOMED PHARMACOTHER, V82, P319, DOI 10.1016/j.biopha.2016.05.015; Zhang X, 2012, CELL PROLIFERAT, V45, P466, DOI 10.1111/j.1365-2184.2012.00833.x; Zhao WW, 2016, CELL ADHES MIGR, V10, P248, DOI 10.1080/19336918.2015.1119361; Zhou XL, 2013, PHYTOMEDICINE, V20, P367, DOI 10.1016/j.phymed.2012.09.021; Zhu ZJ, 2016, MOL CARCINOGEN, V55, P1399, DOI 10.1002/mc.22383	33	32	34	1	14	ELSEVIER IRELAND LTD	CLARE	ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND	0009-2797	1872-7786		CHEM-BIOL INTERACT	Chem.-Biol. Interact.	AUG 1	2017	273						48	55		10.1016/j.cbi.2017.06.003			8	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	FB9OB	WOS:000406467500006	28600121				2022-04-25	
J	Basile, V; Belluti, S; Ferrari, E; Gozzoli, C; Ganassi, S; Quaglino, D; Saladini, M; Imbriano, C				Basile, Valentina; Belluti, Silvia; Ferrari, Erika; Gozzoli, Chiara; Ganassi, Sonia; Quaglino, Daniela; Saladini, Monica; Imbriano, Carol			bis-Dehydroxy-Curcumin Triggers Mitochondrial-Associated Cell Death in Human Colon Cancer Cells through ER-Stress Induced Autophagy	PLOS ONE			English	Article							ENDOPLASMIC-RETICULUM STRESS; BCL-2 FAMILY-MEMBERS; INDUCED APOPTOSIS; SIGNALING PATHWAYS; COLORECTAL-CANCER; GENE-EXPRESSION; UP-REGULATION; IN-VITRO; NF-Y; ACTIVATION	Background: The activation of autophagy has been extensively described as a pro-survival strategy, which helps to keep cells alive following deprivation of nutrients/growth factors and other stressful cellular conditions. In addition to cytoprotective effects, autophagy can accompany cell death. Autophagic vacuoles can be observed before or during cell death, but the role of autophagy in the death process is still controversial. A complex interplay between autophagy and apoptosis has come to light, taking into account that numerous genes, such as p53 and Bcl-2 family members, are shared between these two pathways. Methodology/Principal Findings: In this study we showed a potent and irreversible cytotoxic activity of the stable Curcumin derivative bis-DeHydroxyCurcumin (bDHC) on human colon cancer cells, but not on human normal cells. Autophagy is elicited by bDHC before cell death as demonstrated by increased autophagosome formation -measured by electron microscopy, fluorescent LC3 puncta and LC3 lipidation- and autophagic flux -measured by interfering LC3-II turnover. The accumulation of poly-ubiquitinated proteins and ER-stress occurred upstream of autophagy induction and resulted in cell death. Cell cycle and Western blot analyses highlighted the activation of a mitochondrial-dependent apoptosis, which involves caspase 7, 8, 9 and Cytochrome C release. Using pharmacological inhibitions and RNAi experiments, we showed that ER-stress induced autophagy has a major role in triggering bDHC-cell death. Conclusion/Significance: Our findings describe the mechanism through which bDHC promotes tumor selective inhibition of proliferation, providing unequivocal evidence of the role of autophagy in contrasting the proliferation of colon cancer cells.	[Basile, Valentina; Belluti, Silvia; Gozzoli, Chiara; Ganassi, Sonia; Quaglino, Daniela; Imbriano, Carol] Univ Modena & Reggio Emilia, Dipartimento Sci Vita, Modena, Italy; [Ferrari, Erika; Saladini, Monica] Univ Modena & Reggio Emilia, Dipartimento Sci Chim & Geol, Modena, Italy		Imbriano, C (corresponding author), Univ Modena & Reggio Emilia, Dipartimento Sci Vita, Via Campi 213-D, Modena, Italy.	cimbriano@unimo.it	Saladini, Monica/N-8596-2015; Imbriano, Carol/ABD-8204-2021; Quaglino, Daniela/A-9381-2010; BELLUTI, SILVIA/AAU-2625-2020; Ferrari, Erika/F-7742-2012; Basile, Valentina/S-3828-2016; Imbriano, Carol/C-9376-2015	Saladini, Monica/0000-0003-2515-8317; Imbriano, Carol/0000-0003-2864-4820; Quaglino, Daniela/0000-0002-4302-5078; BELLUTI, SILVIA/0000-0003-0846-9359; Ferrari, Erika/0000-0001-7627-2502; Basile, Valentina/0000-0003-3151-1228; Imbriano, Carol/0000-0003-2864-4820	Associazione Italiana per la Ricerca sul Cancro-MFAGFondazione AIRC per la ricerca sul cancro [6192]; Fondazione Cassa di Risparmio di Vignola	This work was supported by Associazione Italiana per la Ricerca sul Cancro-MFAG (grant number 6192 to CI) and Fondazione Cassa di Risparmio di Vignola to CI and EF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Yao, CW; Kang, KA; Piao, MJ; Ryu, YS; Fernando, PMDJ; Oh, MC; Park, JE; Shilnikova, K; Na, SY; Jeong, SU; Boo, SJ; Hyun, JW				Yao, Cheng Wen; Kang, Kyoung Ah; Piao, Mei Jing; Ryu, Yea Seong; Fernando, Pattage Madushan Dilhara Jayatissa; Oh, Min Chang; Park, Jeong Eon; Shilnikova, Kristina; Na, Soo-Young; Jeong, Seung Uk; Boo, Sun-Jin; Hyun, Jin Won			Reduced Autophagy in 5-Fluorouracil Resistant Colon Cancer Cells	BIOMOLECULES & THERAPEUTICS			English	Article						Autophagy; 5-Fluorouracil; SNUC5/5-FUR; Reactive oxygen species; Colon cancer	DEATH; CHLOROQUINE; ACTIVATION; MECHANISMS; STRESS; ASSAY	We investigated the role of autophagy in SNUC5/5-FUR, 5-fluorouracil (5 -FU) resistant SNUC5 colon cancer cells. SNUC5/5-FUR cells exhibited low level of autophagy, as determined by light microscopy, confocal microscopy, and flow cytometry following acridine orange staining, and the decreased level of GFP-LC3 puncta. In addition, expression of critical autophagic proteins such as Atg5, Beclin-1 and LC3-II and autophagic flux was diminished in SNUC5/5-FUR cells. Whereas production of reactive oxygen species (ROS) was significantly elevated in SNUC5/5-FUR cells, treatment with the ROS inhibitor N-acetyl cysteine further reduced the level of autophagy. Taken together, these results indicate that decreased autophagy is linked to 5 -FU resistance in SNUC5 colon cancer cells.	[Yao, Cheng Wen; Kang, Kyoung Ah; Piao, Mei Jing; Ryu, Yea Seong; Fernando, Pattage Madushan Dilhara Jayatissa; Oh, Min Chang; Park, Jeong Eon; Shilnikova, Kristina; Hyun, Jin Won] Jeju Natl Univ, Sch Med 1, Jeju 63243, South Korea; [Yao, Cheng Wen; Kang, Kyoung Ah; Piao, Mei Jing; Ryu, Yea Seong; Fernando, Pattage Madushan Dilhara Jayatissa; Oh, Min Chang; Park, Jeong Eon; Shilnikova, Kristina; Hyun, Jin Won] Jeju Natl Univ, Inst Nucl Sci & Technol, Jeju 63243, South Korea; [Na, Soo-Young; Jeong, Seung Uk; Boo, Sun-Jin] Jeju Natl Univ, Sch Med 2, Jeju 63241, South Korea		Hyun, JW (corresponding author), Jeju Natl Univ, Sch Med 1, Jeju 63243, South Korea.; Hyun, JW (corresponding author), Jeju Natl Univ, Inst Nucl Sci & Technol, Jeju 63243, South Korea.; Boo, SJ (corresponding author), Jeju Natl Univ, Sch Med 2, Jeju 63241, South Korea.	sunjinboo@jejunu.ac.kr; jinwonh@jejunu.ac.kr			Jeju National University Hospital Research Fund of Jeju National University	This work was supported by a research grant from the Jeju National University Hospital Research Fund of Jeju National University in 2015.	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Ther.	MAY 1	2017	25	3					315	320		10.4062/biomolther.2016.069			6	Biochemistry & Molecular Biology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy	EU7LF	WOS:000401215600012	27737524	Green Submitted, Green Published			2022-04-25	
J	Hu, T; Wang, L; Zhang, L; Lu, L; Shen, J; Chan, RLY; Li, MX; Wu, WKK; To, KKW; Cho, CH				Hu, Tao; Wang, Lin; Zhang, Lin; Lu, Lan; Shen, Jing; Chan, Ruby L. Y.; Li, Mingxing; Wu, William K. K.; To, Kenneth K. W.; Cho, Chi Hin			Sensitivity of apoptosis-resistant colon cancer cells to tanshinones is mediated by autophagic cell death and p53-independent cytotoxicity	PHYTOMEDICINE			English	Article						Ciyptotanshinone; Dihydrotanshinone; Apoptosis resistance; Autophagic cell death; p53-independent cytotoxicity; Colon cancer	MULTIDRUG-RESISTANCE; TUMOR RESISTANCE; SURVIVAL; CRYPTOTANSHINONE; MUTATIONS; PATHWAY; ARREST	Background: Multidrug resistance (MDR) develops in nearly all patients with colon cancer. The reversal of MDR plays an important role in the success of colon cancer chemotherapy. One of the commonest mechanisms conferring MDR is the suppression of apoptosis in cancer cells. Purpose: This study investigated the sensitivity of cryptotanshinone (CTS) and dihydrotanshinone (DTS), two lipophilic tanshinones from a traditional Chinese medicine Salvia miltiorrhiza, in apoptosis-resistant colon cancer cells. Methods: Cell viability was measured by MTT assay. Cell cycle distribution and apoptosis were determined by flow cytometry. Protein levels were analyzed by western blot analysis. The formation of acidic vesicular organelles was visualized by acridine orange staining. Results: Experimental results showed that multidrug-resistant colon cancer cells SW620 Ad300 were sensitive to both CTS and DTS in terms of cell death, but with less induction of apoptosis when compared with the parental cells SW620, suggesting that other types of cell death such as autophagy could occur. Indeed, the two tanshinones induced more LC3B-II accumulation in SW620 Ad300 cells with increased autophagic flux. More importantly, cell viability was increased after autophagy inhibition, indicating that autophagy induced by the two tanshinones was pro-cell death. Besides, the cytotoxic actions of the two tanshinones were p53-independent, which could be useful in inhibiting the growth of apoptosis-resistant cancer cells with p53 defects. Conclusion: The current findings strongly Indicate that both CTS and DTS could inhibit the growth of apoptosis-resistant colon cancer cells through induction of autophagic cell death and p53-independent cytotoxicity. They are promising candidates to be further developed as therapeutic agents in the adjuvant therapy for colon cancer, especially for the apoptosis-resistant cancer types. (C) 2015 Elsevier GmbH. All rights reserved.	[Hu, Tao; Wang, Lin; Zhang, Lin; Lu, Lan; Shen, Jing; Chan, Ruby L. Y.; Li, Mingxing; Cho, Chi Hin] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China; [Wu, William K. K.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anesthesia & Intens Care, Hong Kong, Hong Kong, Peoples R China; [To, Kenneth K. W.] Chinese Univ Hong Kong, Fac Med, Sch Pharm, Hong Kong, Hong Kong, Peoples R China		Hu, T (corresponding author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China.	taohu1985@hotmail.com	Wu, William K.K./A-3277-2009; Hu, Tao/O-2570-2014; Cho, Chi Hin/C-6543-2014; To, Kenneth K W/M-4500-2013	Wu, William K.K./0000-0002-5662-5240; Cho, Chi Hin/0000-0002-7658-3260; To, Kenneth K W/0000-0003-2755-0283; LI, Mingxing/0000-0001-5729-3850; Hu, Tao/0000-0002-0601-3078; WANG, LIN/0000-0001-7883-4900	Innovation and Technology Support Programme, Tier 3/Seed Projects, Innovation and Technology Commission, Hong Kong [ITS/212/12]; General Research Fund, Hong Kong Research Grant Council, Hong Kong [CUHK463613]	This work was supported by Innovation and Technology Support Programme, Tier 3/Seed Projects, Innovation and Technology Commission, Hong Kong (ITS/212/12) and General Research Fund, Hong Kong Research Grant Council, Hong Kong (CUHK463613). We thank Dr. Susan Bates (National Cancer Institute, Bethesda, MD, USA) for providing SW620 parental and resistant cells. We also thank Prof. Bert Vogelstein (Ludwig Center at Johns Hopkins University, Baltimore, MD, USA) for p53<SUP>-/-</SUP> HCT116 cells.	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J	He, G; Wang, Y; Pang, XL; Zhang, B				He, Gang; Wang, Yan; Pang, Xueli; Zhang, Bo			Inhibition of autophagy induced by TSA sensitizes colon cancer cell to radiation	TUMOR BIOLOGY			English	Article						TSA; Colon cancer; Radiosensitivity; Autophagy; Apoptosis	HISTONE DEACETYLASE INHIBITOR; EXPRESSION; THERAPY; DEATH; RADIOSENSITIZATION; TRICHOSTATIN; ACETYLATION; PROGNOSIS; APOPTOSIS; PROTEIN	Radiotherapy is one of the main treatments for clinical cancer therapy. However, its application was limited due to lack of radiosensitivity in some cancers. Trichostatin A (TSA) is a classic histone deacetylases inhibitor (HDACi) that specifically inhibits the biochemical functions of HDAC and is demonstrated to be an active anticancer drug. However, whether it could sensitize colon cancer to radiation is not clear. Our results showed that TSA enhanced the radiosensitivity of colon cancer cells as determined by CCK-8 and clonogenic survival assay. Moreover, apoptotic cell death induced by radiation was enhanced by TSA treatment. Additionally, TSA also induced autophagic response in colon cancer cells, while autophagy inhibition led to cell apoptosis and enhanced the radiosensitivity of colon cancer cells. Our data suggested that inhibition of cytoprotective autophagy sensitizes cancer cell to radiation, which might be further investigated for clinical cancer radiotherapy.	[He, Gang; Wang, Yan; Zhang, Bo] Third Mil Med Univ, Dept Med Genet, Chongqing 400038, Peoples R China; [Pang, Xueli] Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing, Peoples R China		Zhang, B (corresponding author), Third Mil Med Univ, Dept Med Genet, Chongqing 400038, Peoples R China.	pangxueli79@gmail.com; bo_zhang@yahoo.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81272497]	This work was supported by grants from the National Natural Science Foundation of China (no. 81272497).	Akar U, 2008, AUTOPHAGY, V4, P669, DOI 10.4161/auto.6083; [Anonymous], 2013, CANC GENE THER, V20, P375; Benzina S, 2008, CANCER LETT, V264, P63, DOI 10.1016/j.canlet.2008.01.023; Berdasco M, 2010, DEV CELL, V19, P698, DOI 10.1016/j.devcel.2010.10.005; Bolden JE, 2006, NAT REV DRUG DISCOV, V5, P769, DOI 10.1038/nrd2133; Bots M, 2009, CLIN CANCER RES, V15, P3970, DOI 10.1158/1078-0432.CCR-08-2786; Camphausen K, 2007, J CLIN ONCOL, V25, P4051, DOI 10.1200/JCO.2007.11.6202; Cao Y, 2007, CELL RES, V17, P839, DOI 10.1038/cr.2007.78; Carafa V, 2011, RECENT PAT ANTI-CANC, V6, P131, DOI 10.2174/157489211793980088; Caron C, 2005, BIOESSAYS, V27, P408, DOI 10.1002/bies.20210; Chowdhury S, 2011, J BIOL CHEM, V286, P30937, DOI 10.1074/jbc.M110.212035; Dai ZJ, 2013, INT J MOL SCI, V14, P273, DOI 10.3390/ijms14010273; Esteller M, 2007, NAT REV GENET, V8, P286, DOI 10.1038/nrg2005; Fantin VR, 2008, CANCER RES, V68, P3785, DOI 10.1158/0008-5472.CAN-07-6091; Folkvord S, 2009, INT J RADIAT ONCOL, V74, P546, DOI 10.1016/j.ijrobp.2009.01.068; Frew AJ, 2008, P NATL ACAD SCI USA, V105, P11317, DOI 10.1073/pnas.0801868105; Funderburk SF, 2010, TRENDS CELL BIOL, V20, P355, DOI 10.1016/j.tcb.2010.03.002; Gammoh N, 2012, P NATL ACAD SCI USA, V109, P6561, DOI 10.1073/pnas.1204429109; Gore SD, 2006, CANCER RES, V66, P6361, DOI 10.1158/0008-5472.CAN-06-0080; Johnstone RW, 2002, NAT REV DRUG DISCOV, V1, P287, DOI 10.1038/nrd772; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Liu YB, 2013, TOXICOL LETT, V221, P23, DOI 10.1016/j.toxlet.2013.05.643; Livesey KM, 2009, CURR OPIN INVEST DR, V10, P1269; Lovey J, 2013, CANCER LETT, V335, P495, DOI 10.1016/j.canlet.2013.03.012; Mottet D, 2010, CURR CANCER DRUG TAR, V10, P898, DOI 10.2174/156800910793358014; Oh M, 2008, BIOCHEM BIOPH RES CO, V369, P1179, DOI 10.1016/j.bbrc.2008.03.019; Ree AH, 2010, LANCET ONCOL, V11, P459, DOI 10.1016/S1470-2045(10)70058-9; Rhodes LV, 2012, ONCOL REP, V27, P10, DOI 10.3892/or.2011.1488; Sharma S, 2010, CARCINOGENESIS, V31, P27, DOI 10.1093/carcin/bgp220; Sy LK, 2008, CANCER RES, V68, P10229, DOI 10.1158/0008-5472.CAN-08-1983; Weichert W, 2008, LANCET ONCOL, V9, P139, DOI 10.1016/S1470-2045(08)70004-4; Weichert W, 2009, CANCER LETT, V280, P168, DOI 10.1016/j.canlet.2008.10.047	32	22	23	1	10	SPRINGER	DORDRECHT	VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS	1010-4283	1423-0380		TUMOR BIOL	Tumor Biol.	FEB	2014	35	2					1003	1011		10.1007/s13277-013-1134-z			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AB8FT	WOS:000332026300019	24122231				2022-04-25	
J	Patel, S; Waghela, B; Shah, K; Vaidya, F; Mirza, S; Patel, S; Pathak, C; Rawal, R				Patel, Shanaya; Waghela, Bhargav; Shah, Kanisha; Vaidya, Foram; Mirza, Sheefa; Patel, Saumya; Pathak, Chandramani; Rawal, Rakesh			Silibinin, A Natural Blend In Polytherapy Formulation For Targeting Cd44v6 Expressing Colon Cancer Stem Cells	SCIENTIFIC REPORTS			English	Article							INDUCED AUTOPHAGIC DEATH; COLORECTAL-CANCER; TUMOR PROGRESSION; SUPPRESSES GROWTH; POOR-PROGNOSIS; FORCE-FIELD; SIMULATIONS; INHIBITORS; APOPTOSIS; CFLIP(L)	Colon cancer stem cells have been attributed to poor prognosis, therapeutic resistance and aggressive nature of the malignancy. Recent reports associated CD44v6 expression with relapse, metastasis and reduced 5-year survival of colon cancer patients, thereby making it a potential therapeutic target. Thus, in this study, comprehensive prediction and screening of CD44v6 against 1674 lead compounds was conducted. Silibinin was identified as a potential compound targeting CD44v6. Inorder to substantiate these findings, the cytotoxic effect of 5FU, Silibinin and 5FU+ Silibinin was assessed on human colon carcinoma cell line HCT116 derived CD44+ subpopulation. 5FU+ Silibinin inhibited cell proliferation of CD44+ subpopulation at lower concentration than Silibinin standalone. Further, corresponding to CD44v6 knockdown cells, 5FU+ Silibinin treatment significantly decreased CD44v6, Nanog, CTNNB1 and CDKN2A expression whereas increased E-cadherin expression in HCT116 derived CD44+ cells. Moreover, synergistic effect of these drugs suppressed sphere formation, inhibited cell migration, triggered PARP cleavage and perturbation in mitochondrial membrane potential, thereby activating intrinsic apoptotic pathways and induced autophagic cell death. Importantly, 5FU+ Silibinin could inhibit PI3K/MAPK dual activation and arrest the cell cycle at GO/G1 phase. Thus, our study suggests that inhibition of CD44v6 attenuates stemness of colon cancer stem cells and holds a prospect of potent therapeutic target.	[Patel, Shanaya] Ahmedabad Univ, Div Biol & Life Sci, Sch Arts & Sci, Ahmadabad, Gujarat, India; [Patel, Shanaya; Waghela, Bhargav; Shah, Kanisha; Vaidya, Foram; Mirza, Sheefa; Patel, Saumya; Pathak, Chandramani; Rawal, Rakesh] Gujarat Univ, Dept Life Sci, Sch Sci, Ahmadabad, Gujarat, India; [Waghela, Bhargav; Shah, Kanisha; Vaidya, Foram; Mirza, Sheefa; Patel, Saumya; Pathak, Chandramani; Rawal, Rakesh] Indian Inst Adv Res, Dept Cell Biol, Gandhinagar, Gujarat, India		Rawal, R (corresponding author), Gujarat Univ, Dept Life Sci, Sch Sci, Ahmadabad, Gujarat, India.; Rawal, R (corresponding author), Indian Inst Adv Res, Dept Cell Biol, Gandhinagar, Gujarat, India.	rakeshrawal@gujaratuniversity.ac.in	Pathak, Chandramani/E-4662-2016; Mirza, Sheefa/AAQ-8232-2021; Vaidya, Foram/AAI-2713-2021	Pathak, Chandramani/0000-0002-9389-8096; patel, Dr. Saumya/0000-0003-4919-1322	Gujarat Cancer & Research Institute, NCH Campus, Asarwa, Ahmedabad, Gujarat, India; Department of Biotechnology, Ministry of Science & Technology, Govt. of India [6242/P60/RGCB/PMD/DBT/CMPK/2015]	We sincerely appreciate the support by The Gujarat Cancer & Research Institute, NCH Campus, Asarwa, Ahmedabad, Gujarat, India. We also acknowledge Department of Biotechnology, Ministry of Science & Technology, Govt. of India for providing research grant under pilot project for young investigators in Cancer Biology (6242/P60/RGCB/PMD/DBT/CMPK/2015).	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J	Islam, F; Chaousis, S; Wahab, R; Gopalan, V; Lam, AKY				Islam, Farhadul; Chaousis, Stephanie; Wahab, Riajul; Gopalan, Vinod; Lam, Alfred K. -Y.			Protein interactions of FAM134B with EB1 and APC/beta-catenin in vitro in colon carcinoma	MOLECULAR CARCINOGENESIS			English	Article						APC; colorectal cancer; EB1; FAM134B; signaling pathways	CELL LUNG-CANCER; ENDOPLASMIC-RETICULUM TURNOVER; HEREDITARY SENSORY NEUROPATHY; COLORECTAL-CANCER; CLINICOPATHOLOGICAL SIGNIFICANCE; AUTONOMIC NEUROPATHY; ONCOGENIC PROPERTIES; SELECTIVE AUTOPHAGY; PROTEOMIC ANALYSIS; SIGNALING PATHWAY	FAM134B is an autophagy regulator of endoplasmic reticulum and acts as a cancer suppressor in colon cancer. However, the molecular signaling pathways by which FAM134B interacts within colon carcinogenesis is still unknown. Herein, this study aims to determine the interacting partners of FAM134B for the first time in colon cancer and to explore the precise location of FAM134B in cancer signalling pathways. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) followed by anti-FAM134B co-immune precipitation of FAM134B interacting complex was used to identify the potential interactors of FAM134B in colon cancer cells. Western blot and confocal microscopic analysis were used to validate the physical interactions of FAM134B with the interactors. Lentiviral shRNA mediated silencing of FAM134B was used to examine the modulation of FAM134B interactors in cells. We have identified 29 novel binding partners, including CAP1, RPS28, FTH1, KDELR2, MAP4, EB1, PSMD6, PPIB/CYPB etc. Subsequent immunoassays confirmed the direct physical interactions of FAM134B with CAP1, EB1, CYPB, and KDELR2 in colon cancer cells. Exogenous suppression of FAM134B has led to significant upregulation of EB1 as well as reduction of KDELR2 expression. It was noted that overexpression of EB1 promotes WNT/-catenin signaling pathways via inactivating tumor suppressor APC followed by activating -catenin in colorectal carcinogenesis. This study has first time reported the gene signaling networks with which FAM134B interacts and noted that FAM134B is involved in the regulation of WNT/-catenin pathway by EB1-mediated modulating of APC in colon cancer cells.	[Islam, Farhadul; Wahab, Riajul; Gopalan, Vinod; Lam, Alfred K. -Y.] Griffith Univ, Menzies Hlth Inst Queensland, Sch Med, Canc Mol Pathol, Gold Coast, Qld, Australia; [Islam, Farhadul] Univ Rajshahi, Dept Biochem & Mol Biol, Rajshahi, Bangladesh; [Chaousis, Stephanie] Griffith Univ, Australian Rivers Inst, Gold Coast, Qld, Australia; [Chaousis, Stephanie] Griffith Univ, Sch Environm, Gold Coast, Qld, Australia; [Gopalan, Vinod] Griffith Univ, Sch Med Sci, Menzies Hlth Inst Queensland, Gold Coast, Qld, Australia		Gopalan, V (corresponding author), Griffith Univ, Sch Med & Med Sci, Gold Coast Campus, Gold Coast, Qld 4222, Australia.; Lam, AKY (corresponding author), Griffith Med Sch, Pathol, Gold Coast Campus, Gold Coast, Qld 4222, Australia.	v.gopalan@griffith.edu.au; a.lam@griffith.edu.au	Wahab, Riajul/AEC-9343-2022; Lam, Alfred/C-1652-2008; Gopalan, Vinod/C-4269-2016; Islam, Farhadul/R-5643-2017	Lam, Alfred/0000-0003-2771-564X; Gopalan, Vinod/0000-0003-0366-9482; Islam, Farhadul/0000-0001-5262-4702	Menzies Health Institute Queensland, Griffith University	Menzies Health Institute Queensland, Griffith University	Askham JM, 2000, ONCOGENE, V19, P1950, DOI 10.1038/sj.onc.1203498; Baliban RC, 2012, J CLIN PERIODONTOL, V39, P203, DOI 10.1111/j.1600-051X.2011.01805.x; Banerjee B, 2014, J CELL BIOL, V204, P947, DOI 10.1083/jcb.201307119; Bu W, 2003, J BIOL CHEM, V278, P49721, DOI 10.1074/jbc.M306194200; Chiramel AI, 2016, J INFECT DIS, V214, pS319, DOI 10.1093/infdis/jiw270; Dai XF, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-07189-6; Davidson GL, 2012, J NEUROL, V259, P1673, DOI 10.1007/s00415-011-6397-y; Duret C, 2014, MUSCLE NERVE, V49, P774, DOI 10.1002/mus.24145; Fan YC, 2016, ONCOL REP, V36, P1619, DOI 10.3892/or.2016.4936; Fang F, 2009, AM J PATHOL, V174, P297, DOI 10.2353/ajpath.2009.080753; Gainor JF, 2013, ONCOLOGIST, V18, P865, DOI 10.1634/theoncologist.2013-0095; Gemoll T, 2017, ONCOTARGET, V8, P54939, DOI 10.18632/oncotarget.18978; Green RA, 2005, MOL BIOL CELL, V16, P4609, DOI 10.1091/mbc.E05-03-0259; Guo F, 2015, ASIAN PAC J TROP MED, V8, P319, DOI 10.1016/S1995-7645(14)60338-2; Haque MH, 2016, SCI REP-UK, V6, DOI 10.1038/srep29173; Honnappa S, 2005, EMBO J, V24, P261, DOI 10.1038/sj.emboj.7600529; Islam F, 2018, J CELL PHYSIOL, V233, P4479, DOI 10.1002/jcp.26384; Islam F, 2017, EXP CELL RES, V357, P260, DOI 10.1016/j.yexcr.2017.05.021; Islam F, 2017, HUM GENET, V136, P321, DOI 10.1007/s00439-017-1760-4; Islam F, 2017, MOL CARCINOGEN, V56, P238, DOI 10.1002/mc.22488; Kasem K, 2014, EXP MOL PATHOL, V97, P99, DOI 10.1016/j.yexmp.2014.06.002; Kasem K, 2014, EXP MOL PATHOL, V97, P31, DOI 10.1016/j.yexmp.2014.05.001; Kasem K, 2014, EXP CELL RES, V326, P166, DOI 10.1016/j.yexcr.2014.06.013; Khaminets A, 2015, NATURE, V522, P354, DOI 10.1038/nature14498; Kikuchi T, 2012, MOL CELL PROTEOMICS, V11, P916, DOI 10.1074/mcp.M111.015370; Kim MJ, 2013, CANCER LETT, V339, P15, DOI 10.1016/j.canlet.2013.07.027; Kim Y, 2011, HEPATOLOGY, V54, P1661, DOI 10.1002/hep.24539; Kong M, 2011, PSYCHIAT GENET, V21, P37, DOI 10.1097/YPG.0b013e3283413496; Kumar V, 2013, ROBBINS PATHOLOGIC B; Kurth I, 2009, NAT GENET, V41, P1179, DOI 10.1038/ng.464; Lam AKY, 2008, HUM PATHOL, V39, P599, DOI 10.1016/j.humpath.2007.09.001; Lam AKY, 2017, ENDOCR-RELAT CANCER, V24, pR109, DOI 10.1530/ERC-17-0014; Lam AKY, 2011, AM J SURG, V202, P39, DOI 10.1016/j.amjsurg.2010.05.012; Lennemann NJ, 2017, AUTOPHAGY, V13, P322, DOI 10.1080/15548627.2016.1265192; LEWIS MJ, 1992, J MOL BIOL, V226, P913, DOI 10.1016/0022-2836(92)91039-R; Murphy SM, 2012, J NEUROL NEUROSUR PS, V83, P119, DOI 10.1136/jnnp.2010.228965; Rezaul Karim, 2010, Genes Cancer, V1, P251, DOI 10.1177/1947601910365896; Ruggiero C, 2015, ONCOTARGET, V6, P3375, DOI 10.18632/oncotarget.3270; Scheubert L, 2011, DNA RES, V18, P233, DOI 10.1093/dnares/dsr016; SU LK, 1995, CANCER RES, V55, P2972; Subramaniyan B, 2016, BIOMED PHARMACOTHER, V82, P413, DOI 10.1016/j.biopha.2016.05.027; Tang JCO, 2001, CLIN CANCER RES, V7, P1539; Tang WK, 2007, INT J MOL MED, V19, P915; Wahab R, 2017, EUR J CELL BIOL, V96, P487, DOI 10.1016/j.ejcb.2017.07.003; Xie SS, 2015, ONCOL REP, V33, P363, DOI 10.3892/or.2014.3577; Zhang B, 2006, J PROTEOME RES, V5, P2909, DOI 10.1021/pr0600273; Zhang TT, 2017, SCI REP-UK, V7, DOI 10.1038/srep45626	47	13	13	1	15	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0899-1987	1098-2744		MOL CARCINOGEN	Mol. Carcinog.	NOV	2018	57	11					1480	1491		10.1002/mc.22871			12	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	GV7ML	WOS:000446311200005	29964340				2022-04-25	
J	Wang, HP; Ye, T; Cai, YK; Chen, WJ; Xie, HW; Ke, CW				Wang, Huipeng; Ye, Tao; Cai, Yuankun; Chen, Wenjie; Xie, Hongwei; Ke, Chongwei			Downregulation of Ascl2 promotes cell apoptosis by enhancing autophagy in colorectal cancer cells	JOURNAL OF GASTROINTESTINAL ONCOLOGY			English	Article						Autophagy; Ascl2; apoptosis; colorectal cancer (CRC)	BECLIN-1; LC3	Background: Colorectal cancer (CRC) is the third most common cancer, according to recently published literature. While the incidence and the mortality of CRC has decreased due to effective cancer screening measures, there has been an increase in the number of young patients diagnosed with colon cancer due to unclear reasons. As a target molecule of the Wnt signaling pathway, Ascl2 is an important marker of CRC stem cells and plays an important role in maintaining the nature of colon cancer stem/precursor cells. However, the role of Ascl2 in autophagy in CRC cells is rarely elucidated. Methods: In this study, we found that Ascl2 was increased in CRC compared with adjacent tissue. Downregulation of Ascl2 in CRC cells could suppress proliferation and invasion, and induce apoptosis, of CRC cells. Moreover, we found that autophagy-relative protein LC3 increased after Ascl2 knockdown. Furthermore, we treated CRC cells with autophagy inhibitors 3- MA (3-Methyladenine) and CQ (Chloroquine). Results: The results showed that autophagy inhibitors could prevent apoptosis, which was induced by Ascl2 knockdown. Finally, we confirmed that the downregulation of Ascl2 in CRC cells could alleviate the pathological process in vivo by xenograft experiment. Conclusions: Our findings indicated that si-Ascl2 (small/short interfering) exerted a tumor suppression function in CRC by inducing autophagic cell death, and suggest that Ascl2 targeted therapy represents a novel strategy for CRC treatment.	[Wang, Huipeng; Ye, Tao; Cai, Yuankun; Chen, Wenjie; Xie, Hongwei; Ke, Chongwei] Fudan Univ, Peoples Hosp Shanghai 5, Dept Gen Surg, 801 Heqing Rd, Shanghai 200240, Peoples R China		Xie, HW; Ke, CW (corresponding author), Fudan Univ, Peoples Hosp Shanghai 5, Dept Gen Surg, 801 Heqing Rd, Shanghai 200240, Peoples R China.	13816819761@163.com; dr_kecw@163.com			Natural Science Foundation of Minhang, Shanghai [2018MHZ025, 2018MHZ037]; Great Discipline Construction Project from The Fifth People's Hospital of Shanghai [2020WYZDZK02]; Leading Talent Foundation of Minhang, Shanghai [10-1]	This study was supported by the Natural Science Foundation of Minhang, Shanghai (No. 2018MHZ025), Natural Science Foundation of Minhang, Shanghai (No. 2018MHZ037) and the Great Discipline Construction Project from The Fifth People's Hospital of Shanghai (No. 2020WYZDZK02). Leading Talent Foundation of Minhang, Shanghai (No. 10-1).	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Gastrointest. Oncol.	APR	2021	12	2					630	638		10.21037/jgo-21-183			9	Oncology; Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Gastroenterology & Hepatology	RV8MM	WOS:000646081100036	34012655	gold, Green Published			2022-04-25	
J	Shim, BY; Sun, DS; Won, HS; Lee, MA; Hong, SU; Jung, JH; Cho, HM; Ko, YH				Shim, Byoung Yong; Sun, Der Sheng; Won, Hye Sung; Lee, Myung Ah; Hong, Soon Uk; Jung, Ji-Han; Cho, Hyeon-Min; Ko, Yoon Ho			Role of autophagy-related protein expression in patients with rectal cancer treated with neoadjuvant chemoradiotherapy	BMC CANCER			English	Article						Rectal cancer; Neoadjuvant chemoradiotherapy; Autophagy; LC3 beta; Beclin-1; Prognosis	COLORECTAL-CANCER; TUMOR-SUPPRESSOR; COLON-CANCER; PREOPERATIVE RADIOTHERAPY; PROGNOSTIC-SIGNIFICANCE; BECLIN-1; CELLS; GENE; PATTERNS; THERAPY	Background: Autophagy, a cellular degradation process, has complex roles in tumourigenesis and resistance to cancer treatment in humans. The aim of this study was to explore the expression levels of autophagy-related proteins in patients with rectal cancer and evaluate their clinical role in the neoadjuvant chemoradiotherapy setting. Methods: All specimens evaluated were obtained from 101 patients with colorectal cancer who had undergone neoadjuvant chemoradiotherapy and curative surgery. The primary outcomes measured were the expression levels of two autophagy-related proteins (microtubule-associated protein 1 light chain 3 beta (LC3 beta) and beclin-1) by immunohistochemistry and their association with clinicopathological parameters and patient survival. Results: Among the 101 patients, the frequency of high expression of beclin-1 was 31.7 % (32/101) and that of LC3 beta was 46.5 % (47/101). A pathologic complete response was inversely associated with LC3 beta expression (P = 0.003) and alterations in the expression of autophagy-related proteins (P = 0.046). In the multivariate analysis, however, autophagy-related protein expression did not show prognostic significance for relapse-free survival or overall survival. Conclusions: High expression of autophagy-related proteins shows a strong negative association with the efficacy of neoadjuvant chemoradiotherapy in patients with rectal cancer. Autophagy has clear implications as a therapeutic target with which to improve the efficacy of neoadjuvant chemoradiotherapy.	[Shim, Byoung Yong; Sun, Der Sheng; Won, Hye Sung; Lee, Myung Ah; Ko, Yoon Ho] Catholic Univ Korea, Coll Med, Dept Internal Med, Div Oncol, Seoul, South Korea; [Lee, Myung Ah; Ko, Yoon Ho] Catholic Univ Korea, Coll Med, Canc Res Inst, Seoul, South Korea; [Hong, Soon Uk] Chung Ang Univ, Coll Med, Dept Pathol, Seoul 156756, South Korea; [Jung, Ji-Han] Catholic Univ Korea, Coll Med, Dept Hosp Pathol, Seoul, South Korea; [Cho, Hyeon-Min] Catholic Univ Korea, Coll Med, Dept Gen Surg, Seoul, South Korea		Ko, YH (corresponding author), Catholic Univ Korea, Coll Med, Dept Internal Med, Div Oncol, Seoul, South Korea.; Ko, YH (corresponding author), Catholic Univ Korea, Coll Med, Canc Res Inst, Seoul, South Korea.	koyoonho@catholic.ac.kr			Uijeongbu St Mary's Hospital	This study was supported by in part by Uijeongbu St Mary's Hospital research fund (Ko YH and Sun DS).	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J	Huo, HZ; Zhou, ZY; Wang, B; Qin, J; Liu, WY; Gu, Y				Huo, Hai-zhong; Zhou, Zhi-yuan; Wang, Bing; Qin, Jian; Liu, Wen-yong; Gu, Yan			Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Colorectal cancer; AZD-2014; mTOR complexes; Autophagy; Signaling	ACTIVATED PROTEIN-KINASE; DRUG-RESISTANCE; FACTOR RECEPTOR; COLON-CANCER; AUTOPHAGY; PATHWAY; DEATH; HEAD	Colorectal cancer is a major contributor of cancer-related mortality. The mammalian target or rapamycin (mTOR) signaling is frequently hyper-activated in colorectal cancers, promoting cancer progression and chemo-resistance. In the current study, we investigated the anti-colorectal cancer effect of a novel mTOR complex 1 (mTORC1) and mTORC2 dual inhibitor: AZD-2014. In cultured colorectal cancer cell lines, AZD-2014 significantly inhibited cancer cell growth without inducing significant cell apoptosis. AZD-2014 blocked activation of both mTORC1 (S6K and S6 phosphorylation) and mTORC2 (Akt Ser 473 phosphorylation), and activated autophagy in colorectal cancer cells. Meanwhile, autophagy inhibition by 3-methyaldenine (3-MA) and hydroxychloroquine, as well as by siRNA knocking down of Beclin-1 or ATG-7, inhibited AZD-2014-induced cytotoxicity, while the apoptosis inhibitor had no rescue effect. In vivo, AZD-2014 oral administration significantly inhibited the growth of HT-29 cell xenograft in SCID mice, and the mice survival was dramatically improved. At the same time, in xenografted tumors administrated with AZD-2014, the activation of mTORC1 and mTORC2 were largely inhibited, and autophagic markers were significantly increased. Thus, AZD-2014 inhibits colorectal cancer cell growth both in vivo and in vitro. Our results suggest that AZD-2014 may be further investigated for colorectal cancer therapy in clinical trials. (C) 2013 Elsevier Inc. All rights reserved.	[Huo, Hai-zhong; Zhou, Zhi-yuan; Wang, Bing; Qin, Jian; Liu, Wen-yong; Gu, Yan] Shanghai Jiao Tong Univ, Dept Gen Surg, Sch Med, Peoples Hosp 9, Shanghai 200011, Peoples R China		Gu, Y (corresponding author), Shanghai Jiao Tong Univ, Dept Gen Surg, Sch Med, Peoples Hosp 9, 639 Zhizhaoju Rd, Shanghai 200011, Peoples R China.	drguyan@hotmail.com	Gu, Yan/AFQ-1163-2022				Amaravadi RK, 2007, CLIN CANCER RES, V13, P7271, DOI 10.1158/1078-0432.CCR-07-1595; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Bruzzese F, 2006, CLIN CANCER RES, V12, P617, DOI 10.1158/1078-0432.CCR-05-1671; Chen A, 2006, ONCOGENE, V25, P278, DOI [10.1038/sj.onc.1209019, 10.1038/sj.onc.1209573]; Choo AY, 2008, P NATL ACAD SCI USA, V105, P17414, DOI 10.1073/pnas.0809136105; Craighead MW, 1999, J NEUROSCI RES, V57, P236, DOI 10.1002/(SICI)1097-4547(19990715)57:2<236::AID-JNR9>3.0.CO;2-D; Din FVN, 2012, GASTROENTEROLOGY, V142, P1504, DOI 10.1053/j.gastro.2012.02.050; Efeyan A, 2010, CURR OPIN CELL BIOL, V22, P169, DOI 10.1016/j.ceb.2009.10.007; Ekstrand AI, 2010, FAM CANCER, V9, P125, DOI 10.1007/s10689-009-9293-1; Fang DD, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0067258; Gomez-Pinillos A, 2012, HEMATOL ONCOL CLIN N, V26, P483, DOI 10.1016/j.hoc.2012.02.014; Gorlick R, 1999, SEMIN ONCOL, V26, P606; Gustin DM, 2002, CANCER METAST REV, V21, P323, DOI 10.1023/A:1021271229476; Hardie DG, 2012, CHEM BIOL, V19, P1222, DOI 10.1016/j.chembiol.2012.08.019; Huo HZ, 2013, MOL CELL BIOCHEM, V378, P171, DOI 10.1007/s11010-013-1608-8; Juhasz G, 2007, GENE DEV, V21, P3061, DOI 10.1101/gad.1600707; Kim EH, 2007, CANCER RES, V67, P6314, DOI 10.1158/0008-5472.CAN-06-4217; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Longley DB, 2006, BBA-REV CANCER, V1766, P184, DOI 10.1016/j.bbcan.2006.08.001; Mohandas K M, 1999, Indian J Gastroenterol, V18, P118; Pike KG, 2013, BIOORG MED CHEM LETT, V23, P1212, DOI 10.1016/j.bmcl.2013.01.019; Plowey ED, 2008, J NEUROCHEM, V105, P1048, DOI 10.1111/j.1471-4159.2008.05217.x; Sarbassov DD, 2005, SCIENCE, V307, P1098, DOI 10.1126/science.1106148; Scarlatti F, 2008, CELL DEATH DIFFER, V15, P1318, DOI 10.1038/cdd.2008.51; SEGLEN PO, 1982, P NATL ACAD SCI-BIOL, V79, P1889, DOI 10.1073/pnas.79.6.1889; Siegel R, 2012, CA-CANCER J CLIN, V62, P10, DOI 10.3322/caac.20138; Sommer K, 2001, INT J ONCOL, V18, P1145; Sugiyama M, 2009, INT J ONCOL, V34, P339, DOI 10.3892/ijo_00000156; Sun SY, 2013, CANCER LETT, V340, P1, DOI 10.1016/j.canlet.2013.06.017; Zaytseva YY, 2012, CANCER LETT, V319, P1, DOI 10.1016/j.canlet.2012.01.005	31	39	40	0	4	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	JAN 10	2014	443	2					406	412		10.1016/j.bbrc.2013.11.099			7	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	AA5TQ	WOS:000331162900011	24309100				2022-04-25	
J	Xu, JY; Zheng, FC; Yu, WS				Xu, Jiayou; Zheng, Fuchang; Yu, Wensheng			MicroRNA-129-5p-mediated inhibition of autophagy enhanced the radiosensitivity of human colon cancer cells	INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY			English	Review						microRNA-129-5P; autophagy; beclin-1; radiosensitivity; colon cancer	GLIOMA STEM-CELLS; GASTRIC-CANCER; MAMMALIAN AUTOPHAGY; COLORECTAL-CANCER; MALIGNANT GLIOMA; CARCINOMA-CELLS; POOR-PROGNOSIS; EXPRESSION; RADIORESISTANCE; RADIATION	The efficacy and outcome of radiotherapy in the treatment of colon cancer are much limited by radioresistance. Studies show microRNAs are involved in radioresistance in many cancers. In the present study, we aimed to explore the role of microRNA-129-5p in regulating radioresistance of colon cancer cells and its underlying mechanism. In the present study, we established a radioresistant colon cancer cell line. Compared with control group, miRNA-129-5p was significantly reduced whereas the autophagy was enhanced in radioresistant colon cancer cell line. Exotic expression of miRNA-129-5p was capable to inhibit beclin-1, a critical autophagy gene, and suppressed autophagy activity. Furthermore, we found beclin-1 was the direct target of miR-129-5p as evidenced by in silico analysis and luciferase reporter assay. In addition, overexpression of miRNA-129-5p inhibited cell growth and colony formation ability and promoted irradiation-induced apoptosis of radioresistant colon cancer cells. By contrast, overexpression of beclin-1 abolished the effects of miRNA-129-5p. In vivo, miRNA-129-5p sensitized xenograft tumor to irradiation. Taken together, the present study suggested that miRNA-129-5p significantly augmented the radiosensitivity of colon cancer cells through inhibiting beclin-1-mediated autophagy, hinting a promising new molecular target for the treatment of colon cancer.	[Xu, Jiayou; Zheng, Fuchang; Yu, Wensheng] Weifang Peoples Hosp, Dept Gen Surg, 151 Guangwen St, Weifang 261041, Shandong, Peoples R China		Xu, JY (corresponding author), Weifang Peoples Hosp, Dept Gen Surg, 151 Guangwen St, Weifang 261041, Shandong, Peoples R China.	xujiayou121@163.com			Shandong province natural science foundation of China [ZR2009CM116]	Research supported by the Shandong province natural science foundation of China (NO. ZR2009CM116).	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J. Clin. Exp. Pathol.		2016	9	12					12179	12187					9	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	EF5YP	WOS:000390406200001					2022-04-25	
J	Kauntz, H; Bousserouel, S; Gosse, F; Raul, F				Kauntz, Henriette; Bousserouel, Souad; Gosse, Francine; Raul, Francis			Silibinin triggers apoptotic signaling pathways and autophagic survival response in human colon adenocarcinoma cells and their derived metastatic cells	APOPTOSIS			English	Article						Colon cancer; Flavonoids; Apoptosis; Autophagy; TRAIL; Mitochondria	SILYBIN-PHYTOSOME; SUPPRESSES GROWTH; CANCER-CELLS; CYCLE ARREST; DEATH; RESVERATROL; ACTIVATION; TRAIL; CHEMOPREVENTION; PROLIFERATION	Silibinin, a flavonolignan isolated from the milk thistle plant (Silybum marianum), possesses antineoplastic properties. In vitro and in vivo studies have recently shown that silibinin inhibits the growth of colorectal cancer (CRC). The present study investigates the mechanisms of silibinin-induced cell death using an in vitro model of human colon cancer progression, consisting of primary tumor cells (SW480) and their derived metastatic cells (SW620) isolated from a metastasis of the same patient. Silibinin induced apoptotic cell death evidenced by DNA fragmentation and activation of caspase-3 in both cell lines. Silibinin enhanced the expression (protein and mRNA) of TNF-related apoptosis-inducing ligand (TRAIL) death receptors (DR4/DR5) at the cell surface in SW480 cells, and induced their expression in TRAIL-resistant SW620 cells normally not expressing DR4/DR5. Caspase-8 and -10 were activated demonstrating the involvement of the extrinsic apoptotic pathway in silibinin-treated SW480 and SW620 cells. The protein Bid was cleaved in SW480 cells indicating a cross-talk between extrinsic and intrinsic apoptotic pathway. We demonstrated that silibinin activated also the intrinsic apoptotic pathway in both cell lines, including the perturbation of the mitochondrial membrane potential, the release of cytochrome c into the cytosol and the activation of caspase-9. Simultaneously to apoptosis, silibinin triggered an autophagic response. The inhibition of autophagy with a specific inhibitor enhanced cell death, suggesting a cytoprotective function for autophagy in silibinin-treated cells. Taken together, our data show that silibinin initiated in SW480 and SW620 cells an autophagic-mediated survival response overwhelmed by the activation of both the extrinsic and intrinsic apoptotic pathways.	[Kauntz, Henriette; Bousserouel, Souad; Gosse, Francine; Raul, Francis] Univ Strasbourg, IRCAD, Lab Nutr Canc Prevent, EA 4438, F-67091 Strasbourg, France		Raul, F (corresponding author), Univ Strasbourg, IRCAD, Lab Nutr Canc Prevent, EA 4438, 1 Pl Hop, F-67091 Strasbourg, France.	francis.raul@ircad.u-strasbg.fr			Conseil Regional d'Alsace, FranceRegion Grand-Est	Henriette Kauntz is supported by a fellowship provided by the Conseil Regional d'Alsace, France.	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J	Li, CH; Zhang, K; Pan, GZ; Ji, HY; Li, CY; Wang, XW; Hu, X; Liu, RC; Deng, LF; Wang, Y; Yang, LQ; Cui, HJ				Li, Changhong; Zhang, Kui; Pan, Guangzhao; Ji, Haoyan; Li, Chongyang; Wang, Xiaowen; Hu, Xin; Liu, Ruochen; Deng, Longfei; Wang, Yi; Yang, Liqun; Cui, Hongjuan			Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways	JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH			English	Article						Colorectal cancer; Dehydrodiisoeugenol (DEH); Autophagy inhibition; Endoplasmic reticulum (ER) stress; Anticancer agent	COLON-CANCER; CELL-DEATH; ACTIVATION; METABOLITES; MODULATION; EXPRESSION; GUIDELINES; RECEPTORS; APOPTOSIS; DISEASE	Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2 alpha and IRE1 alpha/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1 alpha significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.	[Li, Changhong; Zhang, Kui; Pan, Guangzhao; Ji, Haoyan; Li, Chongyang; Wang, Xiaowen; Hu, Xin; Liu, Ruochen; Deng, Longfei; Yang, Liqun; Cui, Hongjuan] Southwest Univ, Coll Sericulture Text & Biomass Sci, State Key Lab Silkworm Genome Biol, 2 Tiansheng Rd, Chongqing 400716, Peoples R China; [Li, Changhong; Zhang, Kui; Pan, Guangzhao; Ji, Haoyan; Li, Chongyang; Wang, Xiaowen; Hu, Xin; Liu, Ruochen; Deng, Longfei; Yang, Liqun; Cui, Hongjuan] Southwest Univ, Med Res Inst, Canc Ctr, Chongqing 400716, Peoples R China; [Li, Changhong; Wang, Yi; Yang, Liqun; Cui, Hongjuan] Southwest Univ, Peoples Hosp Chongqing 9, Affiliated Hosp, Chongqing 400716, Peoples R China		Yang, LQ (corresponding author), Southwest Univ, Coll Sericulture Text & Biomass Sci, State Key Lab Silkworm Genome Biol, 2 Tiansheng Rd, Chongqing 400716, Peoples R China.; Yang, LQ (corresponding author), Southwest Univ, Med Res Inst, Canc Ctr, Chongqing 400716, Peoples R China.; Yang, LQ (corresponding author), Southwest Univ, Peoples Hosp Chongqing 9, Affiliated Hosp, Chongqing 400716, Peoples R China.	cysylq@swu.edu.cn	Zhang, Kui/AAE-9324-2022	Zhang, Kui/0000-0001-9618-610X	National Key Research and Development Program of China [2016YFC1302204, 2017YFC1308601]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31672496, 31802142, 81872071]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [XDJK2020B006, XDJK2019C089]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2019 T120801, 2017 M620408]; Chongqing Natural Science foundation of Chongqing [cstc2019jcyj-zdxmX0033]; Chongqing University Innovation Team Building Program [CXTDX201601010]; Eyas Program of the Youth Innovative Talents Cultivation in Chongqing [CY200237]	This work was supported by the National Key Research and Development Program of China (2016YFC1302204, 2017YFC1308601), the National Natural Science Foundation of China (31672496, 31802142 and 81872071), project funded by the Fundamental Research Funds for the Central Universities (XDJK2020B006, XDJK2019C089), the China Postdoctoral Science Foundation (2019 T120801 and 2017 M620408), Chongqing Natural Science foundation of Chongqing (cstc2019jcyj-zdxmX0033), Chongqing University Innovation Team Building Program funded projects (CXTDX201601010) and the Eyas Program of the Youth Innovative Talents Cultivation in Chongqing (CY200237).	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Exp. Clin. Cancer Res.	APR 10	2021	40	1							125	10.1186/s13046-021-01915-9			15	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	RL6WB	WOS:000639109700002	33838688	Green Published, gold			2022-04-25	
J	Pal, I; Parida, S; Kumar, BNP; Banik, P; Dey, KK; Chakraborty, S; Bhutia, SK; Mandal, M				Pal, Ipsita; Parida, Sheetal; Kumar, B. N. Prashanth; Banik, Payel; Dey, Kaushik Kumar; Chakraborty, Sandipan; Bhutia, Sujit K.; Mandal, Mahitosh			Blockade of autophagy enhances proapoptotic potential of BI-69A11, a novel Akt inhibitor, in colon carcinoma	EUROPEAN JOURNAL OF PHARMACOLOGY			English	Article						Autophagy; Colon cancer; Apoptosis; Beclin-1; BI-69A11; HSP90	ACTIVATED PROTEIN-KINASE; BECLIN 1; COLORECTAL-CANCER; TARGETING AUTOPHAGY; APOPTOSIS; TUMORIGENESIS; CHLOROQUINE; GROWTH; PHOSPHORYLATION; MUTATIONS	BI-69A11, novel Akt inhibitor, is currently drawing much attention due to its intriguing effect in inducing apoptosis in melanoma, breast, prostate and colon cancer. However, earlier reports reveal that PI3K/Akt/mTOR inhibitors promote autophagy at the early stage as a survival mechanism that might affect its apoptotic potential. It is necessary to investigate whether BI-69A11 mediated apoptosis is associated with autophagy for enhancing its therapeutic efficacy. Here, we found that BI-69A11 induced autophagy at earlier time point through the inhibition of Akt/mTOR/p70S6kinase pathway. Dose-dependent and time-dependent conversion of LC3-I to LC3-II, increased accumulation of LC3-GFP dots in cytoplasm and increase in other autophagic markers such as Beclin-1, firmly supported the fact that BI-69A11 induces autophagy. Atg5, Atg7 and Beclin-1 siRNA mediated genetic attenuation and pre-treatment with pharmacological inhibitor 3-MA and CQ diminished the autophagy and increased the propensity of cell death towards apoptosis. It was also suggested that BI-69A11 mediated interaction between Akt, HSP-90 and Beclin-1 maintained the fine balance between autophagy and apoptosis. Interaction between Beclin-1 and HSP90 is one of the prime causes of induction of autophagy. Here, we also generated a novel combination therapy by pretreatment with CQ that inhibited the autophagy and accelerated the apoptotic potential of BI-69A11. In summary; our findings suggest that induction of autophagy lead to the resistance of colon cancer towards BI-69A11 mediated apoptosis. (C) 2015 Elsevier B.V. All rights reserved.	[Pal, Ipsita; Parida, Sheetal; Kumar, B. N. Prashanth; Banik, Payel; Dey, Kaushik Kumar; Mandal, Mahitosh] Indian Inst Technol, Sch Med Sci & Technol, Kharagpur 721302, W Bengal, India; [Chakraborty, Sandipan] Apollo Gleneagles Hosp, Kolkata, W Bengal, India; [Bhutia, Sujit K.] Natl Inst Technol Rourkela, Dept Life Sci, Rourkela, Odisha, India		Mandal, M (corresponding author), Indian Inst Technol, Sch Med Sci & Technol, Kharagpur 721302, W Bengal, India.	mahitosh@smst.iikgp.ernet.in	Bhusetty Nagesh, Prashanth Kumar/ABH-4999-2020; Dey, Kaushik Kumar/H-5997-2018; Mandal, Mahitosh/Q-7421-2016; Pal, Ipsita/AAX-4410-2020	Bhusetty Nagesh, Prashanth Kumar/0000-0003-3518-405X; Dey, Kaushik Kumar/0000-0002-9594-6362; Mandal, Mahitosh/0000-0003-3861-3323; 	University Grant CommissionUniversity Grants Commission, India [20-12/2009(ii)EU-IV]	We thank University Grant Commission for providing of fellowship (20-12/2009(ii)EU-IV). We thank Dr. Rupesh dash and Priyanka Halder for helpful discussions and proofing of this manuscript. We also thank Dr. P B Fisher and Dr. Maurizio Pellecchia for providing us the key compound BI-69A11 for research purpose and for their kind help.	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J	Devenport, SN; Shah, YM				Devenport, Samantha N.; Shah, Yatrik M.			Functions and Implications of Autophagy in Colon Cancer	CELLS			English	Review						autophagy; nutrient; cancer; colon	HYPOXIA-INDUCED AUTOPHAGY; TUMOR-CELL SURVIVAL; COLORECTAL-CANCER; EPITHELIAL-CELLS; MITOPHAGY; PROTEIN; DEGRADATION; INHIBITION; EXPRESSION; STARVATION	Autophagy is an essential function to breakdown cellular proteins and organelles to recycle for new nutrient building blocks. In colorectal cancer, the importance of autophagy is becoming widely recognized as it demonstrates both pro- and anti-tumorigenic functions. In colon cancer, cell autonomous and non-autonomous roles for autophagy are essential in growth and progression. However, the mechanisms downstream of autophagy (to reduce or enhance tumor growth) are not well known. Additionally, the signals that activate and coordinate autophagy for tumor cell growth and survival are not clear. Here, we highlight the context- and cargo-dependent role of autophagy in proliferation, cell death, and cargo breakdown.	[Devenport, Samantha N.; Shah, Yatrik M.] Univ Michigan, Cellular & Mol Biol, Ann Arbor, MI 48109 USA; [Devenport, Samantha N.; Shah, Yatrik M.] Univ Michigan, Internal Med, Div Gastroenterol, Mol & Integrat Physiol, Ann Arbor, MI 48109 USA; [Devenport, Samantha N.; Shah, Yatrik M.] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA		Shah, YM (corresponding author), Univ Michigan, Cellular & Mol Biol, Ann Arbor, MI 48109 USA.; Shah, YM (corresponding author), Univ Michigan, Internal Med, Div Gastroenterol, Mol & Integrat Physiol, Ann Arbor, MI 48109 USA.; Shah, YM (corresponding author), Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA.	sdevenpo@umich.edu; shahy@umich.edu			NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA148828, R01DK095201, T32GM007315, T32CA140044]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [T32CA140044, R01CA148828] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK095201] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [T32GM007315] Funding Source: NIH RePORTER	This work was supported by the NIH, R01CA148828 and R01DK095201 to Y.M.S, and T32GM007315 and T32CA140044 to S.N.D.	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J	Inoue, T; Hayashi, Y; Tsujii, Y; Yoshii, S; Sakatani, A; Kimura, K; Uema, R; Kato, M; Saiki, H; Shinzaki, S; Iijima, H; Takehara, T				Inoue, Takanori; Hayashi, Yoshito; Tsujii, Yoshiki; Yoshii, Shunsuke; Sakatani, Akihiko; Kimura, Keiichi; Uema, Ryotaro; Kato, Minoru; Saiki, Hirotsugu; Shinzaki, Shinichiro; Iijima, Hideki; Takehara, Tetsuo			Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells	SCIENTIFIC REPORTS			English	Article							MICRORNA TARGET PREDICTION; TUMOR; GROWTH; PROGRESSION; METASTASIS; METABOLISM	Deficiency of p53 in cancer cells activates the transformation of normal tissue fibroblasts into carcinoma-associated fibroblasts; this promotes tumor progression through a variety of mechanisms in the tumor microenvironment. The role of autophagy in carcinoma-associated fibroblasts in tumor progression has not been elucidated. We aimed to clarify the significance of autophagy in fibroblasts, focusing on the TP53 status in co-cultured human colorectal cancer cell lines (TP53-wild-type colon cancer, HCT116; TP53-mutant colon cancer, HT29; fibroblast, CCD-18Co) in vitro. Autophagy in fibroblasts was significantly suppressed in association with ACTA2, CXCL12, TGF beta 1, VEGFA, FGF2, and PDGFRA mRNA levels, when co-cultured with p53-deficient HCT116(sh p53) cells. Exosomes isolated from the culture media of HCT116(sh p53) cells significantly suppressed autophagy in fibroblasts via inhibition of ATG2B. Exosomes derived from TP53-mutant HT29 cells also suppressed autophagy in fibroblasts. miR-4534, extracted from the exosomes of HCT116(sh p53) cells, suppressed ATG2B in fibroblasts. In conclusion, a loss of p53 function in colon cancer cells promotes the activation of surrounding fibroblasts through the suppression of autophagy. Exosomal miRNAs derived from cancer cells may play a pivotal role in the suppression of autophagy.	[Inoue, Takanori; Hayashi, Yoshito; Tsujii, Yoshiki; Yoshii, Shunsuke; Sakatani, Akihiko; Kimura, Keiichi; Uema, Ryotaro; Kato, Minoru; Saiki, Hirotsugu; Shinzaki, Shinichiro; Iijima, Hideki; Takehara, Tetsuo] Osaka Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Suita, Osaka, Japan		Takehara, T (corresponding author), Osaka Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Suita, Osaka, Japan.	takehara@gh.med.osaka-u.ac.jp			Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI) [JP17K15944, JP15K19326, JP19K08420]	This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI JP17K15944 to S.Y., JP15K19326 and JP19K08420 to Y.H.).	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J	Xiao, T; Zhu, W; Huang, W; Lu, SS; Li, XH; Xiao, ZQ; Yi, H				Xiao, Ta; Zhu, Wei; Huang, Wei; Lu, Shan-Shan; Li, Xin-Hui; Xiao, Zhi-Qiang; Yi, Hong			RACK1 promotes tumorigenicity of colon cancer by inducing cell autophagy	CELL DEATH & DISEASE			English	Article							PROTEIN; SENESCENCE; RECEPTOR; ACTIVATION; CARCINOMA; GROWTH; JNK; PHOSPHORYLATION; EXPRESSION; PREDICTOR	RACK1 is upregulated in the various types of human cancers, and considered to play a role in the development and progression of human cancer. However, the role and mechanism of RACK in the colon cancer are poorly understood. In this study, we detected RACK1 expression in 63 normal colonic mucosa, 60 colonic inflammatory polyps, 60 colonic adenomas, 180 colon adenocarcinomas, and 40 lymph node metastases by immunohistochemistry, and observed that RACK1 expression was progressively elevated in the carcinogenic process of human colonic epithelium, and RACK1 expressional levels were positively correlated with the malignant degree and lymph node metastasis of colon cancers, and negatively correlated with the patient survival. With a combination of loss-of-function and gain-of-function approaches, we observed that RACK1 promoted colon cancer cell proliferation, inhibited colon cancer cell apoptosis, and enhanced the anchorage-independent and xenograft growth of colon cancer cells. Moreover, we found that RACK1-induced autophagy of colon cancer cells; RACK1-induced autophagy promoted colon cancer cell proliferation and inhibited colon cancer cell apoptosis. Our data suggest that RACK1 acts as an oncogene in colon cancer, and RACK1-induced autophagy promotes proliferation and survival of colon cancer, highlighting the therapeutic potential of autophagy inhibitor in the colon cancer with high RACK1 expression.	[Xiao, Ta; Zhu, Wei; Huang, Wei; Lu, Shan-Shan; Li, Xin-Hui; Xiao, Zhi-Qiang; Yi, Hong] Cent South Univ, Xiangya Hosp, Res Ctr Carcinogenesis & Targeted Therapy, Changsha 410008, Hunan, Peoples R China; [Xiao, Ta] Chinese Acad Med Sci, Inst Dermatol, Nanjing 210042, Jiangsu, Peoples R China; [Xiao, Ta] Peking Union Med Coll, Nanjing 210042, Jiangsu, Peoples R China; [Zhu, Wei] Cent South Univ, Xiangya Hosp, Dept Pathol, Changsha 410008, Hunan, Peoples R China		Xiao, ZQ; Yi, H (corresponding author), Cent South Univ, Xiangya Hosp, Res Ctr Carcinogenesis & Targeted Therapy, Changsha 410008, Hunan, Peoples R China.	zqxiao2001@hotmail.com; yi_hong@126.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81172302, 81472801, 81672687]	This work was supported by the National Natural Science Foundation of China (81172302, 81472801, and 81672687).	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NOV 19	2018	9								1148	10.1038/s41419-018-1113-9			13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	HA8TC	WOS:000450565200005	30451832	Green Published, gold			2022-04-25	
J	Kaluzki, I; Hailemariam-Jahn, T; Doll, M; Kaufmann, R; Balermpas, P; Zoller, N; Kippenberger, S; Meissner, M				Kaluzki, Irina; Hailemariam-Jahn, Tsige; Doll, Monika; Kaufmann, Roland; Balermpas, Panagiotis; Zoeller, Nadja; Kippenberger, Stefan; Meissner, Markus			Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy	CELLS			English	Article						dimethylfumarate; colorectal carcinoma; p21; cell cycle arrest; cyclin D1; p62; LC3 I/II; caspase-8; autophagy	COLON-CANCER CELLS; TUMOR-CELLS; P21; INDUCTION; EXPRESSION; GROWTH	Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)-assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct anti-tumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.	[Kaluzki, Irina; Hailemariam-Jahn, Tsige; Doll, Monika; Kaufmann, Roland; Zoeller, Nadja; Kippenberger, Stefan; Meissner, Markus] Goethe Univ, Dept Dermatol Venereol & Allergol, D-60323 Frankfurt, Germany; [Balermpas, Panagiotis] Univ Spital Zurich, Dept Radiat Oncol, CH-8091 Zurich, Switzerland		Meissner, M (corresponding author), Goethe Univ, Dept Dermatol Venereol & Allergol, D-60323 Frankfurt, Germany.	irina.kaluzki@kgu.de; rita_th@web.de; monika.doll@kgu.de; roland.kaufmann@kgu.de; panagiotis.balermpas@usz.ch; nadja.zoeller@kgu.de; kippenberger@em.uni-frankfurt.de; markus.meissner@kgu.de	Meissner, Markus/AAP-8179-2020	Balermpas, Panagiotis/0000-0001-5261-6446	Kurt and Eva Herrmann scholarship, 2013; Brigitte and Konstanze Wegener-Stiftung [6b]	This research was funded by the Kurt and Eva Herrmann scholarship, 2013 (I.K.) and the Brigitte and Konstanze Wegener-Stiftung grant number 6b (M.M.).	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J	Fan, XJ; Wang, Y; Wang, L; Zhu, MY				Fan, Xiang-Jun; Wang, Yao; Wang, Lei; Zhu, Mingyan			Salidroside induces apoptosis and autophagy in human colorectal cancer cells through inhibition of PI3K/Akt/mTOR pathway	ONCOLOGY REPORTS			English	Article						autophagy; apoptosis; human colon cancer HT-29 cells; salidroside; PI3K/Akt/mTOR pathways	SIGNALING PATHWAYS; COLON-CANCER; G(2)/M ARREST; CYCLE ARREST; P38 MAPK; DEATH; INDUCTION; PLUMBAGIN; GROWTH; MTOR	The role of salidroside in colon cancer remains unknown. Here we show that salidroside, a phenylpropanoid glycoside extracted from Rhodiola rosea, exhibited potent anti-proliferative properties in human colorectal cancer cells via inducing apoptosis and autophagy. We ascertained that salidroside exerts an inhibitory effect on the proliferation of human colorectal cancer cells in a dose-dependent manner. In addition, salidroside induced cell apoptosis, accompanied by an increase of chromatin condensation and nuclear fragmentation, and a decrease of Bcl-2/Bax protein expression ratio. We also found that salidroside induced autophagy, evidenced by increased LC3(+) autophagic vacuoles, positive acridine orange-stained cells, enhanced conversion of LC3-I to LC3-II, and elevation of Beclin-1. Treatment with autophagy-specific inhibitors [3-methyladenine (3-MA) and bafilomycin A1 (BA)] enhanced salidroside-induced apoptosis, indicating that salidroside-mediated autophagy may protect HT29 cells from undergoing apoptotic cell death. Additionally, salidroside decreased the phosphorylation of PI3K, Akt and mTOR. Treatment with PI3K inhibitor LY294002 augmented the effects of salidroside on the expression of Akt and mTOR. These findings indicate that salidroside could suppress the PI3K/Akt/mTOR signaling pathways. This study may provide a rationale for future clinical application using salidroside as a chemotherapeutic agent for human colorectal cancer.	[Fan, Xiang-Jun; Wang, Yao; Wang, Lei; Zhu, Mingyan] Nantong Univ, Affiliated Hosp, Dept Gen Surg, 20 Xisi Rd, Nantong 226001, Jiangsu, Peoples R China		Zhu, MY (corresponding author), Nantong Univ, Affiliated Hosp, Dept Gen Surg, 20 Xisi Rd, Nantong 226001, Jiangsu, Peoples R China.	zmyntfy@163.com			Technological Innovation and Demonstration of Social Undertakings Projects of Nantong, Jiangsu, China [HS2014049]	This study was supported by the Technological Innovation and Demonstration of Social Undertakings Projects (HS2014049) of Nantong, Jiangsu, China.	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Rep.	DEC	2016	36	6					3559	3567		10.3892/or.2016.5138			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	ED2DG	WOS:000388653200057	27748934	Bronze			2022-04-25	
J	Zhao, YL; Li, ETS; Wang, MF				Zhao, Yueliang; Li, Edmund T. S.; Wang, Mingfu			Alisol B 23-acetate induces autophagic-dependent apoptosis in human colon cancer cells via ROS generation and JNK activation	ONCOTARGET			English	Article						alisol B 23-acetate; autophagy; apoptosis; ROS; JNK	REACTIVE OXYGEN; PROTEIN-KINASES; DEATH; INHIBITION; TRITERPENE; OSTEOSARCOMA; LYMPHOCYTES; MECHANISMS; ALISMATIS; RHIZOMA	Alisol B 23-acetate (AB23A), a natural triterpenoid from the rhizome of Alisma orientale, a Chinese medicinal herb, has multiple physiological activities including anticancer. However, its effect on human colon cancer and the underlying mechanism are not clear. Here, we reported for the first time that AB23A induced cell cycle G(1) phase arrest and apoptotic cell death in colon cancer cells. Autophagy also occurred in AB23A-treated HCT116 cells as evidenced by the accumulation of microtubule-associated protein 1 light chain 3 form II (LC3-II) and degradation of SQSTM1/p62. An autophagy inhibitor, 3-methyladenine (3-MA) was found to attenuate AB23A-mediated autophagy, apoptosis, and cell death, indicating that AB23A-induced apoptotic response was dependent on the induction of autophagy. In addition, the treatment of HCT116 cells with AB23A resulted in the generation of reactive oxygen species (ROS) and phosphorylation of c-Jun N-terminal kinase (JNK). A ROS scavenger, N-acetylcysteine (NAC) and a JNK-specific inhibitor, SP600125 attenuated AB23A-induced autophagy and apoptotic cell death. Moreover, NAC was able to eliminate AB23A-induced JNK phosphorylation. This finding provides a novel mechanism of action of AB23A in colon cancer HCT116 cells that AB23A induces autophagic-dependent apoptotic cell death in colon cancer cells, at least in part, though the accumulation of intracellular ROS and subsequent activation of JNK.	[Zhao, Yueliang; Li, Edmund T. S.; Wang, Mingfu] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China		Wang, MF (corresponding author), Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China.	mfwang@hku.hk	Wang, Mingfu/AAT-3292-2021; Wang, Mingfu/D-3136-2009	Wang, Mingfu/0000-0003-1469-3963	Hong Kong Research Grants Council (GRF)Hong Kong Research Grants Council [17154816]	The research was supported by the Hong Kong Research Grants Council (GRF Project No.: 17154816).	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J	Liang, C; Feng, P; Ku, B; Dotan, I; Canaani, D; Oh, BH; Jung, JU				Liang, Chengyu; Feng, Pinghui; Ku, Bonsu; Dotan, Iris; Canaani, Dan; Oh, Byung-Ha; Jung, Jae U.			Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG	NATURE CELL BIOLOGY			English	Article							CELL-DEATH; IN-VIVO; INDUCED APOPTOSIS; COLON-CANCER; VIRAL BCL-2; GENE; BECLIN-1; INHIBITION; IDENTIFICATION; MACROAUTOPHAGY	Autophagy, the degradation of cytoplasmic components, is an evolutionarily conserved homeostatic process involved in environmental adaptation, lifespan determination and tumour development. The tumor suppressor Beclin1 is part of the PI( 3) kinase class III ( PI( 3) KC3) lipid-kinase complex that induces autophagy. The autophagic activity of the Beclin1-PI( 3) KC3 complex, however, is suppressed by Bcl-2. Here, we report the identification of a novel coiled-coil UV irradiation resistance-associated gene ( UVRAG) as a positive regulator of the Beclin1-PI( 3) KC3 complex. UVRAG, a tumour suppressor candidate that is monoallelically mutated at high frequency in human colon cancers, associates with the Beclin1-Bcl-2-PI( 3) KC3 multiprotein complex, where UVRAG and Beclin1 interdependently induce autophagy. UVRAG-mediated activation of the Beclin1-PI( 3) KC3 complex promotes autophagy and also suppresses the proliferation and tumorigenicity of human colon cancer cells. These results identify UVRAG as an essential component of the Beclin1-PI( 3) KC3 lipid kinase complex that is an important signalling checkpoint for autophagy and tumour-cell growth.	Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA; Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Div Tumor Virol, Southborough, MA 01772 USA; Pohang Univ Sci & Technol, Ctr Biomol Recognit, Dept Life Sci, Pohang 790784, South Korea; Tel Aviv Univ, Dept Biochem, IL-69978 Tel Aviv, Israel		Jung, JU (corresponding author), Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Dept Microbiol & Mol Genet, 1 Pine Hill Dr, Southborough, MA 01772 USA.	jae_jung@hms.harvard.edu	Oh, Byung-Ha/C-2061-2011	Ku, Bonsu/0000-0003-1784-8975; LIANG, CHENGYU/0000-0001-6082-2143	NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA31363, CA91819, CA82057, CA106156] Funding Source: Medline; NCRR NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [RR00168] Funding Source: Medline; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA082057, R01CA106156, R01CA091819, R01CA031363] Funding Source: NIH RePORTER; NATIONAL CENTER FOR RESEARCH RESOURCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [P51RR000168] Funding Source: NIH RePORTER		Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Arico S, 2001, J BIOL CHEM, V276, P35243, DOI 10.1074/jbc.C100319200; Bekri S, 1997, CYTOGENET CELL GENET, V79, P125, DOI 10.1159/000134699; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; de Lima BD, 2005, J GEN VIROL, V86, P31, DOI 10.1099/vir.0.80480-0; Furuya N, 2005, AUTOPHAGY, V1, P46, DOI 10.4161/auto.1.1.1542; Gangappa S, 2002, J EXP MED, V195, P931, DOI 10.1084/jem.20011825; Goi T, 2003, SURG TODAY, V33, P702, DOI 10.1007/s00595-002-2567-y; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Iida A, 2000, HUM GENET, V106, P277, DOI 10.1007/s004390051038; Ionov Y, 2004, ONCOGENE, V23, P639, DOI 10.1038/sj.onc.1207178; Jia L, 1997, BRIT J HAEMATOL, V98, P673, DOI 10.1046/j.1365-2141.1997.2623081.x; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kihara A, 2001, J CELL BIOL, V152, P519, DOI 10.1083/jcb.152.3.519; Klionsky DJ, 2005, J CELL SCI, V118, P7, DOI 10.1242/jcs.01620; Levine B, 2005, CELL, V120, P159, DOI 10.1016/j.cell.2005.01.005; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Liang XH, 1998, J VIROL, V72, P8586, DOI 10.1128/JVI.72.11.8586-8596.1998; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Loh J, 2005, PLOS PATHOG, V1, P80, DOI 10.1371/journal.ppat.0010010; Lum JJ, 2005, NAT REV MOL CELL BIO, V6, P439, DOI 10.1038/nrm1660; Lum JJ, 2005, CELL, V120, P237, DOI 10.1016/j.cell.2004.11.046; Mills KR, 2004, P NATL ACAD SCI USA, V101, P3438, DOI 10.1073/pnas.0400443101; Mizushima N, 2004, MOL BIOL CELL, V15, P1101, DOI 10.1091/mbc.E03-09-0704; Nobukuni T, 2005, P NATL ACAD SCI USA, V102, P14238, DOI 10.1073/pnas.0506925102; Pattingre S, 2005, CELL, V122, P927, DOI 10.1016/j.cell.2005.07.002; Perelman B, 1997, GENOMICS, V41, P397, DOI 10.1006/geno.1997.4623; Polster BM, 2004, BBA-MOL CELL RES, V1644, P211, DOI 10.1016/j.bbamcr.2003.11.001; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Roy DJ, 2000, ARCH VIROL, V145, P2411, DOI 10.1007/s007050070030; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Suzuki K, 2001, EMBO J, V20, P5971, DOI 10.1093/emboj/20.21.5971; Tanida I, 2004, INT J BIOCHEM CELL B, V36, P2503, DOI 10.1016/j.biocel.2004.05.009; Thorburn J, 2005, MOL BIOL CELL, V16, P1189, DOI 10.1091/mbc.E04-10-0906; Vieira OV, 2001, J CELL BIOL, V155, P19, DOI 10.1083/jcb.200107069; Virgin HW, 1997, J VIROL, V71, P5894, DOI 10.1128/JVI.71.8.5894-5904.1997; Wang GH, 1999, J GEN VIROL, V80, P2737, DOI 10.1099/0022-1317-80-10-2737; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	39	766	811	1	62	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	1465-7392	1476-4679		NAT CELL BIOL	Nat. Cell Biol.	JUL	2006	8	7					688	U94		10.1038/ncb1426			25	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	060YJ	WOS:000238837800011	16799551				2022-04-25	
J	Pellerito, C; Emanuele, S; Ferrante, F; Celesia, A; Giuliano, M; Fiore, T				Pellerito, Claudia; Emanuele, Sonia; Ferrante, Francesco; Celesia, Adriana; Giuliano, Michela; Fiore, Tiziana			Tributyltin(IV) ferulate, a novel synthetic ferulic acid derivative, induces autophagic cell death in colon cancer cells: From chemical synthesis to biochemical effects	JOURNAL OF INORGANIC BIOCHEMISTRY			English	Article						Organotin(IV); Ferulic acid; Colon cancer cytotoxicity; Autophagic cell death; p62; LC3	CORRELATED MOLECULAR CALCULATIONS; SPECTROSCOPIC FT-IR; GAUSSIAN-BASIS SETS; OXIDATIVE STRESS; BIOLOGICAL-ACTIVITY; POTENTIAL APPROACH; C-13 NMR; COMPLEXES; APOPTOSIS; SHIFTS	Ferulic acid (FA) is a natural phenolic phytochemical that has low toxicity and exhibits therapeutic effects against various diseases, behaving as an antioxidant. FA also displays modest antitumor properties that have been reported at relatively high concentrations. With the aim of improving the anti-tumor efficacy of FA, we synthesized the novel compound tributyltin(IV) ferulate (TBT-F). The coordination environment at the tin center was investigated spectroscopically. Following synthesis, chemical characterization and computational analysis, we evaluated TBT-F effects in colon cancer cells. The results showed that TBT-F, at nanomolar range concentrations, was capable of reducing the viability of HCT116, HT-29 and Caco-2 colon cancer cells. On the other hand, FA was completely inefficacious at the same treatment conditions. Cell viability reduction induced by TBT-F was associated with G2/M cell cycle arrest, increase in membrane permeabilization and appearance of typical morphological signs. TBT-F-induced cell death seemed not to involve apoptotic or necroptotic markers whereas autophagic vacuoles appearance and increase in LC3-II and p62 autophagic proteins were observed after treatment with the compound. The autophagy inhibitor bafylomicin A1 markedly prevented the effect of TBT-F on colon cancer cells, thus indicating that autophagy is triggered as a cell death process. Taken together, our results strongly suggest that the novel ferulic derivative TBT-F is a promising therapeutic agent for colon cancer since it is capable of triggering autophagic (type-II) cell death that may be important in case of resistance to classic apoptosis.	[Pellerito, Claudia; Ferrante, Francesco; Fiore, Tiziana] Univ Palermo, Dipartimento Fis & Chim Emilio Segre DiFC, Viale Sci,Ed 17, I-90128 Palermo, Italy; [Pellerito, Claudia; Fiore, Tiziana] CIRCMSB, Via Celso Ulpiani 27, I-70125 Bari, Italy; [Emanuele, Sonia; Celesia, Adriana] Univ Palermo, Dipartimento Biomed Neurosci & Diagnost Avanzata, Via Vespro 129, I-90127 Palermo, Italy; [Giuliano, Michela] Univ Palermo, Dipartimento Sci & Tecnol Biol Chim & Farmaceut S, Via Vespro 129, I-90127 Palermo, Italy		Fiore, T (corresponding author), Dipartimento Fis & Chim, Viale Sci,Ed 17, I-90128 Palermo, Italy.	tiziana.fiore@unipa.it			Universita degli Studi di Palermo, Italy [FFR_D08_FIORE]; PON R&C, Infrastrutture e del PO FESR, Regione Sicilia-Misura 4.1.2.A [PONa3_00273]	The AA gratefully acknowledges the financial support of the Universita degli Studi di Palermo, Italy (FFR_D08_FIORE). NMR and ESI-MS experimental data were provided by ATeN Center -Advanced Technologies Network Center -(Universita degli Studi di Palermo, Italy) funded by PON R&C, Infrastrutture (Progetto PONa3_00273) e del PO FESR, Regione Sicilia-Misura 4.1.2.A.	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Inorg. Biochem.	APR	2020	205								110999	10.1016/j.jinorgbio.2020.110999			14	Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	KX8IT	WOS:000522119300017	31986423				2022-04-25	
J	Yu, NH; Zhu, H; Yang, Y; Tao, YM; Tan, FB; Pei, Q; Zhou, Y; Song, XP; Tan, QR; Pei, HP				Yu, Nanhui; Zhu, Hong; Yang, Yuan; Tao, Yiming; Tan, Fengbo; Pei, Qian; Zhou, Yuan; Song, Xiangping; Tan, Qiurong; Pei, Haiping			Combination of Fe/Cu -chelators and docosahexaenoic acid: an exploration for the treatment of colorectal cancer	ONCOTARGET			English	Article						combination of Fe/Cu -chelators and docosahexaenoic acid; myeloid cell leukemia-1 (Mcl-1); apoptosis; ubiquitination; colorectal cancer	IRON CHELATORS; ANTITUMOR-ACTIVITY; SURVIVORSHIP STATISTICS; OXIDATIVE STRESS; COPPER COMPLEX; CELLS; AUTOPHAGY; TARGET; COLON; 5-FLUOROURACIL	Colorectal cancer (CRC) is one of the major causes of cancer deaths in the world. 5-fluorouracil (5-FU) -based chemotherapy is a common choice for patients with CRC; unfortunately, the benefit is rather limited due to the acquisition of drug resistance. Therefore, the alternative therapeutic strategies are required. The activation of autophagic mechanism was considered as the main cause of the acquisition of drug resistance in 5-FU treatment. Docosahexaenoic acid (DHA), a fatty acid, has been regarded as an efficient anticancer agent and can improve the drug resistance in conventional cancer therapy by a low basal level of autophagy in colon cancer cells. Moreover, removal of iron or copper by metal chelators could cause ROS levels increase and mediate cancer cell cytotoxicity led by autophagy. In the present study, we constructed a combination of 5-FU, 1:1 mixture of metal chelators di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride (DpC) and N, N, N', N'-tetrakis-[2-pyridylmethyl]-ethylenediamine (TPEN) named DTN, and DHA to evaluate the anticancer effect of this combination, compared to the traditional 5-FU-based chemotherapy; further we investigated the underlying mechanism. Through inducing ROS-mediated degradation of Mcl-1 ubiquitination, the triple combination of 5-FU, DTN and DHA resulted in the elevated apoptosis in CRC cells, thus to reduce the tumor size and weight. Taken together, this study suggests the triple combination of 5-FU+DTN+DHA exhibits an effective anticancer activity of overcoming drug resistance in colorectal cancer, mechanism as the elevated apoptosis mediated by an increase of ROS and Mcl-1 ubiquitination, may be a novel strategy for clinical colon cancer treatment.	[Yu, Nanhui; Zhu, Hong; Tao, Yiming; Tan, Fengbo; Pei, Qian; Zhou, Yuan; Song, Xiangping; Pei, Haiping] Cent S Univ, Xiangya Hosp, Dept Gastrointestinal Surg, Changsha 410008, Hunan, Peoples R China; [Yu, Nanhui; Tan, Qiurong] Changsha Hosp Maternal & Child Hlth Care, Dept Pharm, Changsha 410007, Hunan, Peoples R China; [Yang, Yuan] Hunan Univ Med, Dept Lab Med, Dong Med Key Lab Hunan Prov, Changsha 418000, Hunan, Peoples R China		Pei, HP (corresponding author), Cent S Univ, Xiangya Hosp, Dept Gastrointestinal Surg, Changsha 410008, Hunan, Peoples R China.	haiping1977pei@163.com	SONG, XIANGPING/AAH-7273-2019	Yu, Nanhui/0000-0001-5474-2198	Key research and development plan and technical innovation guidance project of Hunan Province [2016WK2034]; Natural Science Foundation of Hunan ProvinceNatural Science Foundation of Hunan Province [2016JJ6106]; Scientific Research Project of Hunan province education department [14C0911]; Youth science and Technology Talents of Hunan University of Medicine (China) [[2013] 49-1]; Science and Technology Plan Fund in Hunan Province, People's Republic of China [2015SK2020, 2015WK3011]; CSCO Clinic Tumor Research Foundation [Y-MX2014-002]	This study was sponsored by the Key research and development plan and technical innovation guidance project of Hunan Province (2016WK2034), Natural Science Foundation of Hunan Province (2016JJ6106), Scientific Research Project of Hunan province education department (14C0911), Youth science and Technology Talents of Hunan University of Medicine (No.[2013] 49-1) China), the Science and Technology Plan Fund in Hunan Province, People's Republic of China (2015SK2020 and 2015WK3011) and CSCO Clinic Tumor Research Foundation (Y-MX2014-002).	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J	Osorio-Vega, H; Finol, HJ; Roschman-Gonzalez, A; Sardina, C				Osorio-Vega, H.; Finol, H. J.; Roschman-Gonzalez, A.; Sardina, C.			COLON ADENOCARCINOMA AND CELL DEATH TYPES: AN ULTRASTRUCTURAL STUDY	ACTA MICROSCOPICA			English	Article						Human colon adenocarcinoma; ultrastructure; apoptosis; autophagy; necrosis	APOPTOSIS; AUTOPHAGY; CANCER; NECROSIS	Three forms of cell death were found in human colon adenocarcinoma (HCAC), apoptosis, autophagy, and necrosis, by transmission electron microscopy. Apoptosis was characterized by chromatin hypercondensation and formation of apoptotic bodies, which were covered by plasma membrane. In autophagic cell death, autophagosomes of different complexities were observed along the process of cell degeneration which preceded nuclear collapse. In necrosis, cytoplasmic organelles, most notably mitochondria, were swollen, and plasma membrane was broken down causing the release of the cellular content into the extracellular space.	[Osorio-Vega, H.; Finol, H. J.; Roschman-Gonzalez, A.] Cent Univ Venezuela, Fac Sci, Ctr Electron Microscopy, Caracas, Venezuela; [Sardina, C.] Caracas Univ Hosp, Coloproctol Unit, Caracas, Venezuela		Finol, HJ (corresponding author), Cent Univ Venezuela, Fac Sci, Ctr Electron Microscopy, Caracas, Venezuela.	hector.finol@gmail.com					ANILKUMAR TV, 1992, BRIT J CANCER, V65, P552, DOI 10.1038/bjc.1992.113; Bursch W, 2001, CELL DEATH DIFFER, V8, P569, DOI 10.1038/sj.cdd.4400852; de Bruin EC, 2008, CANCER TREAT REV, V34, P737, DOI 10.1016/j.ctrv.2008.07.001; Edinger AL, 2004, CURR OPIN CELL BIOL, V16, P663, DOI 10.1016/j.ceb.2004.09.011; Eisenberg-Lerner A, 2009, CELL DEATH DIFFER, V16, P966, DOI 10.1038/cdd.2009.33; Fulda S, 2013, CANCER BIOL THER, V14, P999, DOI 10.4161/cbt.26428; GRASLKRAUPP B, 1995, HEPATOLOGY, V21, P1465, DOI 10.1016/0270-9139(95)90071-3; GUNDERSON LL, 1974, CANCER-AM CANCER SOC, V34, P1278, DOI 10.1002/1097-0142(197410)34:4<1278::AID-CNCR2820340440>3.0.CO;2-F; Koehler BC, 2014, WORLD J GASTROENTERO, V20, P1923, DOI 10.3748/wjg.v20.i8.1923; Kroemer G, 2009, CELL DEATH DIFFER, V16, P3, DOI 10.1038/cdd.2008.150; Kubisch J, 2013, SEMIN CANCER BIOL, V23, P252, DOI 10.1016/j.semcancer.2013.06.009; Nunes T, 2014, BIOMED RES INT, V2014, DOI 10.1155/2014/218493; Partik G, 1998, VIRCHOWS ARCH, V432, P415, DOI 10.1007/s004280050185; Schaper J, 1999, CIRC RES, V85, P867, DOI 10.1161/01.RES.85.9.867; Tatebe S, 1996, INT J CANCER, V65, P173, DOI 10.1002/(SICI)1097-0215(19960117)65:2<173::AID-IJC8>3.0.CO;2-W; Todde V, 2009, BBA-MOL BASIS DIS, V1792, P3, DOI 10.1016/j.bbadis.2008.10.016; Vandenabeele P, 2010, NAT REV MOL CELL BIO, V11, P700, DOI 10.1038/nrm2970; Watanabe M, 2002, MICROSC MICROANAL, V8, P375, DOI 10.1017/S1431927602010346; ZAKERI Z, 1995, CELL DEATH DIFFER, V2, P87	19	2	3	0	0	COMITE INTERAMERICANO SOC MICROSCOPIA ELECTRONICA-CIASEM	CARACAS	CARRETERA PANAMERICANA KM 11, APARTADO POSTAL 20632, CARACAS, 1020-A, VENEZUELA	0798-4545	2224-8927		ACTA MICROSC	Acta Microsc.		2016	25	2					65	70					6	Microscopy	Science Citation Index Expanded (SCI-EXPANDED)	Microscopy	DQ0RV	WOS:000378908500003					2022-04-25	
J	Athamneh, K; El Hasasna, H; Al Samri, H; Attoub, S; Arafat, K; Benhalilou, N; Al Rashedi, A; Al Dhaheri, Y; AbuQamar, S; Eid, A; Iratni, R				Athamneh, Khawlah; El Hasasna, Hussain; Al Samri, Halima; Attoub, Samir; Arafat, Kholoud; Benhalilou, Nehla; Al Rashedi, Asma; Al Dhaheri, Yusra; AbuQamar, Synan; Eid, Ali; Iratni, Rabah			Rhus coriaria increases protein ubiquitination, proteasomal degradation and triggers non-canonical Beclin-1-independent autophagy and apoptotic cell death in colon cancer cells	SCIENTIFIC REPORTS			English	Article							MUTANT P53; BREAST-CANCER; MAMMALIAN TARGET; GROWTH; INHIBITION; SYSTEM; L.; MITOCHONDRIA; RESVERATROL; ANTIOXIDANT	Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide. Here, we investigated the anticancer effect of Rhus coriaria extract (RCE) on HT-29 and Caco-2 human colorectal cancer cells. We found that RCE significantly inhibited the viability and colony growth of colon cancer cells. Moreover, RCE induced Beclin-1-independent autophagy and subsequent caspase-7-dependent apoptosis. Blocking of autophagy by chloroquine significantly reduced RCE-induced cell death, while blocking of apoptosis had no effect on RCE-induced cell death. Mechanistically, RCE inactivated the AKT/mTOR pathway by promoting the proteasome-dependent degradation of both proteins. Strikingly, we also found that RCE targeted Beclin-1, p53 and procaspase-3 to degradation. Proteasome inhibition by MG-132 not only restored these proteins to level comparable to control cells, but also reduced RCE-induced cell death and blocked the activation of autophagy and apoptosis. The proteasomal degradation of mTOR, which occurred only 3 hours post-RCE treatment was concomitant with an overall increase in the level of ubiquitinated proteins and translated stimulation of proteolysis by the proteasome. Our findings demonstrate that Rhus coriaria possesses strong anti-colon cancer activity through stimulation of proteolysis as well as induction of autophagic and apoptotic cell death, making it a potential and valuable source of novel therapeutic cancer drug.	[Athamneh, Khawlah; El Hasasna, Hussain; Al Samri, Halima; Benhalilou, Nehla; Al Rashedi, Asma; Al Dhaheri, Yusra; AbuQamar, Synan; Iratni, Rabah] United Arab Emirates Univ, Coll Sci, Dept Biol, POB 15551, Al Ain, U Arab Emirates; [Attoub, Samir; Arafat, Kholoud] United Arab Emirates Univ, Coll Med & Hlth Sci, Dept Pharmacol & Therapeut, POB 17666, Al Ain, U Arab Emirates; [Eid, Ali] Amer Univ Beirut, Fac Med, Dept Pharmacol & Toxicol, POB 11-0236, Beirut, Lebanon		Iratni, R (corresponding author), United Arab Emirates Univ, Coll Sci, Dept Biol, POB 15551, Al Ain, U Arab Emirates.	R_iratni@uaeu.ac.ae	AbuQamar, Synan/AAV-1229-2021; Attoub, Samir/N-6852-2018; Eid, Ali Hussein/ABD-6291-2021	AbuQamar, Synan/0000-0002-2129-7689; Eid, Ali Hussein/0000-0003-3004-5675	UAEU Program for Advanced Research [31S111-UPAR]; Zayed Center for Health Sciences (ZCHS) research grant [31R086]	This work was supported by UAEU Program for Advanced Research (Grant 31S111-UPAR) and by the Zayed Center for Health Sciences (ZCHS) research grant (grant 31R086) to Rabah Iratni.	Abu-Reidah IM, 2015, FOOD CHEM, V166, P179, DOI 10.1016/j.foodchem.2014.06.011; Al Dhaheri Y, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0109630; AlQurashi N, 2013, HUM PATHOL, V44, P2089, DOI 10.1016/j.humpath.2013.03.014; Benbrook D. 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J	Pan, Z; Xie, YP; Bai, J; Lin, QY; Cui, XN; Zhang, NN				Pan, Zhe; Xie, Yunpeng; Bai, Jie; Lin, Qiuyue; Cui, Xiaonan; Zhang, Ningning			Bufalin suppresses colorectal cancer cell growth through promoting autophagy in vivo and in vitro	RSC ADVANCES			English	Article							HUMAN HEPATOCELLULAR-CARCINOMA; INDUCED APOPTOSIS; ARSENIC TRIOXIDE; COLON-CANCER; DEATH; MECHANISMS; PI3K/AKT; ARREST	Specific groups in Asia, including the Chinese, are more susceptible to colorectal cancer (CRC). The best strategy for anticancer drug action is to induce cancer cell apoptosis and autophagy. Bufalin is a potent inducer of apoptosis in some human cancer cell lines, but bufalin has barely been evaluated in colorectal cancer cells as a potent autophagy inducing agent. The aim of this study was to investigate the roles and interactions of bufalin in autophagy and the effects of the drug on human colorectal cancer. We applied bufalin and autophagy inhibitors (CQ and 3-MA) in LoVo cells to investigate their potential anticancer bioactivity under certain concentrations of bufalin to monitor autophagy and cell proliferation in vivo and in vitro. Bufalin induced autophagy of LoVo and inhibited proliferation of LoVo cells. Bufalin inhibited the expression of autophagy-related (ATG) proteins and tumor growth in vivo. Our studies identified that bufalin could potentially be a small molecule inhibitor for cancer therapy.	[Pan, Zhe; Xie, Yunpeng; Lin, Qiuyue; Cui, Xiaonan; Zhang, Ningning] Dalian Med Univ, Affiliated Hosp 1, Dalian 116021, Liaoning, Peoples R China; [Bai, Jie] Dalian Med Univ, Sch Publ Hlth, Dalian 116044, Liaoning, Peoples R China		Cui, XN; Zhang, NN (corresponding author), Dalian Med Univ, Affiliated Hosp 1, Dalian 116021, Liaoning, Peoples R China.	Xiaonan_cui@163.com; zhangningning@dmu.edu.cn	Xie, Yunpeng/AAD-5158-2019		National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81800142, 81600197]; Basic Scientific Research Projects of Colleges and Universities in Liaoning Province [LQ2017021]	This study was supported by the National Natural Science Foundation of China (81800142, 81600197); the funds from Basic Scientific Research Projects of Colleges and Universities in Liaoning Province (LQ2017021).	Andre T, 2009, J CLIN ONCOL, V27, P3109, DOI 10.1200/JCO.2008.20.6771; Bellodi C, 2009, J CLIN INVEST, V119, P1109, DOI 10.1172/JCI35660; Cao BY, 2014, SCI REP-UK, V4, DOI 10.1038/srep05749; Chiu HW, 2009, AUTOPHAGY, V5, P472, DOI 10.4161/auto.5.4.7759; Han KQ, 2007, WORLD J GASTROENTERO, V13, P3374, DOI 10.3748/wjg.v13.i24.3374; He CC, 2009, ANNU REV GENET, V43, P67, DOI 10.1146/annurev-genet-102808-114910; Hu FL, 2014, APOPTOSIS, V19, P210, DOI 10.1007/s10495-013-0914-7; Huang Q, 2016, APOPTOSIS, V21, P749, DOI 10.1007/s10495-016-1243-4; Kang XH, 2013, EVID-BASED COMPL ALT, V2013, DOI 10.1155/2013/243859; Kim DK, 2009, CANCER RES, V69, P923, DOI 10.1158/0008-5472.CAN-08-2115; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Li D, 2009, ANTI-CANCER DRUG, V20, P59, DOI 10.1097/CAD.0b013e3283160fd6; Liu DL, 2011, MED ONCOL, V28, P105, DOI 10.1007/s12032-009-9397-3; Liu YL, 2010, AUTOPHAGY, V6, P1057, DOI 10.4161/auto.6.8.13365; Marchetti S, 2007, BRIT J CANCER, V97, P577, DOI 10.1038/sj.bjc.6603925; Marin JJG, 2012, DRUG METAB REV, V44, P148, DOI 10.3109/03602532.2011.638303; Meng ZQ, 2009, CANCER-AM CANCER SOC, V115, P5309, DOI 10.1002/cncr.24602; Ng SC, 2013, BRIT MED BULL, V105, P29, DOI 10.1093/bmb/lds040; Pattingre S, 2009, J BIOL CHEM, V284, P2719, DOI 10.1074/jbc.M805920200; Qian WB, 2007, LEUKEMIA RES, V31, P329, DOI 10.1016/j.leukres.2006.06.021; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Shintani T, 2004, SCIENCE, V306, P990, DOI 10.1126/science.1099993; Sun L., 2011, J EVIDENCE BASED COM, V2011; Takai N, 2008, INT J MOL MED, V21, P637; Takai N, 2012, ASIAN PAC J CANCER P, V13, P399, DOI 10.7314/APJCP.2012.13.1.399; Watabe M, 1998, ONCOGENE, V16, P779, DOI 10.1038/sj.onc.1201592; Xie CM, 2011, FREE RADICAL BIO MED, V51, P1365, DOI 10.1016/j.freeradbiomed.2011.06.016; Yeh JY, 2003, PROSTATE, V54, P112, DOI 10.1002/pros.10172; Yu L, 2004, SCIENCE, V304, P1500, DOI 10.1126/science.1096645; Zhang NN, 2016, CELL PHYSIOL BIOCHEM, V40, P1559, DOI 10.1159/000453206	31	4	5	5	13	ROYAL SOC CHEMISTRY	CAMBRIDGE	THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND	2046-2069			RSC ADV	RSC Adv.		2018	8	68					38910	38918		10.1039/c8ra06566g			9	Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry	HB5HQ	WOS:000451090800025		gold			2022-04-25	
J	Kim, SW; Lee, JH; Moon, JH; Nazim, UMD; Lee, YJ; Seol, JW; Hur, J; Eo, SK; Lee, JH; Park, SY				Kim, Sung-Wook; Lee, Ju-Hee; Moon, Ji-Hong; Nazim, Uddin M. D.; Lee, You-Jin; Seol, Jae-Won; Hur, Jin; Eo, Seong-Kug; Lee, John-Hwa; Park, Sang-Youel			Niacin alleviates TRAIL-mediated colon cancer cell death via autophagy flux activation	ONCOTARGET			English	Article						niacin; autophagy; TRAIL; death receptor; mitochondrial membrane potential	APOPTOSIS-INDUCING LIGAND; DEFECTIVE APOPTOSIS; PROSTATE-CANCER; NEURONAL CELLS; SURVIVAL; RECEPTORS; PROTEIN; NECROSIS; MITOCHONDRIA; APO2L/TRAIL	Niacin, also known as vitamin B3 or nicotinamide is a water-soluble vitamin that is present in black beans and rice among other foods. Niacin is well known as an inhibitor of metastasis in human breast carcinoma cells but the effect of niacin treatment on TRAIL-mediated apoptosis is unknown. Here, we show that niacin plays an important role in the regulation of autophagic flux and protects tumor cells against TRAIL-mediated apoptosis. Our results indicated that niacin activated autophagic flux in human colon cancer cells and the autophagic flux activation protected tumor cells from TRAIL-induced dysfunction of mitochondrial membrane potential and tumor cell death. We also demonstrated that ATG5 siRNA and autophagy inhibitor blocked the niacin-mediated inhibition of TRAIL-induced apoptosis. Taken together, our study is the first report demonstrating that niacin inhibits TRAIL-induced apoptosis through activation of autophagic flux in human colon cancer cells. And our results also suggest that autophagy inhibitors including genetic and pharmacological tools may be a successful therapeutics during anticancer therapy using TRAIL.	[Kim, Sung-Wook; Lee, Ju-Hee; Moon, Ji-Hong; Nazim, Uddin M. D.; Lee, You-Jin; Seol, Jae-Won; Hur, Jin; Eo, Seong-Kug; Lee, John-Hwa; Park, Sang-Youel] Chonbuk Natl Univ, Biosafety Res Inst, Dept Biochem, Coll Vet Med, Jeonju 561756, Jeonbuk, South Korea		Park, SY (corresponding author), Chonbuk Natl Univ, Biosafety Res Inst, Dept Biochem, Coll Vet Med, Jeonju 561756, Jeonbuk, South Korea.	sypark@chonbuk.ac.kr	Park, Sang-Youel/D-5966-2012	Park, Sang-Youel/0000-0003-0575-6045	National Research Foundation of Korea (NRF) - Korean government (MISP) [2013R1A4A1069486]	This study was supported by a grant from the National Research Foundation of Korea (NRF), funded by the Korean government (MISP) (2013R1A4A1069486).	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J	Greene, LM; Nolan, DP; Regan-Komito, D; Campiani, G; Williams, DC; Zisterer, DM				Greene, Lisa M.; Nolan, Derek P.; Regan-Komito, Daniel; Campiani, Giuseppe; Williams, D. Clive; Zisterer, Daniela M.			Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						pyrrolo-1,5-benzoxazepines autophagy apoptosis	MYELOID-LEUKEMIA CELLS; IN-VITRO; BREAST-CANCER; IMATINIB MESYLATE; TARGETING AGENT; BAFILOMYCIN; LYSOSOMES; FUSION; VIVO; MACROAUTOPHAGY	The pyrrolo-1,5-benzoxazepines (PBOXs) are a novel group of selective apoptotic agents displaying promising therapeutic potential in both ex vivo chemotherapy-refractory patient samples and in vivo murine carcinoma models. In this report, we present novel data concerning the induction of autophagy by the PBOXs in adenocarcinoma-derived colon cancer cells. Autophagy is a lysosome-dependent degradative pathway recently associated with chemotherapy. However, whether autophagy facilitates cell survival in response to chemotherapy or contributes to chemotherapy-induced cell death is highly controversial. Autophagy was identified by enhanced expression of LC3B-II, an autophagosome marker, an increase in the formation of acridine orange-stained cells, indicative of increased vesicle formation and electron microscopic confirmation of autophagic structures. The vacuolar H+ ATPase inhibitor bafilomycin-A1 (BAF-A1) inhibited vesicle formation and enhanced the apoptotic potential of PBOX-6. These findings suggest a cytoprotective role of autophagy in these cells following prolonged exposure to PBOX-6. Furthermore, BAF-A1 and PBOX-6 interactions were determined to be synergistic and caspase-dependent. Potentiation of PBOX-6-induced apoptosis by BAF-A1 was associated with a decrease in the levels of the anti-apoptotic protein, Mcl-1. The data provide evidence that autophagy functions as a survival mechanism in colon cancer cells to PBOX-6-induced apoptosis and a rationale for the use of autophagy inhibitors to further enhance PBOX-6-induced apoptosis in colon cancer.	[Greene, Lisa M.; Nolan, Derek P.; Regan-Komito, Daniel; Williams, D. Clive; Zisterer, Daniela M.] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin 2, Ireland; [Campiani, Giuseppe] European Res Ctr Drug Discovery & Dev, I-53100 Siena, Italy		Zisterer, DM (corresponding author), Univ Dublin Trinity Coll, Sch Biochem & Immunol, 152-160 Pearse St, Dublin 2, Ireland.	dzistrer@tcd.ie		Zisterer, Daniela/0000-0001-5005-1023; Nolan, Derek/0000-0002-3742-4304	Health Research Board Ireland	We would like to thank the Health Research Board Ireland for funding the project.	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J. Oncol.	SEP	2013	43	3					927	935		10.3892/ijo.2013.1989			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	190XD	WOS:000322375900028	23799546	Bronze			2022-04-25	
J	Therachiyil, L; Haroon, J; Sahir, F; Siveen, KS; Uddin, S; Kulinski, M; Buddenkotte, J; Steinhoff, M; Krishnankutty, R				Therachiyil, Lubna; Haroon, Javeria; Sahir, Fairooz; Siveen, Kodappully S.; Uddin, Shahab; Kulinski, Michal; Buddenkotte, Joerg; Steinhoff, Martin; Krishnankutty, Roopesh			Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin	FRONTIERS IN ONCOLOGY			English	Article						colon cancer; HCT 116; HT 29; p53; oxaliplatin; autophagy; therapy; drug resistance	TUMOR-SUPPRESSOR; SER46 PHOSPHORYLATION; COLORECTAL-CANCER; DRUG-RESISTANCE; BAX/BCL-2 RATIO; APOPTOSIS; PROTEIN; ACTIVATION; CHEMOSENSITIVITY; CHEMORESISTANCE	Colorectal cancer (CRC) forms one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancement in cancer therapeutics. About 50% of human CRCs are reported to have defective p53 expression resultant ofTP53gene mutation often contributing to drug resistance. The current study was aimed to investigate the response of wild-typeTP53harboring HCT 116 and mutantTP53harboring HT 29 colon cancer cells to chemotherapeutic drug oxaliplatin (OX) and to elucidate the underlying molecular mechanisms of sensitivity/resistance in correlation to their p53 status. OX inhibited growth of wild-type p53-harboring colon cancer cells via p53/p21-Bax mediated apoptosis. Our study revealed that dysregulated phosphorylation of p53, autophagy as well as cancer stemness attributes the mutant p53-harboring colon cancer cells impaired sensitivity to OX.	[Therachiyil, Lubna; Haroon, Javeria; Sahir, Fairooz; Siveen, Kodappully S.; Uddin, Shahab; Kulinski, Michal; Buddenkotte, Joerg; Steinhoff, Martin; Krishnankutty, Roopesh] Hamad Med Corp, Acad Hlth Syst, Translat Res Inst, Doha, Qatar; [Therachiyil, Lubna] Qatar Univ, Coll Pharm, Dept Pharmaceut Sci, Doha, Qatar; [Uddin, Shahab; Buddenkotte, Joerg; Steinhoff, Martin] Hamad Med Corp, Dept Dermatol & Venereol, Doha, Qatar; [Steinhoff, Martin] Qatar Fdn Educ, Weill Cornell Med Qatar, Dept Med, Doha, Qatar; [Steinhoff, Martin] Weill Cornell Med, Dept Med, New York, NY USA; [Steinhoff, Martin] Qatar Univ, Coll Med, Doha, Qatar		Krishnankutty, R (corresponding author), Hamad Med Corp, Acad Hlth Syst, Translat Res Inst, Doha, Qatar.	rkrishnankutty@hamad.qa	Krishnankutty, Roopesh/M-5836-2015	Krishnankutty, Roopesh/0000-0002-1496-6135; Uddin, Shahab/0000-0003-1886-6710	Medical Research Center at Hamad Medical Corporation [15264/15]	The study was supported by the Medical Research Center at Hamad Medical Corporation (grant: MRC#15264/15).	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J	Sun, GC; Zheng, ZP; Lee, MH; Xu, YJ; Kang, S; Dong, ZG; Wang, MF; Gu, ZN; Li, HT; Chen, W				Sun, Guochuan; Zheng, Zongping; Lee, Mee-Hyun; Xu, Yijuan; Kang, Soouk; Dong, Zigang; Wang, Mingfu; Gu, Zhennan; Li, Haitao; Chen, Wei			Chemoprevention of Colorectal Cancer by Artocarpin, a Dietary Phytochemical from Artocarpus heterophyllus	JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY			English	Article						Artocarpus heterophyllus; artocarpin; colorectal cancer; Akt	MOLECULAR TARGETS; CELLS; MUTATIONS	Artocarpus heterophyllus is an evergreen tree distributed in tropical regions, and its fruit (jackfruit) is well-known as the world's largest tree-borne fruit. Although A. heterophyllus has been widely used in folk medicines against inflammation, its potential in cancer chemoprevention remains unclear. Herein we identified artocarpin from A. heterophyllus as a promising colorectal cancer chemopreventive agent by targeting Akt kinase. Phenotypically, artocarpin exhibited selective cytotoxicity against human colon cancer cells. Artocarpin impaired the anchorage-independent growth capability, suppressed colon cancer cell growth, and induced a G1 phase cell cycle arrest which was followed by apoptotic as well as autophagic cell death. Mechanistic studies revealed that artocarpin directly targeted Akt 1 and 2 kinase activity evidenced by in vitro kinase assay, ex vivo binding assay as well as Akt downstream cellular signal transduction. Importantly, oral administration of artocarpin attenuated colitis-associated colorectal tumorigenesis in mice. Taken together, artocarpin, a bioactive component of A. heterophyllus, might merit investigation as a potential colorectal cancer chemopreventive agent.	[Sun, Guochuan; Zheng, Zongping; Xu, Yijuan; Gu, Zhennan; Li, Haitao; Chen, Wei] Jiangnan Univ, Sch Food Sci & Technol, Wuxi 214122, Peoples R China; [Lee, Mee-Hyun; Kang, Soouk; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA; [Wang, Mingfu] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China; [Chen, Wei] Beijing Technol & Business Univ, Beijing Innovat Ctr Food Nutr & Human Hlth, Beijing 100048, Peoples R China		Li, HT; Chen, W (corresponding author), Jiangnan Univ, Sch Food Sci & Technol, Wuxi 214122, Peoples R China.; Chen, W (corresponding author), Beijing Technol & Business Univ, Beijing Innovat Ctr Food Nutr & Human Hlth, Beijing 100048, Peoples R China.	liht@jiangnan.edu.cn; weichen@jiangnan.edu.cn	Zheng, Zong-Ping/A-7400-2011; Wang, Mingfu/AAT-3292-2021; Wang, Mingfu/D-3136-2009	Zheng, Zong-Ping/0000-0002-0261-3711; Wang, Mingfu/0000-0003-1469-3963	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81402366, 31530056]; Jiangsu Specially Appointed Professor; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [JUSRP11549, JUSRP51501]	This work was supported by the National Natural Science Foundation of China (81402366, 31530056, National Youth 1000 Talents Plan), Jiangsu Specially Appointed Professor, and the Fundamental Research Funds for the Central Universities (JUSRP11549 and JUSRP51501).	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J	Haruki, K; Kosumi, K; Hamada, T; Twombly, TS; Vayrynen, JP; Kim, SA; Masugi, Y; Qian, ZR; Mima, K; Baba, Y; da Silva, A; Borowsky, J; Arima, K; Fujiyoshi, K; Lau, MC; Li, PL; Guo, CG; Chen, Y; Song, MY; Nowak, JA; Nishihara, R; Yanaga, K; Zhang, XH; Wu, KN; Bullman, S; Garrett, WS; Huttenhower, C; Meyerhardt, JA; Giannakis, M; Chan, AT; Fuchs, CS; Ogino, S				Haruki, Koichiro; Kosumi, Keisuke; Hamada, Tsuyoshi; Twombly, Tyler S.; Vayrynen, Juha P.; Kim, Sun A.; Masugi, Yohei; Qian, Zhi Rong; Mima, Kosuke; Baba, Yoshifumi; da Silva, Annacarolina; Borowsky, Jennifer; Arima, Kota; Fujiyoshi, Kenji; Lau, Mai Chan; Li, Peilong; Guo, Chunguang; Chen, Yang; Song, Mingyang; Nowak, Jonathan A.; Nishihara, Reiko; Yanaga, Katsuhiko; Zhang, Xuehong; Wu, Kana; Bullman, Susan; Garrett, Wendy S.; Huttenhower, Curtis; Meyerhardt, Jeffrey A.; Giannakis, Marios; Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji			Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer	JOURNAL OF PATHOLOGY			English	Article						Colorectal neoplasms; Immunology; Microbiology; Microbiome; Molecular pathological epidemiology; Tumour microenvironment	GUT MICROBIOTA; BECLIN 1; EXPRESSION; PROGNOSIS; SURVIVAL; INFECTION; PROTEINS; PATTERNS; ASPIRIN; BINDING	Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow-up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long-interspersed nucleotide element-1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1-low cases, BECN1-intermediate and BECN1-high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29-0.99) and 0.31 (95% confidence interval, 0.16-0.60), respectively (P-trend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (P-trend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (P-trend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.	[Haruki, Koichiro; Kosumi, Keisuke; Hamada, Tsuyoshi; Twombly, Tyler S.; Vayrynen, Juha P.; Kim, Sun A.; Masugi, Yohei; Qian, Zhi Rong; Mima, Kosuke; Baba, Yoshifumi; da Silva, Annacarolina; Borowsky, Jennifer; Arima, Kota; Fujiyoshi, Kenji; Lau, Mai Chan; Li, Peilong; Guo, Chunguang; Chen, Yang; Nowak, Jonathan A.; Nishihara, Reiko; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Program MPE Mol Pathol Epidemiol, 221 Longwood Ave,EBRC Room 404A, Boston, MA 02115 USA; [Haruki, Koichiro; Kosumi, Keisuke; Hamada, Tsuyoshi; Twombly, Tyler S.; Vayrynen, Juha P.; Kim, Sun A.; Masugi, Yohei; Qian, Zhi Rong; Mima, Kosuke; Baba, Yoshifumi; da Silva, Annacarolina; Borowsky, Jennifer; Arima, Kota; Fujiyoshi, Kenji; Lau, Mai Chan; Li, Peilong; Guo, Chunguang; Chen, Yang; Song, Mingyang; Nowak, Jonathan A.; Nishihara, Reiko; Zhang, Xuehong; Wu, Kana; Bullman, Susan; Garrett, Wendy S.; Meyerhardt, Jeffrey A.; Giannakis, Marios; Chan, Andrew T.; Ogino, Shuji] Harvard Med Sch, Boston, MA 02115 USA; [Haruki, Koichiro; Yanaga, Katsuhiko] Jikei Univ, Sch Med, Dept Surg, Tokyo, Japan; [Vayrynen, Juha P.; Bullman, Susan; Garrett, Wendy S.; Meyerhardt, Jeffrey A.; Giannakis, Marios] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA; [Vayrynen, Juha P.] Univ Oulu, Oulu Univ Hosp, Med Res Ctr Oulu, Canc & Translat Med Res Unit, Oulu, Finland; [Qian, Zhi Rong] Sun Yat Sen Univ, Affiliated Hosp 7, Sci Res Ctr, Shenzhen, Peoples R China; [Qian, Zhi Rong] Sun Yat Sen Univ, Affiliated Hosp 7, Digest Dis Ctr, Shenzhen, Peoples R China; [Borowsky, Jennifer] Massachusetts Gen Hosp, Dept Pathol, Ctr Integrated Diagnost, Boston, MA 02114 USA; [Song, Mingyang; Nishihara, Reiko; Wu, Kana] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA; [Song, Mingyang; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA; [Song, Mingyang; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA; [Nishihara, Reiko; Wu, Kana; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA; [Nishihara, Reiko; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA; [Zhang, Xuehong; Wu, Kana; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA; [Bullman, Susan; Garrett, Wendy S.; Huttenhower, Curtis; Giannakis, Marios; Ogino, Shuji] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA; [Garrett, Wendy S.; Chan, Andrew T.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA; [Giannakis, Marios] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA; [Fuchs, Charles S.] Yale Canc Ctr, New Haven, CT USA; [Fuchs, Charles S.] Yale Sch Med, Dept Med, New Haven, CT USA; [Fuchs, Charles S.] Smilow Canc Hosp, New Haven, CT USA; [Ogino, Shuji] Dana Farber Harvard Canc Ctr, Canc Immunol Program, Boston, MA USA; [Ogino, Shuji] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA USA		Ogino, S (corresponding author), Brigham & Womens Hosp, Dept Pathol, Program MPE Mol Pathol Epidemiol, 221 Longwood Ave,EBRC Room 404A, Boston, MA 02115 USA.	sogino@bwh.harvard.edu	Masugi, Yohei/E-6980-2014; Väyrynen, Juha P/B-5023-2018; Lau, Mai Chan/L-5186-2019	Masugi, Yohei/0000-0002-6952-4043; Väyrynen, Juha P/0000-0002-8683-2996; Lau, Mai Chan/0000-0002-7698-4697; Borowsky, Jennifer/0000-0003-3957-1364; Haruki, Koichiro/0000-0002-1686-3228; Li, Peilong/0000-0002-7441-6514; Garrett, Wendy/0000-0002-5092-0150	US National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, U01 CA167552, P50 CA127003, R01 CA118553, R01 CA169141, R01 CA137178, K24 DK098311, R35 CA197735, R01 CA151993, K07 CA190673, K07 CA188126]; Cancer Research UK's Grand Challenge Initiative [C10674/A27140]; Dana-Farber Harvard Cancer Center [2016-02]; Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant [SU2C-AACR-DT22-17]; Project P Fund; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; SU2C; Uehara Memorial FoundationUehara Memorial Foundation; Mitsukoshi Health and Welfare Foundation; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [JP2017-0775, JP2018-60083]; JSPS Fujita Memorial Fund for Medical Research; Australia Awards-Endeavour Scholarships and Fellowships ProgramAustralian GovernmentDepartment of Industry, Innovation and Science; ASCO Conquer Cancer Foundation Career Development Award	This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to MJ Stampfer; UM1 CA186107 to MJ Stampfer; P01 CA55075 to WC Willett; UM1 CA167552 to WC Willett; U01 CA167552 to WC Willett and LA Mucci; P50 CA127003 to CSF; R01 CA118553 to CSF; R01 CA169141 to CSF; R01 CA137178 to ATC; K24 DK098311 to ATC; R35 CA197735 to SO; R01 CA151993 to SO; K07 CA190673 to RN; and K07 CA188126 to XZ); by Cancer Research UK's Grand Challenge Initiative (C10674/A27140 to WSG, MG, CH, and SO); by Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to SO); by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to CSF. and MG), administered by the American Association for Cancer Research, a scientific partner of SU2C; and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and SU2C. KH was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. KK was supported by grants from Overseas Research Fellowship (JP2017-0775) from Japan Society for the Promotion of Science and JSPS Fujita Memorial Fund for Medical Research. KA was supported by a grant from Overseas Research Fellowship (JP2018-60083) from Japan Society for the Promotion of Science. JB was supported by a grant from the Australia Awards-Endeavour Scholarships and Fellowships Program. KF was supported by a fellowship grant from the Uehara Memorial Foundation. MG is supported by an ASCO Conquer Cancer Foundation Career Development Award. ATC is a Stuart and Suzanne Steele MGH Research Scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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Pathol.	APR	2020	250	4					397	408		10.1002/path.5381		FEB 2020	12	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	KU6AT	WOS:000510540000001	31880318	Green Accepted			2022-04-25	
J	Hernandez-Balmaseda, I; Guerra, IR; Declerck, K; Isidron, JAH; Perez-Novo, C; Van Camp, G; De Wever, O; Gonzalez, K; Labrada, M; Carr, A; Dantas-Cassali, G; dos Reis, DC; Delgado-Roche, L; Nunez, RR; Delgado-Hernandez, R; Fernandez, MD; Paz-Lopes, MT; Vanden Berghe, W				Hernandez-Balmaseda, Ivones; Guerra, Idania Rodeiro; Declerck, Ken; Herrera Isidron, Jose Alfredo; Perez-Novo, Claudina; Van Camp, Guy; De Wever, Olivier; Gonzalez, Kethia; Labrada, Mayrel; Carr, Adriana; Dantas-Cassali, Geovanni; dos Reis, Diego Carlos; Delgado-Roche, Livan; Nunez, Roberto Rafael; Delgado-Hernandez, Rene; Fernandez, Miguel David; Paz-Lopes, Miriam T.; Vanden Berghe, Wim			Marine Seagrass Extract of Thalassia testudinum Suppresses Colorectal Tumor Growth, Motility and Angiogenesis by Autophagic Stress and Immunogenic Cell Death Pathways	MARINE DRUGS			English	Article						Thalassia testudinum; cytotoxicity; antitumor; anti-angiogenic; gene expression		Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 mu g/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NF kappa B specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.	[Hernandez-Balmaseda, Ivones; Guerra, Idania Rodeiro; Gonzalez, Kethia; Delgado-Roche, Livan; Nunez, Roberto Rafael; Fernandez, Miguel David] Inst Ciencias Mar ICIMAR, Calle Loma 14 E-35 & 37,Plaza Revoluc, Havana 10400, Cuba; [Declerck, Ken; Perez-Novo, Claudina; Vanden Berghe, Wim] Univ Antwerp, Dept Biomed Sci, Lab Prot Sci Prote & Epigenet Signaling PPES, Campus Drie Eiken,Bldg S,4th Floor,Univ Pl 1, B-2610 Antwerp, Belgium; [Declerck, Ken; Perez-Novo, Claudina; Vanden Berghe, Wim] Univ Antwerp, Dept Biomed Sci, Integrated Personalized & Precis Oncol Network IP, Campus Drie Eiken,Bldg S,4th Floor,Univ Pl 1, B-2610 Antwerp, Belgium; [Herrera Isidron, Jose Alfredo] Univ Habana, Inst Ciencia & Tecnol Mat IMRE, Plaza Revoluc, Havana 10400, Cuba; [Van Camp, Guy] Univ Antwerp, Ctr Med Genet, Prins Boudewijnlaan 43, B-2650 Edegem, Belgium; [Van Camp, Guy] Antwerp Univ Hosp, Prins Boudewijnlaan 43, B-2650 Edegem, Belgium; [De Wever, Olivier] UZ Gent, Canc Res Inst Ghent CRIG, Dept Radiat Oncol & Expt Canc Res, Lab Expt Canc Res, B-9000 Ghent, Belgium; [Labrada, Mayrel; Carr, Adriana] Ctr Mol Immunol, Calle 17, Havana 11300, Cuba; [Dantas-Cassali, Geovanni; dos Reis, Diego Carlos; Paz-Lopes, Miriam T.] Fed Univ Minas Gerais UFMG, Inst Biol Sci ICB, BR-31207901 Belo Horizonte, MG, Brazil; [Delgado-Hernandez, Rene] Univ La Habana, Inst Farm & Alimentos IFAL, UH, Ave 23 21425 Entre 214 & 222, Havana 13600, Cuba; [Delgado-Hernandez, Rene] Univ Santader UDES, Fac Ciencias Nat & Agr, Bucaramanga 680002, Colombia		Guerra, IR (corresponding author), Inst Ciencias Mar ICIMAR, Calle Loma 14 E-35 & 37,Plaza Revoluc, Havana 10400, Cuba.; Vanden Berghe, W (corresponding author), Univ Antwerp, Dept Biomed Sci, Lab Prot Sci Prote & Epigenet Signaling PPES, Campus Drie Eiken,Bldg S,4th Floor,Univ Pl 1, B-2610 Antwerp, Belgium.; Vanden Berghe, W (corresponding author), Univ Antwerp, Dept Biomed Sci, Integrated Personalized & Precis Oncol Network IP, Campus Drie Eiken,Bldg S,4th Floor,Univ Pl 1, B-2610 Antwerp, Belgium.	ivones@icimar.cu; idania.rodeiro@infomed.sld.cu; ken.declerck90@hotmail.com; jose@imre.uh.cu; Claudina.PerezNovo@uantwerpen.be; guy.vancamp@uantwerpen.be; olivier.dewever@ugent.be; kethia@icimar.cu; mayrel@cim.sld.cu; adriana@cim.sld.cu; cassalig@icb.ufmg.br; dcarlosreis@yahoo.com.br; ldelgado@liomont.com.mx; robertico@icimar.cu; rdelgado@ifal.uh.cu; migueldavid@icimar.cu; mtpl@icb.ufmg.br; wim.vandenberghe@uantwerpen.be	Lopes, Miriam T P/A-7732-2015; Van Camp, Guy/F-3386-2013; Hernandez, Rene Delgado/AAS-5111-2021; Berghe, Wim Vanden/S-6425-2018; Novo, Claudina A Perez/E-6098-2011; de wever, olivier/J-3094-2013; Rodeiro Guerra, Idania/H-7713-2014	Lopes, Miriam T P/0000-0001-9980-3169; Van Camp, Guy/0000-0001-5105-9000; Hernandez, Rene Delgado/0000-0001-7051-7871; Berghe, Wim Vanden/0000-0003-0161-7355; Novo, Claudina A Perez/0000-0003-4562-4346; de wever, olivier/0000-0002-5453-760X; Hernandez Balmaseda, Ivones/0000-0001-5276-0851; Herrera Isidron, Jose Alfredo/0000-0003-2244-7180; Rodeiro Guerra, Idania/0000-0002-2692-6050; Labrada Mon, Mayrel/0000-0003-4603-0988	(CITMA), Cuba [P211LH005-019]; (CNPq), BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ) [PVE400768/2014-3]; (Flemish VLIR collaboration program), Belgium [ZEIN2011PR383, ZEIN2016PR418]	This work was supported by P211LH005-019 project (CITMA), Cuba; Visiting Research Program, PVE400768/2014-3 project (CNPq), Brazil, and the projects ZEIN2011PR383 and ZEIN2016PR418 (Flemish VLIR collaboration program), Belgium.	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Drugs	FEB	2021	19	2							52	10.3390/md19020052			17	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	QN8RV	WOS:000622720200001	33499163	Green Published, gold			2022-04-25	
J	Lai, HW; Wei, JCC; Hung, HC; Lin, CC				Lai, Hsin-Wu; Wei, James Cheng-Chung; Hung, Hung-Chang; Lin, Chun-Che			Adenine Inhibits the Growth of Colon Cancer Cells via AMP-Activated Protein Kinase Mediated Autophagy	EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article							COLORECTAL-CANCER; PATHOGENESIS	Background. Adenine is involved in a variety of cell biological processes and has been explored for pharmacological uses. Its therapeutic use for managing cancer is of great interest. In the present study, we investigated the anticancer effects of adenine and the underlying mechanism in colon cancer cells. Methods. Cell viability was measured using the MTT assay. Levels of phosphorylation and protein expression were determined using western blotting. qPCR was carried out to determine the changes in mRNA expression of genes of interest. Results. Adenine significantly inhibited the viability of colon cancer cells, HT29 and Caco-2 cells, in a dose-dependent manner. Adenine induced significant apoptosis in HT29 cells, whereas Caco-2 cells exhibited less apoptotic responses. The data showed that adenine activated AMP-activated protein kinase (AMPK) signaling contributing to autophagic cell death through mTOR in both colon cancer cell lines. Conclusions. Our findings suggest that adenine inhibits the growth of colon cancer cells. Anticancer activity of adenine in colon cancer cells is attributable to the activation of apoptotic signaling and in turn the AMPK/mTOR pathway. Adenine represents a natural compound with anticancer potency.	[Lai, Hsin-Wu; Wei, James Cheng-Chung; Hung, Hung-Chang; Lin, Chun-Che] Chung Shan Med Univ, Inst Med, Taichung, Taiwan; [Lai, Hsin-Wu; Hung, Hung-Chang] Nantou Hosp, Div Gastroenterol, Dept Internal Med, Minist Hlth & Welf, Taipei, Taiwan; [Wei, James Cheng-Chung] Chung Shan Med Univ Hosp, Div Allergy Immunol & Rheumatol, Dept Med, Taichung, Taiwan; [Wei, James Cheng-Chung] China Med Univ, Grad Inst Integrated Med, Taichung, Taiwan; [Hung, Hung-Chang] Cent Taiwan Univ Sci & Technol, Dept Healthcare Adm, Taichung, Taiwan; [Lin, Chun-Che] Chung Shan Med Univ Hosp, Div Gastroenterol, Dept Internal Med, Taichung, Taiwan		Wei, JCC (corresponding author), Chung Shan Med Univ, Inst Med, Taichung, Taiwan.; Wei, JCC (corresponding author), Chung Shan Med Univ Hosp, Div Allergy Immunol & Rheumatol, Dept Med, Taichung, Taiwan.; Wei, JCC (corresponding author), China Med Univ, Grad Inst Integrated Med, Taichung, Taiwan.	wei3228@gmail.com	Wei, James Cheng-Chung/AAL-8947-2020	Wei, James Cheng-Chung/0000-0002-1235-0679			Arnold M, 2017, GUT, V66, P683, DOI 10.1136/gutjnl-2015-310912; Burada F, 2015, WORLD J GASTRO ONCOL, V7, P271, DOI 10.4251/wjgo.v7.i11.271; Carling D, 2017, CURR OPIN CELL BIOL, V45, P31, DOI 10.1016/j.ceb.2017.01.005; Chen CC, 2014, BIOMED RES INT, V2014, DOI 10.1155/2014/692061; Chen SY, 2017, ONCOL LETT, V14, P5575, DOI 10.3892/ol.2017.6890; Cheng YF, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0142283; Han M, 2017, ONCOTARGET, V8, P94286, DOI 10.18632/oncotarget.21690; Hosoi T, 2018, IMMUN INFLAMM DIS, V6, P97, DOI 10.1002/iid3.200; Huang BP, 2015, DNA CELL BIOL, V34, P133, DOI 10.1089/dna.2014.2630; Kim DE, 2015, MOL CELLS, V38, P138, DOI 10.14348/molcells.2015.2193; Kou B, 2017, ONCOL REP, V38, P3137, DOI 10.3892/or.2017.5988; Lai K, 2014, J CLIN PATHOL, V67, P854, DOI 10.1136/jclinpath-2014-202529; Leu JG, 2018, EUR J PHARMACOL, V818, P569, DOI 10.1016/j.ejphar.2017.11.027; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; LUTHJE J, 1989, BLUT, V59, P367, DOI 10.1007/BF00321207; Mogavero A, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-16149-z; Rehman G, 2014, ARCH PHARM, V347, P457, DOI 10.1002/ardp.201300402; Ristica B, 2014, EXP CELL RES, V326, P90, DOI 10.1016/j.yexcr.2014.05.021; Sato K, 2007, CANCER RES, V67, P9677, DOI 10.1158/0008-5472.CAN-07-1462; Scioli MG, 2014, J VASC RES, V51, P327, DOI 10.1159/000365926; Sesen J, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0123721; Silwal P, 2018, KOREAN J PHYSIOL PHA, V22, P379, DOI 10.4196/kjpp.2018.22.4.379; Silwal P, 2015, MOL IMMUNOL, V65, P242, DOI 10.1016/j.molimm.2015.01.021; Watanabe S, 2003, J NEUROSCI RES, V74, P754, DOI 10.1002/jnr.10790; Yoshimi Y, 2003, BRAIN RES, V991, P113, DOI 10.1016/j.brainres.2003.08.017; Young GH, 2015, J PROTEOMICS, V120, P204, DOI 10.1016/j.jprot.2015.03.012	26	6	6	2	3	HINDAWI LTD	LONDON	ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND	1741-427X	1741-4288		EVID-BASED COMPL ALT	Evid.-based Complement Altern. Med.	SEP 12	2019	2019								9151070	10.1155/2019/9151070			7	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	JA2GV	WOS:000487636100003	31611925	Green Published, gold			2022-04-25	
J	Zhang, Y; Zhang, Z; Wang, D; Xu, JZ; Li, YH; Wang, H; Li, J; Mo, SW; Zhang, YC; Lin, YQ; Fan, XZ; Li, EM; Huang, J; Fan, HH; Yi, Y				Zhang, Yang; Zhang, Zheng; Wang, Dong; Xu, Jianzhen; Li, Yanhui; Wang, Hong; Li, Jin; Mo, Shaowen; Zhang, Yuncong; Lin, Yunqing; Fan, Xiuzhao; Li, Enmin; Huang, Jian; Fan, Huihui; Yi, Ying			Multidimensional Integration Analysis of Autophagy-related Modules in Colorectal Cancer	LETTERS IN ORGANIC CHEMISTRY			English	Article						Colorectal cancer; autophagy; co-expression modules; multidimensional analysis; COAD; WGCNA	CELL-DEATH; COLON-CANCER; DIFFERENTIAL EXPRESSION; BIOINFORMATICS RESOURCE; PROTEIN-SYNTHESIS; TUMOR-SUPPRESSOR; UPDATED RESOURCE; GENE-EXPRESSION; APOPTOSIS; DATABASE	Colorectal cancer (CRC) is a common malignant tumor of the digestive tract occurring in the colon, which mainly divided into adenocarcinoma, mucinous adenocarcinoma, and undifferentiated carcinoma. However, autophagy is related to the occurrence and development of various kinds of human diseases such as cancer. There is little research on the relationship between CRC and autophagy. Hence, we performed multidimensional integration analysis to systematically explore potential relationship between autophagy and CRC. Based on gene expression datasets of colon adenocarcinoma (COAD) and protein-protein interactions (PPIs), we first identified 12 autophagy-related modules in COAD using WGCNA. Then, 9 module pairs which with significantly crosstalk were deciphered, a total of 6 functional modules. Autophagy-related genes in these modules were closely related with CRC, emphasizing that the important role of autophagy-related genes in CRC, including PPP2CA and EIF4E, etc. In addition to, by integrating transcription factor (TF)-target and RNA-associated interactions, a regulation network was constructed, in which 42 TFs (including SMAD3 and TPS3, etc.) and 20 miRNAs (including miR-20 and miR-30a, etc.) were identified as pivot regulators. Pivot TFs were mainly involved in cell cycle, cell proliferation and pathways in cancer. And pivot miRNAs were demonstrated associated with CRC. It suggests that these pivot regulators might be have an effect on the development of CRC by regulating autophagy. In a word, our results suggested that multidimensional integration strategy provides a novel approach to discover potential relationships between autophagy and CRC, and further improves our understanding of autophagy and tumor in human.	[Zhang, Yang; Wang, Dong; Huang, Jian] Univ Elect Sci & Technol China, Ctr Informat Biol, Chengdu 610054, Sichuan, Peoples R China; [Zhang, Zheng] Nanjing Audit Univ, Dept Phys Educ, Nanjing, Jiangsu, Peoples R China; [Wang, Dong; Wang, Hong; Li, Jin; Mo, Shaowen; Zhang, Yuncong; Lin, Yunqing; Fan, Xiuzhao; Fan, Huihui; Yi, Ying] Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin, Heilongjiang, Peoples R China; [Xu, Jianzhen; Li, Enmin] Shantou Univ, Med Coll, Key Lab Mol Biol High Canc Incidence Coastal Chao, Shantou 515041, Peoples R China; [Xu, Jianzhen; Li, Enmin] Shantou Univ, Med Coll, Dept Biochem & Mol Biol, Shantou 515041, Peoples R China; [Li, Yanhui] Peking Univ, Hlth Sci Ctr, Inst Cardiovasc Sci, Beijing, Peoples R China; [Li, Yanhui] Peking Univ, Hlth Sci Ctr, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China		Huang, J (corresponding author), Univ Elect Sci & Technol China, Ctr Informat Biol, Chengdu 610054, Sichuan, Peoples R China.; Fan, HH; Yi, Y (corresponding author), Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin, Heilongjiang, Peoples R China.	hj@uestc.edu.cn; fanhuihui@hrbmu.edu.cn; yiying@hrbmu.edu.cn	Huang, Jian/G-8437-2011; Wang, Dong/ABC-2499-2021; Fan, Huihui/AGB-0221-2022	Huang, Jian/0000-0003-3282-8892; Fan, Huihui/0000-0003-4233-5389	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31501075]; Scientific Research Fund of Heilongjiang Provincial Education Department [12541426]	This work was supported by the National Natural Science Foundation of China (31501075); Scientific Research Fund of Heilongjiang Provincial Education Department (12541426).	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Org. Chem.		2019	16	4					340	346		10.2174/1570178615666180914113224			7	Chemistry, Organic	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry	HP5YQ	WOS:000461759900013					2022-04-25	
J	Islam, F; Gopalan, V; Pillai, S; Lu, CT; Kasem, K; Lam, AKY				Islam, Farhadul; Gopalan, Vinod; Pillai, Suja; Lu, Cu-tai; Kasem, Kais; Lam, Alfred King-yin			Promoter hypermethylation inactivate tumor suppressor FAM134B and is associated with poor prognosis in colorectal cancer	GENES CHROMOSOMES & CANCER			English	Article							SQUAMOUS-CELL CARCINOMA; ENDOPLASMIC-RETICULUM TURNOVER; HEREDITARY SENSORY NEUROPATHY; DNA METHYLATION; COLON-CANCER; CLINICOPATHOLOGICAL SIGNIFICANCE; AUTONOMIC NEUROPATHY; SELECTIVE AUTOPHAGY; GENE; MUTATIONS	The present study aims to examine promoter methylation status of FAM134B in a large cohort of patients with colorectal adenocarcinomas. The clinical significances and correlations of FAM134B promoter methylation with its expression are also analysed. Methylation-specific high-resolution melt-curve analysis followed by sequencing was used to identify FAM134B promoter methylation in colorectal adenomas (N = 32), colorectal adenocarcinomas (N = 164), matched adjacent non-neoplastic colorectal mucosae (N = 83) and colon cancer cell lines (N = 4). FAM134B expression was studied by real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blots. FAM134B promoter methylation was more frequent in adenocarcinomas (52%; 85/164) when compared to that of adenomas (28%; 9/32) and non-neoplastic mucosae (35%; 29/83). Cancer cells exhibited higher methylation when compared to non-neoplastic cells. FAM134B promoter methylation was inversely correlated with low FAM134B copy number and mRNA/protein expressions, whereas in-vitro demethylation has restored FAM134B expression in colon cancer cells. FAM134B promoter methylation was associated with high histological grade (P = .025), presence of peri-neural infiltration (P = .012), lymphovascular invasion (P = .021), lymph node metastasis (P = .0001), distant metastasis (P = .0001) and advanced pathological stages (P = .0001). In addition, FAM134B promoter methylation correlated with cancer recurrence and poor survival rates of patients with colorectal adenocarcinomas. To conclude, FAM134B promoter methylation plays a key role in regulating FAM134B expression in vitro and in vivo, which in turn contributes to the prediction of the biological aggressiveness of colorectal adenocarcinomas. Furthermore, FAM134B methylation might act as a marker in predicting clinical prognosis in patients with colorectal adenocarcinomas.	[Islam, Farhadul; Gopalan, Vinod; Pillai, Suja; Kasem, Kais; Lam, Alfred King-yin] Griffith Univ, Sch Med, Canc Mol Pathol, Nathan, Qld, Australia; [Islam, Farhadul; Gopalan, Vinod; Pillai, Suja; Kasem, Kais; Lam, Alfred King-yin] Griffith Univ, Menzies Hlth Inst Queensland, Nathan, Qld, Australia; [Islam, Farhadul] Univ Rajshahi, Dept Biochem & Mol Biol, Rajshahi 6205, Bangladesh; [Pillai, Suja] Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia; [Lu, Cu-tai] Gold Coast Hosp, Dept Surg, Gold Coast, Qld, Australia		Lam, AKY (corresponding author), Griffith Med Sch, Pathol, Gold Coast Campus, Gold Coast, Qld 4222, Australia.	a.lam@griffith.edu.au	Pillai, Suja/AAG-4056-2019; Lam, Alfred/C-1652-2008; Islam, Farhadul/R-5643-2017	Pillai, Suja/0000-0002-6572-1840; Lam, Alfred/0000-0003-2771-564X; Lu, Cu Tai/0000-0001-9565-3749; Islam, Farhadul/0000-0001-5262-4702	Menzies Health Institute Queensland; Griffith UniversityGriffith University	Griffith University; Menzies Health Institute Queensland	BATSAKIS JG, 1985, ANN OTO RHINOL LARYN, V94, P426; Bird A, 2002, GENE DEV, V16, P6, DOI 10.1101/gad.947102; Chiramel AI, 2016, J INFECT DIS, V214, pS319, DOI 10.1093/infdis/jiw270; Dai XF, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-07189-6; Davidson GL, 2012, J NEUROL, V259, P1673, DOI 10.1007/s00415-011-6397-y; Duret C, 2014, MUSCLE NERVE, V49, P774, DOI 10.1002/mus.24145; Fleming M, 2012, J GASTROINTEST ONCOL, V3, P153, DOI 10.3978/j.issn.2078-6891.2012.030; Gallois C, 2016, CRIT REV ONCOL HEMAT, V99, P74, DOI 10.1016/j.critrevonc.2015.11.001; Giovannucci E, 2005, JNCI-J NATL CANCER I, V97, P1317, DOI 10.1093/jnci/dji305; GONZALEZZULUETA M, 1995, CANCER RES, V55, P4531; Gopalan V, 2016, EXP CELL RES, V348, P146, DOI 10.1016/j.yexcr.2016.09.010; Hamilton S. R., 2010, WHO CLASSIFICATION T, V134; Haque MH, 2017, ANAL CHIM ACTA, V976, P84, DOI 10.1016/j.aca.2017.04.034; Haque MH, 2016, SCI REP-UK, V6, DOI 10.1038/srep29173; HARDCASTLE JD, 1984, J ROY SOC MED, V77, P673, DOI 10.1177/014107688407700812; Harris EI, 2008, AM J SURG PATHOL, V32, P1816, DOI 10.1097/PAS.0b013e3181816083; Hinoue T, 2012, GENOME RES, V22, P271, DOI 10.1101/gr.117523.110; Islam F, 2017, EXP CELL RES, V357, P260, DOI 10.1016/j.yexcr.2017.05.021; Islam F, 2017, HUM PATHOL, V62, P141, DOI 10.1016/j.humpath.2017.01.014; Islam F, 2017, HUM GENET, V136, P321, DOI 10.1007/s00439-017-1760-4; Islam F, 2017, MOL CARCINOGEN, V56, P238, DOI 10.1002/mc.22488; Issa JP, 2004, NAT REV CANCER, V4, P988, DOI 10.1038/nrc1507; Jessup JM, 2017, AJCC CANC STAGING MA, P251, DOI DOI 10.1007/978-3-319-40618-3_20; Kasem K, 2014, EXP MOL PATHOL, V97, P99, DOI 10.1016/j.yexmp.2014.06.002; Kasem K, 2014, EXP MOL PATHOL, V97, P31, DOI 10.1016/j.yexmp.2014.05.001; Kasem K, 2014, EXP CELL RES, V326, P166, DOI 10.1016/j.yexcr.2014.06.013; Khaminets A, 2015, NATURE, V522, P354, DOI 10.1038/nature14498; Kong M, 2011, PSYCHIAT GENET, V21, P37, DOI 10.1097/YPG.0b013e3283413496; KRASNA MJ, 1988, CANCER-AM CANCER SOC, V61, P1018, DOI 10.1002/1097-0142(19880301)61:5<1018::AID-CNCR2820610527>3.0.CO;2-H; Kurth I, 2009, NAT GENET, V41, P1179, DOI 10.1038/ng.464; Lam AKY, 2012, INT J COLORECTAL DIS, V27, P1303, DOI 10.1007/s00384-012-1474-y; Liebig C, 2009, CANCER-AM CANCER SOC, V115, P3379, DOI 10.1002/cncr.24396; Melchiotti R, 2014, BMC MED GENET, V15, DOI 10.1186/1471-2350-15-73; Murphy SM, 2012, J NEUROL NEUROSUR PS, V83, P119, DOI 10.1136/jnnp.2010.228965; Okugawa Y, 2015, GASTROENTEROLOGY, V149, P1204, DOI 10.1053/j.gastro.2015.07.011; Rao RV, 2006, CELL DEATH DIFFER, V13, P415, DOI 10.1038/sj.cdd.4401761; Suzuki H, 2004, NAT GENET, V36, P417, DOI 10.1038/ng1330; Tang WK, 2007, INT J MOL MED, V19, P915; van Rijnsoever M, 2002, GUT, V51, P797, DOI 10.1136/gut.51.6.797; Veigl ML, 1998, P NATL ACAD SCI USA, V95, P8698, DOI 10.1073/pnas.95.15.8698; Wojdacz TK, 2008, NAT PROTOC, V3, P1903, DOI 10.1038/nprot.2008.191; Xing X, 2013, BRIT J CANCER, V108, P2542, DOI 10.1038/bjc.2013.251; Yadav Raj Kumar, 2014, J Cancer Prev, V19, P75, DOI 10.15430/JCP.2014.19.2.75; Zhou D, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-03133-w	44	11	11	1	5	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	1045-2257	1098-2264		GENE CHROMOSOME CANC	Gene Chromosomes Cancer	MAY	2018	57	5					240	251		10.1002/gcc.22525			12	Oncology; Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Genetics & Heredity	FY8LP	WOS:000427116500003	29318692	Green Submitted, Green Published			2022-04-25	
J	Kim, H; Yin, KL; Falcon, DM; Xue, X				Kim, Hyeoncheol; Yin, Kunlun; Falcon, Daniel M.; Xue, Xiang			The interaction of Hemin and Sestrin2 modulates oxidative stress and colon tumor growth	TOXICOLOGY AND APPLIED PHARMACOLOGY			English	Article						Sestrin2; Hemin; Oxidative stress; Colorectal cancer; Nuclear factor (erythroid-derived 2)-like 2	COLORECTAL-CANCER; AUTOPHAGIC DEGRADATION; MEAT CONSUMPTION; UP-REGULATION; NITRIC-OXIDE; DNA-DAMAGE; RED MEAT; NRF2; IRON; ACTIVATION	Several large epidemiological and animal studies demonstrate a direct correlation between dietary heme iron intake and/or systemic iron levels and cancer risk in several cancers including colorectal cancer (CRC). However, the precise mechanisms for how heme iron contributes to CRC and how cancer cells respond to heme iron-induced stress are still unclear. Previously we have shown that one of the stress-inducible proteins, Sestrin2 (SESN2), is a novel tumor suppressor in colon by limiting endoplasmic reticulum stress and mammalian target of rapamycin complex 1 (mTORC1) signaling and tumor growth. But the relationship between heme iron and SESN2, especially in the context of colon carcinogenesis, was not investigated previously. Here, we found that hemin dose-dependently increased SESN2 expression in an oxidative stress and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, NRF2)-dependent manner. Since SESN2 overexpression reduced hemin-induced oxidative stress, SESN2 could be an important target of NRF2 exerting antioxidant function. Indeed, expression of several oxidative stress responsive proteins such as NRF2 and its target genes was reduced by SESN2. Although we formerly reported that SESN2 expression was reduced after p53 mutation in colon tumors, mouse colon tumors, which have intact p53 and NRF2, induced SESN2 expression in response to iron stimulus. Although SESN2 overexpression decreased murine colon tumor cell growth both in vitro and in vivo, it rendered colon cancer cells more resistant to hemin-induced apoptosis and therefore promoted tumor growth during hemin treatment. Taken together, although SESN2 generally suppresses tumorigenesis, it can produce tumor-promoting role in iron-rich environment by suppressing oxidative stress-associated cancer cell death.	[Kim, Hyeoncheol; Yin, Kunlun; Falcon, Daniel M.; Xue, Xiang] Univ New Mexico, Dept Biochem & Mol Biol, Albuquerque, NM 87131 USA		Xue, X (corresponding author), Fitz Hall 259,915 Camino de Salud NE, Albuquerque, NM 87131 USA.	xxue@salud.unm.edu	Xue, Xiang/P-9071-2014	Xue, Xiang/0000-0003-4704-1814	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K01DK114390]; American Cancer SocietyAmerican Cancer Society [RSG-18-050-01-NEC]; University of New Mexico Environmental Health Signature Program and Superfund [P42 ES025589]; Dedicated Health Research Funds from the University of New Mexico School of Medicine; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [2P30 CA118100]; Academic Science Education and Research Training program at the University of New Mexico Health Sciences Center(NIGMS Institutional Research and Academic Career Development Award) [K12-GM088021]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA118100] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [K01DK114390] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [P42ES025589] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [K12GM088021] Funding Source: NIH RePORTER	We thank Dr. Weiping Zou at University of Michigan for generously providing MC38 cells, Dr. Jun Hee Lee at University of Michigan for generously providing pLU-CMV-Flag-hSESN2 WT plasmid and editing the manuscript. This work was supported in part by the National Institutes of Health (K01DK114390), a Research Scholar Grant from the American Cancer Society (RSG-18-050-01-NEC), a Research Pilot Project Grant from University of New Mexico Environmental Health Signature Program and Superfund (P42 ES025589), and the Dedicated Health Research Funds from the University of New Mexico School of Medicine. Support for in vivo experiments in this paper was provided by the University of New Mexico Cancer Center Animal Models Shared Resource and a Shared Resources Pilot Project Award, funded by NCI 2P30 CA118100 (PI Willman, C.) "UNM Cancer Center Support Grant". D.M.F was supported by the Academic Science Education and Research Training program at the University of New Mexico Health Sciences Center(NIGMS Institutional Research and Academic Career Development Award; K12-GM088021). The authors have no financial conflicts of interest.	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Xue X, 2016, CELL METAB, V24, P447, DOI 10.1016/j.cmet.2016.07.015; Xue X, 2012, CANCER RES, V72, P2285, DOI 10.1158/0008-5472.CAN-11-3836; Yang JH, 2015, FREE RADICAL BIO MED, V78, P156, DOI 10.1016/j.freeradbiomed.2014.11.002	75	18	18	0	23	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0041-008X	1096-0333		TOXICOL APPL PHARM	Toxicol. Appl. Pharmacol.	JUL 1	2019	374						77	85		10.1016/j.taap.2019.04.025			9	Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Toxicology	IA9RD	WOS:000469893600008	31054940	Green Accepted			2022-04-25	
J	Wu, S; Qiu, YL; Shao, YY; Yin, SS; Wang, R; Pang, X; Ma, JH; Zhang, CZ; Wu, B; Koo, S; Han, LF; Zhang, Y; Gao, XM; Wang, T; Yu, HY				Wu, Song; Qiu, Yuling; Shao, Yingying; Yin, Shuangshuang; Wang, Rui; Pang, Xu; Ma, Junhong; Zhang, Chunze; Wu, Bo; Koo, Sangho; Han, Lifeng; Zhang, Yi; Gao, Xiumei; Wang, Tao; Yu, Haiyang			Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3	FRONTIERS IN PHARMACOLOGY			English	Article						lycorine; STAT3; target; apoptosis; colorectal cancers	PROGRAMMED CELL-DEATH; DNA-BINDING DOMAIN; SIGNALING PATHWAY; CANCER-TREATMENT; AUTOPHAGY; APOPTOSIS; GROWTH; TRANSCRIPTION; METASTASIS; STATISTICS	Signal transducer and activator of transcription 3 (STAT3) is an attractive therapeutic target for cancer treatment. In this study, we identify lycorine is an effective inhibitor of STAT3, leading to repression of multiple oncogenic processes in colon carcinoma. Lycorine selectively inactivates phospho-STAT3 (Tyr-705), and subsequent molecular docking uncovers that lycorine directly binds to the SH2 domain of STAT3. Consequently, we find that lycorine exhibits anti-proliferative activity and induces cell apoptosis on human colorectal cancer (CRC) in vitro. Lycorine induces the activation of the caspase-dependent mitochondrial apoptotic pathway, as indicated by activation of caspase and increase of the ratio of Bax/Bcl-2 and mitochondria! depolarization. Overexpressing STAT3 greatly blocks these effects by lycorine in CRC cells. Finally, lycorine exhibits a potential therapeutic effect in xenograft colorectal tumors by targeting STAT3 without observed toxicity. Taken together, the present study indicates that lycorine acts as a promising inhibitor of STAT3, which blocks tumorigenesis in colon carcinoma.	[Wu, Song; Shao, Yingying; Yin, Shuangshuang; Wang, Rui; Pang, Xu; Han, Lifeng; Zhang, Yi; Gao, Xiumei; Wang, Tao; Yu, Haiyang] Tianjin Univ Tradit Chinese Med, Tianjin State Key Lab Modern Chinese Med, Tianjin, Peoples R China; [Qiu, Yuling] Tianjin Med Univ, Sch Pharm, Tianjin, Peoples R China; [Ma, Junhong] Nankai Hosp, Dept Gastrointestinal Surg, Tianjin, Peoples R China; [Zhang, Chunze] Tianjin Union Med Ctr, Dept Colorectal Surg, Tianjin, Peoples R China; [Wu, Bo] China Med Univ, Sch Fundamental Sci, Shenyang, Liaoning, Peoples R China; [Koo, Sangho] Myongji Univ, Dept Chem, Seoul, South Korea		Wang, T; Yu, HY (corresponding author), Tianjin Univ Tradit Chinese Med, Tianjin State Key Lab Modern Chinese Med, Tianjin, Peoples R China.	wangt@263.net; yuhaiyang19830116@hotmail.com	Koo, Sangho/AAR-4354-2020	Koo, Sangho/0000-0003-4725-1117	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81603253, 21711540293, 81673703, 81602614, 81501578]; Natural Science Foundation of Tianjin CityNatural Science Foundation of Tianjin [15JCYBJC54900, 15PTCYSY00030]; Tianjin Health and Family Planning Commission [2017057]	This work was supported by from National Natural Science Foundation of China (Grant Nos. 81603253 and 21711540293 to HY, Grant No. 81673703 to TW, Grant No. 81602614 to YQ, Grant No. 81501578 to BD), Natural Science Foundation of Tianjin City (Grant No. 15JCYBJC54900 to HY, Grant No. 15PTCYSY00030 to ZL), and Tianjin Health and Family Planning Commission (Grant No. 2017057 to CZ).	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Pharmacol.	AUG 8	2018	9								881	10.3389/fphar.2018.00881			11	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	GP7DB	WOS:000441051500001	30135654	Green Published, gold			2022-04-25	
J	Devenport, SN; Singhal, R; Radyk, MD; Taranto, JG; Kerk, SA; Chen, B; Goyert, JW; Jain, C; Das, NK; Oravecz-Wilson, K; Li, Z; Greenson, JK; Chen, YE; Soleimanpour, SA; Reddy, P; Lyssiotis, CA; Shah, YM				Devenport, Samantha N.; Singhal, Rashi; Radyk, Megan D.; Taranto, Joseph G.; Kerk, Samuel A.; Chen, Brandon; Goyert, Joshua W.; Jain, Chesta; Das, Nupur K.; Oravecz-Wilson, Katherine; Li Zhang; Greenson, Joel K.; Chen, Y. Eugene; Soleimanpour, Scott A.; Reddy, Pavan; Lyssiotis, Costas A.; Shah, Yatrik M.			Colorectal cancer cells utilize autophagy to maintain mitochondrial metabolism for cell proliferation under nutrient stress	JCI INSIGHT			English	Article							INDUCED APOPTOSIS; IRON HOMEOSTASIS; PANETH CELLS; KEY ROLE; MITOPHAGY; INHIBITION; SURVIVAL; MOUSE; MAINTENANCE; EXPRESSION	Cancer cells reprogram cellular metabolism to maintain adequate nutrient pools to sustain proliferation. Moreover, autophagy is a regulated mechanism to break down dysfunctional cellular components and recycle cellular nutrients. However, the requirement for autophagy and the integration in cancer cell metabolism is not clear in colon cancer. Here, we show a cell-autonomous dependency of autophagy for cell growth in colorectal cancer. Loss of epithelial autophagy inhibits tumor growth in both sporadic and colitis-associated cancer models. Genetic and pharmacological inhibition of autophagy inhibits cell growth in colon cancer-derived cell lines and patient-derived enteroid models. Importantly, normal colon epithelium and patient-derived normal enteroid growth were not decreased following autophagy inhibition. To couple the role of autophagy to cellular metabolism, a cell culture screen in conjunction with metabolomic analysis was performed. We identified a critical role of autophagy to maintain mitochondria' metabolites for growth. Loss of mitochondria! recycling through inhibition of mitophagy hinders colon cancer cell growth. These findings have revealed a cell-autonomous role of autophagy that plays a critical role in regulating nutrient pools in vivo and in cell models, and it provides therapeutic targets for colon cancer.	[Devenport, Samantha N.; Chen, Brandon; Shah, Yatrik M.] Univ Michigan, Med Sch, Cellular & Mol Biol, Ann Arbor, MI 48109 USA; [Devenport, Samantha N.; Singhal, Rashi; Radyk, Megan D.; Taranto, Joseph G.; Kerk, Samuel A.; Chen, Brandon; Goyert, Joshua W.; Jain, Chesta; Das, Nupur K.; Li Zhang; Lyssiotis, Costas A.; Shah, Yatrik M.] Univ Michigan, Med Sch, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA; [Oravecz-Wilson, Katherine; Reddy, Pavan] Univ Michigan, Med Sch, Dept Hematol & Oncol, Ann Arbor, MI 48109 USA; [Greenson, Joel K.] Univ Michigan, Med Sch, Dept Pathol, Ann Arbor, MI 48109 USA; [Chen, Y. Eugene] Univ Michigan, Med Sch, Cardiovasc Ctr, Ann Arbor, MI 48109 USA; [Soleimanpour, Scott A.] Univ Michigan, Med Sch, Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA; [Reddy, Pavan; Lyssiotis, Costas A.; Shah, Yatrik M.] Univ Michigan, Med Sch, Rogel Canc Ctr, Ann Arbor, MI 48109 USA; [Lyssiotis, Costas A.; Shah, Yatrik M.] Univ Michigan, Med Sch, Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA		Shah, YM (corresponding author), Univ Michigan, Div Gastroenterol, Dept Mol & Integrat Physiol, Dept Internal Med,Med Sch, Ann Arbor, MI 48109 USA.	shahy@umich.edu	Das, Nupur/AAK-7877-2020	Das, Nupur/0000-0002-5652-1134; Chen, Brandon/0000-0002-6319-2228; Radyk, Megan/0000-0002-3660-2906; Goyert, Joshua/0000-0003-3820-970X; Soleimanpour, Scott/0000-0001-6777-4498; Kerk, Samuel/0000-0001-9786-2245	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA148828, R01DK095201, R01CA245546]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R37CA237421, R01CA248160, R01CA244931, R01CA215607]; University of Michigan GI SPORE Molecular Pathology and Biosample Core [P50CA130810]; Rogel Cancer Center [P30CA046592]; Center for Gastrointestinal Research [DK034933]; Department of DefenseUnited States Department of Defense [CA171086]; US Department of Veterans AffairsUS Department of Veterans Affairs [I01 BX004444]; JDRFJuvenile Diabetes Research Foundation [COE-2019-861, CDA-2016-189, SRA-2018-539];  [R01 DK108921];  [T32 GM007315];  [5 T32 CA140044-9]	This work was supported by NIH grants R01CA148828, R01DK095201, and R01CA245546 to YMS. CAL was supported by the NCI (R37CA237421, R01CA248160, R01CA244931, and R01CA215607). SAS was supported by R01 DK108921. SND was supported by T32 GM007315 and 5 T32 CA140044-9. CAL and YMS are supported by University of Michigan GI SPORE Molecular Pathology and Biosample Core (P50CA130810), Rogel Cancer Center (P30CA046592), and Center for Gastrointestinal Research (DK034933). This work was also supported by the Department of Defense (CA171086, YMS), the US Department of Veterans Affairs (I01 BX004444, SAS), and the JDRF (COE-2019-861, CDA-2016-189, and SRA-2018-539, SAS).	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J	Chen, F; Wang, CC; Kim, E; Harrison, LE				Chen, Fei; Wang, Chia-Chi; Kim, Eugene; Harrison, Lawrence E.			Hyperthermia in combination with oxidative stress induces autophagic cell death in HT-29 colon cancer cells	CELL BIOLOGY INTERNATIONAL			English	Article						Autophagy; Oxidative stress; Colon cancer	MALIGNANT GLIOMA-CELLS; INTRAPERITONEAL CHEMOTHERAPY; APOPTOSIS; SURVIVAL; INDUCTION; CARCINOMA; EFFICACY; SURGERY; ARREST; ROS	The purpose of this study was to evaluate the mechanism of ROS-induced hyperthermic cell death in a colon cancer cell line. HT-29 colon cancer cells were exposed to heat (43 degrees C) in the presence of tert-butyl hydroperoxide (t-BOOH). t-BOOH combined with hyperthermia significantly decreased cell viability as compared with t-BOOH or hyperthermia alone. This decrease in cell numbers was associated with retardation in the S phase transit and not through apoptosis. Cell death was noted to be accompanied by specific features characteristic of autophagy: the presence of cytoplasmic autophagic vacuoles; autophagosome membrane association of microtubule-associated protein light chain 3; accumulation of acidic vesicular organelles; and increased incorporation of MDC in the autophagosome. Thermal sensitization through modulation of cellular ROS may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality. (C) 2008 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.	[Chen, Fei; Wang, Chia-Chi; Kim, Eugene; Harrison, Lawrence E.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Div Surg Oncol, Newark, NJ 07103 USA		Harrison, LE (corresponding author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Div Surg Oncol, 185 S Orange Ave,MSB G524, Newark, NJ 07103 USA.	L.Harrison@UMDNJ.edu					Benhar M, 2002, EMBO REP, V3, P420, DOI 10.1093/embo-reports/kvf094; Butler R, 2000, CELL GROWTH DIFFER, V11, P49; Chen Y, 2005, BIOCHEM BIOPH RES CO, V337, P52, DOI 10.1016/j.bbrc.2005.09.018; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; Coqueret O, 2003, TRENDS CELL BIOL, V13, P65, DOI 10.1016/S0962-8924(02)00043-0; Ellington AA, 2005, CARCINOGENESIS, V26, P159, DOI 10.1093/carcin/bgh297; Furuya N, 2005, AUTOPHAGY, V1, P46, DOI 10.4161/auto.1.1.1542; Hempel SL, 1999, FREE RADICAL BIO MED, V27, P146, DOI 10.1016/S0891-5849(99)00061-1; Hildebrandt B, 2002, CRIT REV ONCOL HEMAT, V43, P33, DOI 10.1016/S1040-8428(01)00179-2; Jin ZY, 2005, CANCER BIOL THER, V4, P139, DOI 10.4161/cbt.4.2.1508; Kanzawa T, 2004, CELL DEATH DIFFER, V11, P448, DOI 10.1038/sj.cdd.4401359; Komata T, 2004, J NEURO-ONCOL, V68, P101, DOI 10.1023/B:NEON.0000027739.33842.6c; Kroemer G, 2005, NAT REV CANCER, V5, P886, DOI 10.1038/nrc1738; Lebedeva IV, 2005, ONCOGENE, V24, P585, DOI 10.1038/sj.onc.1208183; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Miller RA, 2001, CLIN CANCER RES, V7, P3215; Mizushima N, 2004, MOL BIOL CELL, V15, P1101, DOI 10.1091/mbc.E03-09-0704; Ng G, 2005, MOL CARCINOGEN, V43, P183, DOI 10.1002/mc.20097; O'Reilly MA, 2005, ANTIOXID REDOX SIGN, V7, P108, DOI 10.1089/ars.2005.7.108; Ogata M, 2006, MOL CELL BIOL, V26, P9220, DOI 10.1128/MCB.01453-06; Ohshiro K, 2008, AUTOPHAGY, V4, P104, DOI 10.4161/auto.5223; Opipari AW, 2004, CANCER RES, V64, P696, DOI 10.1158/0008-5472.CAN-03-2404; Reichman TW, 2005, J SURG ONCOL, V90, P51, DOI 10.1002/jso.20243; Roninson IB, 2001, DRUG RESIST UPDATE, V4, P303, DOI 10.1054/drup.2001.0213; Rudin CM, 2003, CANCER RES, V63, P312; Tsujimoto Y, 2005, CELL DEATH DIFFER, V12, P1528, DOI 10.1038/sj.cdd.4401777; Vernon CC, 1996, INT J RADIAT ONCOL, V35, P731; Verwaal VJ, 2003, J CLIN ONCOL, V21, P3737, DOI 10.1200/JCO.2003.04.187; Wang CC, 2007, SURGERY, V142, P384, DOI 10.1016/j.surg.2007.03.013; Yuki H, 2003, FREE RADICAL RES, V37, P631, DOI 10.1080/1071576031000088292	30	37	37	0	20	ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD	LONDON	24-28 OVAL RD, LONDON NW1 7DX, ENGLAND	1065-6995			CELL BIOL INT	Cell Biol. Int.	JUL	2008	32	7					715	723		10.1016/j.cellbi.2008.02.010			9	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	369CP	WOS:000260671400001	18396422				2022-04-25	
J	Fesler, A; Guo, SX; Liu, H; Wu, N; Ju, JF				Fesler, Andrew; Guo, Shixiang; Liu, Hua; Wu, Ning; Ju, Jingfang			Overcoming chemoresistance in cancer stem cells with the help of microRNAs in colorectal cancer	EPIGENOMICS			English	Article						apoptosis; autophagy; cancer stem cell; chemoresistance; chemotherapy; colorectal cancer; epigenetic; microenvironment; microRNA; stemness	COLON-CANCER; DIVISION; INHIBITION; EXPRESSION; AUTOPHAGY; DEATH	It has been recognized that acute resistance to chemotherapy mediated by post-transcriptional and translational control is crucial to influence response and survival in cancer treatment. Tumor cells are highly heterogeneous and have the ability to adapt a resistance phenotype through epigenetic regulations such as microRNAs. This poses a major challenge to the treatment of advanced stage colon cancer patients. Colon cancer stem cells have been identified as one of the major contributors to resistance of colon cancer to chemotherapy. Through various mechanisms, these cells are able to resist the effects of traditional chemotherapeutics. The challenge posed by these cells is further enhanced by their plastic nature, where cells can transition between non-stem cancer cells and cancer stem cells creating a moving target. In this editorial, we discuss some of the recent advancements in overcoming chemoresistance associated with colon cancer stem cells with the help of microRNAs.	[Fesler, Andrew; Guo, Shixiang; Liu, Hua; Wu, Ning; Ju, Jingfang] SUNY Stony Brook, Sch Med, Dept Pathol, Stony Brook, NY 11794 USA		Ju, JF (corresponding author), SUNY Stony Brook, Sch Med, Dept Pathol, Stony Brook, NY 11794 USA.	jingfang.ju@stonybrookmedicine.edu			National Institute of Health/National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA15501904, R01CA19709801]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA155019, R01CA197098] Funding Source: NIH RePORTER	This study was supported by National Institute of Health/National Cancer Institute R01CA15501904 (J Ju), R01CA19709801 (J Ju). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.	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J	Dai, XL; Liu, J; Nian, Y; Qiu, MH; Luo, Y; Zhang, JH				Dai, Xiaoli; Liu, Jing; Nian, Yin; Qiu, Ming-Hua; Luo, Ying; Zhang, Jihong			A novel cycloartane triterpenoid from Cimicifuga induces apoptotic and autophagic cell death in human colon cancer HT-29 cells	ONCOLOGY REPORTS			English	Article						Cimicifuga; apoptosis; autophagy; colon cancer cells	COLORECTAL-CANCER; RECEPTOR; PATHWAY	The extract from Cimicifuga, a genus of flowering plants, has been demonstrated to have mainly therapeutic effects on menstrual and menopausal symptoms and also exhibits immunomodulatory, anti-inflammatory and antimicrobial activity. Moreover, the anticancer effects of Cimicifuga have been reported, but the underlying mechanism causing cancer cell death has been poorly described. The present study was designed to investigate the antitumor effects and underlying molecular mechanisms of cimigenol (KY17), a novel cycloartane triterpenoid from Cimicifuga. KY17-induced autophagy and apoptotic cell death in human colon cancer cells (HT-29) was investigated. KY17 treatment induced growth inhibition and apoptotic cell death in a concentration-dependent manner. The induction of apoptosis was confirmed by a change in cell morphology, and an increase in the G2/M phase, as well as increased protein levels of cleaved-caspase-8 and -3; cleavage of poly(ADP-ribose) polymerase (PARP) in the HT-29 cells following KY17 treatment. In addition, autophagy was evaluated by the accumulation of acridine orange, the appearance of green fluorescent protein-light-chain 3 (LC3) punctate structures and increased levels of LC3-II protein expression. Furthermore, combination treatment with the autophagy inhibitor bafilomycin A1 enhanced the induction of apoptosis by KY17. Taken together, the present study provides new insight into the role of KY17 as a potential antitumor compound. Combination of KY17 with an autophagy inhibitor may be a valuable strategy for the chemoprevention or treatment of colon cancer.	[Dai, Xiaoli; Liu, Jing; Luo, Ying; Zhang, Jihong] Kunming Univ Sci & Technol, Fac Med, Lab Mol Genet Aging & Tumor, 727 Jing Ming Nan Rd, Kunming 650500, Yunnan, Peoples R China; [Nian, Yin; Qiu, Ming-Hua] Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China		Zhang, JH (corresponding author), Kunming Univ Sci & Technol, Fac Med, Lab Mol Genet Aging & Tumor, 727 Jing Ming Nan Rd, Kunming 650500, Yunnan, Peoples R China.	zhjihong2000@126.com	Luo, Ying/AAQ-7666-2020		Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81260501, 81560601, 81302670, U1202221]; Nature Science Foundation of Yunnan ProvinceNatural Science Foundation of Yunnan Province [KKSY201460043]	The present study was financially supported by the Natural Science Foundation of China (nos. 81260501, 81560601, 81302670 and U1202221) and the Nature Science Foundation of Yunnan Province (no. KKSY201460043).	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Rep.	APR	2017	37	4					2079	2086		10.3892/or.2017.5444			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EQ5QY	WOS:000398138900019	28260002	Bronze			2022-04-25	
J	Algehani, RA; Abou Khouzam, R; Hegazy, GA; Alamoudi, AA; El-Halawany, AM; El Dine, RS; Ajabnoor, GA; Al-Abbasi, FA; Baghdadi, MA; Elsayed, I; Hattori, M; Al-Abd, AM				Algehani, Rinad A.; Abou Khouzam, Raefa; Hegazy, Gehan A.; Alamoudi, Aliaa A.; El-Halawany, Ali M.; El Dine, Riham S.; Ajabnoor, Ghada A.; Al-Abbasi, Fahad A.; Baghdadi, Mohammed A.; Elsayed, Ibrahim; Hattori, Masao; Al-Abd, Ahmed M.			Colossolactone-G synergizes the anticancer properties of 5-fluorouracil and gemcitabine against colorectal cancer cells	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Colossolactone-G; Gemcitabine; 5-fluorouracil; Colorectal cancer; Apoptosis; Autophagy	COLON-CANCER; IN-VITRO; APOPTOSIS; AUTOPHAGY; RESISTANCE; CYTOTOXICITY; LEUCOVORIN; IRINOTECAN; BAX; DETERMINANTS	Several terpenoids were isolated from Ganoderma colossum with potential chemotherapeutic properties against different solid tumor cells. Herein, we further assessed the potential chemomodulatory effects of colossolactoneG to gemcitabine (GCB) and 5-fluorouracil (5-FU) against colorectal cancer cells. Colossolactone-G induced moderate cell killing effects against both HT-29 and HCT-116 cells, with IC50's of 90.5 +/- 1.7 mu M and 22.3 +/- 3.9 mu M, respectively. Equitoxic combination demonstrated a synergistic effect between colossolactone-G and GCB, or 5-FU with combination indices ranging from 0.22 to 0.67. Both GCB and 5-FU induced moderate cell cycle arrest at G0/G1-phase and S-phase. Despite colossolactone-G's lack of influence on cell cycle distribution, it significantly potentiated GCB- and 5-FU-induced cell cycle arrest. Similarly, colossolactone-G treatment alone did not induce pronounced apoptosis in both cell lines. However, 5-FU and GCB induced significant apoptosis which was further potentiated via combination with colossolactone-G. Furthermore, colossolactone-G significantly increased autophagic cell death response in both HCT-116 and HT-29 cells and potentiated 5-FU- and GCBinduced autophagic cell death. The influence of colossolactone-G alone or in combination with GCB or 5-FU on the apoptosis and autophagy were confirmed by qPCR analysis for the expression of several key apoptosis and autophagy genes such as, TRAIL, TP53INP1, BNIP3, hp62, ATG5, ATG7, Lamp2A and the golden standard for autophagy (LC3-II). In conclusion, a synergistic effect in terms of anticancer properties was observed when colossolactone-G was combined with 5-FU and GCB, where it influenced both apoptosis and autophagic cell death mechanisms.	[Algehani, Rinad A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Jeddah, Saudi Arabia; [Algehani, Rinad A.; Hegazy, Gehan A.; Alamoudi, Aliaa A.; Ajabnoor, Ghada A.] King Abdulaziz Univ, Fac Med, Clin Biochem Dept, Jeddah, Saudi Arabia; [Abou Khouzam, Raefa; Al-Abd, Ahmed M.] Gulf Med Univ, Thumbay Res Inst Precis Med, Ajman, U Arab Emirates; [Hegazy, Gehan A.; Al-Abd, Ahmed M.] Natl Res Ctr, Med Div, Giza, Egypt; [Hegazy, Gehan A.; Alamoudi, Aliaa A.] King Abdulaziz Univ, King Fahad Med Res Ctr, Regenerat Med Unit, Jeddah, Saudi Arabia; [El-Halawany, Ali M.; El Dine, Riham S.] Cairo Univ, Fac Pharm, Dept Pharmacognosy, Cairo, Egypt; [El-Halawany, Ali M.] Nawah Sci, Cairo, Egypt; [Al-Abbasi, Fahad A.] King Abdulaziz Univ, Fac Sci, Dept Biochem, Jeddah, Saudi Arabia; [Baghdadi, Mohammed A.] King Faisal Specialist Hosp & Res Ctr, Res Ctr, Jeddah, Saudi Arabia; [Elsayed, Ibrahim] Cairo Univ, Fac Pharm, Dept Pharmaceut & Ind Pharm, Cairo, Egypt; [Elsayed, Ibrahim; Al-Abd, Ahmed M.] Gulf Med Univ, Coll Pharm, Dept Pharmaceut Sci, PO 4184, Al Jurf, Ajman, U Arab Emirates; [Hattori, Masao] Univ Toyama, Inst Nat Med, Toyama, Japan		Al-Abd, AM (corresponding author), Gulf Med Univ, Coll Pharm, Dept Pharmaceut Sci, PO 4184, Al Jurf, Ajman, U Arab Emirates.	ahmedmalabd@pharma.asu.edu.eg	El-Halawany, Ali M./ABE-2550-2021	Al-Abbasi, Fahad/0000-0001-5609-4913; alamoudi, aliaa/0000-0001-5428-8853; Baghdadi, Mohammed A./0000-0003-1469-3074	King Abdulaziz City for Science and Technology (KACST), Saudi Arabia [1-17-03009-0004]	This research was financially supported by King Abdulaziz City for Science and Technology (KACST), Saudi Arabia, grant number (1-17-03009-0004).	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Pharmacother.	AUG	2021	140								111730	10.1016/j.biopha.2021.111730		MAY 2021	16	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	TE5YU	WOS:000670089200004	34062410	gold			2022-04-25	
J	Tan, SF; Shi, HJ; Ba, MC; Lin, SQ; Tang, HS; Zeng, XQ; Zhang, XL				Tan, Shifan; Shi, Huijuan; Ba, Mingchen; Lin, Shengqv; Tang, Hongsheng; Zeng, Xiaoqi; Zhang, Xiangliang			miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE			English	Article						autophagy; chemoresistance; colon cancer; microRNA	HEPATOCELLULAR-CARCINOMA CELLS; MALIGNANT GLIOMA-CELLS; COLORECTAL-CANCER; INDUCED APOPTOSIS; METASTASIS; CHEMOTHERAPY; RADIATION; CHEMORESISTANCE; CONTRIBUTES; BIOGENESIS	The chemoresistance of colon cancer cells limits the efficacy of chemotherapy. miR-409-3p has been shown to be downregulated in various types of cancer. In the present study, we examined the role of miR-409-3p in colon cancer as well as the effects of miR-409-3p on the sensitivity of colon cancer cells to oxaliplatin. The expression of miR-409 was significantly downregulated in the human colon cancer cell lines compared with the normal colon epithelial cells. Importantly, the miR-409-3p expression levels were lower in human colon cancer patient samples than in normal colon tissues. Moreover, we observed a negative correlation between the miR-409-3p levels and resistance to oxaliplatin: the oxaliplatin-resistant colon cancer cells exhibited significantly downregulated miR-409-3p levels, but higher autophagic activity than the oxaliplatin- sensitive cells. Using bioinformatics analysis, we predicted that miR-409-3p miRNA binds to the key autophagy gene encoding Beclin-1. Our findings indicated that the overexpression of miR-409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR-409-3p enhanced the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR-409-3p. In a xenograft model using nude mice, we examined the effects of miR-409-3p on tumor growth during chemotherapy. miR-409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1. The findings of our study suggest that miR-409-3p is capable of enhancing the chemosensitivity of colon cancer cells by inhibiting Beclin-1-mediated autophagy.	[Tan, Shifan; Ba, Mingchen; Lin, Shengqv; Tang, Hongsheng; Zeng, Xiaoqi; Zhang, Xiangliang] Guangzhou Med Univ, Affiliated Canc Hosp, Sect 2, Dept Abdominal Surg, 78 Hengzhigang Rd, Guangzhou 510095, Guangdong, Peoples R China; [Shi, Huijuan] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Pathol, Guangzhou 510080, Guangdong, Peoples R China		Zhang, XL (corresponding author), Guangzhou Med Univ, Affiliated Canc Hosp, Sect 2, Dept Abdominal Surg, 78 Hengzhigang Rd, Guangzhou 510095, Guangdong, Peoples R China.	zhxl7229@163.com			Guangdong Province Natural Science FundNational Natural Science Foundation of Guangdong Province [S2013010016662]; Health Bureau of Guangdong Province [A2014224, B2014196]; Science and Technology Planning Project of Guangdong Province [2013B021800284]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81201932, 81372493]	The present study was supported by funding from the Guangdong Province Natural Science Fund (no. S2013010016662), the Health Bureau of Guangdong Province (nos. A2014224 and B2014196), the Science and Technology Planning Project of Guangdong Province (no. 2013B021800284) and the National Natural Science Foundation of China (nos. 81201932 and 81372493).	Bartel DP, 2004, CELL, V116, P281, DOI 10.1016/S0092-8674(04)00045-5; Bonetti A, 2014, ANTICANCER RES, V34, P423; Chatterjee A, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0095716; Chen JM, 2014, MED ONCOL, V31, DOI 10.1007/s12032-013-0799-x; Chen MC, 2014, CANCER LETT, V349, P51, DOI 10.1016/j.canlet.2014.03.023; Chen YS, 2013, PATHOL RES PRACT, V209, P562, DOI 10.1016/j.prp.2013.06.006; Coker-Gurkan A, 2014, EXP CELL RES, V328, P87, DOI 10.1016/j.yexcr.2014.07.022; Fujiwara K, 2007, INT J ONCOL, V31, P753; Gordeev S. S., 2014, Voprosy Onkologii (St. Petersburg), V60, P18; He WS, 2012, ONCOL RES, V20, P251, DOI 10.3727/096504013X13589503483012; Helgason GV, 2013, ESSAYS BIOCHEM, V55, P133, DOI [10.1042/bse0550133, 10.1042/BSE0550133]; Herraez E, 2012, MOL PHARMACEUT, V9, P2565, DOI 10.1021/mp300178a; Josson S, 2015, ONCOGENE, V34, P2690, DOI 10.1038/onc.2014.212; Kang R, 2012, AM J OTOLARYNG, V33, P678, DOI 10.1016/j.amjoto.2012.05.005; Kim EJ, 2013, J CELL BIOCHEM, V114, P1248, DOI 10.1002/jcb.24465; Liu ML, 2015, J TRANSL MED, V13, DOI 10.1186/s12967-015-0533-x; Lomonaco SL, 2009, INT J CANCER, V125, P717, DOI 10.1002/ijc.24402; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038/nrm2239; Mendell JT, 2012, CELL, V148, P1172, DOI 10.1016/j.cell.2012.02.005; Mizushima N, 2002, CELL STRUCT FUNCT, V27, P421, DOI 10.1247/csf.27.421; Oh JS, 2010, INT J RADIAT ONCOL, V76, P5, DOI 10.1016/j.ijrobp.2009.08.028; Peng X, 2014, CELL DEATH DIS, V5, DOI 10.1038/cddis.2014.297; Song JR, 2011, J CELL BIOCHEM, V112, P3406, DOI 10.1002/jcb.23274; Song JR, 2009, AUTOPHAGY, V5, P1131, DOI 10.4161/auto.5.8.9996; Tai Jun, 2013, Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, V48, P499; Lopez PJT, 2014, CLIN MED INSIGHTS-GA, V7, P33, DOI 10.4137/CGast.S14039; Touil Y, 2014, CLIN CANCER RES, V20, P837, DOI 10.1158/1078-0432.CCR-13-1854; Walker AS, 2014, J CANCER, V5, P44, DOI 10.7150/jca.7809; Wang P, 2014, ONCOGENE, V33, P514, DOI 10.1038/onc.2012.598; Wang P, 2013, MOL ONCOL, V7, P334, DOI 10.1016/j.molonc.2012.10.011; Weng CH, 2012, CANCER LETT, V323, P171, DOI 10.1016/j.canlet.2012.04.010; Winter J, 2009, NAT CELL BIOL, V11, P228, DOI 10.1038/ncb0309-228; Xu X, 2013, MOL CELLS, V36, P62, DOI 10.1007/s10059-013-0044-7; Zhai H, 2013, ONCOGENE, V32, P1570, DOI 10.1038/onc.2012.167; Zhang XL, 2012, WORLD J GASTROENTERO, V18, P646, DOI 10.3748/wjg.v18.i7.646; Zheng B, 2012, ONCOGENE, V31, P4509, DOI 10.1038/onc.2011.581; Zhou Y, 2014, SCI REP-UK, V4, DOI 10.1038/srep05382; Zhuang WZ, 2009, ACTA BIOCH BIOPH SIN, V41, P341, DOI 10.1093/abbs/gmp028; Zou ZY, 2012, J BIOL CHEM, V287, P4148, DOI 10.1074/jbc.M111.307405	39	67	70	0	7	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1107-3756	1791-244X		INT J MOL MED	Int. J. Mol. Med.	APR	2016	37	4					1030	1038		10.3892/ijmm.2016.2492			9	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	DI4TS	WOS:000373492900018	26935807	Bronze			2022-04-25	
J	Xiong, L; Liu, ZP; Ouyang, GQ; Lin, LW; Huang, H; Kang, HX; Chen, W; Miao, XY; Wen, Y				Xiong, Li; Liu, Zhipeng; Ouyang, Guoqing; Lin, Liangwu; Huang, He; Kang, Hongxiang; Chen, Wei; Miao, Xiongying; Wen, Yu			Autophagy inhibition enhances photocytotoxicity of Photosan-II in human colorectal cancer cells	ONCOTARGET			English	Article						apoptosis; autophagy; photodynamic therapy; colorectal cancer; Photosan-II	THERAPY-INDUCED APOPTOSIS; DOUBLE-EDGED-SWORD; PHOTODYNAMIC THERAPY; IN-VIVO; RESISTANCE; RADIOTHERAPY; MODULATION; INITIATION; SURVIVAL; DEATH	Photodynamic therapy (PDT) has emerged as an attractive therapeutic treatment for colorectal cancer because of its accessibility through endoscopy and its ability to selectively target tumors without destroying the anatomical integrity of the colon. We therefore investigated the therapeutic relevance of the interplay between autophagy and apoptosis in Photosan-II (PS-II)-mediated photodynamic therapy (PS-PDT) in in vitro and in vivo models for human colorectal cancer. We observed that PS-PDT-induced dose-dependently triggered apoptosis and autophagy in both SW620 and HCT116 cells. PS-PDT-treated SW620 cells exhibited nuclear condensation and increased levels of cleaved caspase-3, PARP and Bax, which is reminiscent of apoptosis. PS-PDT also induced autophagic vacuoles, double membrane autophagosome structures and the autophagy-related proteins P62, Bcl-2, ATG7 and LC3-II. In addition, the AKT-mTOR pathway was downregulated, while AMPK was upregulated in PS-PDT-treated cells. Inhibiting autophagy using chloroquine or by downregulating ATG7 using shRNA further upregulated apoptosis, suggesting autophagy was probably was protective to PS-PDT-treated tumor cells. In vivo relevance was demonstrated when a combination of chloroquine and PS-PDT significantly reduced the tumor size in a xenograft mice model. Our findings demonstrate that combination therapy using PS-PDT and autophagy inhibitors may be an effective approach to treating colorectal cancer patients.	[Xiong, Li; Liu, Zhipeng; Ouyang, Guoqing; Miao, Xiongying; Wen, Yu] Cent South Univ, Xiangya Hosp 2, Dept Gen Surg, Changsha, Hunan, Peoples R China; [Lin, Liangwu] Cent South Univ, China State Key Lab Powder Met, Changsha, Hunan, Peoples R China; [Huang, He] Cent South Univ, Xiangya Sch Med, Dept Histol & Embryol, Changsha, Hunan, Peoples R China; [Kang, Hongxiang] Acad Mil Med Sci, Inst Radiat Med, Beijing, Peoples R China; [Chen, Wei] Univ Texas Arlington, Dept Phys, POB 19059, Arlington, TX 76019 USA		Wen, Y (corresponding author), Cent South Univ, Xiangya Hosp 2, Dept Gen Surg, Changsha, Hunan, Peoples R China.	1850129046@qq.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472738, 81372628, 81402536, 31571241, 31660266]; Planned Science and Technology Project of Hunan province [2015GK3117, 2014WK2016]; Changsha Science and Technology Plan [K1205018-31]; Innovation Project of Ministry of Science and Technology [X8C1Y0K9]	This work was supported by the National Natural Science Foundation of China (Grant Nos. 81472738, 81372628, 81402536, 31571241, 31660266), the Planned Science and Technology Project of Hunan province (Grant No. 2015GK3117, 2014WK2016), the Changsha Science and Technology Plan (K1205018-31), and the Innovation Project of Ministry of Science and Technology (Grant No. X8C1Y0K9).	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J	Estrada-Martinez, LE; Moreno-Celis, U; Cervantes-Jimenez, R; Ferriz-Martinez, RA; Blanco-Labra, A; Garcia-Gasca, T				Elena Estrada-Martinez, Laura; Moreno-Celis, Ulisses; Cervantes-Jimenez, Ricardo; Augusto Ferriz-Martinez, Roberto; Blanco-Labra, Alejandro; Garcia-Gasca, Teresa			Plant Lectins as Medical Tools against Digestive System Cancers	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Review						cancer; diagnosis tools; digestive system; plant lectins; therapeutic tools	KOREAN MISTLETOE LECTIN; ELECTROCHEMICAL IMPEDANCE SPECTROSCOPY; MEDIATED DRUG-DELIVERY; MANNOSE-BINDING LECTIN; A-INDUCED AUTOPHAGY; GASTRIC-CANCER; CONCANAVALIN-A; PANCREATIC-CANCER; ESOPHAGEAL ADENOCARCINOMA; IN-VITRO	Digestive system cancers-those of the esophagus, stomach, small intestine, colon-rectum, liver, and pancreas-are highly related to genetics and lifestyle. Most are considered highly mortal due to the frequency of late diagnosis, usually in advanced stages, caused by the absence of symptoms or masked by other pathologies. Different tools are being investigated in the search of a more precise diagnosis and treatment. Plant lectins have been studied because of their ability to recognize and bind to carbohydrates, exerting a variety of biological activities on animal cells, including anticancer activities. The present report integrates existing information on the activity of plant lectins on various types of digestive system cancers, and surveys the current state of research into their properties for diagnosis and selective treatment.	[Elena Estrada-Martinez, Laura; Moreno-Celis, Ulisses; Cervantes-Jimenez, Ricardo; Augusto Ferriz-Martinez, Roberto; Garcia-Gasca, Teresa] Univ Autonoma Queretaro, Fac Ciencias Nat, Santiago De Queretaro 76230, Queretaro, Mexico; [Blanco-Labra, Alejandro] CINVESTAV Unidad Irapuato, Unidad Bioquim & Biotecnol Plantas, Guanajuato 36821, Mexico		Garcia-Gasca, T (corresponding author), Univ Autonoma Queretaro, Fac Ciencias Nat, Santiago De Queretaro 76230, Queretaro, Mexico.	laurel_1610@hotmail.com; ulisses.morenoc@gmail.com; ricardocervantesjimenez@gmail.com; raffer712701@gmail.com; alejandroblancolabra@gmail.com; tggasca@uaq.edu.mx	Ferriz-Martínez, Roberto/Y-8923-2019; Blanco-Labra, Alejandro/K-9071-2019	Ferriz-Martínez, Roberto/0000-0002-2495-6985; GARCIA-GASCA, TERESA/0000-0002-8793-9963; Cervantes Jimenez, Ricardo/0000-0002-8951-4280; Moreno Celis, Ulisses/0000-0003-3751-6601	CONACYTConsejo Nacional de Ciencia y Tecnologia (CONACyT); CONACYT Ciencia Basica [CB-2014-01-241181]; PFCE; FOFI-UAQ	We thank CONACYT for the fellowship for Laura Elena Estrada-Martinez and the financial support of CONACYT Ciencia Basica (CB-2014-01-241181), PFCE-2016 and FOFI-UAQ 2015.	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J	Simone, C				Simone, Cristiano			Signal-dependent control of autophagy and cell death in colorectal cancer cell - The role of the p38 pathway	AUTOPHAGY			English	Article						autophagy; apoptosis; colorectal cancer cells; p38 alpha; programmed cell death type II	HUMAN COLON-CANCER; HT-29 CELLS; MACROAUTOPHAGY; PROTEIN; CHROMATIN; INHIBITION; ACTIVATION; APOPTOSIS; P38-ALPHA; KINASES	Autophogy is a vacuolar process leading to the degradation of long-lived proteins and cytoplasmic organelles in eukaryotes. This process has an important role in normal and cancer cells during adaptation to changing environmental conditions, cellular and tissue remodeling, and cell death. 1,2 To date, several signaling cascades have been described to regulate autophagy in a cell type-specific and signal-dependent manner.(3) We found that pharmacological blockade of the p38 pathway in colorectal cancer cells, either by the inhibitor SB202190 or by genetic ablation of p38 alpha kinase, causes cell cycle arrest and autophagic cell death.(4) In these cells, a complex network of intracellular kinase cascades controls autophagy and survival since the effect of p38 alpha blockade is differentially affected by the pharmacological inhibition of MEK1, Pl(3)K class I and III, and mTOR or by the differentiation status. Collectively, our results suggest an opportunity for exploiting the pharmacological manipulation of the p38 alpha pathway in the treatment of colorectal cancer. Given the number of drugs, currently available or under development, that target the p38 pathway, it stands to reason that elucidating the molecular mechanisms that link p38 and autophagy might have an impact on the clinical translation of these drugs.	Univ Bari, Div Med Genet, Dept Biomed Childhood, I-70124 Bari, Italy; Temple Univ, Coll Sci & Technol, Ctr Biotechnol, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 USA		Simone, C (corresponding author), Univ Bari, Div Med Genet, Dept Biomed Childhood, Piazza G Cesare 11, I-70124 Bari, Italy.	csimone@temple.edu	Simone, Cristiano/K-3452-2018	Simone, Cristiano/0000-0002-2628-7658			Arico S, 2001, J BIOL CHEM, V276, P35243, DOI 10.1074/jbc.C100319200; Botti J, 2006, AUTOPHAGY, V2, P67, DOI 10.4161/auto.2.2.2458; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Chow CW, 2006, CELL, V127, P887, DOI 10.1016/j.cell.2006.11.015; Comes F, 2007, CELL DEATH DIFFER, V14, P693, DOI 10.1038/sj.cdd.4402076; Corcelle E, 2007, AUTOPHAGY, V3, P57, DOI 10.4161/auto.3424; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; Edmunds JW, 2006, SCIENCE, V313, P449, DOI 10.1126/science.1131158; Hiramoto T, 1999, ONCOGENE, V18, P3422, DOI 10.1038/sj.onc.1202691; HOURI JJ, 1993, BIOCHEM BIOPH RES CO, V197, P805, DOI 10.1006/bbrc.1993.2550; Inoki K, 2005, NAT GENET, V37, P19, DOI 10.1038/ng1494; Jin SK, 2007, AUTOPHAGY, V3, P28, DOI 10.4161/auto.3269; Klionsky DJ, 2007, AUTOPHAGY, V3, P181, DOI 10.4161/auto.3678; Kuwamura H, 2007, ONCOL REP, V17, P781; Lee MR, 2005, CURR MED CHEM, V12, P2979, DOI 10.2174/092986705774462914; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Liang C, 2006, NAT CELL BIOL, V8, P688, DOI 10.1038/ncb1426; Lin ZS, 2004, MOL CELL PROTEOMICS, V3, P820, DOI 10.1074/mcp.M400008-MCP200; Marx J, 2006, SCIENCE, V312, P1160, DOI 10.1126/science.312.5777.1160; Moinova HR, 2002, P NATL ACAD SCI USA, V99, P4562, DOI 10.1073/pnas.062459899; Pattingre S, 2003, J BIOL CHEM, V278, P16667, DOI 10.1074/jbc.M210998200; Petiot A, 2000, J BIOL CHEM, V275, P992, DOI 10.1074/jbc.275.2.992; Simone C, 2006, J CELL PHYSIOL, V207, P309, DOI 10.1002/jcp.20514; Simone C, 2004, NAT GENET, V36, P738, DOI 10.1038/ng1378; Tassa A, 2003, BIOCHEM J, V376, P577, DOI 10.1042/BJ20030826; Tsujimoto Y, 2005, CELL DEATH DIFFER, V12, P1528, DOI 10.1038/sj.cdd.4401777; vom Dahl S, 2001, BIOCHEM J, V354, P31, DOI 10.1042/0264-6021:3540031; Yorimitsu T, 2005, CELL DEATH DIFFER, V12, P1542, DOI 10.1038/sj.cdd.4401765	28	39	39	1	4	LANDES BIOSCIENCE	GEORGETOWN	810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA	1554-8627			AUTOPHAGY	Autophagy	SEP-OCT	2007	3	5					468	471		10.4161/auto.4319			4	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	201DR	WOS:000248812200009	17495519	Bronze			2022-04-25	
J	Adiseshaiah, PP; Clogston, JD; McLeland, CB; Rodriguez, J; Potter, TM; Neun, BW; Skoczen, SL; Shanmugavelandy, SS; Kester, M; Stern, ST; McNeil, SE				Adiseshaiah, Pavan P.; Clogston, Jeffrey D.; McLeland, Christopher B.; Rodriguez, Jamie; Potter, Timothy M.; Neun, Barry W.; Skoczen, Sarah L.; Shanmugavelandy, Sriram S.; Kester, Mark; Stern, Stephan T.; McNeil, Scott E.			Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models	CANCER LETTERS			English	Article						Combination therapy; Autophagy; Ceramide	PORCINE KIDNEY-CELLS; INDUCED APOPTOSIS; TARGETING AUTOPHAGY; TUMOR-GROWTH; CERAMIDE; TUMORIGENESIS; CYTOTOXICITY; INDUCTION; DELIVERY; BCL-2	Autophagy, a catabolic survival pathway, is gaining attention as a potential target in cancer. In human liver and colon cancer cells, treatment with an autophagy inducer, nanoliposomal C6-ceramide, in combination with the autophagy maturation inhibitor, vinblastine, synergistically enhanced apoptotic cell death. Combination treatment resulted in a marked increase in autophagic vacuole accumulation and decreased autophagy maturation, without diminution of the autophagy flux protein P62. In a colon cancer xenograft model, a single intravenous injection of the drug combination significantly decreased tumor growth in comparison to the individual treatments. Most importantly, the combination treatment did not result in increased toxicity as assessed by body weight loss. The mechanism of combination treatment-induced cell death both in vitro and in vivo appeared to be apoptosis. Supportive of autophagy flux blockade as the underlying synergy mechanism, treatment with other autophagy maturation inhibitors, but not autophagy initiation inhibitors, were similarly synergistic with C6-ceramide. Additionally, knockout of the autophagy protein Beclin-1 suppressed combination treatment-induced apoptosis in vitro. In conclusion, in vitro and in vivo data support a synergistic antitumor activity of the nanoliposomal C6-ceramide and vinblastine combination, potentially mediated by an autophagy mechanism. (C) 2013 Elsevier Ireland Ltd. All rights reserved.	[Adiseshaiah, Pavan P.; Clogston, Jeffrey D.; McLeland, Christopher B.; Rodriguez, Jamie; Potter, Timothy M.; Neun, Barry W.; Skoczen, Sarah L.; Stern, Stephan T.; McNeil, Scott E.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA; [Shanmugavelandy, Sriram S.; Kester, Mark] Penn State Univ, Dept Pharmacol, Coll Med, Hershey, PA 17033 USA		Stern, ST (corresponding author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA.	sternstephan@mail.nih.gov	Clogston, Jeffrey Dean/AAE-8982-2022; Adiseshaiah, Pavan/R-3917-2018; Kester, Mark/ABG-4615-2020; Nanotechnology Characterization Lab, (NCL)/K-8454-2012	Clogston, Jeffrey Dean/0000-0003-1860-9271; McNeil, Scott/0000-0002-7575-5198	National Cancer Institute, National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [HHSN261200800001E]; Ebberly Fund of Penn State College of Medicine	This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The project was also funded, in part (MK), through support from the Ebberly Fund of Penn State College of Medicine.	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SEP 1	2013	337	2					254	265		10.1016/j.canlet.2013.04.034			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	201JP	WOS:000323138200013	23664889	Green Accepted			2022-04-25	
J	Klose, J; Trefz, S; Wagner, T; Steffen, L; Charrier, AP; Radhakrishnan, P; Volz, C; Schmidt, T; Ulrich, A; Dieter, SM; Ball, C; Glimm, H; Schneider, M				Klose, Johannes; Trefz, Stefan; Wagner, Tobias; Steffen, Luca; Charrier, Arsalie Preissendorfer; Radhakrishnan, Praveen; Volz, Claudia; Schmidt, Thomas; Ulrich, Alexis; Dieter, Sebastian M.; Ball, Claudia; Glimm, Hanno; Schneider, Martin			Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model	PLOS ONE			English	Article							STEM-CELLS; INITIATING CELLS; GROWTH; APOPTOSIS; ANTICANCER; AUTOPHAGY; PEROXISOMES; METABOLISM	Objectives Salinomycin is a polyether antibiotic with selective activity against human cancer stem cells. The impact of salinomycin on patient-derived primary human colorectal cancer cells has not been investigated so far. Thus, here we aimed to investigate the activity of salinomycin against tumor initiating cells isolated from patients with colorectal cancer. Methods Primary tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma were exposed to salinomycin and compared to treatment with 5-FU and oxaliplatin. TICs were injected subcutaneously into NOD/SCID mice to induce a patient-derived mouse xenograft model of colorectal cancer. Animals were treated either with salinomycin, FOLFOX regimen, or salinomycin and FOLFOX. Human colorectal cancer cells were used to delineate an underlying molecular mechanism of salinomycin in this tumor entity. Results Applying TICs isolated from human patients with colorectal liver metastases or from human primary colon carcinoma, we demonstrated that salinomycin exerts increased antiproliferative activity compared to 5-fluorouracil and oxaliplatin treatment. Consistently, salinomycin alone or in combination with FOLFOX exerts superior antitumor activity compared to FOLFOX therapy in a patient-derived mouse xenograft model of colorectal cancer. Salinomycin induces apoptosis of human colorectal cancer cells, accompanied by accumulation of dysfunctional mitochondria and reactive oxygen species. These effects are associated with expressional down-regulation of superoxide dismutase-1 (SOD1) in response to salinomycin treatment. Conclusion Collectively, the results of this pre-clinical study indicate that salinomycin alone or in combination with 5-fluorouracil and oxaliplatin exerts increased antitumoral activity compared to common chemotherapy.	[Klose, Johannes; Trefz, Stefan; Wagner, Tobias; Steffen, Luca; Charrier, Arsalie Preissendorfer; Radhakrishnan, Praveen; Volz, Claudia; Schmidt, Thomas; Ulrich, Alexis; Schneider, Martin] Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany; [Dieter, Sebastian M.; Glimm, Hanno] Natl Ctr Tumor Dis NCT Heidelberg, Translat Funct Canc Genom, Heidelberg, Germany; [Dieter, Sebastian M.; Glimm, Hanno] German Canc Res Ctr, Heidelberg, Germany; [Ball, Claudia; Glimm, Hanno] Natl Ctr Tumor Dis NCT Dresden, Dept Translat Med Oncol, Dresden, Germany; [Ball, Claudia; Glimm, Hanno] German Canc Res Ctr, Dresden, Germany; [Glimm, Hanno] Tech Univ Dresden, Univ Hosp Carl Gustav Carus Dresden, Ctr Personalized Oncol, Dresden, Germany; [Glimm, Hanno] German Consortium Translat Canc Res DKTK Dresden, Dresden, Germany		Klose, J (corresponding author), Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany.	Johannes.Klose@med.uni-heidelberg.de	Schmidt, Thomas/Y-8431-2019	Schmidt, Thomas/0000-0002-7166-3675; Ball, Claudia/0000-0002-1749-3791; Dieter, Sebastian/0000-0003-1324-7638	DFGGerman Research Foundation (DFG)European Commission [KL-2843/2-1]; Deutsche Krebshilfe (German Cancer Aid)Deutsche Krebshilfe; Colon-Resist-Net	This work was supported by DFG grant KL-2843/2-1 to Johannes Klose and by Deutsche Krebshilfe (German Cancer Aid) and Colon-Resist-Net to Claudia Ball and Hanno Glimm. The funder had no role in study design, data collection and analysis, decision to publish, or presentation of the manuscript.	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J	Celesia, A; Morana, O; Fiore, T; Pellerito, C; D'Anneo, A; Lauricella, M; Carlisi, D; De Blasio, A; Calvaruso, G; Giuliano, M; Emanuele, S				Celesia, Adriana; Morana, Ornella; Fiore, Tiziana; Pellerito, Claudia; D'Anneo, Antonella; Lauricella, Marianna; Carlisi, Daniela; De Blasio, Anna; Calvaruso, Giuseppe; Giuliano, Michela; Emanuele, Sonia			ROS-Dependent ER Stress and Autophagy Mediate the Anti-Tumor Effects of Tributyltin (IV) Ferulate in Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						tributyltin (IV) derivative; ROS; oxidative stress; endoplasmic reticulum stress; autophagic cell death	OXIDATIVE STRESS; TRANSCRIPTION FACTOR; KEAP1-NRF2 PATHWAY; DUAL ROLE; APOPTOSIS; P62/SQSTM1; ACTIVATION; CROSSTALK; GENE; NRF2	Organotin compounds represent potential cancer therapeutics due to their pro-apoptotic action. We recently synthesized the novel organotin ferulic acid derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays anti-tumor properties in colon cancer cells related with autophagic cell death. The purpose of the present study was to elucidate the mechanism of TBT-F action in colon cancer cells. We specifically show that TBT-F-dependent autophagy is determined by a rapid generation of reactive oxygen species (ROS) and correlated with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silencing by RNA interference markedly increased the anti-tumor efficacy of the compound. Moreover, as a consequence of ROS production, TBT-F increased the levels of glucose regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP), two ER stress markers. Interestingly, Grp78 silencing produced significant decreasing effects on the levels of the autophagic proteins p62 and LC3-II, while only p62 decreased in CHOP-silenced cells. Taken together, these results indicate that ROS-dependent ER stress and autophagy play a major role in the TBT-F action mechanism in colon cancer cells and open a new perspective to consider the compound as a potential candidate for colon cancer treatment.	[Celesia, Adriana; Lauricella, Marianna; Carlisi, Daniela; Emanuele, Sonia] Univ Palermo, Dept Biomed Neurosci & Adv Diagnost Bind, Biochem Bldg,Via Vespro 129, I-90127 Palermo, Italy; [Morana, Ornella; D'Anneo, Antonella; De Blasio, Anna; Calvaruso, Giuseppe; Giuliano, Michela] Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol STEBICE, Lab Biochem, Via Vespro 129, I-90127 Palermo, Italy; [Fiore, Tiziana; Pellerito, Claudia] Univ Palermo, Dept Phys & Chem Emilio Segre DiFC, Viale Sci,Bldg 17, I-90128 Palermo, Italy; [Fiore, Tiziana; Pellerito, Claudia] Interuniv Consortium Res Chem Met Ions Biol Syst, Piazza Umberto 1, I-170121 Bari, Italy		Emanuele, S (corresponding author), Univ Palermo, Dept Biomed Neurosci & Adv Diagnost Bind, Biochem Bldg,Via Vespro 129, I-90127 Palermo, Italy.; Giuliano, M (corresponding author), Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol STEBICE, Lab Biochem, Via Vespro 129, I-90127 Palermo, Italy.	adriana.celesia@unipa.it; ornella.morana@gmail.com; tiziana.fiore@unipa.it; claudia.pellerito@unipa.it; antonella.danneo@unipa.it; marianna.lauricella@unipa.it; daniela.carlisi@unipa.it; anna.deblasio@unipa.it; giuseppe.calvaruso@unipa.it; michela.giuliano@unipa.it; sonia.emanuele@unipa.it		FIORE, Tiziana/0000-0002-0604-2696; LAURICELLA, Marianna/0000-0002-0157-3834; GIULIANO, Michela/0000-0002-5114-6267; DE BLASIO, Anna/0000-0003-2208-0366; D'ANNEO, Antonella/0000-0002-1785-8236; CARLISI, Daniela/0000-0002-5833-7904	Funding for Basic Activities Related to Research (Ministero dell'Istruzione, dell'Universita e della Ricerca), Italy [FFR-D15_006475]; Agenzia di Sviluppo della Sicilia Occidentale (ASSO s.r.l) [PJ_FUNZ_ATT_COMM_FLAG_D15-FLAG 2018]	This research was funded in part by the Funding for Basic Activities Related to Research (Ministero dell'Istruzione, dell'Universita e della Ricerca (FFR-D15_006475, 2018/2021), Italy, and by Agenzia di Sviluppo della Sicilia Occidentale (ASSO s.r.l, PJ_FUNZ_ATT_COMM_FLAG_D15-FLAG 2018).	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J. Mol. Sci.	NOV	2020	21	21							8135	10.3390/ijms21218135			16	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	OQ9WV	WOS:000589128000001	33143349	Green Published, gold			2022-04-25	
J	Chiou, SK; Hoa, N; Ge, LS; Jadus, MR				Chiou, Shiun-Kwei; Hoa, Neil; Ge, Lisheng; Jadus, Martin R.			Nutrient Availability Alters the Effect of Autophagy on Sulindac Sulfide-Induced Colon Cancer Cell Apoptosis	GASTROENTEROLOGY RESEARCH AND PRACTICE			English	Article							BECLIN 1; SURVIVIN; NSAIDS; DEATH; INHIBITION; MECHANISM; MODEL	Autophagy is a catabolic process by which a cell degrades its intracellular materials to replenish itself. Induction of autophagy under various cellular stress stimuli can lead to either cell survival or cell death via apoptotic and/or autophagic (nonapoptotic) pathways. The NSAID sulindac sulfide induces apoptosis in colon cancer cells. Here, we show that inhibition of autophagy under serum-deprived conditions resulted in significant reductions of sulindac sulfide-induced apoptosis in HT-29 colon cancer cells. In contrast, inhibition of autophagy under conditions where serum is available significantly increased sulindac sulfide-induced apoptosis in HT-29 cells. We previously showed that the apoptosis inhibitor, survivin, plays a role in regulating NSAID-induced apoptosis and autophagic cell death. Here, we show that survivin protein half-life is increased in the presence of autophagy inhibitors under serum-deprived conditions, but not under conditions when serum is available. Thus, the increased levels of survivin may be a factor contributing to inhibition of sulindac sulfide-induced apoptosis under serum-deprived conditions. These results suggest that whether a cell lives or dies due to autophagy induction depends on the balance of factors that regulate both autophagic and apoptotic processes.	[Chiou, Shiun-Kwei; Hoa, Neil; Ge, Lisheng; Jadus, Martin R.] Vet Affairs Med Ctr, Div Res, Long Beach, CA 90822 USA; [Chiou, Shiun-Kwei] Univ Calif Irvine, Dept Med, Orange, CA 92868 USA; [Jadus, Martin R.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, UCI Pathol Dept, Irvine, CA 92697 USA; [Jadus, Martin R.] Univ Calif Irvine, UC Irvine Sch Med, Chao Comprehens Canc Ctr, Neurooncol Program, Orange, CA 92868 USA		Chiou, SK (corresponding author), Vet Affairs Med Ctr, Div Res, 5901 E 7th St, Long Beach, CA 90822 USA.	shiun-kwei.chiou@va.gov			VA Merit Review awardUS Department of Veterans Affairs; SCIRE small grant	This work was funded by the VA Merit Review award, and the SCIRE small grant to S.-K. Chiou.	Abeliovich H, 2000, J CELL BIOL, V151, P1025, DOI 10.1083/jcb.151.5.1025; Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Bauvy C, 2001, EXP CELL RES, V268, P139, DOI 10.1006/excr.2001.5285; Bjorkoy G, 2005, J CELL BIOL, V171, P603, DOI 10.1083/jcb.200507002; Chiou SK, 2007, BIOCHEM PHARMACOL, V74, P1485, DOI 10.1016/j.bcp.2007.07.024; Chiou SK, 2011, BIOCHEM PHARMACOL, V81, P1317, DOI 10.1016/j.bcp.2011.03.019; Dalby KN, 2010, AUTOPHAGY, V6, P322, DOI 10.4161/auto.6.3.11625; Debnath J, 2005, AUTOPHAGY, V1, P66, DOI 10.4161/auto.1.2.1738; Gump JM, 2011, TRENDS CELL BIOL, V21, P387, DOI 10.1016/j.tcb.2011.03.007; Gupta A, 2010, P NATL ACAD SCI USA, V107, P14333, DOI 10.1073/pnas.1000248107; Ichimura Y, 2000, NATURE, V408, P488, DOI 10.1038/35044114; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Kroemer G, 2008, NAT REV MOL CELL BIO, V9, P1004, DOI 10.1038/nrm2529; Kuma A, 2002, J BIOL CHEM, V277, P18619, DOI 10.1074/jbc.M111889200; Lepine S, 2011, J BIOL CHEM, V286, P44380, DOI 10.1074/jbc.M111.257519; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Mandayam S, 2007, APOPTOSIS, V12, P1109, DOI 10.1007/s10495-006-0011-2; Mirzoeva OK, 2011, J MOL MED, V89, P877, DOI 10.1007/s00109-011-0774-y; MORTIMORE GE, 1987, ANNU REV NUTR, V7, P539, DOI 10.1146/annurev.nu.07.070187.002543; Niu TK, 2010, FEBS LETT, V584, P3519, DOI 10.1016/j.febslet.2010.07.018; Pattingre S, 2008, BIOCHIMIE, V90, P313, DOI 10.1016/j.biochi.2007.08.014; Pfaffl MW, 2001, NUCLEIC ACIDS RES, V29, DOI 10.1093/nar/29.9.e45; Saiki S, 2011, AUTOPHAGY, V7, P176, DOI 10.4161/auto.7.2.14074; Tanida I, 2004, J BIOL CHEM, V279, P47704, DOI 10.1074/jbc.M407016200; Thorburn A, 2008, APOPTOSIS, V13, P1, DOI 10.1007/s10495-007-0154-9; Zhang T, 2004, J PHARMACOL EXP THER, V308, P434, DOI 10.1124/jpet.103.059378	27	2	2	0	2	HINDAWI LTD	LONDON	ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND	1687-6121	1687-630X		GASTROENT RES PRACT	Gastroenterol. Res. Pract.		2012	2012								897678	10.1155/2012/897678			9	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	054AS	WOS:000312317000001	23431290	gold, Green Published			2022-04-25	
J	Thyagarajan, A; Jedinak, A; Nguyen, H; Terry, C; Baldridge, LA; Jiang, JH; Sliva, D				Thyagarajan, Anita; Jedinak, Andrej; Nguyen, Hai; Terry, Colin; Baldridge, Lee Ann; Jiang, Jiahua; Sliva, Daniel			Triterpenes From Ganoderma Lucidum Induce Autophagy in Colon Cancer Through the Inhibition of p38 Mitogen-Activated Kinase (p38 MAPK)	NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL			English	Article							WATER-SOLUBLE EXTRACT; CELL-CYCLE ARREST; REI-SHI MYCELIA; HUMAN BREAST; POLYSACCHARIDES ENHANCE; CULTURED MEDIUM; LUNG-CANCER; TUMOR-CELLS; APOPTOSIS; MUSHROOM	Medicinal mushroom Ganoderma lucidum is one of the most esteemed natural products that have been used in the traditional Chinese medicine. In this article, we demonstrate that G. lucidum triterpene extract (GLT) suppresses proliferation of human colon cancer cells HT-29 and inhibits tumor growth in a xenograft model of colon cancer. These effects of GLT are associated with the cell cycle arrest at G0/G1 and the induction of the programmed cell death Type II-autophagy in colon cancer cells. Here, we show that GLT induces formation of autophagic vacuoles and upregulates expression of Beclin-1 (1.3-fold increase) and LC-3 (7.3-fold increase) proteins in colon cancer cells and in tumors in a xenograft model (Beclin-1, 3.9-fold increase; LC-3, 1.9-fold increase). Autophagy is mediated through the inhibition of p38 mitogen-activated protein kinase (p38 MAPK) because p38 MAPK inhibitor, SB202190, induces autophagy and expression of Beclin-1 (1.2-fold increase) and LC-3 (7.4-fold increase), and GLT suppresses phosphorylation of p38 MAPK (approximate to 60% inhibition) in colon cancer cells. Taken together, our data demonstrate a novel mechanism responsible for the inhibition of colon cancer cells by G. lucidum and suggest GLT as natural product for the treatment of colon cancer.	[Sliva, Daniel] Methodist Res Inst, Canc Res Lab, Indianapolis, IN 46202 USA; [Baldridge, Lee Ann; Sliva, Daniel] Indiana Univ, Sch Med, Indianapolis, IN USA		Sliva, D (corresponding author), Methodist Res Inst, Canc Res Lab, 1800 N Capitol Ave,E504, Indianapolis, IN 46202 USA.	dsliva@clarian.org	Jedinak, Andrej/AAB-7354-2020		Methodist Research Institute, Clarian Health, Inc.	This work was supported by the Methodist Research Institute, Clarian Health, Inc. We thank Shailesh Dudhgaonkar for his help with animal experiments.	CHANG AW, 1999, INT J MED MUSHROOMS, V1, P139; Cheung KL, 2008, AAPS J, V10, P277, DOI 10.1208/s12248-008-9032-9; Comes F, 2007, CELL DEATH DIFFER, V14, P693, DOI 10.1038/sj.cdd.4402076; Ellington AA, 2006, CARCINOGENESIS, V27, P298, DOI 10.1093/carcin/bgi214; Ellington AA, 2005, CARCINOGENESIS, V26, P159, DOI 10.1093/carcin/bgh297; Gao JJ, 2002, CHEM PHARM BULL, V50, P837, DOI 10.1248/cpb.50.837; Gao YH, 2005, J MED FOOD, V8, P159, DOI 10.1089/jmf.2005.8.159; Gao YH, 2003, FOOD REV INT, V19, P275, DOI 10.1081/FRI-120023480; Hong KJ, 2004, PHYTOTHER RES, V18, P768, DOI 10.1002/ptr.1495; Hsu CL, 2008, J AGR FOOD CHEM, V56, P3973, DOI 10.1021/jf800006u; Hu HB, 2002, INT J CANCER, V102, P250, DOI 10.1002/ijc.10707; Hua KF, 2007, J CELL PHYSIOL, V212, P537, DOI 10.1002/jcp.21050; Jemal A, 2009, CA-CANCER J CLIN, V59, P225, DOI 10.3322/caac.20006; Jiang JH, 2004, NUTR CANCER, V49, P209, DOI 10.1207/s15327914nc4902_13; Jiang JH, 2004, INT J ONCOL, V24, P1093; Jiang JH, 2006, INT J ONCOL, V29, P695; Kim HJ, 2002, INT J CANCER, V97, P531, DOI 10.1002/ijc.10111; Kirkegaard K, 2004, NAT REV MICROBIOL, V2, P301, DOI 10.1038/nrmicro865; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Lee S, 1998, PLANTA MED, V64, P303, DOI 10.1055/s-2006-957439; Li CJ, 2006, NAT PROD RES, V20, P985, DOI 10.1080/14786410600921466; Li CH, 2005, LIFE SCI, V77, P252, DOI 10.1016/j.lfs.2004.09.045; Li CJ, 2005, NAT PROD RES, V19, P461, DOI 10.1080/14786410412331272077; Li EK, 2007, ARTHRIT RHEUM-ARTHR, V57, P1143, DOI 10.1002/art.22994; LIEU CW, 1992, ANTICANCER RES, V12, P1211; LIN CN, 1991, J NAT PROD, V54, P998, DOI 10.1021/np50076a012; Lin KI, 2006, J BIOL CHEM, V281, P24111, DOI 10.1074/jbc.M601106200; Lin ZB, 2005, J PHARMACOL SCI, V99, P144, DOI 10.1254/jphs.CRJ05008X; Liu J, 2006, BIOL PHARM BULL, V29, P392, DOI 10.1248/bpb.29.392; Lu HM, 2003, ONCOL REP, V10, P375; Lu HM, 2002, INT J MOL MED, V9, P113; LUI B, 2008, CANC LETT; Ma JY, 2002, J NAT PROD, V65, P72, DOI 10.1021/np010385e; Min BS, 2000, CHEM PHARM BULL, V48, P1026; Muller CI, 2006, LEUKEMIA RES, V30, P841, DOI 10.1016/j.leukres.2005.12.004; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; SEGLEN PO, 1982, P NATL ACAD SCI-BIOL, V79, P1889, DOI 10.1073/pnas.79.6.1889; Singletary K, 2008, CANCER EPIDEM BIOMAR, V17, P1596, DOI 10.1158/1055-9965.EPI-07-2917; Sliva D, 2003, J ALTERN COMPLEM MED, V9, P491, DOI 10.1089/107555303322284776; Sliva D, 2001, CANCER INVEST, V19, P783, DOI 10.1081/CNV-100107739; Stanley G, 2005, BIOCHEM BIOPH RES CO, V330, P46, DOI 10.1016/j.bbrc.2005.02.116; Tang GM, 2008, HUM MOL GENET, V17, P1540, DOI 10.1093/hmg/ddn042; Tang W, 2006, LIFE SCI, V80, P205, DOI 10.1016/j.lfs.2006.09.001; Thyagarajan A, 2006, INT J MOL MED, V18, P657; TOTH JO, 1983, TETRAHEDRON LETT, V24, P1081; Wachtel-Galor S, 2004, BRIT J NUTR, V91, P263, DOI 10.1079/BJN20041039; Wang SY, 1997, INT J CANCER, V70, P699, DOI 10.1002/(SICI)1097-0215(19970317)70:6&lt;699::AID-IJC12&gt;3.0.CO;2-5; Wasser SP, 2005, ENCY DIETARY SUPPLEM, P603; World Cancer Research Fund and American Institute for Cancer Rsearch, 2007, FOOD NUTR PHYS ACT P; Wu TS, 2001, J NAT PROD, V64, P1121, DOI 10.1021/np010115w; Xu ZX, 2007, CELL DEATH DIFFER, V14, P1948, DOI 10.1038/sj.cdd.4402207; Yuen JWM, 2008, NUTR CANCER, V60, P109, DOI 10.1080/01635580701525869; Zhu M, 1999, PHYTOTHER RES, V13, P529, DOI 10.1002/(SICI)1099-1573(199909)13:6&lt;529::AID-PTR481&gt;3.0.CO;2-X; Zhu XL, 2007, J ETHNOPHARMACOL, V111, P219, DOI 10.1016/j.jep.2006.11.013	54	87	101	5	37	LAWRENCE ERLBAUM ASSOC INC-TAYLOR & FRANCIS	PHILADELPHIA	325 CHESTNUT STREET, STE 800, PHILADELPHIA, PA 19106 USA	0163-5581			NUTR CANCER	Nutr. Cancer		2010	62	5					630	640	PII 923265873	10.1080/01635580903532390			11	Oncology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Nutrition & Dietetics	615FS	WOS:000279120100009	20574924				2022-04-25	
J	Liu, J; Long, SY; Wang, HN; Liu, NN; Zhang, CC; Zhang, LL; Zhang, YJ				Liu, Jing; Long, Shuaiyu; Wang, Huanan; Liu, Nannan; Zhang, Chuchu; Zhang, Lingling; Zhang, Yingjie			Blocking AMPK/ULK1-dependent autophagy promoted apoptosis and suppressed colon cancer growth	CANCER CELL INTERNATIONAL			English	Article						Colon cancer; Autophagy; Apoptosis; NVP-BEZ235; CQ	ADVANCED SOLID TUMORS; PHASE-I TRIAL; COLORECTAL-CANCER; MTOR; AMPK; NVP-BEZ235; INHIBITOR; PATHWAY; CELLS; HYDROXYCHLOROQUINE	Background Autophagy is an evolutionarily conserved process through which cells degrade and recycle cytoplasm. The relation among autophagy, apoptosis and tumor is highly controversial until now and the molecular mechanism is poorly understood. Methods Cell viability and apoptosis were detected by CCK8, crystal violet staining, Hoechst333342 staining and flow cytometry. The expression of AMPK and ULK1 was analyzed by western blotting. Colon cancer growth suppression by NVP-BEZ235 or CQ in vivo was studied in a tumor xenograft mouse model. Results Our previous study revealed that NVP-BEZ235 suppressed colorectal cancer growth via inducing apoptosis, however later, we found it also initiated autophagy simultaneously. In this present study, our results show that NVP-BEZ235 induced autophagy through AMPK/ULK1 pathway in colon cancer cells. Blocking autophagy by knocking down AMPK or ULK1 inhibited cell proliferation and further promoted NVP-BEZ235 induced apoptosis. Meantime, the autophagy inhibitor chloroquine (CQ) shows obvious effect on inhibiting cell proliferation but not on inducing apoptosis, while it significantly increased NVP-BEZ235 induced apoptosis. Furthermore, the combinational therapy of NVP-BEZ235 and CQ shows synergistic antitumor effects in colon cancer in vivo. Conclusion NVP-BEZ235 induced AMPK/ULK1-dependent autophagy. Targeting this autophagy suppressed colon cancer growth through further promoting apoptosis, which is a potential therapeutic option for clinical patients.	[Liu, Jing; Long, Shuaiyu; Liu, Nannan; Zhang, Chuchu; Zhang, Yingjie] Hunan Univ, Coll Biol, Changsha 410082, Hunan, Peoples R China; [Wang, Huanan; Zhang, Lingling] Cent S Univ, Xiangya Hosp 3, Dept Lab Med, Changsha 410013, Peoples R China; [Wang, Huanan] Zhejiang Univ, Coll Anim Sci, Dept Vet Med, Hangzhou, Peoples R China; [Zhang, Yingjie] Hunan Univ, Shenzhen Inst, Shenzhen, Peoples R China		Zhang, YJ (corresponding author), Hunan Univ, Coll Biol, Changsha 410082, Hunan, Peoples R China.; Zhang, YJ (corresponding author), Hunan Univ, Shenzhen Inst, Shenzhen, Peoples R China.	yingjiezhang@hnu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31801140, 31701132, 31602118]; Basic Research Program of Shenzhen Municipal Science and Technology Innovation Committee [JCYJ20160530192802733]; Fundamental Research Funds for the Central South Universities [531118040098, 14700-502044001]; College of Biology, Hunan University	We would like to thank the support of the National Natural Science Foundation of China (31801140, 31701132 and 31602118), the Basic Research Program of Shenzhen Municipal Science and Technology Innovation Committee (JCYJ20160530192802733), the Fundamental Research Funds for the Central South Universities (Nos. 531118040098 and 14700-502044001), and the start funds from College of Biology, Hunan University.	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DEC 13	2019	19	1							336	10.1186/s12935-019-1054-0			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	KK3LN	WOS:000512647900001	31871431	Green Published, gold			2022-04-25	
J	Pajak, B; Kania, E; Gajkowska, B; Orzechowski, A				Pajak, Beata; Kania, Elzbieta; Gajkowska, Barbara; Orzechowski, Arkadiusz			Verapamil-induced autophagy-like process in colon adenocarcinoma COLO 205 cells; the ultrastructural studies	PHARMACOLOGICAL REPORTS			English	Article						verapamil; autophagy; transmission electron microscopy; colon cancer; cell death	ENDOPLASMIC-RETICULUM STRESS; CANCER; PROTEIN; DEATH; PROTEASOME	Background: Verapamil (Ver) is a well known, worldwide used drug to correct cardiac arrhythmias. The main Ver target is the L-type calcium channel. Modulation of calcium homeostasis vaulted Ver into use in medical applications. Methods: To examine COLO 205 cells morphology after Ver treatment, an electron microscopy technique was used. Results: This study shows ultrastructural evidence that Ver initiates autophagy-like process in human colon adenocarcinoma COLO 205 cells. TEM photographs revealed the presence of differently developed autophagic vacuoles in response to Ver administration. Furthermore, extensive ultrastructural cell alterations confirmed that cancer cells died via necrosis or apoptosis, as demonstrated by ruptured plasma membrane or condensed chromatin, respectively. Conclusions: It is the evidence that apoptosis resistant COLO 205 cells are overruled by autophagy-like process. Autophagy-like cell death could be a promising venue to delete cancer cells. Ver appears to be a new potentially effective anticancer compound.	[Pajak, Beata; Kania, Elzbieta; Gajkowska, Barbara; Orzechowski, Arkadiusz] Polish Acad Sci, Mossakowski Med Res Ctr, PL-02105 Warsaw, Poland; [Orzechowski, Arkadiusz] Warsaw Univ Life Sci SGGW, Fac Vet Med, Dept Physiol Sci, PL-02776 Warsaw, Poland		Pajak, B (corresponding author), Polish Acad Sci, Mossakowski Med Res Ctr, Pawinskiego 5, PL-02105 Warsaw, Poland.	bepaj@wp.pl		Pajak, Beata/0000-0002-3565-8860	Ministry of Science and Higher Education in PolandMinistry of Science and Higher Education, Poland [NN 401 031 538]; Ministry of Science and Higher Education For Young Outstanding Scientists in PolandMinistry of Science and Higher Education, Poland	Support for this work was provided by grant No. NN 401 031 538 from the Ministry of Science and Higher Education in Poland. Beata Pajak is granted by fellowship from the Ministry of Science and Higher Education For Young Outstanding Scientists in Poland.	Borges NCD, 2005, J CHROMATOGR B, V827, P165, DOI 10.1016/j.jchromb.2005.07.012; Capiod T., 2007, V45, P405; Chen X, 2002, J BIOL CHEM, V277, P13045, DOI 10.1074/jbc.M110636200; Ding WX, 2008, AUTOPHAGY, V4, P141, DOI 10.4161/auto.5190; Kuo TC, 2011, BIOCHEM PHARMACOL, V81, P1136, DOI 10.1016/j.bcp.2011.02.013; Loza J, 1995, BONE S4, V16, p314S; Malhotra JD, 2007, ANTIOXID REDOX SIGN, V9, P2277, DOI 10.1089/ars.2007.1782; Meister S, 2010, NEOPLASIA, V12, P550, DOI 10.1593/neo.10228; Notte A, 2011, BIOCHEM PHARMACOL, V82, P427, DOI 10.1016/j.bcp.2011.06.015; Pajak B, 2007, ANTI-CANCER DRUG, V18, P55, DOI 10.1097/CAD.0b013e32800fee9e; Pajak Beata, 2004, Postepy Hig Med Dosw (Online), V58, P428; Sun Y, 2009, POSTGRAD MED J, V85, P134, DOI 10.1136/pgmj.2008.072629; Suwalsky M, 2010, J CHIL CHEM SOC, V55, P1, DOI 10.4067/S0717-97072010000100002; Ugocsai K, 2005, IN VIVO, V19, P433; Wagner-Souza K, 2008, INT J MOL MED, V22, P237, DOI 10.3892/ijmm_00000014; Wang XT, 2000, AM J PATHOL, V157, P1549, DOI 10.1016/S0002-9440(10)64792-X; Zhang KZ, 2008, NATURE, V454, P455, DOI 10.1038/nature07203	17	14	14	0	4	POLISH ACAD SCIENCES INST PHARMACOLOGY	KRAKOW	SMETNA 12, 31-343 KRAKOW, POLAND	1734-1140			PHARMACOL REP	Pharmacol. Rep.	JUL-AUG	2012	64	4					991	996					6	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	028KF	WOS:000310420500024	23087153				2022-04-25	
J	An, CH; Kim, MS; Yoo, NJ; Park, SW; Lee, SH				An, Chang Hyeok; Kim, Min Sung; Yoo, Nam Jin; Park, Sang Wook; Lee, Sug Hyung			Mutational and expressional analyses of ATG5, an autophagy-related gene, in gastrointestinal cancers	PATHOLOGY RESEARCH AND PRACTICE			English	Article						ATG5; Autophagy; Mutation; Expression; Cancer	INACTIVATING MUTATIONS; MICROSATELLITE INSTABILITY; APOPTOSIS; DEATH; CARCINOMAS; NECROSIS; ROLES	There is mounting evidence that alterations of cell death processes are involved in cancer pathogenesis. ATG5 is a key regulator of autophagic and apoptotic cell death. The aim of this study was to see whether alterations of ATG5 protein expression and somatic mutation of ATG5 gene are features of human gastrointestinal cancers. In this study, we analyzed ATG5 somatic mutation in 45 gastric, 45 colorectal, and 45 hepatocellular carcinomas by single-strand conformation polymorphism (SSCP). Also, we analyzed ATG5 protein expression in 100 gastric, as well as in 95 colorectal and hepatocellular carcinomas using immunohistochemistry. Overall, we detected two somatic missense mutations of ATG5 gene in the coding sequences p.Leu112Phe and p.His41Tyr. The mutations were observed in one gastric and one hepatocellular carcinoma. Immunohistochemically, ATG5 protein was well expressed in normal stomach, colon, and liver epithelial cells, while it was lost in 21 (21%) of the gastric carcinomas, in 22 (23%) of the colorectal carcinomas, and in 5 (10%) of the hepatocellular carcinomas. Our data suggest that ATG5 gene could be altered in gastrointestinal cancers at the mutational or expressional level. Despite the low incidences of the alterations, our data led us to conclude that somatic mutation and loss of expression of ATG5 gene might play a role in gastrointestinal cancer pathogenesis by altering autophagic and apoptotic cell death. (C) 2011 Elsevier GmbH. All rights reserved.	[Kim, Min Sung; Yoo, Nam Jin; Park, Sang Wook; Lee, Sug Hyung] Catholic Univ Korea, Coll Med, Dept Pathol, Seoul, South Korea; [An, Chang Hyeok] Catholic Univ Korea, Coll Med, Dept Gen Surg, Seoul, South Korea		Lee, SH (corresponding author), Catholic Univ Korea, Coll Med, Dept Pathol, Seoul, South Korea.	suhulee@catholic.ac.kr			National Research Foundation of KoreaNational Research Foundation of Korea [2009-007-1498]	This study was supported by a grant from National Research Foundation of Korea (2009-007-1498).	Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Baehrecke EH, 2005, NAT REV MOL CELL BIO, V6, P505, DOI 10.1038/nrm1666; Edinger AL, 2004, CURR OPIN CELL BIOL, V16, P663, DOI 10.1016/j.ceb.2004.09.011; Hammond EM, 1998, FEBS LETT, V425, P391, DOI 10.1016/S0014-5793(98)00266-X; Hanahan D, 2000, CELL, V100, P57, DOI 10.1016/S0092-8674(00)81683-9; Kang MR, 2009, J PATHOL, V217, P702, DOI 10.1002/path.2509; Kim HS, 2003, GASTROENTEROLOGY, V125, P708, DOI 10.1016/S0016-5085(03)01059-X; Kim MS, 2008, HUM PATHOL, V39, P1059, DOI 10.1016/j.humpath.2007.11.013; Klionsky DJ, 2007, NAT REV MOL CELL BIO, V8, P931, DOI 10.1038/nrm2245; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Lee JW, 2007, APMIS, V115, P750, DOI 10.1111/j.1600-0463.2007.apm_640.x; Lee JW, 2004, CARCINOGENESIS, V25, P1371, DOI 10.1093/carcin/bgh145; Lee SH, 1999, ONCOGENE, V18, P3754, DOI 10.1038/sj.onc.1202769; LEITHAUSER F, 1993, LAB INVEST, V69, P415; MARX J, 2001, HUM PATHOL, V32, P461; Pattingre S, 2005, CELL, V122, P927, DOI 10.1016/j.cell.2005.07.002; Pyo JO, 2005, J BIOL CHEM, V280, P20722, DOI 10.1074/jbc.M413934200; Reed JC, 2000, AM J PATHOL, V157, P1415, DOI 10.1016/S0002-9440(10)64779-7; Shin MS, 2002, BLOOD, V99, P4094, DOI 10.1182/blood.V99.11.4094; Tanida I, 2002, J BIOL CHEM, V277, P13739, DOI 10.1074/jbc.M200385200; Yousefi S, 2006, NAT CELL BIOL, V8, P1124, DOI 10.1038/ncb1482	21	54	59	0	11	ELSEVIER GMBH, URBAN & FISCHER VERLAG	JENA	OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY	0344-0338			PATHOL RES PRACT	Pathol. Res. Pract.		2011	207	7					433	437		10.1016/j.prp.2011.05.002			5	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	802GJ	WOS:000293497000006	21664058				2022-04-25	
J	Salesse, L; Lucas, C; Hoang, MHT; Sauvanet, P; Rezard, A; Rosenstiel, P; Damon-Soubeyrand, C; Barnich, N; Godfraind, C; Dalmasso, G; Nguyen, HTT				Salesse, Laurene; Lucas, Cecily; Hoang, My Hanh Thi; Sauvanet, Pierre; Rezard, Alexandra; Rosenstiel, Philip; Damon-Soubeyrand, Christelle; Barnich, Nicolas; Godfraind, Catherine; Dalmasso, Guillaume; Nguyen, Hang Thi Thu			Colibactin-Producing Escherichia coli Induce the Formation of Invasive Carcinomas in a Chronic Inflammation-Associated Mouse Model	CANCERS			English	Article						colorectal cancer; microbiota; colibactin-producing E; coli; autophagy; toxin	AUTOPHAGY-RELATED SIGNATURE; COLORECTAL-CANCER; TUMOR-GROWTH; MICROBIOTA; CARCINOGENESIS; IDENTIFICATION; GENES; GUT	Simple Summary Changes in the composition of the intestinal flora have been reported in patients with colorectal cancer, the second leading cause of cancer death in the world, with an increase in so-called "harmful" bacteria. Among these, Escherichia coli producing colibactin, a toxin that causes DNA damage, has attracted the interest of many research groups. Here, we showed that infection of wild-type mice with a colibactin-producing E. coli (CoPEC) strain, isolated from a patient with colorectal cancer, combined with chronic inflammation induced the formation of invasive colonic tumors, i.e., tumors that spread beyond epithelial layer and grow into surrounding tissues. We also showed that autophagy, a cell defense process, is necessary to inhibit the tumorigenesis induced by CoPEC. Thus, this work highlights the role of CoPEC as a driver of colorectal cancer development, and suggests that targeting autophagy could be a promising strategy to inhibit the protumoral effects of these bacteria. Background: Escherichia coli producing the genotoxin colibactin (CoPEC or colibactin-producing E. coli) abnormally colonize the colonic mucosa of colorectal cancer (CRC) patients. We previously showed that deficiency of autophagy in intestinal epithelial cells (IECs) enhances CoPEC-induced colorectal carcinogenesis in Apc(Min/+) mice. Here, we tested if CoPEC trigger tumorigenesis in a mouse model lacking genetic susceptibility or the use of carcinogen. Methods: Mice with autophagy deficiency in IECs (Atg16l1( increment IEC)) or wild-type mice (Atg16l1(flox/flox)) were infected with the CoPEC 11G5 strain or the mutant 11G5 increment clbQ incapable of producing colibactin and subjected to 12 cycles of DSS treatment to induce chronic colitis. Mouse colons were used for histological assessment, immunohistochemical and immunoblot analyses for DNA damage marker. Results: 11G5 or 11G5 increment clbQ infection increased clinical and histological inflammation scores, and these were further enhanced by IEC-specific autophagy deficiency. 11G5 infection, but not 11G5 increment clbQ infection, triggered the formation of invasive carcinomas, and this was further increased by autophagy deficiency. The increase in invasive carcinomas was correlated with enhanced DNA damage and independent of inflammation. Conclusions: CoPEC induce colorectal carcinogenesis in a CRC mouse model lacking genetic susceptibility and carcinogen. This work highlights the role of (i) CoPEC as a driver of CRC development, and (ii) autophagy in inhibiting the carcinogenic properties of CoPEC.	[Salesse, Laurene; Lucas, Cecily; Hoang, My Hanh Thi; Sauvanet, Pierre; Rezard, Alexandra; Barnich, Nicolas; Godfraind, Catherine; Dalmasso, Guillaume; Nguyen, Hang Thi Thu] Univ Clermont Auvergne, M2iSH, UMR 1071 Inserm, INRAE USC 2018,CRNH, F-63001 Clermont Ferrand, France; [Hoang, My Hanh Thi] Vietnam Natl Univ VNU, Univ Sci, Dept Cell Biol, Fac Biol, Hanoi 100000, Vietnam; [Sauvanet, Pierre] CHU Estaing, Dept Digest & Hepatobiliary Surg, F-63001 Clermont Ferrand, France; [Rosenstiel, Philip] Univ Kiel, Inst Clin Mol Biol, D-24148 Kiel, Germany; [Rosenstiel, Philip] Univ Hosp Schleswig Holstein, D-24148 Kiel, Germany; [Damon-Soubeyrand, Christelle] Univ Clermont Auvergne, CNRS UMR 6293 INSERM U110, GReD, F-63001 Clermont Ferrand, France; [Godfraind, Catherine] CHU Gabriel Montpied, Dept Pathol, F-63001 Clermont Ferrand, France		Nguyen, HTT (corresponding author), Univ Clermont Auvergne, M2iSH, UMR 1071 Inserm, INRAE USC 2018,CRNH, F-63001 Clermont Ferrand, France.	laurene.salesse@uca.fr; cecily.lucas@uca.fr; thi_my_hanh.hoang@uca.fr; pierre.sauvanet@uca.fr; alexandra.rezard@uca.fr; p.rosenstiel@mucosa.de; christelle.soubeyrand-damon@uca.fr; nicolas.barnich@uca.fr; cgodfraind@chu-clermontferrand.fr; guillaume.dalmasso@uca.fr; hang.nguyen@uca.fr	Nguyen, Hang/N-2441-2018	Nguyen, Hang/0000-0001-7431-5126; Lucas, Cecily/0000-0002-4276-723X	Ministere de la Recherche et de la Technologie, Inserm (Institut national de la sante et de la recherche medicale) [UMR1071]; Agence Nationale de la Recherche of the French government through the program "Investissements d'Avenir"French National Research Agency (ANR) [16-IDEX-0001 I-SITE CAP 20-25]; European Union FP7 People Marie Curie International Incoming Fellowship; DFG (Deutsche Forschungsgemeinschaft) ExC Precision Medicine in Chronic InflammationGerman Research Foundation (DFG); INRAE (Institut national de recherche en agriculture, alimentation et environnement; USC 2018)	This research was funded by the Ministere de la Recherche et de la Technologie, Inserm (Institut national de la sante et de la recherche medicale; UMR1071), INRAE (Institut national de recherche en agriculture, alimentation et environnement; USC 2018), the Agence Nationale de la Recherche of the French government through the program "Investissements d'Avenir" (16-IDEX-0001 I-SITE CAP 20-25) (to Hang Nguyen), the European Union FP7 People Marie Curie International Incoming Fellowship (to Hang Nguyen) and the DFG (Deutsche Forschungsgemeinschaft) ExC Precision Medicine in Chronic Inflammation and the CRC1182 project C2 (to Philip Rosenstiel).	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J	Che, J; Wang, WS; Huang, Y; Zhang, L; Zhao, J; Zhang, P; Yuan, XL				Che, Jing; Wang, Wenshan; Huang, Yu; Zhang, Lu; Zhao, Jing; Zhang, Peng; Yuan, Xianglin			miR-20a inhibits hypoxia-induced autophagy by targeting ATG5/FIP200 in colorectal cancer	MOLECULAR CARCINOGENESIS			English	Article						ATG5; autophagy; colorectal cancer; FIP200; hypoxia; miR-20a	COLON-CANCER; REGULATES AUTOPHAGY; BREAST-CANCER; MICROENVIRONMENT; CONTRIBUTES; METASTASIS; MACHINERY; FIP200; PROGRESSION; STARVATION	Autophagy is a highly conserved lysosome-mediated protective cellular process in which cytosolic components, including damaged organelles and long-lived proteins, are cleared. Many studies have shown that autophagy was upregulated in hypoxic regions. However, the precise molecular mechanism of hypoxia-induced autophagy in colorectal cancer (CRC) is still elusive. In this study, we found that miR-20a was significantly downregulated under hypoxia in colon cancer cells, and overexpression of miR-20a alleviated hypoxia-induced autophagy. Moreover, miR-20a inhibits the hypoxia-induced autophagic flux by targeting multiple key regulators of autophagy, including ATG5 and FIP200. Furthermore, by dual-luciferase assay we demonstrated that miR-20a directly targeted the 3 '-untranslated region of ATG5 and FIP200, regulating their messenger RNA and protein levels. In addition, reintroduction of exogenous ATG5 or FIP200 partially reversed miR-20a-mediated autophagy inhibition under hypoxia. A negative correlation between miR-20a and its target genes is observed in the hypoxic region of colon cancer tissues. Taken together, our findings suggest that hypoxia-mediated autophagy was regulated by miR-20a/ATG5/FI200 signaling pathway in CRC. miR-20a-mediated autophagy defect that might play an important role in hypoxia-induced autophagy during colorectal tumorigenesis.	[Che, Jing; Huang, Yu; Zhang, Lu; Zhao, Jing; Zhang, Peng; Yuan, Xianglin] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Oncol, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China; [Che, Jing] Wuhan Univ, Coll Life Sci, Natl Demonstrat Ctr Expt Biol, Wuhan, Hubei, Peoples R China; [Wang, Wenshan] Univ Penn, Dept Cell & Dev Biol, Inst Diabet Obes & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA		Zhang, P (corresponding author), Huazhong Univ Sci & Technol, Tongji Hosp, Dept Oncol, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China.	pengzhang@tjh.tjmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81202095, 81441087]	National Natural Science Foundation of China, Grant/Award Numbers: 81202095, 81441087	Azab AK, 2012, BLOOD, V119, P5782, DOI 10.1182/blood-2011-09-380410; Bracken CP, 2016, NAT REV GENET, V17, P719, DOI 10.1038/nrg.2016.134; Brenner H, 2014, LANCET, V383, P1490, DOI 10.1016/S0140-6736(13)61649-9; Caporarello N, 2017, MOL MED REP, V16, P4393, DOI 10.3892/mmr.2017.7179; 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Zhang Y, 2014, CARDIOVASC RES, V102, P68, DOI 10.1093/cvr/cvu011	65	20	21	8	16	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0899-1987	1098-2744		MOL CARCINOGEN	Mol. Carcinog.	JUL	2019	58	7					1234	1247		10.1002/mc.23006			14	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	IC2KR	WOS:000470789200013	30883936				2022-04-25	
J	Lee, JH; Yun, CW; Han, YS; Kim, S; Jeong, D; Kwon, HY; Kim, H; Baek, MJ; Lee, SH				Lee, Jun Hee; Yun, Chul Won; Han, Yong-Seok; Kim, SangMin; Jeong, Dongjun; Kwon, Hyog Young; Kim, Hyeongjoo; Baek, Moo-Jun; Lee, Sang Hun			Melatonin and 5-fluorouracil co-suppress colon cancer stem cells by regulating cellular prion protein-Oct4 axis	JOURNAL OF PINEAL RESEARCH			English	Article						cancer stem cell; cellular prion protein; melatonin; Oct4	EPITHELIAL-MESENCHYMAL TRANSITION; HEAT-SHOCK PROTEINS; TUMOR PROGRESSION; OCT4; AUTOPHAGY; APOPTOSIS; EXPRESSION; CARCINOMA; PROMOTES; INHIBITION	Melatonin suppresses tumor development. However, the exact relationship between melatonin and cancer stem cells (CSCs) is poorly understood. This study found that melatonin inhibits colon CSCs by regulating the PrPC-Oct4 axis. In specimens from patients with colorectal cancer, the expressions of cellular prion protein (PrPC) and Oct4 were significantly correlated with metastasis and tumor stages. Co-treatment with 5-fluorouracil (5-FU) and melatonin inhibited the stem cell markers Oct4, Nanog, Sox2, and ALDH1A1 by downregulating PrPC. In this way, tumor growth, proliferation, and tumor-mediated angiogenesis were suppressed. In colorectal CSCs, PRNP overexpression protects Oct4 against inhibition by 5-FU and melatonin. In contrast, Nanog, Sox2, and ALDH1A1 have no such protection. These results indicate that PrPC directly regulates Oct4, whereas it indirectly regulates Nanog, Sox2, and ALDH1A1. Taken together, our findings suggest that co-treatment with anticancer drug and melatonin is a potential therapy for colorectal cancer. Furthermore, PrPC maintains cancer stemness during tumor progression. Therefore, targeting the PrPC-Oct4 axis may prove instrumental in colorectal cancer therapy.	[Lee, Jun Hee] Univ Alabama Birmingham, Sch Med, Dept Pharmacol & Toxicol, Birmingham, AL USA; [Yun, Chul Won; Han, Yong-Seok; Kim, SangMin; Lee, Sang Hun] Soonchunhyang Univ, Seoul Hosp, Med Sci Res Inst, Seoul, South Korea; [Jeong, Dongjun] Soonchunhyang Univ, Coll Med, Dept Pathol, Cheonan, South Korea; [Kwon, Hyog Young] Soonchunhyang Univ, Soonchunhyang Inst Medi Bio Sci SIMS, Cheonan, South Korea; [Kim, Hyeongjoo] Soonchunhyang Univ, Coll Med, Soonchunhyang Med Sci Res Inst, Cheonan, South Korea; [Baek, Moo-Jun] Soonchunhyang Univ, Coll Med, Dept Surg, Cheonan, South Korea; [Lee, Sang Hun] Soonchunhyang Univ, Coll Med, Dept Biochem, Cheonan, South Korea		Lee, SH (corresponding author), Soonchunhyang Univ, Seoul Hosp, Med Sci Res Inst, Seoul, South Korea.	jhlee0407@sch.ac.kr; ykckss1114@nate.com	Baek, Moo-Jun/W-1736-2019; lee, sang hun/Q-4650-2019	Baek, Moo-Jun/0000-0003-3567-6687; lee, sang hun/0000-0002-9005-5966	National Research Foundation of KoreaNational Research Foundation of Korea [NRF2016R1D-1A3B01007727, NRF2017M3A9B4032528]	National Research Foundation of Korea, Grant/Award Number: NRF2016R1D-1A3B01007727 and NRF2017M3A9B4032528	BOUSQUET PF, 1995, CANCER RES, V55, P1176; Bu PC, 2013, CELL STEM CELL, V12, P602, DOI 10.1016/j.stem.2013.03.002; Buldak RJ, 2015, MOL MED REP, V12, P2275, DOI 10.3892/mmr.2015.3599; Casado-Zapico S, 2010, J PINEAL RES, V48, P72, DOI 10.1111/j.1600-079X.2009.00727.x; Cheng YY, 2014, MOL CARCINOGEN, V53, P686, DOI 10.1002/mc.22021; Dai XZ, 2013, ONCOL REP, V29, P155, DOI 10.3892/or.2012.2086; de Wit M, 2012, GUT, V61, P855, DOI 10.1136/gutjnl-2011-300511; Du L, 2013, CANCER RES, V73, P2682, DOI 10.1158/0008-5472.CAN-12-3759; Esch D, 2013, NAT CELL BIOL, V15, P295, DOI 10.1038/ncb2680; Ferlay J, 2013, EUR J CANCER, V49, P1374, DOI 10.1016/j.ejca.2012.12.027; Garcia JJ, 2014, J PINEAL RES, V56, P225, DOI 10.1111/jpi.12128; Hong Y, 2014, J PINEAL RES, V56, P264, DOI 10.1111/jpi.12119; Hu TS, 2008, CANCER RES, V68, P6533, DOI 10.1158/0008-5472.CAN-07-6642; Iglesia RP, 2017, STEM CELL RES THER, V8, DOI 10.1186/s13287-017-0518-1; Izumiya M, 2012, ANTICANCER RES, V32, P3847; Jan JE, 2009, J PINEAL RES, V46, P1, DOI 10.1111/j.1600-079X.2008.00628.x; Kim KJ, 2013, J PINEAL RES, V54, P264, DOI 10.1111/j.1600-079X.2012.01030.x; Kim Ran-Ju, 2011, Lab Anim Res, V27, P147, DOI 10.5625/lar.2011.27.2.147; Kreso A, 2014, CELL STEM CELL, V14, P275, DOI 10.1016/j.stem.2014.02.006; Lee JH, 2017, ONCOGENE, V36, P6555, DOI 10.1038/onc.2017.263; Lee JH, 2018, BIOMOL THER, V26, P313, DOI 10.4062/biomolther.2017.033; Lee JH, 2018, ANTICANCER RES, V38, P1993, DOI 10.21873/anticanres.12437; Leon J, 2014, J PINEAL RES, V56, P415, DOI 10.1111/jpi.12131; Li QQ, 2009, CELL MOL LIFE SCI, V66, P504, DOI 10.1007/s00018-008-8548-6; Li QQ, 2011, CANCER SCI, V102, P400, DOI 10.1111/j.1349-7006.2010.01811.x; Lianos GD, 2015, CANCER LETT, V360, P114, DOI 10.1016/j.canlet.2015.02.026; Lin YJ, 2012, MOL CELL, V48, P627, DOI 10.1016/j.molcel.2012.08.030; Linden R, 2012, CELL MOL LIFE SCI, V69, P1105, DOI 10.1007/s00018-011-0847-7; Lopes MH, 2015, ONCOGENE, V34, P3305, DOI 10.1038/onc.2014.261; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; Martin-Lanneree S, 2014, FRONT CELL DEV BIOL, V2, DOI 10.3389/fcell.2014.00055; Mirzaei MR, 2016, CELL J, V17, P608; Peralta OA, 2011, DIFFERENTIATION, V81, P68, DOI 10.1016/j.diff.2010.09.181; Plaimee P, 2015, CELL PROLIFERAT, V48, P67, DOI 10.1111/cpr.12158; Ricci-Vitiani L, 2007, NATURE, V445, P111, DOI 10.1038/nature05384; Santos TG, 2015, PRION, V9, P165, DOI 10.1080/19336896.2015.1027855; Siegel RL, 2017, CA-CANCER J CLIN, V67, P7, DOI 10.3322/caac.21387; Singh BN, 2012, BIOCHEM PHARMACOL, V84, P1154, DOI 10.1016/j.bcp.2012.08.007; Su SC, 2017, J PINEAL RES, V62, DOI 10.1111/jpi.12370; Su ZY, 2015, MOL CANCER, V14, DOI 10.1186/s12943-015-0321-5; Wang QW, 2012, ONCOL REP, V28, P2029, DOI 10.3892/or.2012.2025; Wang XQ, 2010, HEPATOLOGY, V52, P528, DOI 10.1002/hep.23692; Wang YJ, 2015, AM J PHYSIOL-CELL PH, V309, pC709, DOI 10.1152/ajpcell.00212.2015; Weissmann C, 2004, NAT REV MICROBIOL, V2, P861, DOI 10.1038/nrmicro1025; Wen KM, 2013, CANCER LETT, V333, P56, DOI 10.1016/j.canlet.2013.01.009; White E, 2012, NAT REV CANCER, V12, P401, DOI 10.1038/nrc3262; Yin X, 2015, J HEMATOL ONCOL, V8, DOI 10.1186/s13045-015-0119-3; Young MM, 2012, J BIOL CHEM, V287, P12455, DOI 10.1074/jbc.M111.309104; Zomosa-Signoret V, 2008, VET RES, V39, DOI 10.1051/vetres:2007048	49	57	58	1	20	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0742-3098	1600-079X		J PINEAL RES	J. Pineal Res.	NOV	2018	65	4							e12519	10.1111/jpi.12519			16	Endocrinology & Metabolism; Neurosciences; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Endocrinology & Metabolism; Neurosciences & Neurology; Physiology	GX8YF	WOS:000448081600004	30091203				2022-04-25	
J	Phan, T; Nguyen, VH; Salazar, MA; Wong, P; Diamond, DJ; Yim, JH; Melstrom, LG				Phan, Thuy; Nguyen, Vu H.; Salazar, Marcela A'lincourt; Wong, Paul; Diamond, Don J.; Yim, John H.; Melstrom, Laleh G.			Inhibition of Autophagy Amplifies Baicalein-Induced Apoptosis in Human Colorectal Cancer	MOLECULAR THERAPY-ONCOLYTICS			English	Article							PROTEIN-KINASE; COLON-CANCER; CELL-DEATH; PATHWAY; TNFRSF10C; VIRUS	Baicalein is a Chinese herbal compound extracted from Scutel-laria baicalensis that has anti-tumor properties. The aim of this study was to elucidate the mechanisms of action of baicalein against human colorectal cancer cell lines and to assess whether the anti-proliferative effects of baicalein may be amplified with autophagy inhibition. Human colon cancer cell lines (HT-29, HCT-116, SW480, and SW620) were treated with baicalein alone and in combination with the autophagy inhibitor chloroquine (CQ). Baicalein reduced cell viability in all four colon cancer lines in a dose-dependent fashion. Combination treatment of baicalein and the autophagy inhibitor CQ significantly decreased cell viability compared with baicalein alone in HT-29 and HCT-116 cell lines. Western blot analysis of the HCT-116 cell line treated with both baicalein and CQ demonstrated increased expression of LC3-II, a component of autophagy. The combination of baicalein with CQ culminated in activation of caspase-3-mediated apoptosis. These findings demonstrate that inhibition of autophagy enhanced apoptotic cell death induced by baicalein treatment in colon cancer cell lines. Future work will assess other targetable apoptotic pathways activated by baicalein and autophagy inhibition.	[Phan, Thuy; Wong, Paul; Yim, John H.; Melstrom, Laleh G.] City Hope Med Ctr, Dept Surg, 1500 E Duarte Rd, Duarte, CA 91010 USA; [Melstrom, Laleh G.] City Hope Med Ctr, Dept Immunooncol, Duarte, CA 91010 USA; [Nguyen, Vu H.; Salazar, Marcela A'lincourt; Diamond, Don J.] City Hope Med Ctr, Dept Hematol, Duarte, CA 91010 USA		Melstrom, LG (corresponding author), City Hope Med Ctr, Dept Surg, 1500 E Duarte Rd, Duarte, CA 91010 USA.	lmelstrom@coh.org		Wong, Paul/0000-0002-5833-0331			Advani S, 2019, J SURG ONCOL, V119, P642, DOI 10.1002/jso.25441; Bie B., BIOMED PHARMACOTHER, V93, P1285; Chao JI, 2007, MOL CANCER THER, V6, P3039, DOI 10.1158/1535-7163.MCT-07-0281; Chen KJ, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0057704; Cheng YH, 2012, TOXICOL APPL PHARM, V263, P360, DOI 10.1016/j.taap.2012.07.010; Cheng Y, 2009, PROSTATE, V69, P327, DOI 10.1002/pros.20882; Chughtai SA, 1999, ONCOGENE, V18, P657, DOI 10.1038/sj.onc.1202340; D'Arcy MS, 2019, CELL BIOL INT, V43, P582, DOI 10.1002/cbin.11137; de Oliveira MR, 2015, PHARMACOL RES, V100, P296, DOI 10.1016/j.phrs.2015.08.021; Ding Y, 2014, ARCH VIROL, V159, P3269, DOI 10.1007/s00705-014-2192-2; Dou Jie, 2018, Oncotarget, V9, P20089, DOI 10.18632/oncotarget.24015; Elmore S, 2007, TOXICOL PATHOL, V35, P495, DOI 10.1080/01926230701320337; Fakih MG, 2015, J CLIN ONCOL, V33, P1809, DOI 10.1200/JCO.2014.59.7633; Gao JB, 2011, MOL CANCER THER, V10, P1774, DOI 10.1158/1535-7163.MCT-11-0304; Gao Y, 2016, MED CHEM RES, V25, P1515, DOI 10.1007/s00044-016-1607-x; Gilmore TD, 1996, ONCOGENE, V13, P1367; Huang Y, 2012, J EXP CLIN CANC RES, V31, DOI 10.1186/1756-9966-31-48; Ji S, 2015, J ETHNOPHARMACOL, V176, P475, DOI 10.1016/j.jep.2015.11.018; Jing K, 2012, EXP MOL MED, V44, P69, DOI 10.3858/emm.2012.44.2.028; Kim Dong Hwan, 2014, J Cancer Prev, V19, P153, DOI 10.15430/JCP.2014.19.3.153; Kim DH, 2013, INT J ONCOL, V43, P1652, DOI 10.3892/ijo.2013.2086; Kim SJ, 2012, MOL MED REP, V6, P1443, DOI 10.3892/mmr.2012.1085; Klionsky DJ, 2016, AUTOPHAGY, V12, P1, DOI 10.1080/15548627.2015.1100356; Levy JMM, 2017, NAT REV CANCER, V17, P528, DOI 10.1038/nrc.2017.53; Li HL, 2013, MOL MED REP, V7, P266, DOI 10.3892/mmr.2012.1123; Liu Y, 2019, ONCOL LETT, V18, P3188, DOI 10.3892/ol.2019.10617; Macartney-Coxson DP, 2008, BMC CANCER, V8, DOI 10.1186/1471-2407-8-187; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Mizushima N, 2007, GENE DEV, V21, P2861, DOI 10.1101/gad.1599207; Mizushima N, 2011, ANNU REV CELL DEV BI, V27, P107, DOI 10.1146/annurev-cellbio-092910-154005; Moghaddam E, 2014, SCI REP-UK, V4, DOI 10.1038/srep05452; Murphy TM, 2008, ENDOCR-RELAT CANCER, V15, P11, DOI 10.1677/ERC-07-0208; Pang HX, 2016, CLIN DRUG INVEST, V36, P713, DOI 10.1007/s40261-016-0418-7; Sandhu J, 2019, J SURG ONCOL, V119, P564, DOI 10.1002/jso.25421; Siegel RL, 2019, CA-CANCER J CLIN, V69, P7, DOI 10.3322/caac.21551; Su MQ, 2018, INT J ONCOL, V53, P750, DOI 10.3892/ijo.2018.4402; Tanenbaum DG, 2016, J GASTROINTEST ONCOL, V7, P306, DOI 10.21037/jgo.2015.11.04; Taniguchi H, 2008, CANCER RES, V68, P8918, DOI 10.1158/0008-5472.CAN-08-1120; Wang CZ, 2020, CLIN TRANSL ONCOL, V22, P1013, DOI 10.1007/s12094-019-02225-5; Wang M, 2019, AM J TRANSL RES, V11, P3341; Wang QD, 2003, J BIOL CHEM, V278, P51091, DOI 10.1074/jbc.M306541200; Wang YF, 2015, PHYTOTHER RES, V29, P674, DOI 10.1002/ptr.5298; Wang YJ, 2015, CANCER LETT, V358, P170, DOI 10.1016/j.canlet.2014.12.033; Wen X, 2013, FREE RADICAL BIO MED, V65, P402, DOI 10.1016/j.freeradbiomed.2013.07.013; White E, 2015, CLIN CANCER RES, V21, P5037, DOI 10.1158/1078-0432.CCR-15-0490; White E, 2012, NAT REV CANCER, V12, P401, DOI 10.1038/nrc3262; Yan WJ, 2018, DRUG DES DEV THER, V12, P3961, DOI 10.2147/DDDT.S181939; Yang ZF, 2010, NAT CELL BIOL, V12, P814, DOI 10.1038/ncb0910-814; Zhang S, 2019, J EXP CLIN CANC RES, V38, DOI 10.1186/s13046-018-0985-y; Zhong XC, 2019, J CANCER PREV, V24, P129, DOI 10.15430/JCP.2019.24.2.129	50	6	7	4	23	CELL PRESS	CAMBRIDGE	50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA	2372-7705			MOL THER-ONCOLYTICS	Mol. Ther.-Oncolytics	DEC 16	2020	19						1	7		10.1016/j.omto.2020.08.016			7	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	PG9LE	WOS:000600047100001	33024814	Green Published, gold			2022-04-25	
J	Wen, YA; Xing, XP; Harris, JW; Zaytseva, YY; Mitov, MI; Napier, DL; Weiss, HL; Evers, BM; Gao, TY				Wen, Yang-An; Xing, Xiaopeng; Harris, Jennifer W.; Zaytseva, Yekaterina Y.; Mitov, Mihail I.; Napier, Dana L.; Weiss, Heidi L.; Evers, B. Mark; Gao, Tianyan			Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer	CELL DEATH & DISEASE			English	Article							BODY-MASS INDEX; COLORECTAL-CANCER; PROTEIN-KINASE; CA2+ INFLUX; OBESITY; CELLS; METABOLISM; PHLPP; CHEMOTHERAPY; PROGRESSION	Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to the cancer cells. Uptake of fatty acids allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid beta-oxidation. Mechanistically, co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize fatty acids and blocked the growth-promoting effect of adipocytes. In addition, we found that adipocytes stimulated the expression of genes associated with cancer stem cells and downregulated genes associated with intestinal epithelial cell differentiation in primary colon cancer cells and mouse tumor organoids. Importantly, the presence of adipocytes promoted the growth of xenograft tumors in vivo. Taken together, our results show that adipocytes in the tumor microenvironment serve as an energy provider and a metabolic regulator to promote the growth and survival of colon cancer cells.	[Wen, Yang-An; Xing, Xiaopeng; Harris, Jennifer W.; Zaytseva, Yekaterina Y.; Mitov, Mihail I.; Napier, Dana L.; Weiss, Heidi L.; Evers, B. Mark; Gao, Tianyan] Univ Kentucky, Markey Canc Ctr, Lexington, KY USA; [Harris, Jennifer W.; Evers, B. Mark] Univ Kentucky, Dept Surg, Lexington, KY USA; [Zaytseva, Yekaterina Y.] Univ Kentucky, Dept Toxicol & Canc Biol, Lexington, KY USA; [Gao, Tianyan] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA		Gao, TY (corresponding author), Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA.	tianyan.gao@uky.edu			National Center for Advancing Translational Sciences (NIH) [UL1TR000117]; Redox Metabolism, Biospecimen and Tissue Procurement; Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center [P30CA177558];  [R01CA133429]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA133429, P30CA177558, R01CA208343] Funding Source: NIH RePORTER; NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000117] Funding Source: NIH RePORTER	This work was supported by R01CA133429 (TG) and the National Center for Advancing Translational Sciences (NIH) through grant UL1TR000117. The studies were conducted with support provided by the Redox Metabolism, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558).	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FEB	2017	8								e2593	10.1038/cddis.2017.21			12	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	EK1JD	WOS:000393680700013	28151470	Green Published, gold			2022-04-25	
J	Peng, Y; Miao, HM; Wu, S; Yang, WW; Zhang, Y; Xie, GF; Xie, X; Li, JJ; Shi, CM; Ye, LL; Sun, W; Wang, LT; Liang, HJ; Ou, JJ				Peng, Yuan; Miao, Hongming; Wu, Shuang; Yang, Weiwen; Zhang, Yue; Xie, Ganfeng; Xie, Xiong; Li, Jianjun; Shi, Chunmeng; Ye, Lilin; Sun, Wei; Wang, Liting; Liang, Houjie; Ou, Juanjuan			ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2	AUTOPHAGY			English	Article						ABHD5; autophagy; colorectal cancer; genome instability; tumorigenesis	ADIPOSE TRIGLYCERIDE LIPASE; TUMOR-SUPPRESSOR; BECLIN 1; MOLECULAR-MECHANISMS; GENE-TRANSCRIPTION; HEPATIC STEATOSIS; CELL-DEATH; CLEAVAGE; LIVER; METABOLISM	Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene BECN1 (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.	[Peng, Yuan; Miao, Hongming; Wu, Shuang; Yang, Weiwen; Zhang, Yue; Xie, Ganfeng; Xie, Xiong; Li, Jianjun; Liang, Houjie; Ou, Juanjuan] Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing 400038, Peoples R China; [Peng, Yuan; Miao, Hongming; Wu, Shuang; Yang, Weiwen; Zhang, Yue; Xie, Ganfeng; Xie, Xiong; Li, Jianjun; Liang, Houjie; Ou, Juanjuan] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China; [Shi, Chunmeng] Third Mil Med Univ, Chongqing Engn Res Ctr Nanomed, State Key Labortory Trauma Burns & Combined Injur, Inst Combined Injury,Coll Prevent Med, Chongqing, Peoples R China; [Ye, Lilin] Third Mil Med Univ, Inst Immunol, Chongqing, Peoples R China; [Sun, Wei; Wang, Liting] Third Mil Med Univ, Biomed Anal Ctr, Chongqing, Peoples R China		Liang, HJ; Ou, JJ (corresponding author), Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing 400038, Peoples R China.; Liang, HJ; Ou, JJ (corresponding author), Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China.	lianghoujie@sina.com; ojj521000@sina.com	miao, hongming/AAV-8561-2020	Ye, Lilin/0000-0003-0778-3311; Shi, Chunmeng/0000-0002-8264-738X	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81370063, 81172114, 81302136, 81272364]; National Basic Research Program of China (973 Program)National Basic Research Program of China [2014CB560703]	This work was supported in part by grant numbers 81370063 (J.O.), 81172114 (J.L.), grant numbers 81302136 (H.M.) and 81272364 (H.L.) from the National Natural Science Foundation of China, and 2014CB560703 (H.L.) from the National Basic Research Program of China (973 Program).	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J	Tang, Y; Chen, Y; Jiang, H; Nie, D				Tang, Y.; Chen, Y.; Jiang, H.; Nie, D.			Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death	CELL DEATH AND DIFFERENTIATION			English	Article						short-chain fatty acids; autophagy; apoptosis; mitochondrial; colon cancer	ACTIVATED PROTEIN-KINASE; PERMEABILITY TRANSITION; OXIDATIVE STRESS; PROSTATE-CANCER; CYTOCHROME-C; PHOSPHORYLATION; INDUCTION; CASPASE-3; BUTYRATE; SURVIVAL	Short-chain fatty acids (SCFAs) are the major by-products of bacterial fermentation of undigested dietary fibers in the large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development, and reduced p62/SQSTM1 expression. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPK alpha phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of Lambda psi. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate-induced apoptosis through activation of caspase-7 and caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis. Cell Death and Differentiation (2011) 18, 602-618; doi:10.1038/cdd.2010.117; published online 8 October 2010	[Tang, Y.; Chen, Y.; Jiang, H.; Nie, D.] So Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, Springfield, IL 62794 USA; [Tang, Y.; Chen, Y.; Jiang, H.; Nie, D.] Simmons Canc Inst, Springfield, IL USA; [Tang, Y.; Jiang, H.] So Illinois Univ, Mol Biol Microbiol & Biochem Grad Program, Grad Sch, Carbondale, IL 62901 USA		Nie, D (corresponding author), So Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, POB 19626, Springfield, IL 62794 USA.	dnie@siumed.edu					Amaravadi RK, 2007, CLIN CANCER RES, V13, P7271, DOI 10.1158/1078-0432.CCR-07-1595; Aoyama M, 2010, NUTRITION, V26, P653, DOI 10.1016/j.nut.2009.07.006; Chen Y, 2007, CANCER RES, V67, P10361, DOI 10.1158/0008-5472.CAN-06-4758; Chiang GG, 2005, J BIOL CHEM, V280, P25485, DOI 10.1074/jbc.M501707200; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; Cook SI, 1998, ALIMENT PHARM THER, V12, P499, DOI 10.1046/j.1365-2036.1998.00337.x; CUMMINGS JH, 1984, SCAND J GASTROENTERO, V19, P89; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; Dennis PB, 2001, SCIENCE, V294, P1102, DOI 10.1126/science.1063518; Emerling BM, 2009, FREE RADICAL BIO MED, V46, P1386, DOI 10.1016/j.freeradbiomed.2009.02.019; Eskelinen EL, 2002, MOL BIOL CELL, V13, P3355, DOI 10.1091/mbc.E02-02-0114; HAGUE A, 1995, INT J CANCER, V60, P400, DOI 10.1002/ijc.2910600322; HEERDT BG, 1994, CANCER RES, V54, P3288; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; Inoki K, 2003, CELL, V115, P577, DOI 10.1016/S0092-8674(03)00929-2; Jan G, 2002, CELL DEATH DIFFER, V9, P179, DOI 10.1038/sj.cdd.4400935; Kanno T, 2004, FREE RADICAL RES, V38, P27, DOI 10.1080/10715760310001626266; Kanzawa T, 2003, CANCER RES, V63, P2103; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Komatsu M, 2006, NATURE, V441, P880, DOI 10.1038/nature04723; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Lakhani SA, 2006, SCIENCE, V311, P847, DOI 10.1126/science.1115035; Lemasters JJ, 2005, REJUV RES, V8, P3, DOI 10.1089/rej.2005.8.3; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Ly JD, 2003, APOPTOSIS, V8, P115, DOI 10.1023/A:1022945107762; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; McGarry JD, 2002, DIABETES, V51, P7, DOI 10.2337/diabetes.51.1.7; Medina V, 1997, CANCER RES, V57, P3697; Meley D, 2006, J BIOL CHEM, V281, P34870, DOI 10.1074/jbc.M605488200; Pullen N, 1997, FEBS LETT, V410, P78, DOI 10.1016/S0014-5793(97)00323-2; Rodenburg W, 2008, BMC GENOMICS, V9, DOI 10.1186/1471-2164-9-144; Rodriguez-Enriquez S, 2004, INT J BIOCHEM CELL B, V36, P2463, DOI 10.1016/j.biocel.2004.04.009; Ruemmele FM, 1999, CELL DEATH DIFFER, V6, P729, DOI 10.1038/sj.cdd.4400545; Rutter GA, 2003, BIOCHEM J, V375, P1, DOI 10.1042/BJ20030048; Scherz-Shouval R, 2007, EMBO J, V26, P1749, DOI 10.1038/sj.emboj.7601623; SEGLEN PO, 1992, EXPERIENTIA, V48, P158, DOI 10.1007/BF01923509; Stein SC, 2000, BIOCHEM J, V345, P437, DOI 10.1042/0264-6021:3450437; TROCK B, 1990, JNCI-J NATL CANCER I, V82, P650, DOI 10.1093/jnci/82.8.650; Zhang HF, 2008, J BIOL CHEM, V283, P10892, DOI 10.1074/jbc.M800102200; Zong HH, 2002, P NATL ACAD SCI USA, V99, P15983, DOI 10.1073/pnas.252625599	40	101	105	1	28	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	1350-9047	1476-5403		CELL DEATH DIFFER	Cell Death Differ.	APR	2011	18	4					602	618		10.1038/cdd.2010.117			17	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	734DY	WOS:000288314800004	20930850	Green Accepted, hybrid, Green Published			2022-04-25	
J	Hu, T; Li, Z; Gao, CY; Cho, CH				Hu, Tao; Li, Zhen; Gao, Chun-Ying; Cho, Chi Hin			Mechanisms of drug resistance in colon cancer and its therapeutic strategies	WORLD JOURNAL OF GASTROENTEROLOGY			English	Review						Colon cancer; Drug resistance; ATP-binding cassette transporters; Evasion of apoptosis; Autophagy	GROWTH-FACTOR-RECEPTOR; OVERCOMING MULTIDRUG-RESISTANCE; SYNTHETASE GENE-EXPRESSION; CETUXIMAB PLUS IRINOTECAN; TYROSINE-KINASE INHIBITOR; AUTOPHAGIC CELL-DEATH; COLORECTAL-CANCER; BREAST-CANCER; P-GP; PHASE-I	Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.	[Hu, Tao; Cho, Chi Hin] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China; [Li, Zhen] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA; [Gao, Chun-Ying] Univ Washington, Sch Pharm, Dept Pharmaceut, Seattle, WA 98195 USA		Hu, T (corresponding author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China.	taohu1985@hotmail.com	Cho, Chi Hin/C-6543-2014; Hu, Tao/O-2570-2014	Cho, Chi Hin/0000-0002-7658-3260; Hu, Tao/0000-0002-0601-3078			Ahmed-Belkacem A, 2005, CANCER RES, V65, P4852, DOI 10.1158/0008-5472.CAN-04-1817; Ahmed-Belkacem A, 2007, J MED CHEM, V50, P1933, DOI 10.1021/jm061450q; Attardi LD, 2004, NAT GENET, V36, P7, DOI 10.1038/ng0104-7; Benhattar J, 1996, INT J CANCER, V69, P190, DOI 10.1002/(SICI)1097-0215(19960621)69:3<190::AID-IJC7>3.0.CO;2-V; BENSON AB, 1985, CANCER TREAT REP, V69, P795; Bentires-Alj M, 2003, ONCOGENE, V22, P90, DOI 10.1038/sj.onc.1206056; Besbes S, 2016, CRIT REV ONCOL HEMAT, V100, P32, DOI 10.1016/j.critrevonc.2016.02.003; 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Gastroenterol.	AUG 14	2016	22	30					6876	6889		10.3748/wjg.v22.i30.6876			14	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	DS4SC	WOS:000380770400010	27570424	Green Published, hybrid	Y	N	2022-04-25	
J	Lee, M; Yang, CW; Song, G; Lim, W				Lee, Minkyeong; Yang, Changwon; Song, Gwonhwa; Lim, Whasun			Eupatilin Impacts on the Progression of Colon Cancer by Mitochondria Dysfunction and Oxidative Stress	ANTIOXIDANTS			English	Article						eupatilin; colon cancer; apoptosis; oxidative stress; drug resistance	WILD-TYPE; ARTEMISIA PLANTS; CELL-DEATH; APOPTOSIS; AUTOPHAGY; PROLIFERATION; MIGRATION; SURVIVAL; INVASION; CYCLE	Colon cancer is one of the most frequently diagnosed cancer types. Some colon cancer cases resist standard anticancer drugs. Therefore, many studies have focused on developing therapeutic supplements using natural products with low side effects and broad physiological activity. Eupatilin is a flavonoid that is mainly extracted from artemisia and promotes apoptosis in numerous cancer types. However, since the current understanding of its physiological mechanisms on colon cancer cells is insufficient, we investigated how eupatilin affects the growth of two colon cancer cell lines, namely HCT116 and HT29. Our results showed that eupatilin inhibits cell viability and induces apoptosis accompanied by mitochondrial depolarization. It also induces oxidative stress in colon cancer cells and regulates the expression of proteins involved in the endoplasmic reticulum stress and autophagic process. Moreover, eupatilin may target the PI3K/AKT and mitogen-activated protein kinase (MAPK) signaling pathways in colon cancer cells. It also prevents colon cancer cell invasion. Furthermore, eupatilin has a synergistic effect with 5-fluorouracil (5-FU; a standard anticancer drug) on 5-FU-resistant HCT116 cells. These results suggest that eupatilin can be developed as an adjuvant to enhance traditional anticancer drugs in colon cancer.	[Lee, Minkyeong; Lim, Whasun] Kookmin Univ, Coll Sci & Technol, Dept Food & Nutr, Seoul 02707, South Korea; [Yang, Changwon; Song, Gwonhwa] Korea Univ, Coll Life Sci & Biotechnol, Inst Anim Mol Biotechnol, Seoul 02841, South Korea; [Yang, Changwon; Song, Gwonhwa] Korea Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 02841, South Korea		Lim, W (corresponding author), Kookmin Univ, Coll Sci & Technol, Dept Food & Nutr, Seoul 02707, South Korea.; Song, G (corresponding author), Korea Univ, Coll Life Sci & Biotechnol, Inst Anim Mol Biotechnol, Seoul 02841, South Korea.; Song, G (corresponding author), Korea Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 02841, South Korea.	m2019546@kookmin.ac.kr; ycw117@korea.ac.kr; ghsong@korea.ac.kr; wlim@kookmin.ac.kr	Yang, Changwon/AAV-7336-2021; Lim, Whasun/AAP-3156-2020	Yang, Changwon/0000-0001-5326-9124; Lim, Whasun/0000-0002-1328-0465	National Research Foundation of Korea (NRF) - Korea government (MSIT) [2021R1A2C2005841, 2021R1C1C1009807]	This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1A2C2005841 & 2021R1C1C1009807).	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J	Wang, S; Li, LM; Zhou, YG; He, Y; Wei, YS; Tao, AL				Wang, Shan; Li, Linmei; Zhou, Yaguang; He, Ying; Wei, Yisheng; Tao, Ailin			Heterotypic cell-in-cell structures in colon cancer can be regulated by IL-6 and lead to tumor immune escape	EXPERIMENTAL CELL RESEARCH			English	Article						Cell-in-cell; Colorectal cancer; Lymphocyte; IL-6; Autophagy; Immune escape	CANNIBALISM; AUTOPHAGY; ENTOSIS; RESISTANCE; DEATH	Heterotypic CICs (cell-in-cell structures) have been found between tumor cells and various immune cells in a variety of cancer tissues. The frequency of CICs has been found to correlate with tumor malignancy in some studies but not in others. Herein, we examined in depth the CICs observed in colon cancer to determine their potential significance in disease progression. Heterotypic CICs were observed by histochemistry between epithelial cells and lymphocytes in an expanded spectrum of colon tissue from colitis to cancer and in vitro studies were performed using the colonic tumor cell line HCT8 and human peripheral blood lymphocytes. Our data revealed that the CICs formed by colonic epithelial cells and infiltrated lymphocytes not only positively correlated with tumor malignancy but also were upregulated by the inflammatory cytokine IL-6. In addition, we observed that colon cancer cells could initiate autophagy for survival after cytotoxic lymphocyte internalization and that IL-6 could also be involved in this process to promote the death of lymphocytes in CIC structures. Furthermore, certain changes were observed in tumor cells after experiencing CICs. Our findings suggest that CICs formed by colon cancer cells and lymphocytes contribute to tumor escape from immune surveillance, which could be facilitated by IL-6, and might represent a previously undescribed pathway for tumor cells to adapt and evade host immune defense.	[Wang, Shan; Li, Linmei; He, Ying; Tao, Ailin] Guangzhou Med Univ, Guangdong Prov Key Lab Allergy & Clin Immunol, Ctr Inflammat Immunol & Immune Mediated Dis, State Key Lab Resp Dis,Affiliated Hosp 2, Guangzhou 510260, Guangdong, Peoples R China; [Zhou, Yaguang; Wei, Yisheng] Guangzhou Med Univ, Affiliated Hosp 2, Dept Gastrointestinal Surg, Guangzhou 510260, Guangdong, Peoples R China		Tao, AL (corresponding author), Guangzhou Med Univ, Guangdong Prov Key Lab Allergy & Clin Immunol, Ctr Inflammat Immunol & Immune Mediated Dis, State Key Lab Resp Dis,Affiliated Hosp 2, Guangzhou 510260, Guangdong, Peoples R China.; Wei, YS (corresponding author), Guangzhou Med Univ, Affiliated Hosp 2, Dept Gastrointestinal Surg, Guangzhou 510260, Guangdong, Peoples R China.	taoailin@gzhmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81871266]; Guangzhou Science and Technology Plan Foundation [201604020008]	This work was supported by the National Natural Science Foundation of China (81402025, Shan Wang), the National Natural Science Foundation of China (81871266, Ailin Tao), Guangzhou Science and Technology Plan Foundation (201604020008).	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J	Rodriguez, ME; Catrinacio, C; Ropolo, A; Rivarola, VA; Vaccaro, MI				Rodriguez, M. E.; Catrinacio, C.; Ropolo, A.; Rivarola, V. A.; Vaccaro, M. I.			A novel HIF-1 alpha/VMP1-autophagic pathway induces resistance to photodynamic therapy in colon cancer cells	PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES			English	Article							INDUCED AUTOPHAGY; HIF-1-ALPHA STABILIZATION; TRANSCRIPTIONAL ACTIVITY; TUMOR HYPOXIA; APOPTOSIS; PROMOTES; CHEMOTHERAPY; MECHANISMS; INDUCTION; PROTEIN	Colon cancer is the third most frequent cancer and the fourth most common cause of cancer-related mortality worldwide and the standard therapy is surgical resection plus adjuvant chemotherapy. Photodynamic therapy (PDT) has been proposed as an adjuvant therapy because it can prevent the tumor recurrence after surgical excision in colon cancer patients. Hypoxia is a common feature in solid tumors and leads to chemo/radioresistance. Recently, it has been shown that in response to hypoxia, cells can induce HIF-1 alpha-mediated autophagy to survive in this hostile microenvironment. Moreover, hypoxia and autophagy have been implicated in the resistance to antitumor PDT. However, the molecular signals by which HIF-1 alpha induces autophagy in the PDT context have not been studied yet. Here we evaluate the interplay between HIF-1 alpha and autophagy as well as the underlying mechanism in the PDT resistance of colon cancer cells. Our study demonstrates that HIF-1 alpha stabilization significantly increases VMP1-related autophagy through binding to hypoxia responsive elements in the VMP1 promoter. We show that HIF-1 alpha-induced autophagy increases colon cancer cell survival as well as decreases cell death after PDT. Moreover, here we demonstrate that HIF-1 alpha-induced autophagy is mediated by VMP1 expression, since the downregulation of VMP1 by the RNA interference strategy reduces HIF-1 alpha-induced autophagy and cell survival after PDT. In conclusion, PDT induces autophagy as a survival mechanism and the induction of the novel HIF-1 alpha/VMP1-autophagic pathway may explain, at least in part, the resistance of colon cancer cells to PDT. The knowledge of the molecular mechanisms involved in PDT resistance may lead to more accurate therapeutic strategies.	[Rodriguez, M. E.; Rivarola, V. A.] Univ Nacl Rio Cuarto, Dept Biol Mol, RA-5800 Cordoba, Argentina; [Rodriguez, M. E.; Catrinacio, C.; Ropolo, A.; Vaccaro, M. I.] Univ Buenos Aires, CONICET, Fac Farm & Bioquim, Inst Bioquim & Med Mol IBIMOL, Buenos Aires, DF, Argentina		Vaccaro, MI (corresponding author), Univ Buenos Aires, CONICET, Fac Farm & Bioquim, Inst Bioquim & Med Mol IBIMOL, Buenos Aires, DF, Argentina.	mvaccaro@ffyb.uba.ar	Vaccaro, Maria I./L-8348-2017; Rodriguez, Matias/Q-4760-2017	Ropolo, Alejandro/0000-0003-4321-196X; Rivarola, v/0000-0001-7924-1445; Vaccaro, Maria/0000-0002-2456-747X; Rodriguez, Matias/0000-0002-5819-670X			Amelio I, 2015, TRENDS BIOCHEM SCI, V40, P425, DOI 10.1016/j.tibs.2015.04.007; Balamurugan K, 2016, INT J CANCER, V138, P1058, DOI 10.1002/ijc.29519; BARR H, 1990, BRIT J CANCER, V62, P730, DOI 10.1038/bjc.1990.368; Brown JM, 2004, NAT REV CANCER, V4, P437, DOI 10.1038/nrc1367; Brown SB, 2004, LANCET ONCOL, V5, P497, DOI 10.1016/S1470-2045(04)01529-3; Casas A, 2011, CURR MED CHEM, V18, P2486, DOI 10.2174/092986711795843272; Castano AP, 2005, PHOTODIAGN PHOTODYN, V2, P1, DOI 10.1016/S1572-1000(05)00030-X; Choi H, 2016, AUTOPHAGY, V12, P1631, DOI 10.1080/15548627.2016.1192753; Cosse JP, 2008, ANTI-CANCER AGENT ME, V8, P790, DOI 10.2174/187152008785914798; Curtis MJ, 2015, BRIT J PHARMACOL, V172, P3461, DOI 10.1111/bph.12856; De Greef K, 2016, WORLD J GASTROENTERO, V22, P7215, DOI 10.3748/wjg.v22.i32.7215; Del Bello B, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0057236; Dewaele M, 2011, J CELL MOL MED, V15, P1402, DOI 10.1111/j.1582-4934.2010.01118.x; Fan CD, 2006, BIOORGAN MED CHEM, V14, P3218, DOI 10.1016/j.bmc.2005.12.035; FOSTER TH, 1991, RADIAT RES, V126, P296, DOI 10.2307/3577919; Francois A, 2011, INT J ONCOL, V39, P1537, DOI 10.3892/ijo.2011.1174; Gariboldi MB, 2015, CANCER LETT, V364, P156, DOI 10.1016/j.canlet.2015.05.008; Grasso D, 2011, J BIOL CHEM, V286, P8308, DOI 10.1074/jbc.M110.197301; Harhaji-Trajkovic L, 2009, J CELL MOL MED, V13, P3644, DOI 10.1111/j.1582-4934.2009.00663.x; Heaney RM, 2015, WORLD J GASTRO ONCOL, V7, P445, DOI 10.4251/wjgo.v7.i12.445; Ji ZY, 2006, CANCER LETT, V244, P182, DOI 10.1016/j.canlet.2005.12.010; Jung SN, 2008, CARCINOGENESIS, V29, P713, DOI 10.1093/carcin/bgn032; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Klionsky DJ, 2005, J CELL SCI, V118, P7, DOI 10.1242/jcs.01620; LaGory EL, 2016, NAT CELL BIOL, V18, P356, DOI 10.1038/ncb3330; Lee JY, 2013, CELL PHYSIOL BIOCHEM, V32, P417, DOI 10.1159/000354448; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Li YN, 2014, TOXICOL LETT, V224, P165, DOI 10.1016/j.toxlet.2013.10.029; Lin L, 2015, MOL CELL ONCOL, V2, DOI 10.4161/23723556.2014.985913; Liu DL, 2011, MED ONCOL, V28, P105, DOI 10.1007/s12032-009-9397-3; Liu T, 2014, INT J MOL MED, V33, P1236, DOI 10.3892/ijmm.2014.1661; Lo Re AE, 2012, J BIOL CHEM, V287, P25325, DOI 10.1074/jbc.M112.370809; Lopez-Sanchez LM, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0099143; Ma XH, 2011, CLIN CANCER RES, V17, P3478, DOI 10.1158/1078-0432.CCR-10-2372; Maycotte P, 2012, AUTOPHAGY, V8, P200, DOI 10.4161/auto.8.2.18554; Michiels C, 2016, BBA-REV CANCER, V1866, P76, DOI 10.1016/j.bbcan.2016.06.004; Sanabria LM, 2013, BBA-REV CANCER, V1835, P36, DOI 10.1016/j.bbcan.2012.10.001; Mitra S, 2006, MOL CANCER THER, V5, P3268, DOI 10.1158/1535-7163.MCT-06-0421; Molejon MI, 2013, AUTOPHAGY, V9, P933, DOI 10.4161/auto.24390; Molejon MI, 2013, SCI REP-UK, V3, DOI 10.1038/srep01055; O'Donovan TR, 2011, AUTOPHAGY, V7, P509, DOI 10.4161/auto.7.5.15066; Oniszczuk A, 2016, BIOMED PHARMACOTHER, V83, P912, DOI 10.1016/j.biopha.2016.07.058; Pardo R, 2010, PANCREATOLOGY, V10, P19, DOI 10.1159/000264680; Pericas JM, 2016, NEW ENGL J MED, V375, P387, DOI [10.1056/NEJMra1513581, 10.1056/NEJMc1604867]; Ropolo A, 2007, J BIOL CHEM, V282, P37124, DOI 10.1074/jbc.M706956200; Scherz-Shouval R, 2007, EMBO J, V26, P1749, DOI 10.1038/sj.emboj.7601623; Shibata T, 2000, GENE THER, V7, P493, DOI 10.1038/sj.gt.3301124; Shishkova N, 2013, J Gastrointest Cancer, V44, P251, DOI 10.1007/s12029-013-9496-4; Sitnik TM, 1998, BRIT J CANCER, V77, P1386, DOI 10.1038/bjc.1998.231; Sun Y, 2015, INT J ONCOL, V46, P750, DOI 10.3892/ijo.2014.2745; Terman A, 2005, CARDIOVASC RES, V68, P355, DOI 10.1016/j.cardiores.2005.08.014; Tittarelli A, 2015, J BIOL CHEM, V290, P23670, DOI 10.1074/jbc.M115.651547; Tu PH, 2016, ONCOL REP, V35, P3209, DOI 10.3892/or.2016.4703; Vaccaro MI, 2008, AUTOPHAGY, V4, P388, DOI 10.4161/auto.5656; Vordermark D, 2005, CANCER LETT, V230, P122, DOI 10.1016/j.canlet.2004.12.040; Wei MF, 2014, AUTOPHAGY, V10, P1179, DOI 10.4161/auto.28679; Wilkinson S, 2009, GENE DEV, V23, P1283, DOI 10.1101/gad.521709; Yang X, 2015, CELL BIOSCI, V5, DOI 10.1186/s13578-015-0005-2; Yoo JO, 2012, INT REV CEL MOL BIO, V295, P139, DOI 10.1016/B978-0-12-394306-4.00010-1	60	32	33	4	28	SPRINGERNATURE	LONDON	CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND	1474-905X	1474-9092		PHOTOCH PHOTOBIO SCI	Photochem. Photobiol. Sci.	NOV 1	2017	16	11					1631	1642		10.1039/c7pp00161d			12	Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics; Chemistry	FM2HV	WOS:000414806700006	28936522				2022-04-25	
J	Zhao, YL; Fan, DM; Zheng, ZP; Li, ETS; Chen, F; Cheng, KW; Wang, MF				Zhao, Yueliang; Fan, Daming; Zheng, Zong-Ping; Li, Edmund T. S.; Chen, Feng; Cheng, Ka-Wing; Wang, Mingfu			8-C-(E-phenylethenyl)quercetin from onion/beef soup induces autophagic cell death in colon cancer cells through ERK activation	MOLECULAR NUTRITION & FOOD RESEARCH			English	Article						Autophagy; Colon cancer; ERK activation; 8-C-(E-phenylethenyl)quercetin; Onion; beef soup	HETEROCYCLIC AMINE FORMATION; MAILLARD REACTION; BEEF PATTIES; SIGNALING PATHWAY; PHENYLACETALDEHYDE; INHIBITION; PREVENTION; THERAPY; DISEASE; GROWTH	ScopeQuercetin, a flavonoid, widely distributed in edible fruits and vegetables, was reported to effectively inhibit 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) formation in a food model (roast beef patties) with itself being converted into a novel compound 8-C-(E-phenylethenyl)quercetin (8-CEPQ). Here we investigated whether 8-CEPQ could be formed in a real food system, and tested its anticancer activity in human colon cancer cell lines. Methods and resultsLC-MS was applied for the determination of 8-CEPQ formation in onion/beef soup. Anticancer activity of 8-CEPQ was evaluated by using cell viability assay and flow cytometry. Results showed that 8-CEPQ suppressed proliferationand caused G(2) phase arrest in colon cancer cells. Based on immunofluorescent staining assay, western blot assay, and RNA knockdown data, we found that 8-CEPQ did not cause apoptotic cell death. Instead, it induced autophagic cell death. Moreover, treatment with 8-CEPQ induced phosphorylation of extracellular signal-regulated kinase (ERK). Inhibition of ERK phosphorylation by the mitogen-activated protein kinasekinase (MEK)/ERK inhibitor U0126 attenuated 8-CEPQ-induced autophagy and reversed 8-CEPQ-mediated cell growth inhibition. ConclusionOur results demonstrate that 8-CEPQ, a novel quercetin derivative, could be formed in onion/beef soup. 8-CEPQ inhibited colon cancer cell growth by inducing autophagic cell death through ERK activation.	[Zhao, Yueliang; Fan, Daming; Zheng, Zong-Ping; Li, Edmund T. S.; Wang, Mingfu] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China; [Chen, Feng; Cheng, Ka-Wing] Peking Univ, Inst Food & Bioresource Engn, Coll Engn, Beijing, Peoples R China		Cheng, KW (corresponding author), Peking Univ, Inst Food & Bioresource Engn, Coll Engn, Beijing, Peoples R China.	kwcheng@pku.edu.cn; mfwang@hku.hk	Cheng, Ka Wing/V-9433-2019; Wang, Mingfu/AAT-3292-2021; Zheng, Zong-Ping/A-7400-2011; Wang, Mingfu/D-3136-2009	Zheng, Zong-Ping/0000-0002-0261-3711; Wang, Mingfu/0000-0003-1469-3963; Cheng, Ka Wing/0000-0002-1201-312X; Fan, Daming/0000-0002-4907-9034	Hong Kong Research Grants Council (GRF Project) [17154816]	The research was supported by the Hong Kong Research Grants Council (GRF Project No.: 17154816). The authors would like to thank Ms. Dorothy M.C. Chan and Ms. Iris M.Y. Tse for their technical support and kind advice on this research.	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J	Xu, ZH; Yang, KL; Li, XH				Xu, Zhiheng; Yang, Kailun; Li, Xiaohua			Inhibitory effect of glucocorticoid receptor on colorectal cancer growth by inhibiting glycolysis through autophagy	MATERIALS EXPRESS			English	Article						Colon Cancer; LoVo Cells; Glucocorticoid Receptor; Glycolysis	NUMBER VARIATION ANALYSIS; MAGNETIC NANOPARTICLES; EXPRESSION; METABOLISM; GLUCOSE; TARGET; CELLS; LIVER; GLUCONEOGENESIS; CORTISOL	Glucocorticoid receptor (GR) affects the development and progression of most malignant tumors by regulating autophagy. The GR gene is not expressed in colon cancer. To explore the role and mechanism of GR in colon cancer, dexamethasone (DXM) was used to stimulate the expression of GR. The expression of the autophagy markers Beclin 1 (BECN1) and light chain 3 (LC3B) was then detected by qRT-PCR and western blotting. The effects of the differential expression of GR on autophagy, ATP, lactic acid accumulation, and glucose utilization in colon cancer cells were studied. Differential expression of GR affected glycolysis, apoptosis, and migration of colon cancer cells, as determined by flow cytometry and cell viability and migration assays, respectively. The DXM-induced elevation of GR expression significantly promoted the expression of the autophagy-related genes BECN1 and LC3B, and decreased the ATP production, lactic acid accumulation, and glucose uptake in colon cancer cells. These events resulted in the inhibition of colon cancer cell growth, which also involved decreased cell viability and mobility and increased rate of apoptosis. These findings indicate that the GR can promote autophagy and inhibit glycolysis in colon cancer cells, reduce their proliferation and migration, and promote their apoptosis in vitro.	[Xu, Zhiheng] Guangzhou Univ Tradit Chinese Med, Gastrointestinal Thyroid Surg, Affiliated Hosp 1, Guangzhou 510405, Guangdong, Peoples R China; [Yang, Kailun; Li, Xiaohua] Guangzhou Univ Chinese Med, Clin Med Inst 1, Guangzhou 510405, Guangdong, Peoples R China		Xu, ZH (corresponding author), Guangzhou Univ Tradit Chinese Med, Gastrointestinal Thyroid Surg, Affiliated Hosp 1, Guangzhou 510405, Guangdong, Peoples R China.	994830503@qq.com					Canalis E, 2002, J PEDIATR ENDOCR MET, V15, P1341; Chen SY, 2017, ONCOL LETT, V14, P5575, DOI 10.3892/ol.2017.6890; Chen Z, 2018, NANOSCI NANOTECH LET, V10, P60, DOI 10.1166/nnl.2018.2595; De P, 2014, ONCOTARGET, V5, P4581, DOI 10.18632/oncotarget.2127; Deng J., 2019, AUTOPHAGY, P1; Ding LJ, 2017, PHARMACOLOGY, V99, P188, DOI 10.1159/000452340; Grempler R, 2007, DIABETES, V56, P2235, DOI 10.2337/db06-1660; Guan J, 2017, ARCH PATHOL LAB MED, V141, P851, DOI 10.5858/arpa.2016-0361-RA; Guo CM, 2014, ENDOCRINOLOGY, V155, P3017, DOI 10.1210/en.2013-1848; Hong H., 2010, CANCER, V101, P83; Hong M, 2013, CLIN EXP VACCINE RES, V2, P66, DOI 10.7774/cevr.2013.2.1.66; Huang R., 2019, SMALL, V15, P1; Johnson J A, 1972, Adv Metab Disord, V60, P1; Kalaitzis J, 2010, WORLD J SURG ONCOL, V8, DOI 10.1186/1477-7819-8-17; Kawaguchi T, 2001, P NATL ACAD SCI USA, V98, P13710, DOI 10.1073/pnas.231370798; Kawamura A, 1998, NEUROL MED-CHIR, V38, P633, DOI 10.2176/nmc.38.633; Kim ST, 2012, REPROD SCI, V19, P92, DOI 10.1177/1933719111414209; Ladoire S, 2015, AUTOPHAGY, V11, P1878, DOI 10.1080/15548627.2015.1082022; Liu HN, 2017, J BIOMED NANOTECHNOL, V13, P1333, DOI 10.1166/jbn.2017.2418; Liu JT, 2016, MED ONCOL, V33, DOI 10.1007/s12032-015-0721-9; Liu M, 2015, THERANOSTICS, V5, P71, DOI 10.7150/thno.10117; Marek CB, 2011, CHEM-BIOL INTERACT, V193, P22, DOI 10.1016/j.cbi.2011.04.010; Marin-Hernandez A, 2006, FEBS J, V273, P1975, DOI 10.1111/j.1742-4658.2006.05214.x; MelendezHevia E, 1997, EUR J BIOCHEM, V244, P527, DOI 10.1111/j.1432-1033.1997.t01-1-00527.x; Mou XB, 2016, CHINESE CHEM LETT, V27, P1661, DOI 10.1016/j.cclet.2016.04.005; Nakahira K, 2013, AM J PHYSIOL-LUNG C, V305, pL93, DOI 10.1152/ajplung.00072.2013; Rui LY, 2014, COMPR PHYSIOL, V4, P177, DOI 10.1002/cphy.c130024; Salska A, 2016, ACTA CARDIOL, V71, P505, DOI [10.1080/AC.71.5.3167493, 10.2143/AC.71.5.3167493]; Schembri J, 2017, ANN GASTROENTEROL, V30, P257, DOI 10.20524/aog.2017.0126; Sun Ye, 2018, Acta Veterinaria et Zootechnica Sinica, V49, P2340; Sundahl N, 2015, PHARMACOL THERAPEUT, V152, P28, DOI 10.1016/j.pharmthera.2015.05.001; Teles M, 2013, MAR BIOTECHNOL, V15, P104, DOI 10.1007/s10126-012-9467-y; Teng JA, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0149822; Xiao XY, 2013, J TRANSL MED, V11, DOI 10.1186/1479-5876-11-151; Yang HW, 2017, J BIOMED NANOTECHNOL, V13, P655, DOI 10.1166/jbn.2017.2386; Zhang E., 2011, PLOS ONE, V6, P1	36	3	3	0	7	AMER SCIENTIFIC PUBLISHERS	VALENCIA	26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA	2158-5849	2158-5857		MATER EXPRESS	Mater. Express	MAR	2020	10	3					363	373		10.1166/mex.2020.1648			11	Nanoscience & Nanotechnology; Materials Science, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics; Materials Science	KR7ET	WOS:000517779400006					2022-04-25	
J	Sheng, QS; Li, F; Chen, GP; Li, JC; Li, J; Wang, YF; Lu, YY; Li, Q; Li, MQ; Chai, KQ				Sheng, Qinsong; Li, Fei; Chen, Guanping; Li, Jiacheng; Li, Jing; Wang, YiFan; Lu, Yingyan; Li, Qun; Li, Mingqian; Chai, Kequn			Ursolic Acid Regulates Intestinal Microbiota and Inflammatory Cell Infiltration to Prevent Ulcerative Colitis	JOURNAL OF IMMUNOLOGY RESEARCH			English	Article							SIGNALING PATHWAYS; COLORECTAL-CANCER; GROWTH; MODEL; ANTIBACTERIAL; MECHANISMS; APOPTOSIS; AUTOPHAGY; SEQUENCES	Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disorder in the colon and rectum leading to low life-quality and high societal costs. Ursolic acid (UA) is a natural product with pharmacological and biological activities. The studies are aimed at investigating the protective and treatment effects of UA against the dextran sulfate sodium- (DSS-) induced UC mouse model and its underlying mechanism. UA was orally administered at different time points before and after the DSS-induced model. Mice body weight, colon length, and histological analysis were used to evaluate colon tissue damage and therapeutic evaluation. Intestinal transcriptome and microbe 16 s sequencing was used to analyze the mechanisms of UA in the prevention and treatment of UC. The early prevention effect of UA could effectively delay mouse weight loss and colon length shorten. UA alleviated UC inflammation and lowered serum and colon IL-6 levels. Three classical inflammatory pathways: MAPKs, IL-6/STAT3, and PI3K were downregulated by UA treatment. The proportion of macrophages and neutrophils in inflammatory cell infiltration was reduced in UA treatment groups. UA could significantly reduce the richness of intestinal flora to avoid the inflammatory response due to the destruction of the intestinal epithelial barrier. The function of UA against UC was through reducing intestinal flora abundance and regulating inflammatory and fatty acid metabolism signaling pathways to affect immune cell infiltration and cytokine expression.	[Sheng, Qinsong] Zhejiang Univ, Affiliated Hosp 1, Dept Colorectal & Anal Surg, Coll Med, Hangzhou, Peoples R China; [Li, Fei; Li, Jiacheng; Li, Qun] Sichuan Normal Univ, Coll Life Sci, Chengdu 610101, Sichuan, Peoples R China; [Li, Fei; Chen, Guanping; Li, Jiacheng; Li, Jing; Wang, YiFan; Lu, Yingyan; Li, Mingqian; Chai, Kequn] Zhejiang Acad Tradit Chinese Med, Tongde Hosp Zhejiang Prov, Canc Inst Integrated Tradit Chinese & Western Med, Hangzhou 310012, Zhejiang, Peoples R China		Li, MQ; Chai, KQ (corresponding author), Zhejiang Acad Tradit Chinese Med, Tongde Hosp Zhejiang Prov, Canc Inst Integrated Tradit Chinese & Western Med, Hangzhou 310012, Zhejiang, Peoples R China.	shengqinsong@zju.edu.cn; 1689458645@qq.com; beyond_cgp@163.com; 1767371131@qq.com; lijing87.2.8@163.com; yifan.wang11@foxmail.com; 1416941280@qq.com; liqun01234@163.com; limingqian613@163.com; ckq_official@163.com		Li, Mingqian/0000-0002-3296-6868	Natural Science Foundation of Zhejiang provinceNatural Science Foundation of Zhejiang Province [LY19H280005, LY18H160018, LQ19H030004]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81673809, 82074093]; Scientific and Technological Program of Zhejiang province [2017F10024]; Traditional Chinese Medicine Scientific Program of Zhejiang province [2016ZQ002]	The work was supported by grants from the Natural Science Foundation of Zhejiang province (Grant Nos. LY19H280005, LY18H160018, and LQ19H030004), National Natural Science Foundation of China (Grant Nos. 81673809 and 82074093), Scientific and Technological Program of Zhejiang province (Grant No. 2017F10024), and Traditional Chinese Medicine Scientific Program of Zhejiang province (Grant No. 2016ZQ002).	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Res.	MAY 3	2021	2021								6679316	10.1155/2021/6679316			16	Immunology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology	SX1CY	WOS:000664950500001	34007853	gold, Green Published			2022-04-25	
J	Ahn, CH; Jeong, EG; Lee, JW; Kim, MS; Kim, SH; Kim, SS; Yoo, NJ; Lee, SH				Ahn, Chang Hyeok; Jeong, Eun Goo; Lee, Jong Woo; Kim, Min Sung; Kim, Sung Hee; Kim, Sung Soo; Yoo, Nam Jin; Lee, Sug Hyung			Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers	APMIS			English	Article						Beclin-1; autophagy; expression; gastric cancer; colorectal cancer	TUMOR-SUPPRESSOR; INACTIVATING MUTATIONS; INDUCED APOPTOSIS; GENE; TUMORIGENESIS; CARCINOMAS; CASPASE-9; DEATH	Autophagy plays important roles in both cell death and cell survival. Beclin-1, a key regulator of autophagy formation, has been considered as a haploinsufficient tumor suppressor. Loss of expression or point mutation could serve as a mechanism of loss of beclin-1 tumor suppressor function in cancers. However, our recent study revealed that point mutation of the beclin-1 gene is a rare event in common human cancers. In this study we investigated beclin-1 protein expression in 103 colorectal and 60 gastric carcinoma tissues by immunohistochemistry using a tissue microarray approach. In the cancers, expression of beclin-1 was detected in 95% of the colorectal carcinomas and 83% of the gastric carcinomas. In contrast, normal mucosal cells of both stomach and colon showed no or very weak expression of beclin-1. There was no significant association of beclin-1 expression with clinocopathologic characteristics, including invasion, metastasis and stage. The beclin-1 expression of colorectal and gastric cancers in the present study is quite in contrast to that of the breast cancers in the previous study, which showed a decreased beclin-1 expression in breast cancer cells compared to normal breast cells. Our data indicate that beclin-1 inactivation by loss of expression may not occur in colorectal and gastric cancers. Rather, increased expression of beclin-1 in the malignant colorectal and gastric epithelial cells compared to their normal mucosal epithelial cells suggests that neo-expression of beclin-1 may play a role in both colorectal and gastric tumorigenesis.	[Jeong, Eun Goo; Lee, Jong Woo; Kim, Min Sung; Kim, Sung Hee; Yoo, Nam Jin; Lee, Sug Hyung] Catholic Univ, Coll Med, Dept Pathol, Seoul 137701, South Korea; [Ahn, Chang Hyeok] Catholic Univ, Coll Med, Dept Surg, Seoul 137701, South Korea; [Kim, Sung Hee] Catholic Univ, Coll Med, Dept Internal Med, Seoul 137701, South Korea		Lee, SH (corresponding author), Catholic Univ, Coll Med, Dept Pathol, 505 Banpo Dong, Seoul 137701, South Korea.	suhulee@catholic.ac.kr					Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Baehrecke EH, 2005, NAT REV MOL CELL BIO, V6, P505, DOI 10.1038/nrm1666; Daniel F, 2006, WORLD J GASTROENTERO, V12, P2895, DOI 10.3748/wjg.v12.i18.2895; Edinger AL, 2004, CURR OPIN CELL BIOL, V16, P663, DOI 10.1016/j.ceb.2004.09.011; Furuya D, 2005, EXP CELL RES, V307, P26, DOI 10.1016/j.yexcr.2005.02.023; Hanahan D, 2000, CELL, V100, P57, DOI 10.1016/S0092-8674(00)81683-9; Kim HS, 2003, GASTROENTEROLOGY, V125, P708, DOI 10.1016/S0016-5085(03)01059-X; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Lee JW, 2007, APMIS, V115, P750, DOI 10.1111/j.1600-0463.2007.apm_640.x; Lee SH, 1999, ONCOGENE, V18, P3754, DOI 10.1038/sj.onc.1202769; Liang C, 2006, NAT CELL BIOL, V8, P688, DOI 10.1038/ncb1426; Liang XH, 1998, J VIROL, V72, P8586, DOI 10.1128/JVI.72.11.8586-8596.1998; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Liang XH, 2001, CANCER RES, V61, P3443; Marx J, 2006, SCIENCE, V312, P1160, DOI 10.1126/science.312.5777.1160; Miracco C, 2007, INT J ONCOL, V30, P429; Pattingre S, 2005, CELL, V122, P927, DOI 10.1016/j.cell.2005.07.002; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Reed JC, 2000, AM J PATHOL, V157, P1415, DOI 10.1016/S0002-9440(10)64779-7; Shin MS, 2002, BLOOD, V99, P4094, DOI 10.1182/blood.V99.11.4094; Yoo NJ, 2007, APMIS, V115, P354, DOI 10.1111/j.1600-0463.2007.apm_632.x; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	22	168	187	1	21	BLACKWELL PUBLISHING	OXFORD	9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND	0903-4641			APMIS	APMIS	DEC	2007	115	12					1344	1349		10.1111/j.1600-0463.2007.00858.x			6	Immunology; Microbiology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Microbiology; Pathology	244IM	WOS:000251859600003	18184403				2022-04-25	
J	Cho, YY; Kim, DJ; Lee, HS; Jeong, CH; Cho, EJ; Kim, MO; Byun, S; Lee, KY; Yao, K; Carper, A; Langfald, A; Bode, AM; Dong, ZG				Cho, Yong-Yeon; Kim, Dong Joon; Lee, Hye Suk; Jeong, Chul-Ho; Cho, Eun-Jin; Kim, Myong-Ok; Byun, Sanguine; Lee, Kun-Yeong; Yao, Ke; Carper, Andria; Langfald, Alyssa; Bode, Ann M.; Dong, Zigang			Autophagy and Cellular Senescence Mediated by Sox2 Suppress Malignancy of Cancer Cells	PLOS ONE			English	Article							INHIBITION; INDUCTION; GROWTH; DEATH; PTEN; PLURIPOTENCY; MECHANISMS; PHENOTYPE; APOPTOSIS; PATHWAY	Autophagy is a critical cellular process required for maintaining cellular homeostasis in health and disease states, but the molecular mechanisms and impact of autophagy on cancer is not fully understood. Here, we found that Sox2, a key transcription factor in the regulation of the "stemness'' of embryonic stem cells and induced-pluripotent stem cells, strongly induced autophagic phenomena, including intracellular vacuole formation and lysosomal activation in colon cancer cells. The activation occurred through Sox2-mediated ATG10 gene expression and resulted in the inhibition of cell proliferation and anchorage-independent colony growth ex vivo and tumor growth in vivo. Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a), p21 and phosphorylated p53 (Ser15). Notably, knockdown of ATG10 in Sox2-expressing colon cancer cells restored cancer cell properties. Taken together, our results demonstrated that regulation of autophagy mediated by Sox2 is a mechanism-driven novel strategy to treat human colon cancers.	[Kim, Dong Joon; Jeong, Chul-Ho; Cho, Eun-Jin; Kim, Myong-Ok; Byun, Sanguine; Lee, Kun-Yeong; Yao, Ke; Carper, Andria; Langfald, Alyssa; Bode, Ann M.; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA; [Cho, Yong-Yeon; Lee, Hye Suk] Catholic Univ Korea, Coll Pharm, Gyeonggi Do, South Korea		Cho, YY (corresponding author), Catholic Univ Korea, Coll Pharm, Gyeonggi Do, South Korea.	yongyeon@catholic.ac.kr; zgdong@hi.umn.edu	Byun, Sanguine/AAR-5451-2021; Cho, Yong-Yeon/AAD-4263-2020	Byun, Sanguine/0000-0003-3903-5887	Hormel Foundation; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA111536, CA120388, CA077646, R37CA081064, ES016548]; Catholic University of Korea [M-2011-B0002-00025]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA120388, R01CA111536, R37CA081064, R01CA077646] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [R01ES016548] Funding Source: NIH RePORTER	This work was supported in part by The Hormel Foundation and National Institutes of Health grants CA111536, CA120388, CA077646, R37CA081064 and ES016548, and by the Research Fund, M-2011-B0002-00025 of The Catholic University of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Zhang, R; Xu, J; Zhao, J; Bai, JH				Zhang, Rui; Xu, Jian; Zhao, Jian; Bai, Jinghui			Mir-30d suppresses cell proliferation of colon cancer cells by inhibiting cell autophagy and promoting cell apoptosis	TUMOR BIOLOGY			English	Article						MiR-30d; colon cancer; apoptosis; autophagy	LUNG-CANCER; COLORECTAL-CANCER; UBIQUITIN LIGASES; MIRNA EXPRESSION; PROSTATE-CANCER; BREAST-CANCER; REGULATOR; PATHWAY	MiR-30 family plays an important role in the tumorigenesis of human cancers. The aim of the study is to investigate the role of miR-30d in human colon cancer cell lines and explore the molecular mechanism in the proliferation of colon cancer cells. The expression of miR-30d was determined by real-time polymerase chain reaction assay in colon cancer cell lines (HCT15, HCT116, HT-29, DLD-1, and SW480) and the results demonstrated that miR-30d level was significantly decreased in human colon cancer cell lines, compared with normal colon epithelial cell line. Transfection with miR-30d mimics inhibited cell proliferation, and transfection with miR-30d inhibitors significantly promoted cell viability of colon cancer cells. Furthermore, TargetScan analysis predicted that miR-30d interacted with messenger RNA on its 3 boxed times untranslated region of ATG5, phosphoinositide 3-kinase, and Beclin1 to negatively regulate cell autophagy in colon cancer cells. Moreover, transfection with miR-30d induced cell arrest at G2/M phase of HT-29 cells. Overexpression of miR-30d mimics inhibited cell viability probably due to the inhibition of cell autophagy and promotion of cell apoptosis. Thus, MiR-30d inhibited cell autophagy by directly targeting messenger RNA of ATG5, phosphoinositide 3-kinase, and Beclin1 and promoted cell apoptosis of human colon cancer cells. It is helpful to clarify the function of miR-30d in tumorigenesis of human cancers.	[Zhang, Rui; Xu, Jian; Zhao, Jian] China Med Univ, Canc Hosp, Liaoning Canc Hosp & Inst, Dept Colorectal Surg, Shenyang, Peoples R China; [Bai, Jinghui] China Med Univ, Canc Hosp, Liaoning Canc Hosp & Inst, Dept Internal Med, 44 Xiaoheyan Rd, Shenyang 110042, Liaoning, Peoples R China		Bai, JH (corresponding author), China Med Univ, Canc Hosp, Liaoning Canc Hosp & Inst, Dept Internal Med, 44 Xiaoheyan Rd, Shenyang 110042, Liaoning, Peoples R China.	baijinghuibio@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672427]	The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Fund from the National Natural Science Foundation of China (Grant No. 81672427).	Ganju A, 2017, DRUG DISCOV TODAY, V22, P424, DOI 10.1016/j.drudis.2016.10.014; Gaziel-Sovran A, 2011, CANCER CELL, V20, P104, DOI 10.1016/j.ccr.2011.05.027; Gray RT, 2016, CANCER EPIDEMIOL, V45, P71, DOI 10.1016/j.canep.2016.10.004; Hulf T, 2011, BMC GENOMICS, V12, DOI 10.1186/1471-2164-12-54; Jia KG, 2016, MOL MED REP, V14, P184, DOI 10.3892/mmr.2016.5246; Kara M, 2016, GENE, V587, P173, DOI 10.1016/j.gene.2016.05.006; Kobayashi N, 2012, ONCOTARGET, V3, P1455; Lin J, 2016, TUMOR BIOL, V37, P15835, DOI 10.1007/s13277-016-5410-6; Liu YQ, 2014, ASIAN PAC J CANCER P, V15, P2169, DOI 10.7314/APJCP.2014.15.5.2169; McGuire S, 2014, ADV NUTR, V5, P456, DOI 10.3945/an.114.006171; Mei Q, 2014, EXPERT REV ANTICANC, V14, P1515, DOI 10.1586/14737140.2014.953935; Moriarity A, 2016, THER ADV MED ONCOL, V8, P276, DOI 10.1177/1758834016646734; Nishitani H, 2006, EMBO J, V25, P1126, DOI 10.1038/sj.emboj.7601002; Peng Li, 2010, Zhonghua Gan Zang Bing Za Zhi, V18, P148, DOI 10.3760/cma.j.issn.1007-3418.2010.02.017; Ramalingam Satish, 2015, Curr Pharmacol Rep, V1, P141; Salim H, 2012, BRIT J CANCER, V107, P1361, DOI 10.1038/bjc.2012.382; Schulman BA, 2000, NATURE, V408, P381, DOI 10.1038/35042620; Sharif S, 2012, CURR COLORECT CANC R, V8, P225, DOI 10.1007/s11888-012-0132-7; Su SF, 2013, ONCOGENE, V32, P4694, DOI 10.1038/onc.2012.483; Vorvis C, 2016, FUTURE ONCOL, V12, P1135, DOI 10.2217/fon-2015-0050; Wu CL, 2013, CELL SIGNAL, V25, P1212, DOI 10.1016/j.cellsig.2013.01.028; Xu TS, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0152792; Xuan HQ, 2015, BIOCHEMISTRY-MOSCOW+, V80, P276, DOI 10.1134/S0006297915030037; Yang XJ, 2013, BIOCHEM BIOPH RES CO, V431, P617, DOI 10.1016/j.bbrc.2012.12.083; Zhang WC, 2014, TUMOR BIOL, V35, P6235, DOI 10.1007/s13277-014-2202-8; Zhang Y, 2014, BIOCHEM PHARMACOL, V87, P562, DOI 10.1016/j.bcp.2013.12.004	26	29	32	4	12	SAGE PUBLICATIONS LTD	LONDON	1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND	1010-4283	1423-0380		TUMOR BIOL	Tumor Biol.	JUN 27	2017	39	6					1	9	703984	10.1177/1010428317703984			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EZ2OX	WOS:000404549700001	28651493	gold			2022-04-25	
J	Zhang, HH; Cao, RH; Zeng, F; Fan, WX; Guo, L; Ma, Q; Ke, SB				Zhang, Huihui; Cao, Rihui; Zeng, Feng; Fan, Wenxi; Guo, Liang; Ma, Qin; Ke, Shaobo			Bivalent beta-Carbolines Inhibit Colorectal Cancer Growth through Inducing Autophagy	CHEMICAL & PHARMACEUTICAL BULLETIN			English	Article						bivalent beta-carboline; antiproliferative; colorectal cancer; autophagy	DERIVATIVES; DESIGN; ALKALOIDS; MECHANISM	In this study, a series of alkyl diamine linked bivalent beta-carbolines was synthesized and evaluated as antitumor agent. The results demonstrated that most compounds displayed good antiproliferative activities with IC50 value lower than 10 mu M against a panel of human tumor cell lines, and compound 8 was found to be the most potent antiproliferative agent with IC50 value of 1.39, 1.96, 1.42, 1.49, 1.32, 1.96 and 1.63 mu M against human breast cancer cell line (MCF-7), human adenocarcinoma cell line (769-P), human malighant melanoma cell line (A375), human ovarian cancer cell line (SK-OV-3), human colon carcinoma cell line (HCT-116), human gastric cancer cell line (BGC-823) and human esophageal squamous carcinoma cell line (Eca-109), respectively. Further investigations on mechanism of action of this class of compound demonstrated that the representative compound 8 inhibited colorectal cancer growth through inducing autophagy.	[Zhang, Huihui] Hunan Normal Univ, Sch Med, Dept Lab Med, Coll Key Lab Study & Discovery Small Targeted Mol, Changsha 410013, Hunan, Peoples R China; [Cao, Rihui] Sun Yat Sen Univ, Sch Chem, 135 Xin Gang West Rd, Guangzhou 510275, Peoples R China; [Zeng, Feng; Ke, Shaobo] Wuhan Univ, Renmin Hosp, Ctr Canc, Wuhan 430060, Peoples R China; [Fan, Wenxi; Guo, Liang; Ma, Qin] Xinjiang Huashidan Pharmaceut Co Ltd, 45 He Nan East Rd, Urumqi 830011, Peoples R China		Ke, SB (corresponding author), Wuhan Univ, Renmin Hosp, Ctr Canc, Wuhan 430060, Peoples R China.	kkkwhu@sina.com			General Project of Hunan Health Commission [C2016045]; National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [81602450]; Chen Xiaoping Hepatobiliary and Panpancreatic Malignant Tumors Research Fund of Hubei Province [CXPJJH11900001-2019348]; Huxiang High-Level Talent Innovation Team [2018RS3072]	This work was supported by grants from General Project of Hunan Health Commission (C2016045) and National Natural Science Foundation of China (NSFC) [81602450] and Chen Xiaoping Hepatobiliary and Panpancreatic Malignant Tumors Research Fund of Hubei Province, CXPJJH11900001-2019348 and Huxiang High-Level Talent Innovation Team (2018RS3072).	Amaravadi R, 2016, GENE DEV, V30, P1913, DOI 10.1101/gad.287524.116; Barbosa VA, 2011, BIOORGAN MED CHEM, V19, P6400, DOI 10.1016/j.bmc.2011.08.059; Cao RH, 2007, CURR MED CHEM, V14, P479, DOI 10.2174/092986707779940998; Cao RH, 2013, EUR J MED CHEM, V60, P135, DOI 10.1016/j.ejmech.2012.11.045; Chaires JB, 1997, J MED CHEM, V40, P261, DOI 10.1021/jm9607414; Chen Q, 2016, BIOORG MED CHEM LETT, V26, P5065, DOI 10.1016/j.bmcl.2016.08.084; Chen YF, 2015, BIOORG MED CHEM LETT, V25, P3873, DOI 10.1016/j.bmcl.2015.07.058; Galluzzi L, 2017, NAT REV DRUG DISCOV, V16, P487, DOI 10.1038/nrd.2017.22; Ge D, 2020, CHEM PHARM BULL, V68, P244, DOI 10.1248/cpb.c19-00851; Gu HL, 2018, INT J MOL SCI, V19, DOI 10.3390/ijms19103179; Guo L, 2018, EUR J MED CHEM, V147, P253, DOI 10.1016/j.ejmech.2018.02.003; Jemal A, 2008, CA-CANCER J CLIN, V58, P71, DOI 10.3322/CA.2007.0010; Li SZ, 2013, BIOCHEM BIOPH RES CO, V437, P325, DOI 10.1016/j.bbrc.2013.06.088; Li SZ, 2019, EUR J MED CHEM, V162, P666, DOI 10.1016/j.ejmech.2018.11.048; Li Y, 2018, EUR J MED CHEM, V152, P516, DOI 10.1016/j.ejmech.2018.05.003; Liang X, 2014, CELL BIOSCI, V4, DOI 10.1186/2045-3701-4-10; Lin YC, 2017, KAOHSIUNG J MED SCI, V33, P215, DOI 10.1016/j.kjms.2017.01.004; Nawrocki ST, 2020, CANCERS, V12, DOI 10.3390/cancers12103005; PHILLIPS DR, 1992, INVEST NEW DRUG, V10, P79, DOI 10.1007/BF00873121; Shi BX, 2013, EUR J MED CHEM, V60, P10, DOI 10.1016/j.ejmech.2012.11.033; Sun BL, 2021, CHEM PHARM BULL, V69, P472, DOI 10.1248/cpb.c21-00021; Tsuchiya H, 1999, CHEM PHARM BULL, V47, P440, DOI 10.1248/cpb.47.440; Yun CW, 2018, INT J MOL SCI, V19, DOI 10.3390/ijms19113466; Zhang GX, 2013, EUR J MED CHEM, V65, P21, DOI 10.1016/j.ejmech.2013.04.031; Zhang XF, 2016, SCI REP-UK, V6, DOI 10.1038/srep33204; Zhang ZY, 2017, EUR J MED CHEM, V140, P239, DOI 10.1016/j.ejmech.2017.09.017	26	0	0	7	7	PHARMACEUTICAL SOC JAPAN	TOKYO	2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN	0009-2363			CHEM PHARM BULL	Chem. Pharm. Bull.	NOV	2021	69	11					1104	1109					6	Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Chemistry	XG8AG	WOS:000724969900010	34719593	gold			2022-04-25	
J	Yoo, BH; Khan, IA; Koomson, A; Gowda, P; Sasazuki, T; Shirasawa, S; Gujar, S; Rosen, KV				Yoo, Byong Hoon; Khan, Iman Aftab; Koomson, Ananda; Gowda, Pramod; Sasazuki, Takehiko; Shirasawa, Senji; Gujar, Shashi; Rosen, Kirill V.			Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells	AUTOPHAGY			English	Article						apoptosis; ATG12; autophagy; colorectal cancer; RAS	K-RAS; PROTEIN-KINASE; UP-REGULATION; INDUCED TRANSFORMATION; EXTRACELLULAR-MATRIX; PROMOTES APOPTOSIS; COLORECTAL TUMORS; MEK INHIBITION; COLON-CANCER; AUTOPHAGY	Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.	[Yoo, Byong Hoon; Khan, Iman Aftab; Koomson, Ananda; Gowda, Pramod; Rosen, Kirill V.] Dalhousie Univ, Dept Pediat, Atlantic Res Ctr, Halifax, NS, Canada; [Yoo, Byong Hoon; Khan, Iman Aftab; Koomson, Ananda; Gowda, Pramod; Rosen, Kirill V.] Dalhousie Univ, Dept Biochem & Mol Biol, Atlantic Res Ctr, Halifax, NS, Canada; [Sasazuki, Takehiko] Kyushu Univ, Inst Adv Study, Fukuoka, Japan; [Shirasawa, Senji] Fukuoka Univ, Dept Cell Biol, Fac Med, Fukuoka, Japan; [Shirasawa, Senji] Fukuoka Univ, Ctr Adv Mol Med, Fukuoka, Japan; [Gujar, Shashi] Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada		Rosen, KV (corresponding author), Atlantic Res Ctr, CRC, Rm C-304,5849 Univ Ave,POB 15000, Halifax, NS B3H 4R2, Canada.	kirill.rosen@dal.ca		Gujar, Shashi/0000-0002-5427-0829; Rosen, Kirill/0000-0002-4317-9907	IWK Health Center; Canadian Institutes of Health Research/ Nova Scotia Regional Partnership Program (CIHR/NS RPP) [125109]; IWK Health Center Research Associateship	This study was supported by the Canadian Institutes of Health Research/Nova Scotia Regional Partnership Program (CIHR/NS RPP) operating grant 125109 and a grant from the IWK Health Center.; Byong Yoo was a recipient of the IWK Health Center Research Associateship.	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J	Yang, CG; Zhang, YB; Du, WF; Cheng, HG; Li, CB				Yang, Chenggang; Zhang, Yanbo; Du, Wenfeng; Cheng, Honggang; Li, Chaobin			Eukaryotic translation initiation factor 3 subunit G promotes human colorectal cancer	AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH			English	Article						EIF3G; colorectal cancer; proliferation; apoptosis; autophagy	AUTOPHAGY; EIF3; OVEREXPRESSION; CHEMOTHERAPY; PROGRESSION; RESECTION	In this study, we investigated the role of eukaryotic translation initiation factor 3 subunit G (EIF3G) in colorectal cancer. Immunohistochemical analysis showed higher EIF3G expression in stage IV human colorectal cancer tissues than in adjacent normal tissues (P<0.01). EIF3G short hairpin RNA (shRNA) knockdown in HCT116 colon cancer cells reduced proliferation and increased apoptosis as compared to control. EIF3G knockdown also increased autophagy and reduced mTOR signaling, as evidenced by low phospho-AKT, phospho-S6K and phospho-4EBP1 levels. Functional experiments indicated that overexpression of EIF3G promoted HCT-116 cells proliferation, migration and xenograft tumor growth. Finally, we observed lower xenograft tumor weights and volumes with EIF3G-silenced HCT116 cells than with control cells. These findings demonstrate that EIF3G promotes colon cancer growth and is a potential therapeutic target.	[Yang, Chenggang; Zhang, Yanbo; Du, Wenfeng; Cheng, Honggang; Li, Chaobin] Liaocheng Peoples Hosp, Dept Gastrointestinal Surg, 67 Dongchang West Rd, Liaocheng 252000, Shandong, Peoples R China		Yang, CG (corresponding author), Liaocheng Peoples Hosp, Dept Gastrointestinal Surg, 67 Dongchang West Rd, Liaocheng 252000, Shandong, Peoples R China.	baker-ham123@163.com			Shandong Provincial Natural Science Foundation, ChinaNatural Science Foundation of Shandong Province [ZR2015HL082]	This study was supported by ZR2015HL082 Shandong Provincial Natural Science Foundation, China ZR2015HL082.	Baba Y, 2011, CANCER-AM CANCER SOC, V117, P1399, DOI 10.1002/cncr.25630; Dang SP, 2015, STEM CELL RES THER, V6, DOI 10.1186/s13287-015-0245-4; De Roock W, 2010, LANCET ONCOL, V11, P753, DOI 10.1016/S1470-2045(10)70130-3; Dienstmann R, 2011, CANCER J, V17, P114, DOI 10.1097/PPO.0b013e318212f844; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Fernandez-Peralta AM, 2005, CANCER GENET CYTOGEN, V157, P18, DOI 10.1016/j.cancergencyto.2004.05.008; Gao Y, 2015, MED ONCOL, V32, DOI 10.1007/s12032-015-0518-x; Haigis KM, 2008, NAT GENET, V40, P600, DOI 10.1038/ng.115; Hershey JWB, 2015, BBA-GENE REGUL MECH, V1849, P792, DOI 10.1016/j.bbagrm.2014.10.005; House MG, 2011, ANN SURG, V254, P851, DOI 10.1097/SLA.0b013e31822f4f88; Jager S, 2012, NATURE, V481, P365, DOI 10.1038/nature10719; Kroemer G, 2010, MOL CELL, V40, P280, DOI 10.1016/j.molcel.2010.09.023; Lin YY, 2016, FEBS OPEN BIO, V6, P1201, DOI 10.1002/2211-5463.12137; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; Modelska A, 2015, CELL DEATH DIS, V6, DOI 10.1038/cddis.2014.542; Negri FV, 2010, BRIT J CANCER, V102, P162, DOI 10.1038/sj.bjc.6605471; Nesbit AD, 2015, PHOTOSYNTH RES, V126, P147, DOI 10.1007/s11120-015-0074-4; Sartore-Bianchi A, 2009, CANCER RES, V69, P1851, DOI 10.1158/0008-5472.CAN-08-2466; Sha Z, 2009, MOL CELL, V36, P141, DOI 10.1016/j.molcel.2009.09.026; Siegel RL, 2018, CA-CANCER J CLIN, V68, P7, DOI 10.3322/caac.21442; Smith MD, 2016, STRUCTURE, V24, P886, DOI 10.1016/j.str.2016.02.024; Society. AC, 2014, COL CANC FACTS FIG 2; Sonenberg N, 2009, CELL, V136, P731, DOI 10.1016/j.cell.2009.01.042; Spilka R, 2013, CANCER LETT, V340, P9, DOI 10.1016/j.canlet.2013.06.019; Tomlinson JS, 2007, J CLIN ONCOL, V25, P4575, DOI 10.1200/JCO.2007.11.0833; Unbehaun A, 2004, GENE DEV, V18, P3078, DOI 10.1101/gad.1255704; Zhang LL, 2007, J BIOL CHEM, V282, P5790, DOI 10.1074/jbc.M606284200; Zheng QL, 2016, MOL MED REP, V13, P2973, DOI 10.3892/mmr.2016.4935; Zhou CS, 2005, BMC BIOL, V3, DOI 10.1186/1741-7007-3-14	29	8	8	0	1	E-CENTURY PUBLISHING CORP	MADISON	40 WHITE OAKS LN, MADISON, WI 53711 USA	1943-8141			AM J TRANSL RES	Am. J. Transl. Res.		2019	11	2					612	+					13	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	HN2FN	WOS:000460001200008	30899366				2022-04-25	
J	Zhang, Y; Liu, Y; Zhou, YX; Zheng, ZM; Tang, WQ; Song, MZ; Wang, JL; Wang, KP				Zhang, Yu; Liu, Yan; Zhou, Yinxing; Zheng, Ziming; Tang, Wenqi; Song, Mengzi; Wang, Jinglin; Wang, Kaiping			Lentinan inhibited colon cancer growth by inducing endoplasmic reticulum stress-mediated autophagic cell death and apoptosis	CARBOHYDRATE POLYMERS			English	Article						Lentinan; Direct antitumour; NOD; SCID mice; Endoplasmic reticulum stress; Autophagy; Apoptosis	ER STRESS; POLYSACCHARIDE LENTINAN; HUMANIZED MICE; CYCLE ARREST; IN-VITRO; EDODES; CROSSTALK; KINASES; MODEL; VIVO	Lentinan (SLNT) has been shown to be directly cytotoxic to cancer cells. However, this direct antitumour effect has not been thoroughly investigated in vivo, and the mechanism remains unclear. We aimed to examine the direct antitumour effect of SLNT on human colon cancer and the mechanism in vivo and in vitro. SLNT significantly inhibited tumour growth and induced autophagy and endoplasmic reticulum stress (ERS) in HT-29 cells and tumour-bearing nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice. Experiments with the autophagy inhibitors chloroquine (CQ) and 3-methyladenine (3-MA) showed that autophagy facilitated the antitumour effect of SLNT. Moreover, ERS was identified as the common upstream regulator of SLNT-induced increases in Ca2+concentrations, autophagy and apoptosis by using ERS inhibitors. In summary, our study demonstrated that SLNT exerted direct antitumour effects on human colon cancer via ERS-mediated autophagy and apoptosis, providing a novel understanding of SLNT as an anti-colon cancer therapy.	[Zhang, Yu; Liu, Yan; Zheng, Ziming; Wang, Jinglin] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430030, Peoples R China; [Zhang, Yu; Liu, Yan; Zheng, Ziming; Wang, Jinglin] Hubei Prov Clin Res Ctr Precis Med Crit Illness, Wuhan 430030, Peoples R China; [Zhou, Yinxing; Tang, Wenqi; Song, Mengzi; Wang, Kaiping] Huazhong Univ Sci & Technol, Tongji Med Coll Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China		Wang, JL (corresponding author), Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430030, Peoples R China.; Wang, JL (corresponding author), Hubei Prov Clin Res Ctr Precis Med Crit Illness, Wuhan 430030, Peoples R China.; Wang, KP (corresponding author), Huazhong Univ Sci & Technol, Tongji Med Coll Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China.	linlinvc202@163.com; wkpzcq@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81974509]	This work is supported by the National Natural Science Foundation of China (Grant No. 81974509). The authors thank the Analysis and Testing Center of Huazhong University of Science and Technology for their technical assistance.	Amaravadi RK, 2019, CANCER DISCOV, V9, P1167, DOI 10.1158/2159-8290.CD-19-0292; Bakchoul T, 2015, J THROMB HAEMOST, V13, P872, DOI 10.1111/jth.12879; Bian YC, 2020, INT J BIOL MACROMOL, V162, P107, DOI 10.1016/j.ijbiomac.2020.06.054; Bisen PS, 2010, CURR MED CHEM, V17, P2419, DOI 10.2174/092986710791698495; Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI 10.3322/caac.21492; Chen YJ, 2019, CELL DEATH DIS, V10, DOI 10.1038/s41419-019-2004-4; Cheng X, 2017, CELL DEATH DIS, V8, DOI 10.1038/cddis.2017.384; Ciechomska IA, 2013, ONCOGENE, V32, P1518, DOI 10.1038/onc.2012.174; Deniaud A, 2008, ONCOGENE, V27, P285, DOI 10.1038/sj.onc.1210638; Driscoll J. 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Polym.	SEP 1	2021	267								118154	10.1016/j.carbpol.2021.118154		MAY 2021	13	Chemistry, Applied; Chemistry, Organic; Polymer Science	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Polymer Science	SU4DA	WOS:000663089200009	34119128				2022-04-25	
J	Xiong, HY; Guo, XL; Bu, XX; Zhang, SS; Ma, NN; Song, JR; Hu, F; Tao, SF; Sun, K; Li, R; Wu, MC; Wei, LX				Xiong, Hai-yan; Guo, Xian-ling; Bu, Xin-xin; Zhang, Shan-shan; Ma, Nan-nan; Song, Jian-rui; Hu, Fei; Tao, Shuang-fen; Sun, Kai; Li, Rong; Wu, Meng-chao; Wei, Li-xin			Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell	CANCER LETTERS			English	Article						Autophagic cell death; Apoptosis; Bax; PUMA; mTOR	MALIGNANT GLIOMA-CELLS; MAMMALIAN TARGET; TUMOR-SUPPRESSOR; KINASE-B; APOPTOSIS; INHIBITION; PROTEIN; DISEASE; MACROAUTOPHAGY; CHEMOTHERAPY	Autophagy is a membrane process that results in the transporting of cellular contents to lysosomes for degradation. Autophagic cell death is another way of programed cell death called type If PCD, which has complicated connection with apoptosis, both of these two types of cell death play an important role in tumor development. In this study, we investigated chemotherapeutic agent induced cell death pathway in wild type (WT), Bax(-/-) and PUMA(-/-) HCT116 cells. Bax or PUMA deficient cells had similar chemosensitivity to VV7 cells but were defective in undergoing apoptosis. The results of electron microscopy and GFP-LC3 localization assay showed that autophagy was induced in Bax or PUMA deficient cells but not in WT cells. mTOR activity was decreased in Bax or PUMA deficient cells which further indicated the up-regulation of autophagy. Inhibition of autophagy by 3-Methyladenine (3-MA) decreased the cell death in Bax or PUMA deficient cells. Taken together, these results suggest that autophagic cell death can be used as an alternative cell death pathway in apoptosis defective cells and may bring a new target for cancer therapy. (C) 2009 Elsevier Ireland Ltd. All rights reserved.	[Xiong, Hai-yan; Guo, Xian-ling; Bu, Xin-xin; Zhang, Shan-shan; Ma, Nan-nan; Song, Jian-rui; Hu, Fei; Tao, Shuang-fen; Sun, Kai; Li, Rong; Wu, Meng-chao; Wei, Li-xin] Second Mil Med Univ, Tumor Immunol & Gene Therapy Ctr, Eastern Hepatobiliary Surg Hosp, Shanghai 200438, Peoples R China		Wei, LX (corresponding author), Second Mil Med Univ, Tumor Immunol & Gene Therapy Ctr, Eastern Hepatobiliary Surg Hosp, 225 Changhai Rd, Shanghai 200438, Peoples R China.	lixinwei@smmu.edu.cn	ma, nan/AAF-6968-2020	ma, nan/0000-0003-4006-1003	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30700981, 30801347, 0870974]; Commission of Science and Technology of Shanghai MunicipalityScience & Technology Commission of Shanghai Municipality (STCSM) [045407047, 08XD14003]; National Key Sci-Tech Special Project of China [2008ZX10002-019, 2008ZX10002-025]	We thank Dr. Chuanshu Huang for providing us with cell line and Dr. Shengkan Jin for providing us with the GFP-LC3 plasmid. This project was supported by the Special Funds for National Natural Science Foundation of China (Grant Nos.: 30700981, 30801347 and 0870974), the Commission of Science and Technology of Shanghai Municipality (Grant Nos.: 045407047 and 08XD14003), National Key Sci-Tech Special Project of China (Grant Nos.: 2008ZX10002-019 and 2008ZX10002-025).	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FEB 1	2010	288	1					68	74		10.1016/j.canlet.2009.06.039			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	561PY	WOS:000274991700009	19660860				2022-04-25	
J	Sha, MQ; Mao, GX; Wang, GF; Chen, YF; Wu, XJ; Wang, Z				Sha, Mingquan; Mao, Genxiang; Wang, Guofu; Chen, Yufeng; Wu, Xiaojian; Wang, Zhen			DZNep inhibits the proliferation of colon cancer HCT116 cells by inducing senescence and apoptosis	ACTA PHARMACEUTICA SINICA B			English	Article						EZH2; Human colon cancer HCT116 cells; DZNep; Anti-cancer mechanisms	ZESTE HOMOLOG 2; HISTONE METHYLTRANSFERASE EZH2; COLORECTAL-CANCER; POLYCOMB PROTEIN; ENHANCER; GROWTH; AUTOPHAGY; THERAPY; GENE	EZH2 is over-expressed in human colon cancer and is closely associated with tumor proliferation, metastasis and poor prognosis. Targeting and inhibiting EZH2 may he an effective therapeutic strategy for colon cancer. 31Deazaneplanocin A (DZNeN, as an EZH2 inhibitor, can suppress cancer cell growth. However, the anti-cancer role of DZNep in colon cancer cells has been rarely studied. In this study, we demonstrate that DZNep can inhibit the growth and survival of colon cancer HCT116 cells by inducing cellular senescence and apoptosis. The study provides a novel view of anti-cancer mechanisms of DZNep in human colon cancer cells. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.	[Sha, Mingquan; Wang, Zhen] Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China; [Sha, Mingquan; Wang, Zhen] Peking Union Med Coll, Beijing 100050, Peoples R China; [Mao, Genxiang; Wang, Guofu] Zhejiang Hosp, Zhejiang Prov Key Lab Geriatr, Hangzhou 310013, Zhejiang, Peoples R China; [Mao, Genxiang; Wang, Guofu] Zhejiang Hosp, Geriatr Inst Zhejiang Prov, Hangzhou 310013, Zhejiang, Peoples R China; [Chen, Yufeng; Wu, Xiaojian] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou 510635, Guangdong, Peoples R China		Wu, XJ (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou 510635, Guangdong, Peoples R China.	wxjmqy2003@yahoo.com; wangzhen@imb.pumc.edu.cn		Wang, Zhen/0000-0002-6377-3890	Sino-Singapore Collaboration Project from the Ministry of Science and Technology (MOST) of China [2013DFG32990]; National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [81373438, 31201040]; National Mega-Project for Innovative Drugs by MOST [2012ZX09301002-001-015]	This project is co-sponsored by Sino-Singapore Collaboration Project from the Ministry of Science and Technology (MOST) of China (No. 2013DFG32990), National Natural Science Foundation of China (NSFC Nos. 81373438 and 31201040), and National Mega-Project for Innovative Drugs by MOST (No. 2012ZX09301002-001-015).	Bai J, 2014, CELL PROLIFERAT, V47, P211, DOI 10.1111/cpr.12103; Bai J, 2014, DNA CELL BIOL, V33, P337, DOI 10.1089/dna.2014.2340; Bardhan Kankana, 2013, Cancers (Basel), V5, P676, DOI 10.3390/cancers5020676; Benoit YD, 2013, EXP CELL RES, V319, P1463, DOI 10.1016/j.yexcr.2013.04.006; Benoit YD, 2013, J CELL PHYSIOL, V228, P764, DOI 10.1002/jcp.24224; Choi HJ, 2009, BMC GASTROENTEROL, V9, DOI 10.1186/1471-230X-9-39; Chu IM, 2008, NAT REV CANCER, V8, P253, DOI 10.1038/nrc2347; Crea F, 2012, CANCER METAST REV, V31, P753, DOI 10.1007/s10555-012-9387-3; Ferraro A, 2013, INT J BIOCHEM CELL B, V45, P243, DOI 10.1016/j.biocel.2012.10.009; Fussbroich B, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0021651; Ishikawa S, 2014, INT J CANCER, V135, P2528, DOI 10.1002/ijc.28672; Jung HY, 2013, MOL CELL, V52, P193, DOI 10.1016/j.molcel.2013.08.028; Kikuchi J, 2012, LUNG CANCER, V78, P138, DOI 10.1016/j.lungcan.2012.08.003; Kumari A, 2015, CELL DEATH DIFFER, V22, P311, DOI 10.1038/cdd.2014.146; Li L, 2014, ONCOTARGETS THER, V7, P1817, DOI 10.2147/OTT.S48409; Luo ZG, 2012, CANCER RES, V72, P3360, DOI 10.1158/0008-5472.CAN-12-0388; Mosieniak G, 2012, MECH AGEING DEV, V133, P444, DOI 10.1016/j.mad.2012.05.004; Ougolkov AV, 2008, CLIN CANCER RES, V14, P6790, DOI 10.1158/1078-0432.CCR-08-1013; Shen L, 2013, ONCOTARGETS THER, V6, P321, DOI 10.2147/OTT.S42453; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Tan J, 2007, GENE DEV, V21, P1050, DOI 10.1101/gad.1524107; Tonini T, 2008, J CELL PHYSIOL, V214, P295, DOI 10.1002/jcp.21241; Tsang DPF, 2011, J GASTROEN HEPATOL, V26, P19, DOI 10.1111/j.1440-1746.2010.06447.x; Wang Y, 2014, MOL CARCINOG; Wu Z, 2011, CELL DEATH DIFFER, V18, P1771, DOI 10.1038/cdd.2011.48	25	21	24	2	12	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES	BEIJING	C/O EDITORIAL BOARD OF ACTA PHARMACEUTICA SINICA, 1 XIANNONGTAN ST, BEIJING, 100050, PEOPLES R CHINA	2211-3835	2211-3843		ACTA PHARM SIN B	Acta Pharm. Sin. B	MAY	2015	5	3					188	193		10.1016/j.apsb.2015.01.011			6	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	CP6PE	WOS:000360008900003	26579445	Green Published, gold			2022-04-25	
J	Qu, JY; Zeng, C; Zou, TT; Chen, X; Yang, XL; Lin, ZH				Qu, Junyan; Zeng, Cheng; Zou, Tingting; Chen, Xu; Yang, Xiaolong; Lin, Zhenghong			Autophagy Induction by Trichodermic Acid Attenuates Endoplasmic Reticulum Stress-Mediated Apoptosis in Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						TDA; ER stress; apoptosis; autophagy; colorectal cancer	UNFOLDED PROTEIN RESPONSE; COLORECTAL-CANCER; ER-STRESS; M-COPA; GOLGI SYSTEM; DEATH; TUMOR; ACTIVATION; PATHWAY; THAPSIGARGIN	Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1 alpha/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC.	[Qu, Junyan; Zeng, Cheng; Zou, Tingting; Chen, Xu; Lin, Zhenghong] Chongqing Univ, Sch Life Sci, Chongqing 401331, Peoples R China; [Yang, Xiaolong] South Cent Univ Nationalities, Sch Pharmaceut Sci, Modernizat Engn Technol Res Ctr Ethn Minor Med Hu, Wuhan 430074, Peoples R China		Lin, ZH (corresponding author), Chongqing Univ, Sch Life Sci, Chongqing 401331, Peoples R China.; Yang, XL (corresponding author), South Cent Univ Nationalities, Sch Pharmaceut Sci, Modernizat Engn Technol Res Ctr Ethn Minor Med Hu, Wuhan 430074, Peoples R China.	qujunyan1229@yeah.net; cqzengcheng@163.com; tingtzou1997@163.com; chenxu_2021@163.com; yxl19830915@mail.scuec.edu.cn; zhenghonglin@cqu.edu.cn		Lin, Zhenghong/0000-0002-6354-0042	Natural Science FoundationNational Natural Science Foundation of China (NSFC) [cstc2020jcyj-msxmX0154]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31571454, 81872755, 82073714]; Talented Youth Cultivation Program from "the Fundamental Research Funds for the Central Universities", South-Central University for Nationalities [CZP20008]	This work was supported by Natural Science Foundation Project of CQ CSTC' (Grant cstc2020jcyj-msxmX0154 to Zhenghong Lin), supported by the National Natural Science Foundation of China (Grant No. 31571454 to Zhenghong Lin, and 81872755 and 82073714 to Xiao-long Yang), and supported by the Talented Youth Cultivation Program from "the Fundamental Research Funds for the Central Universities", South-Central University for Nationalities (No. CZP20008 to Xiao-long Yang).	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J. Mol. Sci.	JUN	2021	22	11							5566	10.3390/ijms22115566			19	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	SQ1WC	WOS:000660149000001	34070303	gold, Green Published			2022-04-25	
J	Lin, LT; Uen, WC; Choong, CY; Shi, YC; Lee, BH; Tai, CJ; Tai, CJ				Lin, Liang-Tzung; Uen, Wu-Ching; Choong, Chen-Yen; Shi, Yeu-Ching; Lee, Bao-Hong; Tai, Cheng-Jeng; Tai, Chen-Jei			Paris Polyphylla Inhibits Colorectal Cancer Cells via Inducing Autophagy and Enhancing the Efficacy of Chemotherapeutic Drug Doxorubicin	MOLECULES			English	Article						folk medicine; DLD-1 cells; doxorubicin; chemotherapy; drug resistance	COMPLEMENTARY/ALTERNATIVE MEDICINE; APOPTOSIS; SURVIVAL; THERAPY; COLON	Colorectal cancer is one of the most common cancers worldwide and chemotherapy is the main approach for the treatment of advanced and recurrent cases. Developing an effective complementary therapy could help to improve tumor suppression efficiency and control adverse effects from chemotherapy. Paris polyphylla is a folk medicine for treating various forms of cancer, but its effect on colorectal cancer is largely unexplored. The aim of the present study is to investigate the tumor suppression efficacy and the mechanism of action of the ethanolic extract from P. polyphylla (EEPP) in DLD-1 human colorectal carcinoma cells and to evaluate its combined effect with chemotherapeutic drug doxorubicin. The data indicated that EEPP induced DLD-1 cell death via the upregulation of the autophagy markers, without triggering p53- and caspase-3-dependent apoptosis. Moreover, EEPP treatment in combination with doxorubicin enhanced cytotoxicity in these tumor cells. Pennogenin 3-O-beta-chacotrioside and polyphyllin VI were isolated from EEPP and identified as the main candidate active components. Our results suggest that EEPP deserves further evaluation for development as complementary chemotherapy for colorectal cancer.	[Lin, Liang-Tzung] Taipei Med Univ, Coll Med, Sch Med, Dept Microbiol & Immunol, Taipei 11042, Taiwan; [Lin, Liang-Tzung] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 11042, Taiwan; [Uen, Wu-Ching] Fujen Catholic Univ, Sch Med, New Taipei 24205, Taiwan; [Uen, Wu-Ching] Shin Kong Wu Ho Su Mem Hosp, Dept Hematol & Oncol, Taipei 11042, Taiwan; [Choong, Chen-Yen; Shi, Yeu-Ching; Lee, Bao-Hong; Tai, Cheng-Jeng] Taipei Med Univ Hosp, Div Hematol & Oncol, Dept Internal Med, Taipei 11042, Taiwan; [Tai, Cheng-Jeng] Taipei Med Univ, Coll Med, Sch Med, Div Hematol & Oncol,Dept Internal Med, Taipei 11042, Taiwan; [Tai, Chen-Jei] Taipei Univ Hosp, Dept Chinese Med, Taipei 11042, Taiwan; [Tai, Chen-Jei] Taipei Med Univ Hosp, Tradit Herbal Med Res Ctr, Taipei 11042, Taiwan; [Tai, Chen-Jei] Taipei Med Univ, Coll Med, Sch Med, Dept Obstet & Gynecol, Taipei 11042, Taiwan		Tai, CJ (corresponding author), Taipei Univ Hosp, Dept Chinese Med, Taipei 11042, Taiwan.; Tai, CJ (corresponding author), Taipei Med Univ Hosp, Tradit Herbal Med Res Ctr, Taipei 11042, Taiwan.; Tai, CJ (corresponding author), Taipei Med Univ, Coll Med, Sch Med, Dept Obstet & Gynecol, Taipei 11042, Taiwan.	ltlin@tmu.edu.tw; m002047@ms.skh.org.tw; chenyen@tmu.edu.tw; jasmineycs@yahoo.com.tw; f96b47117@ntu.edu.tw; cjtai@tmu.edu.tw; chenjtai@tmu.edu.tw		Lin, Liang-Tzung/0000-0001-7374-7234	Taipei Medical University [108-TMU-TMUH-05]; Taipei Medical University Hospital [108-TMU-TMUH-05]; Ministry of Science and Technology (Taiwan, R.O.C.)Ministry of Science and Technology, Taiwan [MOST-106-2320-B-038-017]	This research work and subsidiary spending were supported by the Taipei Medical University and Taipei Medical University Hospital (108-TMU-TMUH-05), and the Ministry of Science and Technology (MOST-106-2320-B-038-017) (Taiwan, R.O.C.).	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J	Li, TY; Chiang, BH				Li, Ting-Yi; Chiang, Been-Huang			6-shogaol induces autophagic cell death then triggered apoptosis in colorectal adenocarcinoma HT-29 cells	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Colorectal cancer; HT 29; 6-shogaol; Autophagy; Apoptosis	REGULATES AUTOPHAGY; ACTIVATION; ARREST	6-shogaol is a phytochemical of dietary ginger, we found that 6-shogaol could induced both autophagic and apoptotic death in human colon adenocarcinoma (HT-29) cells. Results of this study showed that 6-shogal induced cell cycle arrest, autophagy, and apoptosis in HT-29 cells in a time sequence. After 6 h, 6-shogal induced apparent G2/M arrest, then the HT-29 cells formed numerous autophagosomes in each phase of the cell cycle. After 18 h, increases in acidic vesicles and LAMP-1 (Lysosome-associated membrane proteins 1) showed that 6-shogaol had caused autophagic cell death. After 24 h, cell shrinkage and Caspase-3/7 activities rising, suggesting that apoptotic cell death had increased. And after 48 h, the result of TUNEL assay indicated the highest occurrence of apoptosis upon 6-shogaol treatment. It appeared that apoptosis is triggered by autophagy in 6-shogaol treated HT-29 cells, the damage of autophagic cell death initiated apoptosis program. (C) 2017 Elsevier Masson SAS. All rights reserved.	[Li, Ting-Yi; Chiang, Been-Huang] Natl Taiwan Univ, Inst Food Sci & Technol, Taipei 10617, Taiwan		Chiang, BH (corresponding author), Natl Taiwan Univ, Inst Food Sci & Technol, 1,Sect 4,Roosevelt Rd, Taipei 106, Taiwan.	bhchiang@ntu.edu.tw					Akimoto M., 2015, PLOS ONE, V10; Annamalai G, 2016, BIOMED PHARMACOTHER, V82, P226, DOI 10.1016/j.biopha.2016.04.044; Chen CY, 2007, J AGR FOOD CHEM, V55, P948, DOI 10.1021/jf0624594; Dancey J, 2010, NAT REV CLIN ONCOL, V7, P209, DOI 10.1038/nrclinonc.2010.21; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; Dugasani S, 2010, J ETHNOPHARMACOL, V127, P515, DOI 10.1016/j.jep.2009.10.004; Ellington AA, 2005, CARCINOGENESIS, V26, P159, DOI 10.1093/carcin/bgh297; Esposti DD, 2010, AUTOPHAGY, V6, P172, DOI 10.4161/auto.6.1.10699; Franke J, 2014, BMC VET RES, V10, DOI 10.1186/1746-6148-10-119; Gan FF, 2011, APOPTOSIS, V16, P856, DOI 10.1007/s10495-011-0611-3; Gao C, 2010, NAT CELL BIOL, V12, P781, DOI 10.1038/ncb2082; Geng JF, 2008, EMBO REP, V9, P859, DOI 10.1038/embor.2008.163; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Grivennikov SI, 2010, CELL, V140, P883, DOI 10.1016/j.cell.2010.01.025; Hu R, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0039664; Hung JY, 2009, J AGR FOOD CHEM, V57, P9809, DOI 10.1021/jf902315e; Ishiguro K, 2008, FEBS LETT, V582, P3531, DOI 10.1016/j.febslet.2008.09.027; Kaminskyy V, 2011, AUTOPHAGY, V7, P83, DOI 10.4161/auto.7.1.13893; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Kim KW, 2006, J BIOL CHEM, V281, P36883, DOI 10.1074/jbc.M607094200; Knecht E, 2009, CELL MOL LIFE SCI, V66, P2427, DOI 10.1007/s00018-009-0030-6; Kourtis N, 2009, CELL DEATH DIFFER, V16, P21, DOI 10.1038/cdd.2008.120; Kumar D, 2013, MOL CANCER, V12, DOI 10.1186/1476-4598-12-171; Lebovitz CB, 2012, CLIN CANCER RES, V18, P1214, DOI 10.1158/1078-0432.CCR-11-2465; Liang C, 2006, NAT CELL BIOL, V8, P688, DOI 10.1038/ncb1426; Ohsumi Y, 2001, NAT REV MOL CELL BIO, V2, P211, DOI 10.1038/35056522; Pan MH, 2008, CHEM SOC REV, V37, P2558, DOI 10.1039/b801558a; Pan MH, 2008, MOL NUTR FOOD RES, V52, P527, DOI 10.1002/mnfr.200700157; Ramakrishnan S, 2007, AUTOPHAGY, V3, P512; Ray A, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0137614; Saiki S, 2011, AUTOPHAGY, V7, P176, DOI 10.4161/auto.7.2.14074; Scarlatti F, 2008, CELL DEATH DIFFER, V15, P1318, DOI 10.1038/cdd.2008.51; Tait SWG, 2010, NAT REV MOL CELL BIO, V11, P621, DOI 10.1038/nrm2952; Takahashi Y, 2007, NAT CELL BIOL, V9, P1142, DOI 10.1038/ncb1634; Wei QY, 2005, J ETHNOPHARMACOL, V102, P177, DOI 10.1016/j.jep.2005.05.043; Weng CJ, 2012, MOL NUTR FOOD RES, V56, P1304, DOI 10.1002/mnfr.201200173; Wu JJ, 2015, EUR J PHARMACOL, V762, P449, DOI 10.1016/j.ejphar.2015.06.032; Yang Chao, 2001, Electric Power Automation Equipment, V21, P1; Yang ZNJ, 2011, MOL CANCER THER, V10, P1533, DOI 10.1158/1535-7163.MCT-11-0047	39	14	17	0	10	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER	ISSY-LES-MOULINEAUX	65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE	0753-3322	1950-6007		BIOMED PHARMACOTHER	Biomed. Pharmacother.	SEP	2017	93						208	217		10.1016/j.biopha.2017.06.038			10	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	FE0PU	WOS:000407923000023	28641163				2022-04-25	
J	Karakas, HE; Gozuacik, D				Karakas, Hacer Ezgi; Gozuacik, Devrim			Autophagy and cancer	TURKISH JOURNAL OF BIOLOGY			English	Review						Autophagy; stress; cancer; tumor; oncogenes; tumor suppressors; metastasis; cell death; chemotherapy	INTERACTING FACTOR-I; CHAPERONE-MEDIATED AUTOPHAGY; TUMOR-SUPPRESSOR GENE; UNC-51-LIKE KINASE 1; INDUCED CELL-DEATH; DECREASED EXPRESSION; REGULATES AUTOPHAGY; POOR-PROGNOSIS; BREAST-CANCER; COLON-CANCER	Autophagy is an evolutionary conserved intracellular degradation and stress response mechanism that is mainly responsible for the breakdown and recycling of cytoplasmic materials, including long-lived proteins, protein aggregates, and damaged organelles. In this way, autophagy provides the cell with building blocks and allows the maintenance of homeostasis under stress conditions such as growth factor deficiency, nutrient deprivation, hypoxia, and toxins. Consequently, abnormalities of autophagy contribute to a number of pathologies ranging from neurodegenerative diseases to cancer. Autophagy was reported to have a dual role in cancer. Depending on cancer stage, autophagy seems to act as tumor suppressor or as a mechanism supporting tumor growth and spread. In this review, we provide a summary of the relevant literature and discuss the role of autophagy in cancer formation and chemotherapy responses.	[Karakas, Hacer Ezgi; Gozuacik, Devrim] Sabanci Univ, Fac Engn & Nat Sci, Mol Biol Genet & Bioengn Program, Istanbul, Turkey		Gozuacik, D (corresponding author), Sabanci Univ, Fac Engn & Nat Sci, Mol Biol Genet & Bioengn Program, Istanbul, Turkey.	dgozuacik@sabanciuniv.edu	Devrim, Gozuacik/C-3330-2008; Karakas, Hacer Ezgi/B-6566-2016	Devrim, Gozuacik/0000-0001-7739-2346; Karakas, Hacer Ezgi/0000-0001-5368-5064	Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112T685]; Sabanci UniversitySabanci University; EMBO Strategic Development Installation Grant (EMBO-SDIG); Turkish Academy of Sciences (TUBA) GEBIP awardTurkish Academy of Sciences; TUBITAK-BIDEB scholarship for PhD studiesTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)	We are grateful to Amal Araciche, Peter Schuller, Cenk Kig Kumsal Ayse Tekirdag, and Yunus Akkoc for critical reading of the manuscript. This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK), grant number 112T685, and Sabanci University. DG is the recipient of an EMBO Strategic Development Installation Grant (EMBO-SDIG) and Turkish Academy of Sciences (TUBA) GEBIP award. HEK was supported by a TUBITAK-BIDEB scholarship for PhD studies.	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J. Biol.		2014	38	6					720	739		10.3906/biy-1408-16			20	Biology	Science Citation Index Expanded (SCI-EXPANDED)	Life Sciences & Biomedicine - Other Topics	AU2FF	WOS:000345431100004		Bronze, Green Submitted			2022-04-25	
J	Wu, L; He, K; Ding, QS; Wang, Z; Xiang, GA; Yu, HG				Wu Lu; He Ke; Ding Qianshan; Wang Zhen; Xiang Guoan; Yu Honggang			Apatinib has anti-tumor effects and induces autophagy in colon cancer cells	IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES			English	Article						Apatinib; Apoptosis; Autophagy; Colon cancer; Migration; mTOR	GASTRIC-CANCER; COLORECTAL-CANCER; TYROSINE KINASE; INHIBITOR; GROWTH; DISEASE; PHARMACOKINETICS; METABOLISM; PROTEINS; YN968D1	Objective(s): Apatinib recently has been used to treat patients with gastric cancer, but the function of apatinib in colon cancer remains unclear. This study was conducted to investigate the impacts of apatinib on the biological function and its potential mechanism of colon cancer cells in vitro. Materials and Methods: The effect of apatinib in colon cancer cells were detected by assessing cell viability, migration and invasion capabilities. Apoptosis cells and the cell cycle distribution of colon cancer cells were analyzed by flow cytometry. The potential mechanism was investigated via autophagy related proteins and pathways in vitro. Results: The proliferation, migration and invasion of colon cancer cells were inhibited when they were treated with different concentration of apatinib (20, 40 mu M). When HCT116 and SW480 cells were treated with apatinib at the concentration of 20 mu M, the apoptosis percentage were 3.7% and 5.8% respectively. As the drug concentration increased to 40 mu M., the the apoptosis percentage increased to 11.9% and 13.5%. Meanwhile, cell cycle was also altered. Furthermore, apatinib inhibited the expression of AKT-mTOR signaling pathway and increased the expression of LC3-II. Conclusion: Apatinib can significantly inhibit the malignant phenotype of colon cancer cells, and it was involved in regulation of autophagy.	[Wu Lu; Ding Qianshan; Yu Honggang] Wuhan Univ, Dept Gastroenterol, Renmin Hosp, Wuhan 430060, Hubei, Peoples R China; [Wu Lu] Wuhan Univ, Hubei Key Lab Digest Syst, Renmin Hosp, Wuhan, Hubei, Peoples R China; [He Ke; Xiang Guoan] Guangdong Second Prov Gen Hosp, Dept Gen Surg, Guangzhou, Guangdong, Peoples R China; [Wang Zhen] Jiangsu Hengrui Med Co Ltd, Lian Yungang 222047, Peoples R China		Yu, HG (corresponding author), Wuhan Univ, Renmin Hosp, Dept Gastroenterol, Hubei Key Lab Digest Syst, Zhangzhidong Rd 99, Wuhan 430061, Hubei, Peoples R China.	yhg_rmhwh@163.com					AHLBERG J, 1985, EXP MOL PATHOL, V42, P78, DOI 10.1016/0014-4800(85)90020-6; Aoyama T, 2016, NAT REV CLIN ONCOL, V13, P268, DOI 10.1038/nrclinonc.2016.53; Brenner H, 2014, LANCET, V383, P1490, DOI 10.1016/S0140-6736(13)61649-9; Chan MMK, 2015, BIOL-TARGETS THER, V9, P93, DOI 10.2147/BTT.S62777; Chatterjee S, 2013, J CLIN INVEST, V123, P1732, DOI 10.1172/JCI65385; Ding JF, 2013, DRUG METAB DISPOS, V41, P1195, DOI 10.1124/dmd.112.050310; Ding JF, 2012, J CHROMATOGR B, V895, P108, DOI 10.1016/j.jchromb.2012.03.027; Fontanella C, 2014, ANN TRANSL MED, V2, DOI 10.3978/j.issn.2305-5839.2014.08.14; Fornaro L, 2016, J CLIN ONCOL; Gill S, 2003, ALIMENT PHARM THER, V18, P683, DOI 10.1046/j.1365-2036.2003.01735.x; Hu T, 2016, WORLD J GASTROENTERO, V22, P6876, DOI 10.3748/wjg.v22.i30.6876; Ivy SP, 2009, NAT REV CLIN ONCOL, V6, P569, DOI 10.1038/nrclinonc.2009.130; Jayson GC, 2016, LANCET, V388, P518, DOI 10.1016/S0140-6736(15)01088-0; Kim J, 2011, NAT CELL BIOL, V13, P132, DOI 10.1038/ncb2152; Lee JJ, 2014, CLIN COLORECTAL CANC, V13, P135, DOI 10.1016/j.clcc.2014.02.001; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Li J, 2010, BMC CANCER, V10, DOI 10.1186/1471-2407-10-529; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Parkin DM, 2001, LANCET ONCOL, V2, P533, DOI 10.1016/S1470-2045(01)00486-7; Roviello G, 2016, EXPERT REV GASTROENT, V10, P887, DOI 10.1080/17474124.2016.1209407; Roviello G, 2016, CANCER LETT, V372, P187, DOI 10.1016/j.canlet.2016.01.014; Schaaf MBE, 2016, FASEB J, V30, P3961, DOI 10.1096/fj.201600698R; Scott AJ, 2015, DRUG TODAY, V51, P223, DOI 10.1358/dot.2015.51.4.2320599; Thomas Hilary, 2003, Cancer Control, V10, P159; Tian S, 2011, CANCER SCI, V102, P1374, DOI 10.1111/j.1349-7006.2011.01939.x; Wullschleger S, 2006, CELL, V124, P471, DOI 10.1016/j.cell.2006.01.016; Yang J, 2013, INT J BIOL SCI, V9, P1121, DOI 10.7150/ijbs.6666	27	37	41	1	11	MASHHAD UNIV MED SCIENCES	MASHHAD	VICE-CHANCELLOR FOR RES CTR OFF IJBMS, DANESHGAH ST, PO BOX 9138813944 - 445, MASHHAD, 00000, IRAN	2008-3866	2008-3874		IRAN J BASIC MED SCI	Iran. J. Basic Med. Sci.	SEP	2017	20	9					990	995					6	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	FF7RC	WOS:000409212700004	29085592				2022-04-25	
J	Li, J; Hou, N; Faried, A; Tsutsumi, S; Takeuchi, T; Kuwano, H				Li, Jie; Hou, Ni; Faried, Ahmad; Tsutsumi, Soichi; Takeuchi, Toshiyuki; Kuwano, Hiroyuki			Inhibition of Autophagy by 3-MA Enhances the Effect of 5-FU-Induced Apoptosis in Colon Cancer Cells	ANNALS OF SURGICAL ONCOLOGY			English	Article							1ST-LINE TREATMENT; ADJUVANT TREATMENT; COLORECTAL-CANCER; MAMMALIAN TARGET; DEATH; PROTEINS; 5-FLUOROURACIL; TUMORIGENESIS; FLUOROURACIL; MECHANISMS	5-fluorouracil-(5-FU)-based adjuvant chemotherapy is widely used for the treatment of colorectal cancer. However, 5-FU resistance in the course of treatment has become more common. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Two colon-cancer-derived cell lines, colon26 and HT29, were used to investigate the effect of 5-FU, 3-methyladenine (3-MA, an autophagy inhibitor), or their combination on apoptotic cell death and autophagy. MTT assay, Hochest plus propidium iodide (PI) staining, and DNA fragmentation assay were used to observe apoptosis. Meanwhile, monodansylcadaverine (MDC) was used to detect autophagy. Finally, immunoblotting assay was used to explore the molecular change that occurred. We observed the apoptosis induced by 5-FU in colon cancer cells. Meanwhile, autophagy was also stimulated. The combination treatment of 3-MA and 5-FU significantly increased the apoptotic cell death. By isolating the subcellular fractions of mitochondria and cytosol, we observed that the release of cytochrome c was increased in combination-treated cells. Cytochrome c resulted in the activation of caspase-3, thus activating PARP. Moreover, the anti-apoptotic protein, Bcl-xL, was significantly downregulated by 3-MA. Our results suggest that 5-FU-induced apoptosis in colon cancer cells can be enhanced by the inhibitor of autophagy, 3-MA. Autophagy might play a role as a self-defense mechanism in 5-FU-treated colon cancer cells, and its inhibition could be a promising strategy for the adjuvant chemotherapy of colon cancer.	[Li, Jie; Faried, Ahmad; Tsutsumi, Soichi; Kuwano, Hiroyuki] Gunma Univ, Grad Sch Med, Dept Gen Surg Sci Surg 1, Gunma 3718511, Japan; [Hou, Ni; Takeuchi, Toshiyuki] Gunma Univ, Inst Mol & Cellular Regulat, Dept Mol Med, Maebashi, Gunma 371, Japan		Li, J (corresponding author), Gunma Univ, Grad Sch Med, Dept Gen Surg Sci Surg 1, Gunma 3718511, Japan.	lijie@med.gunma-u.ac.jp			21st Century COE Program, JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of Science (JSPS)Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science	This work was supported by the 21st Century COE Program, Japan and the Japan Society for the Promotion of Science (JSPS) for A. Faried.	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Surg. Oncol.	MAR	2009	16	3					761	771		10.1245/s10434-008-0260-0			11	Oncology; Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Surgery	407GN	WOS:000263351700029	19116755				2022-04-25	
J	Tanabe, H; Kuribayashi, K; Tsuji, N; Tanaka, M; Kobayashi, D; Watanabe, N				Tanabe, Hiromi; Kuribayashi, Kageaki; Tsuji, Naoki; Tanaka, Maki; Kobayashi, Daisuke; Watanabe, Naoki			Sesamin induces autophagy in colon cancer cells by reducing tyrosine phosphorylation of EphA1 and EphB2	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						sesamin; autophagy; EphA1; EphB2; colorectal cancer; receptor tyrosine kinase	COLORECTAL-CANCER; PROTEIN-DEGRADATION; TUMOR-SUPPRESSOR; INHIBITION; RECEPTOR; PROLIFERATION; MECHANISMS; GENE; RATS; HYPERTENSION	Receptor tyrosine kinase EphB2 and autophagic machinery are known as tumor suppressors; however, the connection remains to be elucidated. Here, we show the link between EphB2 and autophagy. Sesamin, a major lignan in sesame oil, induced autophagy in the human colon cancer cell lines HT29 and LS180, as shown by electron microscopy, as well as Western blotting and immunofluorescence imaging using an anti-LC3 antibody. Receptor tyrosine kinase array analysis revealed that sesamin treatment increased the levels of unphosphorylated -EphA1 and EphB2 in HT29 cells. Silencing of EphA1 and EphB2 blocked sesamin-induced autophagy as well as sesamin-induced loss of cell viability. These results show that EphA1 and EphB2 play a critical role in this process. The present study reveals a novel function for EphA1 and EphB2 in the induction of autophagy, suggesting a tumor suppressor role for these proteins in colorectal cancer.	[Tanabe, Hiromi; Kuribayashi, Kageaki; Tsuji, Naoki; Tanaka, Maki; Kobayashi, Daisuke; Watanabe, Naoki] Sapporo Med Univ, Sch Med, Dept Clin Lab Med, Chuo Ku, Sapporo, Hokkaido 0608543, Japan		Watanabe, N (corresponding author), Sapporo Med Univ, Sch Med, Dept Clin Lab Med, Chuo Ku, South 1,West 16, Sapporo, Hokkaido 0608543, Japan.	watanabn@sapmed.ac.jp		Kuribayashi, Kageaki/0000-0002-4618-1543			Alazzouzi H, 2005, CANCER RES, V65, P10170, DOI 10.1158/0008-5472.CAN-05-2580; Batlle E, 2005, NATURE, V435, P1126, DOI 10.1038/nature03626; CANUTO RA, 1993, CARCINOGENESIS, V14, P2581, DOI 10.1093/carcin/14.12.2581; COCKLE SM, 1984, BIOCHEM J, V221, P53, DOI 10.1042/bj2210053; Cortina C, 2007, NAT GENET, V39, P1376, DOI 10.1038/ng.2007.11; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; GRONOSTAJSKI RM, 1984, J CELL PHYSIOL, V119, P127, DOI 10.1002/jcp.1041190120; GUNN JM, 1977, NATURE, V266, P58, DOI 10.1038/266058a0; Guo DL, 2006, CARCINOGENESIS, V27, P454, DOI 10.1093/carcin/bgi259; Harikumar KB, 2010, MOL CANCER RES, V8, P751, DOI 10.1158/1541-7786.MCR-09-0565; Hippert MM, 2006, CANCER RES, V66, P9349, DOI 10.1158/0008-5472.CAN-06-1597; HIROSE N, 1991, J LIPID RES, V32, P629; Holmberg J, 2006, CELL, V125, P1151, DOI 10.1016/j.cell.2006.04.030; Jubb AM, 2005, CLIN CANCER RES, V11, P5181, DOI 10.1158/1078-0432.CCR-05-0143; KISEN GO, 1993, CARCINOGENESIS, V14, P2501, DOI 10.1093/carcin/14.12.2501; Klionsky DJ, 2007, NAT REV MOL CELL BIO, V8, P931, DOI 10.1038/nrm2245; KNECHT E, 1984, EXP CELL RES, V154, P224, DOI 10.1016/0014-4827(84)90682-7; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Levine B, 2008, NAT CELL BIOL, V10, P637, DOI 10.1038/ncb0608-637; Levine B, 2007, NATURE, V446, P745, DOI 10.1038/446745a; Li J, 2010, EUR J CANCER, V46, P1900, DOI 10.1016/j.ejca.2010.02.021; LOCKWOOD TD, 1982, BIOCHEM J, V206, P251, DOI 10.1042/bj2060251; MATSUMURA Y, 1995, BIOL PHARM BULL, V18, P1016, DOI 10.1248/bpb.18.1016; Miyahara Y, 2000, INT J MOL MED, V6, P43; Mizushima N, 2007, GENE DEV, V21, P2861, DOI 10.1101/gad.1599207; Munafo DB, 2001, J CELL SCI, V114, P3619; Nabekura T, 2008, CANCER CHEMOTH PHARM, V62, P867, DOI 10.1007/s00280-007-0676-4; Noguchi T, 2001, HYPERTENS RES, V24, P735, DOI 10.1291/hypres.24.735; Ogawa Hiroshi, 1995, Clinical and Experimental Pharmacology and Physiology, V22, pS310, DOI 10.1111/j.1440-1681.1995.tb02932.x; Pasquale EB, 2008, CELL, V133, P38, DOI 10.1016/j.cell.2008.03.011; Pasquale EB, 2010, NAT REV CANCER, V10, P165, DOI 10.1038/nrc2806; PRAML C, 1995, ONCOGENE, V11, P1357; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; SCHWARZE PE, 1985, EXP CELL RES, V157, P15, DOI 10.1016/0014-4827(85)90148-X; Vasilcanu D, 2004, ONCOGENE, V23, P7854, DOI 10.1038/sj.onc.1208065; Yokota T, 2007, CANCER SCI, V98, P1447, DOI 10.1111/j.1349-7006.2007.00560.x; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100; Zogopoulos G, 2008, PLOS ONE, V3, DOI 10.1371/journal.pone.0002885	39	18	20	0	3	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1019-6439			INT J ONCOL	Int. J. Oncol.	JUL	2011	39	1					33	40		10.3892/ijo.2011.1011			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	775ZS	WOS:000291504900005	21503576	Bronze			2022-04-25	
J	Feng, Q; Wang, HJ; Pang, JY; Ji, LY; Han, JD; Wang, Y; Qi, XX; Liu, ZQ; Lu, LL				Feng, Qian; Wang, Haojia; Pang, Jiaying; Ji, Liyan; Han, Jiada; Wang, Ying; Qi, Xiaoxiao; Liu, Zhongqiu; Lu, Linlin			Prevention of Wogonin on Colorectal Cancer Tumorigenesis by Regulating p53 Nuclear Translocation	FRONTIERS IN PHARMACOLOGY			English	Article						wogonin; colorectal cancer; p53 nuclear translocation; endoplasmic reticulum stress; apoptosis; autophagy	ENDOPLASMIC-RETICULUM STRESS; APOPTOSIS; AUTOPHAGY; PATHWAYS; DEATH; CELLS; GRP78	The tumor suppressor protein p53 plays an important role in the development and progression of colon cancer, and the subcellular organelle localization directly affects its function. Wogonin (5,7-dihydroxy-8-methoxyflavone), a mono-flavonoid extracted from root of Scutellaria baicalensis Georgi, possesses acceptable toxicity and has been used in colorectal cancer (CRC) chemoprevention in pre-clinical trials by oncologist. However, the underlying anti-colon cancer mechanisms of wogonin are not yet fully understood. In the present study, the effect of wogonin on the initiation and development of colitis-associated cancer through p53 nuclear translocation was explored. AOM-DSS CRC animal model and human CRC HCT-116 cell model were used to evaluate the in vivo and in vitro anti-colon cancer action of wogonin. We observed that wogonin showed a dramaticlly preventive effect on colon cancer. Our results showed that wogonin caused apoptotic cell death in human CRC HCT-116 cell through increased endoplasmic reticulum (ER) stress. Meanwhile, excessive ER stress facilitated the cytoplasmic localization of p53 through increasing phosphor-p53 at S315 and S376 sites, induced caspase-dependent apoptosis and inhibited autophagy. Furthermore, we verified the chemoprevention effect and toxicity of wogonin in vivo by utilizing an AOM-DSS colon cancer animal model. We found that wogonin not only reduced tumor multiplicity, preserved colon length to normal (6.79 +/- 0.34 to 7.41 +/- 0.56, P < 0.05) but also didn't induce side effects on various organs. In conclusion, these results explain the anti-tumor effect of wogonin in CRC and suggest wogonin as a potential therapeutic candidate for the therapeutic strategy in CRC treatment.	[Feng, Qian; Wang, Haojia; Pang, Jiaying; Ji, Liyan; Han, Jiada; Wang, Ying; Qi, Xiaoxiao; Liu, Zhongqiu; Lu, Linlin] Guangzhou Univ Chinese Med, Int Inst Translat Chinese Med, Guangzhou, Guangdong, Peoples R China; [Feng, Qian] Guangzhou Univ Chinese Med, Postdoctoral Res Stn, Guangzhou, Guangdong, Peoples R China		Liu, ZQ; Lu, LL (corresponding author), Guangzhou Univ Chinese Med, Int Inst Translat Chinese Med, Guangzhou, Guangdong, Peoples R China.	liuzq@gzucm.edu.cn; lllu@gzucm.edu.cn	Liu, Zhongqiu/ABB-8204-2021; lu, Linlin/K-6600-2016	lu, Linlin/0000-0002-9943-2422	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81473410, 81503466]; Science and Technology Project of Guangzhou City [151800014]; Guangdong Natural Science Foundation Province [2015AD030312012]; Traditional Chinese Medicine Bureau of Guangdong Province [20174004]	This project was supported by the grants of the National Natural Science Foundation of China (Grant Nos. 81473410 and 81503466), the Science and Technology Project of Guangzhou City (Grant No. 151800014), the Guangdong Natural Science Foundation Province (Grant No. 2015AD030312012), and the Traditional Chinese Medicine Bureau of Guangdong Province (Grant No. 20174004).	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Pharmacol.	NOV 23	2018	9								1356	10.3389/fphar.2018.01356			11	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	HB5IS	WOS:000451094200001	30532707	Green Published, gold			2022-04-25	
J	Ragusa, S; Cheng, J; Ivanov, KI; Zangger, N; Ceteci, F; Bernier-Latmani, J; Milatos, S; Joseph, JM; Tercier, S; Bouzourene, H; Bosman, FT; Letovanec, I; Marra, G; Gonzalez, M; Cammareri, P; Sansom, OJ; Delorenzi, M; Petrova, TV				Ragusa, Simone; Cheng, Jianpin; Ivanov, Konstantin I.; Zangger, Nadine; Ceteci, Fatih; Bernier-Latmani, Jeremiah; Milatos, Stavros; Joseph, Jean-Marc; Tercier, Stephane; Bouzourene, Hanifa; Bosman, Fredrik T.; Letovanec, Igor; Marra, Giancarlo; Gonzalez, Michel; Cammareri, Patrizia; Sansom, Owen J.; Delorenzi, Mauro; Petrova, Tatiana V.			PROX1 Promotes Metabolic Adaptation and Fuels Outgrowth of Wnt(high) Metastatic Colon Cancer Cells	CELL REPORTS			English	Article							STEM-CELLS; BRAF; CHLOROQUINE; PROGRESSION; TRANSITION; EXPRESSION; EXPANSION; AUTOPHAGY; KRAS	The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a proapoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1(+) cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1(+) cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.	[Ragusa, Simone; Cheng, Jianpin; Ivanov, Konstantin I.; Bernier-Latmani, Jeremiah; Milatos, Stavros; Delorenzi, Mauro; Petrova, Tatiana V.] CHU Vaudois, Dept Oncol, CH-1066 Lausanne, Switzerland; [Ragusa, Simone; Cheng, Jianpin; Ivanov, Konstantin I.; Bernier-Latmani, Jeremiah; Milatos, Stavros; Delorenzi, Mauro; Petrova, Tatiana V.] Univ Lausanne, CH-1066 Lausanne, Switzerland; [Petrova, Tatiana V.] Univ Lausanne, Dept Biochem, CH-1066 Lausanne, Switzerland; [Petrova, Tatiana V.] Ecole Polytech Fed Lausanne, Swiss Inst Canc Res, CH-1015 Lausanne, Switzerland; [Zangger, Nadine; Delorenzi, Mauro] Swiss Inst Bioinformat, SIB Bioinformat Core Facil, CH-1015 Lausanne, Switzerland; [Ceteci, Fatih; Cammareri, Patrizia; Sansom, Owen J.] Cancer Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland; [Joseph, Jean-Marc; Tercier, Stephane] CHU Vaudois, Serv Chirurg Pediat, CH-1011 Lausanne, Switzerland; [Bouzourene, Hanifa] Univ Lausanne, UNISciences, UniLabs, CH-1066 Lausanne, Switzerland; [Bosman, Fredrik T.; Letovanec, Igor] CHU Vaudois, Inst Univ Pathol, CH-1011 Lausanne, Switzerland; [Marra, Giancarlo] Univ Zurich, Instit Mol Canc Res, CH-8057 Zurich, Switzerland; [Gonzalez, Michel] CHU Vaudois, Div Thorac Surg, CH-1011 Lausanne, Switzerland; [Delorenzi, Mauro] Univ Lausanne, Ludwig Ctr Canc Res, CH-1066 Lausanne, Switzerland		Petrova, TV (corresponding author), CHU Vaudois, Dept Oncol, CH-1066 Lausanne, Switzerland.	tatiana.petrova@unil.ch	Ivanov, Konstantin/C-4644-2015	Ivanov, Konstantin/0000-0001-9198-5674; Cammareri, Patrizia/0000-0002-5888-6903; Bernier-Latmani, Jeremiah/0000-0002-6407-1049; Sansom, Owen J./0000-0001-9540-3010; gonzalez, michel/0000-0001-8705-4279	Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission [PPP0033-114898, 31003A-141225]; Swiss Bridge Foundation; NCCR Molecular OncologySwiss National Science Foundation (SNSF); Association for the International Cancer Research UK; Oncosuisse [KLS-02570-02-2010]; CRUKCancer Research UK; ERCEuropean Research Council (ERC)European Commission; EUEuropean Commission [278568]; Medic Foundation; Cancer Research UKCancer Research UK [12481] Funding Source: researchfish	We thank P. Andreux and K. Schoonjans for help with metabolic experiments; I. Stamenkovic for critical comments; M. De Palma for help with lentivirus preparation; J. Huelsken for intestinal organoid protocols; S. Robin for villin-CreERT2 mice; M. Jaquet, C. Beauverd, and R. Haider for technical assistance; F. Derouet for tail vein injections; and A. Sabine for help with graphism. We thank Lausanne Genomics Technologies Facility, the Cellular Imaging Facility, Mouse Pathology Facility, and Mouse Animal Facility of the University of Lausanne. The work was supported by Swiss National Science Foundation (PPP0033-114898 to T.V.P. and 31003A-141225 to G.M.), Swiss Bridge Foundation, NCCR Molecular Oncology, Association for the International Cancer Research UK, Oncosuisse (KLS-02570-02-2010), CRUK, ERC investigator award ''COLONCAN'' (to O.J.S.), EU FP7 grant no. 278568 ''PRIMES,'' and Medic Foundation.	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J	Coker-Gurkan, A; Arisan, ED; Obakan, P; Akalln, K; Ozbey, U; Palavan-Unsal, N				Coker-Gurkan, Ajda; Arisan, Elif Damla; Obakan, Pinar; Akalln, Kubra; Ozbey, Utku; Palavan-Unsal, Narcin			Purvalanol induces endoplasmic reticulum stress-mediated apoptosis and autophagy in a time-dependent manner in HCT116 colon cancer cells	ONCOLOGY REPORTS			English	Article						purvalanol; endoplasmic reticulum stress; autophagy; apoptosis; colon cancer	UNFOLDED PROTEIN RESPONSE; POLYAMINE CATABOLIC PATHWAY; TRANSCRIPTION FACTORS; CARCINOMA CELLS; ER STRESS; INHIBITORS; INDUCTION; KINASES; CHOP; CALRETICULIN	Purvalanol, a novel cyclin-dependent kinase inhibitor, is referred to as a strong apoptotic inducer which causes cell cycle arrest in various cancer cells such as prostate, breast and colon cancer cell lines. Various physiological and pathological conditions such as glucose starvation, inhibition of protein glycosylation and oxidative stress may cause an accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response (UPR) and autophagy. Lacking proteosomal function on aggregates of unfolded proteins, ER stress may induce autophagic machinery. Autophagy, an evolutionarily conserved process, is characterized by massive degradation of cytosolic contents. In the present study, our aim was to determine the time-dependent, ER-mediated apoptotic and autophagy induction of purvalanol in HCT 116 colon cancer cells. Fifteen micromoles of purvalanol induced a reduction in cell viability by 20 and 35% within 24 and 48 h, respectively. HCT 116 colon cancer cells were exposed to purvalanol, which activated ER stress via upregulation of PERK, IREl alpha gene expression, eIF-2 alpha phosphorylation and ATF-6 cleavage at early time-points in the HCT 116 colon cancer cells. Moreover, we determined that during purvalanol-mediated ER stress, autophagic machinery was also activated prior to apoptotic cell death finalization. Beclin-1 and Atg-5 expression levels were upregulated and LC3 was cleaved after a 6 h purvalanol treatment. Purvalanol induced mitochondrial membrane potential loss, caspase-7 and caspase-3 activation and PARP cleavage following a 48 h treatment. Thus, we conclude that the anticancer effect of purvalanol in HCT 116 cells was due to ER stress-mediated apoptosis; however, purvalanol triggered autophagy, which functions as a cell survival mechanism at early time-points.	[Coker-Gurkan, Ajda; Arisan, Elif Damla; Obakan, Pinar; Akalln, Kubra; Ozbey, Utku; Palavan-Unsal, Narcin] Istanbul Kultur Univ, Dept Mol Biol & Genet, Sci & Letters Fac, TR-34156 Bakirkoy Istanbul, Turkey		Coker-Gurkan, A (corresponding author), Istanbul Kultur Univ, Dept Mol Biol & Genet, Sci & Letters Fac, Atakoy Campus, TR-34156 Bakirkoy Istanbul, Turkey.	a.coker@iku.edu.tr	Arisan, Elif Damla/W-8682-2019; Arisan, ElifDamla/AAB-1173-2021; OBAKAN, PINAR/D-2836-2015	Arisan, Elif Damla/0000-0002-4844-6381; Unsal Palavan, Narcin/0000-0002-2945-540X; Gurkan, Ajda/0000-0003-1475-2417	Istanbul Kultur University Scientific Projects Support CenterIstanbul Kultur University; TUBITAK Scientific Projects Support CenterTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [2209]	The present study was supported by the Istanbul Kultur University Scientific Projects Support Center and the TUBITAK Scientific Projects Support Center (2209 program).	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Rep.	JUN	2015	33	6					2761	2770		10.3892/or.2015.3918			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CI8YX	WOS:000355058700014	25901510	Bronze			2022-04-25	
J	Zhu, JH; Liu, MH; Liu, YF; Zhang, YT; Yang, B; Zhang, W				Zhu, Jinhua; Liu, Meihui; Liu, Yuanfen; Zhang, Yiting; Yang, Bing; Zhang, Wei			Zoledronic Acid Regulates Autophagy and Induces Apoptosis in Colon Cancer Cell Line CT26	BIOMED RESEARCH INTERNATIONAL			English	Article							COLORECTAL-CANCER; POPULATION; INHIBITION; DISEASE; GROWTH	Zoledronic acid (ZOL) is the third generation of bisphosphonates, which can inhibit many tumors growth, especially to inhibit the growth of colon cancer. However, the molecular mechanism is still very mysterious. In this study, we observed that ZOL could regulate CT26 colon cancer cells autophagy, promote CT26 cells apoptosis, and inhibit CT26 cells proliferation. Western blotting analysis showed that proapoptosis protein caspase-3 was basically unchanged, whereas the expression of the activated caspase-3 was significantly increased, after CT26 cells were treated with different doses of zoledronic acid. Western blot also showed that ZOL could significantly affect the expression of p-p53 and autophagy-related proteins beclin-1 and p62. In conclusion, the antitumor effect of ZOL on CT26 colon cancer cells in vitro is achieved by apoptosis induction and autophagy regulation, resulting in inhibition of cell proliferation.	[Zhu, Jinhua; Liu, Meihui; Liu, Yuanfen; Zhang, Wei] Jiangsu Hlth Vocat Coll, Nanjing, Jiangsu, Peoples R China; [Zhang, Yiting] Nanjing Univ, Coll Med, Nanjing, Jiangsu, Peoples R China; [Yang, Bing] Nanjing Univ Chinese Med, Sch Pharm, Nanjing, Jiangsu, Peoples R China		Zhang, W (corresponding author), Jiangsu Hlth Vocat Coll, Nanjing, Jiangsu, Peoples R China.	zydzw0810@163.com			Health Department of Jiangsu Province [H201430]	This study was supported by the Medical Research Projects of the Health Department of Jiangsu Province (H201430).	Al-Agha AE, 2015, SAUDI MED J, V36, P1312, DOI 10.15537/smj.2015.11.12590; Baykan EK, 2014, OSTEOPOROSIS INT, V25, P2221, DOI 10.1007/s00198-014-2752-z; Burada F, 2015, WORLD J GASTRO ONCOL, V7, P271, DOI 10.4251/wjgo.v7.i11.271; Evdokiou A., BONE, V33; Grizzo FMF, 2015, CALCIFIED TISSUE INT, V97, P421, DOI 10.1007/s00223-015-0028-z; Han FS, 2016, ASIAN PAC J TROP MED, V9, P164, DOI 10.1016/j.apjtm.2016.01.005; Heravi RE, 2012, GENES GENOM, V34, P199, DOI 10.1007/s13258-011-0168-0; Kato J., INT J CANC, V138, P1516; Lin JF, 2011, J UROLOGY, V185, P1490, DOI 10.1016/j.juro.2010.11.045; Morad SAF, 2013, BIOCHEM PHARMACOL, V85, P1057, DOI 10.1016/j.bcp.2013.01.015; Neville-Webbe HL, 2003, PALLIATIVE MED, V17, P539, DOI 10.1191/0269216303pm800ra; Ochiai H, 2012, SURG TODAY, V42, P164, DOI 10.1007/s00595-011-0044-1; Pedersen JW, 2013, BRIT J CANCER, V108, P107, DOI 10.1038/bjc.2012.517; Sakitani K., 2015, BMC CANCER, V15, P1; Singh T, 2015, J DRUG TARGET, V23, P1, DOI 10.3109/1061186X.2014.950668; Tamura T, 2011, ONCOL REP, V25, P1139, DOI 10.3892/or.2011.1152; Wan Y, 2014, ONCOL LETT, V7, P1738, DOI 10.3892/ol.2014.1959; Wang IT, 2014, TUMOR BIOL, V35, P11913, DOI 10.1007/s13277-014-2460-5; Yang SY, 2009, TRENDS MOL MED, V15, P225, DOI 10.1016/j.molmed.2009.03.003; Zhao YL, 2016, EUR J CANCER, V68, P38, DOI 10.1016/j.ejca.2016.09.001	20	6	6	0	1	HINDAWI LTD	LONDON	ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND	2314-6133	2314-6141		BIOMED RES INT	Biomed Res. Int.		2017	2017								7203584	10.1155/2017/7203584			6	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	FR2NI	WOS:000418903500001	29457036	Green Published, gold			2022-04-25	
J	Scarlatti, F; Bauvy, C; Ventruti, A; Sala, G; Cluzeaud, F; Vandewalle, A; Ghidoni, R; Codogno, P				Scarlatti, F; Bauvy, C; Ventruti, A; Sala, G; Cluzeaud, F; Vandewalle, A; Ghidoni, R; Codogno, P			Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1	JOURNAL OF BIOLOGICAL CHEMISTRY			English	Article							ISOLATED RAT HEPATOCYTES; PROGRAMMED CELL-DEATH; HUMAN COLON-CANCER; INDUCED APOPTOSIS; SIGNAL-TRANSDUCTION; AUTOPHAGIC VACUOLES; TUMOR-SUPPRESSOR; HT-29 CELLS; GROWTH ARREST; AKT KINASE	The sphingolipid ceramide is involved in the cellular stress response. Here we demonstrate that ceramide controls macroautophagy, a major lysosomal catabolic pathway. Exogenous C-2-ceramide stimulates macroautophagy (proteolysis and accumulation of autophagic vacuoles) in the human colon cancer HT-29 cells by increasing the endogenous pool of long chain ceramides as demonstrated by the use of the ceramide synthase inhibitor fumonisin B-1. Ceramide reverted the interleukin 13-dependent inhibition of macroautophagy by interfering with the activation of protein kinase B. In addition, C-2-ceramide stimulated the expression of the autophagy gene product beclin 1. Ceramide is also the mediator of the tamoxifen-dependent accumulation of autophagic vacuoles in the human breast cancer MCF-7 cells. Monodansylcadaverine staining and electron microscopy showed that this accumulation was abrogated by myriocin, an inhibitor of de novo synthesis ceramide. The tamoxifen-dependent accumulation of vacuoles was mimicked by 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthase. 1-Phenyl-2-decanoylamino-3-morpholino-1-propanol, tamoxifen, and C-2-ceramide stimulated the expression of beclin 1, whereas myriocin antagonized the tamoxifen-dependent up-regulation. Tamoxifen and C-2-ceramide interfere with the activation of protein kinase B, whereas myriocin relieved the inhibitory effect of tamoxifen. In conclusion, the control of macroautophagy by ceramide provides a novel function for this lipid mediator in a cell process with major biological outcomes.	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Biol. Chem.	APR 30	2004	279	18					18384	18391		10.1074/jbc.M313561200			8	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	815KP	WOS:000221041500036	14970205	hybrid			2022-04-25	
J	Athamneh, K; Alneyadi, A; Alsamri, H; Alrashedi, A; Palakott, A; El-Tarabily, KA; Eid, AH; Al Dhaheri, Y; Iratni, R				Athamneh, Khawlah; Alneyadi, Aysha; Alsamri, Halima; Alrashedi, Asma; Palakott, Abdulrasheed; El-Tarabily, Khaled A.; Eid, Ali H.; Al Dhaheri, Yusra; Iratni, Rabah			Origanum majorana Essential Oil Triggers p38 MAPK-Mediated Protective Autophagy, Apoptosis, and Caspase-Dependent Cleavage of P70S6K in Colorectal Cancer Cells	BIOMOLECULES			English	Article						Origanum majorana; colon cancer; autophagy; apoptosis; p38MAPK; p70S6K	ANTIMICROBIAL ACTIVITY; MAMMALIAN TARGET; L.; KINASE; TUMORIGENESIS; SUPPRESSION; INHIBITION; RESISTANCE; LIFE	Colorectal cancer (CRC) is the third most common type of cancer in terms of incidence and mortality worldwide. Here we have investigated the anti-colon cancer potential of Origanum majorana essential oil (OMEO) and its underlying mechanisms of action. We showed that OMEO significantly inhibited the cellular viability and colony growth of human HT-29 colorectal cancer cells. OMEO induced protective autophagy, associated with downregulation of the mTOR/p70S6K pathway, and activated caspase-8 and caspase-9-dependent apoptosis. Blockade of autophagy with 3-methyladenine (3-MA) and chloroquine (CQ), two autophagy inhibitors, potentiated the OMEO-induced apoptotic cell death. Inversely, inhibition of apoptosis with the pan-caspase inhibitor, Z-VAD-FMK, significantly reduced cell death, suggesting that apoptosis represents the main mechanism of OMEO-induced cell death. Mechanistically, we found that OMEO induces protective autophagy and apoptotic cells death via the activation of the p38 MAPK signaling pathway. Pharmacological inhibition of p38 MAPK by the p38 inhibitors SB 202190 and SB 203580 not only significantly decreased apoptotic cell death, but also reduced the autophagy level in OMEO treated HT-29 cells. Strikingly, we found that OMEO also induces p38 MAPK-mediated caspase-dependent cleavage of p70S6K, a protein reported to be overexpressed in colon cancer and associated with drug resistance. Our findings suggest that OMEO inhibits colon cancer through p38 MAPK-mediated protective autophagy and apoptosis associated with caspase-dependent cleavage of p70S6K. To the best of our knowledge, this study is the first to report on the implications of the p38 MAPK signaling pathway in targeting p70S6K to caspase cleavage.	[Athamneh, Khawlah; Alneyadi, Aysha; Alsamri, Halima; Alrashedi, Asma; Palakott, Abdulrasheed; El-Tarabily, Khaled A.; Al Dhaheri, Yusra; Iratni, Rabah] United Arab Emirates Univ, Coll Sci, Dept Biol, POB 15551, Al Ain, U Arab Emirates; [El-Tarabily, Khaled A.] United Arab Emirates Univ, Khalifa Ctr Genet Engn & Biotechnol, POB 15551, Al Ain, U Arab Emirates; [Eid, Ali H.] Amer Univ Beirut, Fac Med, Dept Pharmacol & Toxicol, Beirut 11072020, Lebanon		Iratni, R (corresponding author), United Arab Emirates Univ, Coll Sci, Dept Biol, POB 15551, Al Ain, U Arab Emirates.	200834888@uaeu.ac.ae; 200907889@uaeu.ac.ae; 200813902@uaeu.ac.ae; 201003061@uaeu.ac.ae; abdulrasheed1984@uaeu.ac.ae; ktarabily@uaeu.ac.ae; ae81@aub.edu.lb; yusra.aldhaheri@uaeu.ac.ae; R_iratni@uaeu.ac.ae	El-Tarabily, Khaled/AAD-9835-2019; Eid, Ali Hussein/ABD-6291-2021	El-Tarabily, Khaled/0000-0002-8189-7088; Eid, Ali Hussein/0000-0003-3004-5675; Alneyadi, Aysha/0000-0002-6450-4713	Al Jalila FoundationAl Jalila Foundation (AJF) [21S102-AJF2018007]; UAEU Start-Up grant [31S260]	This work was supported by the Al Jalila Foundation (Grant #21S102-AJF2018007) and by the UAEU Start-Up grant (Grant #31S260).	Adorjan B, 2010, FLAVOUR FRAG J, V25, P407, DOI 10.1002/ffj.2024; Al Dhaheri Y, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0068808; Al Dhaheri Y, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0056649; Al-Howiriny T, 2009, AM J CHINESE MED, V37, P531, DOI 10.1142/S0192415X0900703X; Amor G, 2019, MOLECULES, V24, DOI 10.3390/molecules24224021; Balunas MJ, 2005, LIFE SCI, V78, P431, DOI 10.1016/j.lfs.2005.09.012; Benbrook D. 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J	Huangfu, LT; Liang, HH; Wang, GJ; Su, XM; Li, LQ; Du, ZM; Hu, MY; Dong, YC; Bai, X; Liu, TY; Yang, BF; Shan, HL				Huangfu, Longtao; Liang, Haihai; Wang, Guojie; Su, Xiaomin; Li, Linqiang; Du, Zhimin; Hu, Meiyu; Dong, Yuechao; Bai, Xue; Liu, Tianyi; Yang, Baofeng; Shan, Hongli			miR-183 regulates autophagy and apoptosis in colorectal cancer through targeting of UVRAG	ONCOTARGET			English	Article						autophagy; UVRAG; miR-183; apoptosis; colorectal cancer	CELL-DEATH; SIGNALING NETWORKS; INHIBIT AUTOPHAGY; COLON-CANCER; BECLIN 1; MICRORNA; STARVATION; COMPLEX; METASTASIS; EXPRESSION	Ultraviolet radiation resistance-associated gene (UVRAG) is a well-known regulator of autophagy by promoting autophagosome formation and maturation. Multiple studies have implicated UVRAG in the pathogenesis of colorectal cancer. However, the mechanisms underlying the regulation of UVRAG are unclear. Here, we describe miR-183 as a new autophagy-inhibiting miRNA. Our results showed that induction of autophagy lead to down-regulation of miR-183 in colorectal cancer cells. And, over-expression of miR-183 resulted in the attenuation of rapamycinor starvation-induced autophagy in cancer cells, whereas inhibition of endogenous miR-183 stimulated autophagy and apoptosis. Additionally, either autophagy inhibitor 3-MA or pan-caspase inhibitor Z-VAD-FMK respectively or both treatments reversed AMO-183-induced cell death. Further studies showed that UVRAG is a target of miR183 and as a key regulator promotes autophagy and apoptosis. More importantly, overexpression of UVRAG rescued autophagic activity and induced apoptosis in presence of miR-183. Therefore, the present study investigated the promoting effect of miR-183 on colorectal cancer progression, which was considered to be mediated by autophagy and apoptosis through targeting of UVRAG.	[Huangfu, Longtao; Liang, Haihai; Wang, Guojie; Su, Xiaomin; Hu, Meiyu; Dong, Yuechao; Bai, Xue; Liu, Tianyi; Yang, Baofeng; Shan, Hongli] Harbin Med Univ, Key Lab Cardiovasc Res, State Prov Key Labs Biomed Pharmaceut China, Dept Pharmacol,Minist Educ, Harbin 150081, Heilongjiang, Peoples R China; [Li, Linqiang] Harbin Med Univ, Affiliated Hosp 1, Dept Gen Surg, Harbin 150081, Heilongjiang, Peoples R China; [Du, Zhimin] Harbin Med Univ, Affiliated Hosp 2, Inst Clin Pharm, Harbin 150081, Heilongjiang, Peoples R China		Shan, HL (corresponding author), Harbin Med Univ, Key Lab Cardiovasc Res, State Prov Key Labs Biomed Pharmaceut China, Dept Pharmacol,Minist Educ, Harbin 150081, Heilongjiang, Peoples R China.	shanhongli@ems.hrbmu.edu.cn		Su, Xiaomin/0000-0002-1621-4009	National Basic Research Program of China (973 program)National Basic Research Program of China [2013CB531104]; Funds for Creative Research Groups of the National Natural Science Foundation of China [81421063]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81230081, 31450009]; Postgraduate Research Innovation Fund of Harbin Medical University [YJSCX2014-13HYD]	This study was supported by National Basic Research Program of China (973 program, 2013CB531104); the Funds for Creative Research Groups of the National Natural Science Foundation of China (81421063); the Major Program of National Natural Science Foundation of China (81230081); and the National Natural Science Foundation of China (31450009); and the Postgraduate Research Innovation Fund of Harbin Medical University (YJSCX2014-13HYD).	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J	Paul, S; Roy, D; Pati, S; Sa, G				Paul, Silpita; Roy, Dia; Pati, Subhadip; Sa, Gaurisankar			The Adroitness of Andrographolide as a Natural Weapon Against Colorectal Cancer	FRONTIERS IN PHARMACOLOGY			English	Review						Colorectal cancer; Andrographolide; Phytochemical; immunomodulator; Antitumor	ISLAND METHYLATOR PHENOTYPE; SOLID LIPID NANOPARTICLES; TRAIL-INDUCED APOPTOSIS; AUTOPHAGIC CELL-DEATH; IN-VITRO; TUMOR-GROWTH; COLON-CANCER; IMMUNOMODULATORY ACTIVITY; TISSUE DISTRIBUTION; LIVER-CANCER	The conventional carcinoma treatment generally encompasses the employment of radiotherapy, chemotherapy, surgery or use of cytotoxic drugs. However, recent advances in pharmacological research have divulged the importance of traditional treatments in cancer. The aim of the present review is to provide an overview of the importance of one such medicinal herb of Chinese and Indian origin: Andrographis paniculate on colorectal cancer with special emphasis on its principal bioactive component andrographolide (AGP) and its underlying mechanisms of action. AGP has long been known to possess medicinal properties. Studies led by numerous groups of researchers shed light on its molecular mechanism of action. AGP has been shown to act in a multi-faceted manner in context of colorectal cancer by targeting matrix metalloproteinase-9, Toll-like receptor or NF kappa B signaling pathways. In this review, we highlighted the recent studies that show that AGP can act as an effective immunomodulator by harnessing effective anti-tumor immune response. Recent studies strongly recommend further research on this compound and its analogues, especially under in-vivo condition to assess its actual potential as a prospective and efficient candidate against colorectal cancer. The current review deals with the roles of this phytomedicine in context of colorectal cancer and briefly describes its perspectives to emerge as an essential anti-cancer drug candidate. Finally, we also point out the drawbacks and difficulties in administration of AGP and indicate the use of nano-formulations of this phytomedicine for better therapeutic efficacy.	[Paul, Silpita; Roy, Dia; Pati, Subhadip; Sa, Gaurisankar] Bose Inst, Div Mol Med, Kolkata, India		Sa, G (corresponding author), Bose Inst, Div Mol Med, Kolkata, India.	gauri@jcbose.ac.in			Department of Biotechnology, Department of Science and Technology, Government of IndiaDepartment of Science & Technology (India)Department of Biotechnology (DBT) India	This work was supported by research grants Department of Biotechnology, Department of Science and Technology, Government of India. GS is National Academy of Science (India) Platinum Jubilee Senior Scientist.	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Pharmacol.	NOV 2	2021	12								731492	10.3389/fphar.2021.731492			14	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	WY9JV	WOS:000719594100001	34795581	gold, Green Published			2022-04-25	
J	Sena, P; Mariani, F; Mancini, S; Benincasa, M; Magnani, G; Pedroni, M; Palumbo, C; Roncucci, L				Sena, Paola; Mariani, Francesco; Mancini, Stefano; Benincasa, Marta; Magnani, Giulia; Pedroni, Monica; Palumbo, Carla; Roncucci, Luca			Autophagy is upregulated during colorectal carcinogenesis, and in DNA microsatellite stable carcinomas	ONCOLOGY REPORTS			English	Article						autophagy; colorectal carcinogenesis; microadenoma; aberrant crypt foci; DNA microsatellite instability	CANCER-ASSOCIATED FIBROBLASTS; MISMATCH REPAIR; COLON-CANCER; GENOMIC INSTABILITY; THERAPEUTIC TARGET; BECLIN 1; EXPRESSION; LC3; 5-FLUOROURACIL; CHEMOTHERAPY	Cancer cells are exposed to a wide range of stress sources, such as nutrient deprivation and hypoxia, as well as cytotoxic chemotherapy and radiotherapy. Certain forms of stress can also promote survival activating the metabolic autophagy pathway in cancer cells. Autophagy is dramatically increased in cancer cells. In these conditions, it is becoming evident that autophagy protects cells, by providing an alternative energy source and by eliminating dysfunctional organelles or proteins. Its role in tumorigenesis is more controversial and both the presence and the absence of autophagy have been implicated. Autophagy is known to be associated with the poor outcome of patients with various types of cancers, and its effectiveness as a prognostic marker in colorectal cancer was demonstrated by several studies. The inhibition of autophagy may be a potential therapeutic target in colorectal cancer. In vitro experiments have shown that the inhibition of autophagy increases 5-FU-induced apoptosis. There are two trials currently investigating the addition of chloroquine to 5-FU-based chemotherapy and bevacizumab. In the present study, we evaluated the expression of LC3B-II in samples of human colorectal microadenomas (i.e., dysplastic aberrant crypt foci) and carcinomas compared to normal mucosa. Furthermore, the expression pattern of LC3B-II was assessed in carcinomas classified as DNA microsatellite stable (MSS) and unstable (MSI). Thus, immunofluorescence techniques coupled with confocal microscopy and immunoblot experiments were performed. The results clearly showed a significant increase in expression of the autophagic key factor in microadenomas and carcinomas with respect to normal mucosa. In MSS carcinomas, the level of LC3B-II expression was higher than that in the MSI carcinomas.	[Sena, Paola; Benincasa, Marta; Palumbo, Carla] Univ Modena & Reggio Emilia, Dept Biomed Metab & Neurosci, Sect Human Morphol, I-41125 Modena, Italy; [Mariani, Francesco; Mancini, Stefano; Magnani, Giulia; Pedroni, Monica; Roncucci, Luca] Univ Modena & Reggio Emilia, Dept Diagnost & Clin Med & Publ Hlth, I-41125 Modena, Italy		Roncucci, L (corresponding author), Univ Modena & Reggio Emilia, Dept Diagnost & Clin Med & Publ Hlth, Via Pozzo 71, I-41125 Modena, Italy.	luca.roncucci@unimore.it	Mancini, Stefano/B-1190-2016; Sena, Paola/G-9394-2016; Magnani, Giulia/AGM-1833-2022; Roncucci, Luca/L-1392-2016; Palumbo, Carla/V-5905-2019	Mancini, Stefano/0000-0002-7350-5603; Sena, Paola/0000-0003-4724-8786; Roncucci, Luca/0000-0002-0410-1760; Palumbo, Carla/0000-0003-0587-0112	Associazione per la Ricerca sui Tumori Intestinali (ARTI)	The present study was supported by funds of the Associazione per la Ricerca sui Tumori Intestinali (ARTI), which also provided support to G.M. The authors wish to thank the Centro Interdipartimentale Grandi Strumenti (CIGS) of the University of Modena and Reggio Emilia, for software, instrument availability and assistance.	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Rep.	DEC	2015	34	6					3222	3230		10.3892/or.2015.4326			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CV9OR	WOS:000364617000047	26502823	Bronze, Green Submitted			2022-04-25	
J	Ji, ML; Feng, QY; He, GD; Yang, LL; Tang, WT; Lao, XY; Zhu, DX; Lin, Q; Xu, PP; Wei, Y; Xu, JM				Ji, Meiling; Feng, Qingyang; He, Guodong; Yang, Liangliang; Tang, Wentao; Lao, Xinyuan; Zhu, Dexiang; Lin, Qi; Xu, Pingping; Wei, Ye; Xu, Jianmin			Silencing homeobox C6 inhibits colorectal cancer cell proliferation	ONCOTARGET			English	Article						colorectal cancer; proliferation; HOXC6; autophagy; mTOR	GENE-PRODUCT EXPRESSION; IMMUNOCYTOCHEMICAL DETECTION; PROSTATE-CANCER; HOXC6 EXPRESSION; AUTOPHAGY; B4; B3; CARCINOMAS; RECEPTOR; DISEASE	Homeobox C6 (HOXC6), a member of the homeobox family that encodes highly conserved transcription factors, plays a vital role in various carcinomas. In this study, we used a tissue microarray (TMA) consisting of 462 CRC samples to demonstrate that HOXC6 is more abundantly expressed in colorectal cancer (CRC) tissues than adjacent normal mucosa. Clinicopathological data indicated that higher HOXC6 expression correlated with poor overall survival and was associated with primary tumor location in the right colon, primary tumor (pT) stage 3/4 and primary node (pN) stage 1/2. Multivariate analysis showed that high HOXC6 expression was an independent risk factor for poor CRC patient prognosis. HOXC6 downregulation via lentivirus-mediated expression of HOXC6-targeting shRNA reduced HCT116 cell viability and colony formation in vitro, and reduced growth of subcutaneous xenografts in nude mouse. HOXC6 thus appears to promote CRC cell proliferation and tumorigenesis through autophagy inhibition and mTOR pathway activation.	[Ji, Meiling; Feng, Qingyang; He, Guodong; Yang, Liangliang; Tang, Wentao; Lao, Xinyuan; Zhu, Dexiang; Lin, Qi; Xu, Pingping; Wei, Ye; Xu, Jianmin] Fudan Univ, Zhongshan Hosp, Dept Gen Surg, Shanghai 200433, Peoples R China		Wei, Y; Xu, JM (corresponding author), Fudan Univ, Zhongshan Hosp, Dept Gen Surg, Shanghai 200433, Peoples R China.	wei.ye@zs-hospital.sh.cn; xujmin@aliyun.com		Yang, Liangliang/0000-0002-6909-8363	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81272390, 81372315]; National High Technology Research and Development ProgramNational High Technology Research and Development Program of China [2012AA02A506]	This work was supported by grants from the National Natural Science Foundation of China (81272390, 81372315) and the National High Technology Research and Development Program (2012AA02A506).	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J	Paillas, S; Causse, A; Marzi, L; De Medina, P; Poirot, M; Denis, V; Vezzio-Vie, N; Espert, L; Arzouk, H; Coquelle, A; Martineau, P; Del Rio, M; Pattingre, S; Gongora, C				Paillas, Salome; Causse, Annick; Marzi, Laetitia; De Medina, Philippe; Poirot, Marc; Denis, Vincent; Vezzio-Vie, Nadia; Espert, Lucile; Arzouk, Hayat; Coquelle, Arnaud; Martineau, Pierre; Del Rio, Maguy; Pattingre, Sophie; Gongora, Celine			MAPK14/p38 alpha confers irinotecan resistance to TP53-defective cells by inducing survival autophagy	AUTOPHAGY			English	Article						MAPK14/p38; survival autophagy; irinotecan resistance; colon cancer; chemotherapy	ACTIVATED PROTEIN-KINASE; CANCER CELLS; COLON-CANCER; COLORECTAL-CANCER; CYCLE ARREST; IN-VIVO; P38; P38-ALPHA; EXPRESSION; PHOSPHORYLATION	Recently we have shown that the mitogen-activated protein kinase (MAPK) MAPK14/p38 alpha is involved in resistance of colon cancer cells to camptothecin-related drugs. Here we further investigated the cellular mechanisms involved in such drug resistance and showed that, in HCT116 human colorectal adenocarcinoma cells in which TP53 was genetically ablated (HCT116-TP53KO), overexpression of constitutively active MAPK14/p38a decreases cell sensitivity to SN-38 (the active metabolite of irinotecan), inhibits cell proliferation and induces survival-autophagy. Since autophagy is known to facilitate cancer cell resistance to chemotherapy and radiation treatment, we then investigated the relationship between MAPK14/p38 alpha, autophagy and resistance to irinotecan. We demonstrated that induction of autophagy by SN38 is dependent on MAPK14/p38 alpha activation. Finally, we showed that inhibition of MAPK14/p38 alpha or autophagy both sensitizes HCT116-TP53KO cells to drug therapy. Our data proved that the two effects are interrelated, since the role of autophagy in drug resistance required the MAPK14/p38 alpha. Our results highlight the existence of a new mechanism of resistance to camptothecin-related drugs: upon SN38 induction, MAPK14/p38 alpha is activated and triggers survival-promoting autophagy to protect tumor cells against the cytotoxic effects of the drug. Colon cancer cells could thus be sensitized to drug therapy by inhibiting either MAPK14/p38 or autophagy.	[Paillas, Salome; Causse, Annick; Marzi, Laetitia; Denis, Vincent; Vezzio-Vie, Nadia; Arzouk, Hayat; Coquelle, Arnaud; Martineau, Pierre; Del Rio, Maguy; Pattingre, Sophie; Gongora, Celine] IRCM, Montpellier, France; [Paillas, Salome; Causse, Annick; Marzi, Laetitia; Denis, Vincent; Vezzio-Vie, Nadia; Arzouk, Hayat; Coquelle, Arnaud; Martineau, Pierre; Del Rio, Maguy; Pattingre, Sophie; Gongora, Celine] Univ Montpellier I, Montpellier, France; [Paillas, Salome; Causse, Annick; Marzi, Laetitia; Denis, Vincent; Vezzio-Vie, Nadia; Arzouk, Hayat; Coquelle, Arnaud; Martineau, Pierre; Del Rio, Maguy; Pattingre, Sophie; Gongora, Celine] INSERM, U896, Montpellier, France; [Paillas, Salome; Causse, Annick; Marzi, Laetitia; Denis, Vincent; Vezzio-Vie, Nadia; Arzouk, Hayat; Coquelle, Arnaud; Martineau, Pierre; Del Rio, Maguy; Pattingre, Sophie; Gongora, Celine] CRLC Val dAurelle Paul Lamarque, Montpellier, France; [Espert, Lucile] CNRS UMI UMII, UMR5236, CPBS, Montpellier, France; [De Medina, Philippe; Poirot, Marc] Fac Med Toulouse, INSERM, U563, F-31073 Toulouse, Haute Garonne, France		Gongora, C (corresponding author), IRCM, Montpellier, France.	celine.gongora@inserm.fr	Espert, Lucile/ABF-5614-2021; de Medina, Philippe/X-1358-2019; Poirot, Marc/C-7613-2009; Coquelle, Arnaud/AAE-5425-2020; Martineau, Pierre/N-4386-2017	Poirot, Marc/0000-0002-5711-6624; Martineau, Pierre/0000-0002-7993-7183; Pattingre, Sophie/0000-0001-6284-6050; GONGORA, Celine/0000-0001-9034-4031; de Medina, Philippe/0000-0002-9618-3133	INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm)European Commission	Funds for this research were provided by INSERM.	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J	Moon, JH; Jeong, JK; Park, SY				Moon, Ji-Hong; Jeong, Jae-Kyo; Park, Sang-Youel			Deferoxamine inhibits TRAIL-mediated apoptosis via regulation of autophagy in human colon cancer cells	ONCOLOGY REPORTS			English	Article						deferoxamine; TRAIL; autophagy; colon cancer	IRON CHELATION; COLORECTAL-CANCER; ANTICANCER DRUGS; HYPOXIA; SURVIVAL; MECHANISMS; DEATH; TUMORIGENESIS; EXPRESSION; LYSOSOMES	Deferoxamine (DFO), an iron chelator, has numerous clinical applications for patients presenting with iron overload in regards to the improvement in the quality of life and overall survival. In addition, experimental iron chelators have demonstrated potent anticancer properties. The present study investigated the effects of DFO on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in colon cancer cells and and the mechanism involved. The experimental results showed that DFO treatment inhibited TRAIL-mediated cancer cell apoptosis by increasing Akt activation and decreasing caspase activation in human colon cancer cells. Furthermore, DFO treatment induced autophagy flux, and chloroquine, an autophagy inhibitor, blocked DFO-mediated inhibition of TRAIL-induced apoptosis. The present study demonstrated that DFO inhibited TRAIL-mediated tumor cell death via the autophagy pathway, and the results suggest that potent anticancer agent, DFO, can be an inhibitor against antitumor therapy including TRAIL protein.	[Moon, Ji-Hong; Jeong, Jae-Kyo; Park, Sang-Youel] Chonbuk Natl Univ, Biosafety Res Inst, Coll Vet Med, Jeonju 561756, Jeonbuk, South Korea		Park, SY (corresponding author), Chonbuk Natl Univ, Biosafety Res Inst, Coll Vet Med, Jeonju 561756, Jeonbuk, South Korea.	sypark@chonbuk.ac.kr	jeong, jae-kyo/ABC-5156-2020; Park, Sang-Youel/D-5966-2012	Park, Sang-Youel/0000-0003-0575-6045	National Research Foundation of Korea (NRF) - Korean Government [2013R1A1A2063931]	This study was supported by a grant from the National Research Foundation of Korea (NRF), funded by the Korean Government (2013R1A1A2063931).	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Rep.	MAR	2015	33	3					1171	1176		10.3892/or.2014.3676			6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CB6KL	WOS:000349735800019	25524470	Bronze			2022-04-25	
J	Aydinlik, S; Erkisa, M; Ari, F; Celikler, S; Ulukaya, E				Aydinlik, Seyma; Erkisa, Merve; Ari, Ferda; Celikler, Serap; Ulukaya, Engin			Palladium (II) Complex Enhances ROS-Dependent Apoptotic Effects via Autophagy Inhibition and Disruption of Multiple Signaling Pathways in Colorectal Cancer Cells	ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY			English	Article						Apoptosis; autophagy; metal-based compounds; ROS; colorectal cancer; chloroquine	PLATINUM(II) SACCHARINATE COMPLEXES; COLON-CANCER; CYTOTOXIC ACTIVITY; IN-VITRO; 5-FLUOROURACIL; CHLOROQUINE; CHEMOTHERAPY; BEVACIZUMAB; COMBINATION; ACTIVATION	Background: Inhibition of autophagy is reported to be a therapeutically effective strategy in overcoming resistance that is a deadly outcome in cancer. One of the most common reasons for chemo-resistance to treatment is the patients with tumors exhibiting a KRAS mutation, which occurs in approximately 40% of colorectal cancer patients. Objective: Hence, we assessed whether a Palladium (Pd)(II) complex is a promising anticancer complex, compared to 5-fluorouracil in KRAS wt HT-29 and KRAS mutant HCT-15 cells. Methods: HCT-15 and HT-29 cells were used for colorectal cancer and Chloroquine (CQ) was used as an inhibitor of autophagy. In this context, cells were treated with Pd(II) complex and 5-FU in combination with CQ for 48h and cell viability was measured by SRB assay. Cell death mode was examined with M30 and M65 ELISA assays, using annexin V/propidium iodide. Autophagy was determined by Acridine Orange (AO) staining. Furthermore, the expressions of various autophagy and apoptosis-related proteins were evaluated with Western blotting. Luminex assay and the level of Reactive Oxygen Species (ROS) were examined. Results: Cell viability was found to decrease in a dose-dependent manner and CQ enhanced cytotoxic effect in Pd(II) and 5-FU treated cells in colorectal cancer cells. Our data showed that inhibition of autophagic flux significantly increased intrinsic apoptosis through the activation of ROS. We showed that combinatorial treatment with CQ induced apoptosis via the caspase-dependent mitochondrial pathway. Luminex analysis revealed that the combination resulted in a down-regulation of NF-?B/AKT/CREB signaling pathways in both cell lines, however, decreased Erk1/2 protein expression was only observed after treatment with CQ combination in HCT-15 cells. Conclusion: We suggest that the inhibition of autophagy along with Pd(II) and 5-FU treatment has a synergistic effect on KRAS-mutant colorectal cancer cells. Autophagy inhibition by CQ promotes apoptosis via blockade of the NF-?B/AKT/CREB and activation of ROS.	[Aydinlik, Seyma; Ari, Ferda; Celikler, Serap] Uludag Univ, Fac Arts & Sci, Dept Biol, Bursa, Turkey; [Erkisa, Merve] Istinye Univ, Mol Canc Res Ctr, Istanbul, Turkey; [Ulukaya, Engin] Istinye Univ, Dept Clin Biochem, Fac Med, Istanbul, Turkey		Ulukaya, E (corresponding author), Istinye Univ, Dept Clin Biochem, Fac Med, Istanbul, Turkey.	eulukaya@istinye.edu.tr	Aydinlik, Seyma/ABI-2909-2020; Arı, Ferda/AAG-7012-2021	Aydinlik, Seyma/0000-0001-5238-2432; Arı, Ferda/0000-0002-6729-7908; Ulukaya, Engin/0000-0003-4875-5472; Erkisa Genel, Merve/0000-0002-3127-742X	Scientific Research Projects Foundation (BAP) of the Uludag University of TurkeyUludag University; OUAP(T) [-2015/19]	This work was supported by funds from the Scientific Research Projects Foundation (BAP) of the Uludag University of Turkey [Project No. OUAP(T)-2015/19].	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Chem.		2021	21	6					1284	1291		10.2174/1871520620666200929153804			8	Oncology; Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	QT0QB	WOS:000626296300001	32990544				2022-04-25	
J	Pourhanifeh, MH; Vosough, M; Mahjoubin-Tehran, M; Hashemipour, M; Nejati, M; Abbasi-Kolli, M; Sahebkar, A; Mirzaei, H				Pourhanifeh, Mohammad Hossein; Vosough, Massoud; Mahjoubin-Tehran, Maryam; Hashemipour, Maryam; Nejati, Majid; Abbasi-Kolli, Mohammad; Sahebkar, Amirhossein; Mirzaei, Hamed			Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers	PHARMACOLOGICAL RESEARCH			English	Review						MicroRNA; Autophagy; Gastrointestinal cancer; Gastric cancer; Liver cancer; Pancreatic cancer; Esophageal cancer; Colorectal cancer; Biomarker; Epigenetic	HEPATOCELLULAR-CARCINOMA CELLS; PHASE-III TRIAL; CONFERS 5-FLUOROURACIL RESISTANCE; ADVANCED PANCREATIC-CANCER; COLORECTAL-CANCER; GASTRIC-CANCER; INHIBITS AUTOPHAGY; COLON-CANCER; DOWN-REGULATION; ENHANCES CHEMOSENSITIVITY	Gastrointestinal (GI) cancers with a high incidence rate and adverse complications are associated with severe morbidity and mortality around the world. It is well recognized that early detection of the disease results in longer survival rate and better quality of life. Autophagy, an intracellular regulatory process, has been shown to play an essential role in the pathogenesis of various malignancies including GI cancers. MicroRNAs (miRNAs) are small non-coding RNAs that have regulatory functions in tumor cells and possess potential diagnostic values in early detection of cancers. It has been recently demonstrated that these molecules have modulatory effects on multiple steps of autophagy process occurring in GI malignancies. In this review, we aimed to highlight the role of autophagy-related microRNAs on GI cancer as potential targets for cancer therapy.	[Pourhanifeh, Mohammad Hossein] FDA, Halal Res Ctr IRI, Tehran, Iran; [Vosough, Massoud] ACECR, Royan Inst Stem Cell Biol & Technol, Dept Regenerat Med, Cell Sci Res Ctr, Tehran, Iran; [Mahjoubin-Tehran, Maryam] Mashhad Univ Med Sci, Student Res Comm, Mashhad, Razavi Khorasan, Iran; [Mahjoubin-Tehran, Maryam] Mashhad Univ Med Sci, Fac Med, Dept Med Biotechnol, Mashhad, Razavi Khorasan, Iran; [Hashemipour, Maryam] Kashan Univ Med Sci, Sch Med, Kashan, Iran; [Nejati, Majid] Kashan Univ Med Sci, Anat Sci Res Ctr, Inst Basic Sci, Kashan, Iran; [Abbasi-Kolli, Mohammad] Tarbiat Modares Univ, Fac Med Sci, Dept Med Genet, Tehran, Iran; [Sahebkar, Amirhossein] Mashhad Univ Med Sci, Neurogen Inflammat Res Ctr, Mashhad, Razavi Khorasan, Iran; [Sahebkar, Amirhossein] Mashhad Univ Med Sci, Sch Pharm, Mashhad, Razavi Khorasan, Iran; [Mirzaei, Hamed] Kashan Univ Med Sci, Res Ctr Biochem & Nutr Metab Dis, Inst Basic Sci, Kashan, Iran; [Sahebkar, Amirhossein] Mashhad Univ Med Sci, Biotechnol Res Ctr, Pharmaceut Technol Inst, Mashhad, Razavi Khorasan, Iran		Mirzaei, H (corresponding author), Kashan Univ Med Sci, Res Ctr Biochem & Nutr Metab Dis, Inst Basic Sci, Kashan, Iran.; Sahebkar, A (corresponding author), Mashhad Univ Med Sci, Biotechnol Res Ctr, Pharmaceut Technol Inst, Mashhad, Razavi Khorasan, Iran.	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Res.	NOV	2020	161								105133	10.1016/j.phrs.2020.105133			16	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	PI3JG	WOS:000600990100034	32822869				2022-04-25	
J	Chen, WTL; Yang, HB; Ke, TW; Liao, WL; Hung, SY				Chen, William Tzu-Liang; Yang, Han-Bin; Ke, Tao-Wei; Liao, Wen-Ling; Hung, Shih-Ya			Serum DJ-1 Is a Biomarker of Colorectal Cancer and DJ-1 Activates Mitophagy to Promote Colorectal Cancer Progression	CANCERS			English	Article						autophagy; biomarker; colorectal cancer; DJ-1; mitophagy	COLON-CANCER; EXPRESSION; AUTOPHAGY; INVASION; PATHWAY; PROTEIN; PARKIN; CELLS; MITOCHONDRIA; MECHANISMS	Simple Summary Colorectal cancer is common cancer, and currently used serum markers for detecting colorectal cancer lack excellent diagnostic accuracy. In the present study, we collected matched tumor and adjacent normal tissues and serum from patients and cancer cells to demonstrate the clinical value of DJ-1 in colorectal cancer and the role of DJ-1-induced mitophagy in colorectal cancer progression. Our data indicate that DJ-1 might be clinically valuable as serum and tissue biomarkers for predicting the TNM (tumor-node-metastasis) stage in colorectal cancer patients. Besides, DJ-1 knockdown enhanced intracellular reactive oxygen species generation and damaged mitochondrial accumulation and mitophagy inhibition in metastatic colorectal adenocarcinoma cells. Since DJ-1-induced mitophagy promotes tumor progression, DJ-1 inhibition is a potential therapeutic strategy for colorectal cancer treatment. Colorectal cancer is the second most common cancer and the third cancer-associated death in Taiwan. Currently used serum markers for detecting colorectal cancer lack excellent diagnostic accuracy, which results in colorectal cancer being often recognized too late for successful therapy. Mitophagy is the selective autophagic degradation of damaged or excessive mitochondria. DJ-1 is an antioxidant protein that attenuates oxidative stress and maintains mitochondrial quality through activating mitophagy. Mitophagy activation contributes to anti-cancer drug resistance. However, the role of DJ-1-induced mitophagy in colorectal cancer progression remains unclear. In the present study, we collected matched tumor and adjacent normal tissues and serum from patients and cancer cells to demonstrate the clinical value and physiological function of DJ-1 in colorectal cancer. We found that DJ-1 increased in tumor tissues and serum; it was positively correlated with TNM (tumor-node-metastasis) stages of colorectal cancer patients. Through stable knockdown DJ-1 expression in metastatic colorectal adenocarcinoma cells SW620, DJ-1 knockdown inhibited cancer cell survival, migration, and colony formation. In SW620 cells, DJ-1 knockdown induced an incomplete autophagic response that did not affect ATP production; DJ-1 knockdown enhanced intracellular reactive oxygen species generation and damaged mitochondrial accumulation and mitophagy inhibition. It suggests that DJ-1 knockdown inhibits mitophagy that causes metastatic colorectal adenocarcinoma cells to be unable to remove damaged mitochondria and further enhance cancer cell apoptosis. Our data indicate that DJ-1 might be clinically valuable as serum and tissue biomarkers for predicting the TNM stage in colorectal cancer patients. Since DJ-1-induced mitophagy promotes tumor progression, DJ-1 inhibition is a potential therapeutic strategy for colorectal cancer treatment.	[Chen, William Tzu-Liang] China Med Univ, Sch Med, Taichung 40402, Taiwan; [Chen, William Tzu-Liang] China Med Univ, Dept Colorectal Surg, Hsinchu Hosp, Zhubei City 30272, Taiwan; [Yang, Han-Bin] China Med Univ, PhD Program Aging, Taichung 40402, Taiwan; [Ke, Tao-Wei] China Med Univ Hosp, Div Colorectal Surg, Taichung 40447, Taiwan; [Liao, Wen-Ling] China Med Univ, Grad Inst Integrated Med, Taichung 40202, Taiwan; [Liao, Wen-Ling] China Med Univ Hosp, Ctr Personalized Med, Dept Med Res, Taichung 40447, Taiwan; [Hung, Shih-Ya] China Med Univ Hosp, Dept Med Res, Div Surg, Taichung 40447, Taiwan; [Hung, Shih-Ya] China Med Univ, Grad Inst Acupuncture Sci, Taichung 40402, Taiwan		Hung, SY (corresponding author), China Med Univ Hosp, Dept Med Res, Div Surg, Taichung 40447, Taiwan.; Hung, SY (corresponding author), China Med Univ, Grad Inst Acupuncture Sci, Taichung 40402, Taiwan.	wtchen@mail.cmuh.org.tw; alex23206567@yahoo.com.tw; D18047@mail.cmuh.org.tw; wl0129@mail.cmu.edu.tw; shihyahung@mail.cmu.edu.tw	Chen, William Tzu-Liang/ABA-5673-2021		Ministry of Science and Technology of TaiwanMinistry of Science and Technology, Taiwan [MOST 108-2320-B-039-029-MY3]; China Medical UniversityChina Medical University [CMU109-MF-49]	This work was supported by grants from the Ministry of Science and Technology of Taiwan (MOST 108-2320-B-039-029-MY3) and China Medical University (CMU109-MF-49).	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J	Liu, S; Li, X; Li, Q; Liu, HJ; Shi, YL; Zhuo, HQ; Li, CS; Zhu, HJ				Liu, Shuai; Li, Xin; Li, Qing; Liu, Hongjun; Shi, Yulong; Zhuo, Hongqing; Li, Chensheng; Zhu, Huijuan			Silencing Livin improved the sensitivity of colon cancer cells to 5-fluorouracil by regulating crosstalk between apoptosis and autophagy	ONCOLOGY LETTERS			English	Article						apoptosis; autophagy; chemotherapeutic sensitivity; colon cancer; Livin	COLORECTAL-CANCER; PROTEIN FAMILY; GENE-EXPRESSION; CHEMOSENSITIVITY; PROLIFERATION; RESISTANCE; INHIBITOR; SURVIVAL; IAP; CISPLATIN	Colorectal cancer (CRC) is the third most common cause of cancer-associated mortality worldwide. Currently, 5-fluorouracil (5-FU) remains a widely used chemotherapeutic drug in the treatment of CRC; however, 5-FU resistance during treatment has become a common problem. Livin, a member of the inhibitor of apoptosis protein family, is considered to be associated with tumor resistance to chemotherapy. In the present study, Livin-silenced cells were generated by introducing a lentivirus into HCT116 and SW620 colon cancer cell lines. Acridine orange/ethidium bromide staining was used as an indicator of cell death. Western blot analysis was performed to detect protein expression levels, and transmission electron microscopy was used to assess autophagy. The half-maximal inhibitory concentration of 5-FU in colon cancer cells was evaluated using a Cell Counting Kit-8 assay. The results of the present study confirmed that silencing Livin significantly enhanced colon cancer cell death in the presence of 5-FU, increased expression levels of various apoptosis-and autophagyassoci-ated proteins and augmented chemotherapeutic sensitivity to 5-FU. Furthermore, the present study demonstrated that this effect may be reversed when autophagy or apoptosis was inhibited, indicating that apoptosis and autophagy were involved in this process. The protein kinase B signaling pathway and B-cell lymphoma-2 expression levels significantly decreased following Livin knockdown, suggesting they may contribute to the regulation of apoptosis and autophagy crosstalk, which caused the Livin knockdown-induced cell death observed.	[Liu, Shuai; Li, Xin; Li, Qing] Shandong Univ, Shandong Prov Hosp, Dept Urol, Jinan 250012, Shandong, Peoples R China; [Li, Qing] Yucheng Peoples Hosp, Dept Urol, Yucheng 251200, Shandong, Peoples R China; [Liu, Hongjun; Shi, Yulong; Zhuo, Hongqing; Li, Chensheng] Shandong Univ, Shandong Prov Hosp, Dept Gastrointestinal Surg, 324 Jinan Rd, Jinan 250012, Shandong, Peoples R China; [Zhu, Huijuan] Kaifeng Childrens Hosp Henan Prov, Dept Pharm, Intravenous Admixture Serv, Kaifeng 475000, Henan, Peoples R China		Li, CS (corresponding author), Shandong Univ, Shandong Prov Hosp, Dept Gastrointestinal Surg, 324 Jinan Rd, Jinan 250012, Shandong, Peoples R China.	chensheng76@163.com			Shandong Key Research and Development Project [2014GSF118134, 2015GSF118055]; Medicine and Healthcare Technology Development Project of Shandong Province [2014WS0341]; Natural Science Foundation of Shandong ProvinceNatural Science Foundation of Shandong Province [BS2010YY060, ZR2014HM111, ZR2014HP105]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81602227]	The present study was supported by the Shandong Key Research and Development Project (grant nos. 2014GSF118134 and 2015GSF118055), the Medicine and Healthcare Technology Development Project of Shandong Province (grant no. 2014WS0341), the Natural Science Foundation of Shandong Province (grant nos. BS2010YY060, ZR2014HM111 and ZR2014HP105) and the National Natural Science Foundation of China (grant no. 81602227).	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Lett.	MAY	2018	15	5					7707	7715		10.3892/ol.2018.8282			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GF3DN	WOS:000431825900214	29740490	Green Published, gold, Green Submitted			2022-04-25	
J	Wang, YF; Lin, KL; Xu, TC; Wang, LL; Fu, LY; Zhang, GM; Ai, J; Jiao, YJ; Zhu, RR; Han, XY; Cai, H				Wang, Yongfeng; Lin, Kaili; Xu, Tianchun; Wang, Liuli; Fu, Liangyin; Zhang, Guangming; Ai, Jing; Jiao, Yajun; Zhu, Rongrong; Han, Xiaoyong; Cai, Hui			Development and validation of prognostic model based on the analysis of autophagy-related genes in colon cancer	AGING-US			English	Article						colon cancer; autophagy; gene signature; prognosis model; immune microenvironment	COLORECTAL-CANCER; TUMOR PROGRESSION; PROTEIN; PREDICT; ATG101; LNCRNA	Background: Autophagy, a process of self-digestion, is closely related to multiple biological processes of colon cancer. This study aimed to construct and evaluate prognostic signature of autophagy-related genes (ARGs) to predict overall survival (OS) in colon cancer patients. Materials and Methods: First, a total of 234 ARGs were downloaded via The Cancer Genome Atlas (TCGA) database. Based on the TCGA dataset, differentially expressed ARGs were identified in colon cancer. The univariate and multivariate Cox regression analysis was performed to screen prognostic ARGs to construct the prognostic model. The feasibility of the prognostic model was evaluated using receiver operating characteristic curves and Kaplan-Meier curves. A prognostic model integrating the gene signature with clinical parameters was established with a nomogram. Results: We developed an autophagy risk signature based on the 6 ARGs (ULK3, ATG101, MAP1LC3C, TSC1, DAPK1, and SERPINA1). The risk score was positively correlated with poor outcome and could independently predict prognosis. Furthermore, the autophagy-related signature could effectively reflect the levels of immune cell type fractions and indicate an immunosuppressive microenvironment. Conclusion: We innovatively identified and validated 6 autophagy-related gene signature that can independently predict prognosis and reflect overall immune response intensity in the colon cancer microenvironment.	[Wang, Yongfeng; Fu, Liangyin; Zhang, Guangming; Ai, Jing; Zhu, Rongrong; Cai, Hui] Univ Chinese Med, Clin Med Coll Gansu 1, Lanzhou 730000, Gansu, Peoples R China; [Wang, Yongfeng; Wang, Liuli; Cai, Hui] Gansu Prov Hosp, Gen Surg Clin Med Ctr, Lanzhou 730000, Gansu, Peoples R China; [Wang, Liuli] Lanzhou Univ, Clin Med Coll 1, Lanzhou 730000, Gansu, Peoples R China; [Lin, Kaili; Jiao, Yajun; Han, Xiaoyong] Ning Xia Med Univ, Grad Sch, Yinchuan 750004, Ning Xia, Peoples R China; [Wang, Yongfeng; Cai, Hui] Gansu Prov Hosp, Key Lab Mol Diagnost & Precis Med Surg Oncol Gans, Lanzhou 730000, Gansu, Peoples R China; [Xu, Tianchun] Gansu Prov Hosp, Intelligent Med Lab, Lanzhou 730000, Gansu, Peoples R China		Cai, H (corresponding author), Univ Chinese Med, Clin Med Coll Gansu 1, Lanzhou 730000, Gansu, Peoples R China.; Cai, H (corresponding author), Gansu Prov Hosp, Gen Surg Clin Med Ctr, Lanzhou 730000, Gansu, Peoples R China.; Cai, H (corresponding author), Gansu Prov Hosp, Key Lab Mol Diagnost & Precis Med Surg Oncol Gans, Lanzhou 730000, Gansu, Peoples R China.	caialonteam@163.com			Natural Science Foundation of Gansu Province, China [18JR3RA052]; Lanzhou Talent Innovation and Entrepreneurship Project Task Contract [2016-RC-56]; Gansu Da Vinci robot highend diagnosis and treatment team construction project; National Key Research and Development Program [2018YFC1311500]; 2021 Graduate Innovation Fund Project of Gansu University of Chinese Medicine [2021CX54]	This study was supported by Natural Science Foundation of Gansu Province, China (No.18JR3RA052), Lanzhou Talent Innovation and Entrepreneurship Project Task Contract (No. 2016-RC-56), Gansu Da Vinci robot highend diagnosis and treatment team construction project, National Key Research and Development Program (No. 2018YFC1311500), and 2021 Graduate Innovation Fund Project of Gansu University of Chinese Medicine, No. 2021CX54.	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J	Luo, Y; Yoneda, J; Ohmori, H; Sasaki, T; Shimbo, K; Eto, S; Kato, Y; Miyano, H; Kobayashi, T; Sasahira, T; Chihara, Y; Kuniyasu, H				Luo, Yi; Yoneda, Junya; Ohmori, Hitoshi; Sasaki, Takamitsu; Shimbo, Kazutaka; Eto, Sachise; Kato, Yumiko; Miyano, Hiroshi; Kobayashi, Tsuyoshi; Sasahira, Tomonori; Chihara, Yoshitomo; Kuniyasu, Hiroki			Cancer Usurps Skeletal Muscle as an Energy Repository	CANCER RESEARCH			English	Article							GLYCATION END-PRODUCTS; PYRUVATE-KINASE; AMINO-ACIDS; PROTEIN HMGB1; COLON-CANCER; METABOLISM; METASTASIS; AMPHOTERIN; GLUTAMINE; SYSTEM	Cancer cells produce energy through aerobic glycolysis, but contributions of host tissues to cancer energy metabolism are unclear. In this study, we aimed to elucidate the cancer-host energy production relationship, in particular, between cancer energy production and host muscle. During the development and progression of colorectal cancer, expression of the secreted autophagy-inducing stress protein HMGB1 increased in the muscle of tumor-bearing animals. This effect was associated with decreased expression of pyruvate kinase PKM1 and pyruvate kinase activity in muscle via the HMGB1 receptor for advanced glycation endproducts (RAGE). However, muscle mitochondrial energy production was maintained. In contrast, HMGB1 addition to colorectal cancer cells increased lactate fermentation. In the muscle, HMGB1 addition induced autophagy by decreasing levels of active mTOR and increasing autophagy-associated proteins, plasma glutamate, and C-13-glutamine incorporation into acetyl-Co Lambda. In a mouse model of colon carcinogenesis, a temporal increase in HMGB1 occurred in serum and colonic mucosa with an increase in autophagy associated with altered plasma free amino acid levels, increased glutamine, and decreased PKM1 levels. These differences were abolished by administration of an HMGB1 neutralizing antibody. Similar results were obtained in a mouse xenograft model of human colorectal cancer. Taken together, our findings suggest that HMGB1 released during tumorigenesis recruits muscle to supply glutamine to cancer cells as an energy source. (C)2013 AACR.	[Luo, Yi; Ohmori, Hitoshi; Sasahira, Tomonori; Chihara, Yoshitomo; Kuniyasu, Hiroki] Nara Med Univ, Dept Mol Pathol, Kashihara, Nara 6348521, Japan; [Yoneda, Junya; Shimbo, Kazutaka; Eto, Sachise; Kato, Yumiko; Miyano, Hiroshi; Kobayashi, Tsuyoshi] Ajinomoto Co Inc, Inst Innovat, Kawasaki, Kanagawa, Japan; [Sasaki, Takamitsu] Fukuoka Univ, Sch Med, Dept Gastrointestinal Surg, Minami Ku, Fukuoka 81401, Japan		Kuniyasu, H (corresponding author), Nara Med Univ, Dept Mol Pathol, 840 Shijo Cho, Kashihara, Nara 6348521, Japan.	cooninh@zb4.so-net.ne.jp			Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [23659188, 23590430, 24590450]	This work was supported in part by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (23659188, 23590430, and 24590450).	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JAN 1	2014	74	1					330	340		10.1158/0008-5472.CAN-13-1052			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	284DZ	WOS:000329297600032	24197136	Bronze			2022-04-25	
J	Huo, HZ; Wang, B; Qin, J; Guo, SY; Liu, WY; Gu, Y				Huo, Hai-zhong; Wang, Bing; Qin, Jian; Guo, Shan-yu; Liu, Wen-yong; Gu, Yan			AMP-activated protein kinase (AMPK)/Ulk1-dependent autophagic pathway contributes to C6 ceramide-induced cytotoxic effects in cultured colorectal cancer HT-29 cells	MOLECULAR AND CELLULAR BIOCHEMISTRY			English	Article						C6 ceramide; AMPK/Ulk1 pathway; Autophagy; Colorectal cancer	COLON-CANCER; INDUCED APOPTOSIS; DRUG-RESISTANCE; UPSTREAM KINASE; MELANOMA-CELLS; GROWTH; DEATH; PHOSPHORYLATION; CHEMOTHERAPY; INHIBITION	Colorectal cancer is the second leading cause of cancer-related deaths. Drug resistance and/or off-target toxicity against normal cells limit the effectiveness of current chemotherapies for the treatment of colorectal cancer. In the current study, we studied the potential cytotoxic effects of short-chain and cell-permeable C6 ceramide in cultured colorectal cancer HT-29 cells and focused on the underlying mechanisms. We observed that C6 ceramide-induced HT-29 cell death and growth inhibition in a dose-and time-dependent manner. However, no significant apoptosis was observed in C6 ceramide-treated HT-29 cells. Our data support that autophagy contributed to C6 ceramide-induced cytotoxic effects, as autophagy inhibitors, 3-methyladenine (3-MA) and hydroxychloroquine, inhibited C6 ceramide's effect; however, autophagy activators, everolimus (RAD001) and temsirolimus, mimicked C6 ceramide effects and induced HT-29 cell death. Further, we indentified that AMP-activated protein kinase (AMPK)/Ulk1 signaling was required for autophagy induction by C6 ceramide, and AMPK silencing by a specific short hairpin RNA suppressed C6 ceramide-induced autophagy and cytotoxic effects. Reversely, forced activation of AMPK by its activator AICAR or by genetic manipulation caused autophagic death in HT-29 cells, which was inhibited by 3-MA. Our results suggest that autophagy, but not apoptosis, is a major contributor for C6 ceramide-induced cytotoxic effects in HT-29 cells, and activation of AMPK/Ulk1 is required for the process.	[Huo, Hai-zhong; Wang, Bing; Qin, Jian; Guo, Shan-yu; Liu, Wen-yong; Gu, Yan] Shanghai Jiao Tong Univ, Sch Med, Dept Gen Surg, Peoples Hosp 9, Shanghai 200011, Peoples R China		Gu, Y (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Dept Gen Surg, Peoples Hosp 9, 639 Zhizhaoju Rd, Shanghai 200011, Peoples R China.	drguyan@hotmail.com	Gu, Yan/AFQ-1163-2022		National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC)	Funding/Support: This study was supported in part by the National Natural Science Foundation of China.	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Cell. Biochem.	JUN	2013	378	1-2					171	181		10.1007/s11010-013-1608-8			11	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	134BG	WOS:000318184100019	23508272				2022-04-25	
J	Ren, SX; Shen, J; Cheng, ASL; Lu, L; Chan, RLY; Li, ZJ; Wang, XJ; Wong, CCM; Zhang, L; Ng, SSM; Chan, FL; Chan, FKL; Yu, J; Sung, JJY; Wu, WKK; Cho, CH				Ren, Shun X.; Shen, Jin; Cheng, Alfred S. L.; Lu, Lan; Chan, Ruby L. Y.; Li, Zhi J.; Wang, Xiao J.; Wong, Clover C. M.; Zhang, Lin; Ng, Simon S. M.; Chan, Franky L.; Chan, Francis K. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.; Cho, Chi H.			FK-16 Derived from the Anticancer Peptide LL-37 Induces Caspase-Independent Apoptosis and Autophagic Cell Death in Colon Cancer Cells	PLOS ONE			English	Article							HUMAN ANTIMICROBIAL PEPTIDE; TUMOR-SUPPRESSOR; GLIOMA-CELLS; P53; CARCINOMA; BAX; INHIBITION; EXPRESSION; BILAYERS; MICELLES	Host immune peptides, including cathelicidins, have been reported to possess anticancer properties. We previously reported that LL-37, the only cathelicidin in humans, suppresses the development of colon cancer. In this study, the potential anticancer effect of FK-16, a fragment of LL-37 corresponding to residues 17 to 32, on cultured colon cancer cells was evaluated. FK-16 induced a unique pattern of cell death, marked by concurrent activation of caspase-independent apoptosis and autophagy. The former was mediated by the nuclear translocation of AIF and EndoG whereas the latter was characterized by enhanced expression of LC3-I/II, Atg5 and Atg7 and increased formation of LC3-positive autophagosomes. Knockdown of Atg5 or Atg7 attenuated the cytotoxicity of FK-16, indicating FK-16-induced autophagy was pro-death in nature. Mechanistically, FK-16 activated nuclear p53 to upregulate Bax and downregulate Bcl-2. Knockdown of p53, genetic ablation of Bax, or overexpression of Bcl-2 reversed FK-16-induced apoptosis and autophagy. Importantly, abolition of AIF/EndoG-dependent apoptosis enhanced FK-16-induced autophagy while abolition of autophagy augmented FK-16-induced AIF2/EndoG-dependent apoptosis. Collectively, FK-16 induces caspase-independent apoptosis and autophagy through the common p53-Bcl-2/Bax cascade in colon cancer cells. Our study also uncovered previously unknown reciprocal regulation between these two cell death pathways.	[Ren, Shun X.; Shen, Jin; Lu, Lan; Chan, Ruby L. Y.; Li, Zhi J.; Wong, Clover C. M.; Zhang, Lin; Chan, Franky L.; Cho, Chi H.] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China; [Cheng, Alfred S. L.; Wang, Xiao J.; Chan, Francis K. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.] Chinese Univ Hong Kong, Inst Digest Dis, Li Ka Shing Inst Hlth, Hong Kong, Hong Kong, Peoples R China; [Cheng, Alfred S. L.; Wang, Xiao J.; Chan, Francis K. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China; [Ng, Simon S. M.] Chinese Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China		Wu, WKK (corresponding author), Chinese Univ Hong Kong, Inst Digest Dis, Li Ka Shing Inst Hlth, Hong Kong, Hong Kong, Peoples R China.	wukakei@cuhk.edu.hk	Sung, Joseph J. Y./R-3203-2018; Chan, Franky L./M-1043-2018; Ng, Simon S. M./M-1219-2018; Cho, Chi Hin/C-6543-2014; ZHANG, Lin/O-9109-2015; Wu, William K.K./A-3277-2009; Yu, Jun/D-8569-2015; Chan, Francis K. L./F-4851-2010; Cheng, Alfred SL/C-3327-2014	Sung, Joseph J. Y./0000-0003-3125-5199; Chan, Franky L./0000-0003-0567-2052; Ng, Simon S. M./0000-0002-5389-9297; Cho, Chi Hin/0000-0002-7658-3260; ZHANG, Lin/0000-0003-1634-3780; Wu, William K.K./0000-0002-5662-5240; Yu, Jun/0000-0001-5008-2153; Chan, Francis K. 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J	Koustas, E; Papavassiliou, AG; Karamouzis, MV				Koustas, Evangelos; Papavassiliou, Athanasios G.; Karamouzis, Michalis V.			The role of autophagy in the treatment of BRAF mutant colorectal carcinomas differs based on microsatellite instability status	PLOS ONE			English	Article							GROWTH-FACTOR RECEPTOR; COLON-CANCER; INHIBITORS; EGFR; PD-L1; TUMORIGENESIS; LYMPHOCYTES; COMBINATION; ACTIVATION; EXPRESSION	Autophagy has been identified as a catabolic mechanism in cells but its' role in cancer remains controversial. Autophagy has been characterized either as tumor suppressor or inducer mechanism in many tumor types. Monoclonal antibodies against EGFR (cetuximab and panitumumab) represent a major step in the treatment of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy which reveals a potential resistance mechanism to these agents. The last years immunotherapy appears to be a novel promising strategy for the treatment of patients with solid tumors, including colorectal cancer. Checkpoint inhibitors, such as anti-PD1 (nivolumab and pembrolizumab) and antiCTLA-4 (ipilimumab) antibodies have already been developed and applied in mCRC patients with MSI-H phenotype. The association between mtBRAF and autophagy or MSI status has already been characterized. In our study, we identify the autophagy initiation through anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma cell lines according to microsatellite status. The combination of autophagy inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors appears to be the best treatment approach for microsatellite instability high and stable colorectal cancer cell lines, respectively. Both combinatorial approaches reduce cell viability through the induction of apoptotic cell death. The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.	[Koustas, Evangelos; Papavassiliou, Athanasios G.; Karamouzis, Michalis V.] Univ Athens, Sch Med, Dept Biol Chem, Mol Oncol Unit, Athens, Greece; [Karamouzis, Michalis V.] Univ Athens, Sch Med, Laiko Gen Hosp, Dept Internal Med 1, Athens, Greece		Karamouzis, MV (corresponding author), Univ Athens, Sch Med, Dept Biol Chem, Mol Oncol Unit, Athens, Greece.; Karamouzis, MV (corresponding author), Univ Athens, Sch Med, Laiko Gen Hosp, Dept Internal Med 1, Athens, Greece.	mkaramouz@med.uoa.gr	Koustas, Evangelos/ABE-9336-2020; Karamouzis, Michalis/AAD-2860-2020	Karamouzis, Michalis/0000-0003-1369-8201	Hellenic Foundation for Research and Innovation (HFRI); General Secretariat for Research and Technology (GSRT), under the HFRI PhD Fellowship [GA. 665 (14482)]; Institute of Molecular Medicine and Biomedical Research	The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT), under the HFRI PhD Fellowship grant [GA. 665 (14482)] (to EK) and Institute of Molecular Medicine and Biomedical Research (to MVK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Selvakumaran, M; Amaravadi, RK; Vasilevskaya, IA; O'Dwyer, PJ				Selvakumaran, Muthu; Amaravadi, Ravi K.; Vasilevskaya, Irina A.; O'Dwyer, Peter J.			Autophagy Inhibition Sensitizes Colon Cancer Cells to Antiangiogenic and Cytotoxic Therapy	CLINICAL CANCER RESEARCH			English	Article							HYPOXIA-INDUCED AUTOPHAGY; HEPATOCELLULAR-CARCINOMA; COLORECTAL-CANCER; FLUOROURACIL; BEVACIZUMAB; LEUCOVORIN; BNIP3; ANGIOGENESIS; OXALIPLATIN; IRINOTECAN	Purpose: Autophagy is a critical survival pathway for cancer cells under conditions of nutrient or oxygen limitation, or cell stress. As a consequence of antiangiogenic therapy, solid tumors encounter hypoxia induction and imbalances in nutrient supply. We wished to determine the role of autophagy in protection of tumor cells from the effects of antiangiogenic therapy and chemotherapy. We examined the effect of inhibiting autophagy on hypoxic colon cancer cells in vitro and on bevacizumab- and oxaliplatin-treated mouse xenografts in vivo. Experimental Design: The autophagic response to hypoxia and DNA-damaging agents was assessed by fluorescent microscopic imaging, autophagy-related gene expression, and by electron microscopic ultrastructural analysis. Pharmacologic and molecular approaches to autophagy inhibition were taken in a panel of colon cancer cell lines. Mouse xenograft models were treated with combinations of oxaliplatin, bevacizumab, and chloroquine to assess effects on tumor growth reduction and on pharmacodynamic markers of autophagy inhibition. Results: Autophagy was induced in colon cancer models by exposure to both hypoxia and oxaliplatin. Inhibition of autophagy, either with chloroquine or by downregulation of beclin1 or of ATG5, enhanced sensitivity to oxaliplatin under normal and hypoxic conditions in a synergistic manner. Both bevacizumab and oxaliplatin treatments activate autophagy in HT29 murine xenografts. The addition of chloroquine to bevacizumab- based treatment provided greater tumor control in concert with evidence of autophagy inhibition. Conclusions: These findings implicate autophagy as a mechanism of resistance to antiangiogenic therapies and support investigation of inhibitory approaches in the management of this disease. (C) 2013 AACR.	[Selvakumaran, Muthu; Amaravadi, Ravi K.; Vasilevskaya, Irina A.; O'Dwyer, Peter J.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19014 USA		O'Dwyer, PJ (corresponding author), Univ Penn, 16 Penn Tower,3400 Spruce St, Philadelphia, PA 19014 USA.	peter.odwyer@uphs.upenn.edu			National Cancer Institute (NCI)/NIH/Department of Health and Human Services (DHHS) [CA49820, CA158377]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA049820, R01CA158377] Funding Source: NIH RePORTER	This work is supported in part by CA49820 and CA158377 from National Cancer Institute (NCI)/NIH/Department of Health and Human Services (DHHS).	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J	Raina, K; Agarwal, C; Wadhwa, R; Serkova, NJ; Agarwal, R				Raina, Komal; Agarwal, Chapla; Wadhwa, Ritambhara; Serkova, Natalie J.; Agarwal, Rajesh			Energy deprivation by silibinin in colorectal cancer cells A double-edged sword targeting both apoptotic and autophagic machineries	AUTOPHAGY			English	Article						colorectal cancer; silibinin; autophagy; oxidative stress; energy restrictions	ACTIVATED PROTEIN-KINASE; MONITORING AUTOPHAGY; CHEMOPREVENTIVE AGENT; ELECTRON-MICROSCOPY; SUPPRESSES GROWTH; MAMMALIAN-CELLS; CULTURED-CELLS; COLON-CANCER; HT-29 CELLS; DEATH	Small molecules with the potential to initiate different types of programmed cell death could be useful adjunct therapy' where current anticancer modalities fail to generate significant activity due to a defective apoptotic machinery or resistance of cancer cells to the specific death mechanism induced by that treatment. The current study identified silibinin, for the first time, as one such natural agent, having dual efficacy against colorectal cancer (CRC) cells. First, silibinin rapidly induced oxidative stress in CRC SW480 cells due to reactive oxygen species (ROS) generation with a concomitant dissipation of mitchondrial potential ((m)) and cytochrome c release leading to mild apoptosis as a biological effect. However, with increased exposure to silibinin, cytoplasmic vacuolization intensified within the cells followed by sequestration of the organelles, which inhibits the further release of cytochrome c. Interestingly, this decrease in apoptotic response correlated with increased autophagic events as evidenced by tracking the dynamics of LC3-II within the cells. Mechanistic studies revealed that silibinin strongly inhibited PIK3CA-AKT-MTOR but activated MAP2K1/2-MAPK1/3 pathways for its biological effects. Corroborating these effects, endoplasmic reticulum stress was generated and glucose uptake inhibition as well as energy restriction were induced by silibinin, thus, mimicking starvation-like conditions. Further, the cellular damage to tumor cells by silibinin was severe and irreparable due to sustained interference in essential cellular processes such as mitochondrial metabolism, phospholipid and protein synthesis, suggesting that silibinin harbors a deadly double-edged sword' against CRC cells thereby further advocating its clinical effectiveness against this malignancy.	[Raina, Komal; Agarwal, Chapla; Wadhwa, Ritambhara; Agarwal, Rajesh] Univ Colorado, Dept Pharmacal Sci, Skaggs Sch Pharm, Aurora, CO 80045 USA; [Serkova, Natalie J.] Univ Colorado, Dept Anesthesiol & Radiol, Aurora, CO USA; [Agarwal, Chapla; Serkova, Natalie J.; Agarwal, Rajesh] Univ Colorado, Ctr Canc, Aurora, CO USA		Agarwal, R (corresponding author), Univ Colorado, Dept Pharmacal Sci, Skaggs Sch Pharm, Anschutz Med Campus, Aurora, CO 80045 USA.	rajesh.agarwal@ucdenver.edu			University of Colorado Cancer Center [CA046934]; Colorado Clinical and Translational Sciences Institute [RR025780]; RO1 grant [CA112304]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA112304, P30CA046934] Funding Source: NIH RePORTER; NATIONAL CENTER FOR RESEARCH RESOURCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [UL1RR025780] Funding Source: NIH RePORTER	Supported by RO1 grant CA112304, University of Colorado Cancer Center P30 grant CA046934, and Colorado Clinical and Translational Sciences Institute UL1 award RR025780.	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J	Sharma, T; Radosevich, JA; Mandal, CC				Sharma, Tanu; Radosevich, James A.; Mandal, Chandi C.			Dual Role of microRNAs in Autophagy of Colorectal Cancer	ENDOCRINE METABOLIC & IMMUNE DISORDERS-DRUG TARGETS			English	Review						Colorectal cancer; microRNA; autophagy; non-coding RNA; tumor suppressor; tumor promoter	CONFERS 5-FLUOROURACIL RESISTANCE; COLON-CANCER; INHIBITS AUTOPHAGY; CELLS PROLIFERATION; THERAPEUTIC TARGET; TUMOR-CELLS; GROWTH; MECHANISMS; EXPRESSION; APOPTOSIS	Autophagy is an evolutionarily conserved pathway that eliminates unwanted proteins out of the cell and increases cell survival. However, dysfunctional autophagy is associated with cancer progression, cellular adaptation, cancer metastasis and makes it an attractive therapeutic target. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that usually bind to 3'UTR of mRNAs. This interaction eventually inhibits protein synthesis by repressing translation and/or by degrading mRNAs. miRNAs play a crucial role in the regulation of autophagy and also behave as both tumor suppressors and promoters in colorectal cancer. This paper defines an overall molecular view of how miRNAs regulate the dual role of autophagy in colorectal cancer. It also highlights how long noncoding RNAs modulate miRNAs expression to regulate autophagy in colorectal cancer. Thus, targeting autophagy by miRNAs seems to be a potential therapeutic strategy for colorectal cancer.	[Sharma, Tanu; Mandal, Chandi C.] Cent Univ Rajasthan, Dept Biochem, NH-8 Bandarsindri, Ajmer 305817, Rajasthan, India; [Radosevich, James A.] Univ Illinois, Coll Dent, Dept Oral Med & Diagnost Sci, Chicago, IL 60612 USA		Mandal, CC (corresponding author), Cent Univ Rajasthan, Dept Biochem, NH-8 Bandarsindri, Ajmer 305817, Rajasthan, India.	chandicmandal@gmail.com		Mandal, Chandi/0000-0002-2292-6635; Radosevich, James A/0000-0003-4633-480X	Department of Biotechnology [6242-P9/RGCB/PMD/DBT/CCML/2015]; University Grant CommissionUniversity Grants Commission, India [3049/2014 (BSR)]; Department of Science and Technology (India)-Russian Foundation for Basic Research [INT/RUS/RFBR/P-256]	The study was funded by the Department of Biotechnology (Grant Number: 6242-P9/RGCB/PMD/DBT/CCML/2015], University Grant Commission [Grant Number: 3049/2014 (BSR)] and Department of Science and Technology (India)-Russian Foundation for Basic Research (Grant Number: INT/RUS/RFBR/P-256).	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Metab. Immune Disord.-Drug Targets		2021	21	1					56	66		10.2174/1871530320666200519075908			11	Endocrinology & Metabolism; Immunology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Endocrinology & Metabolism; Immunology; Pharmacology & Pharmacy	QA4UO	WOS:000613440100008	32427088				2022-04-25	
J	Reszegi, A; Horvath, Z; Karaszi, K; Regos, E; Postnikova, V; Tatrai, P; Kiss, A; Schaff, Z; Kovalszky, I; Baghy, K				Reszegi, Andrea; Horvath, Zsolt; Karaszi, Katalin; Regos, Eszter; Postnikova, Victoria; Tatrai, Peter; Kiss, Andras; Schaff, Zsuzsa; Kovalszky, Ilona; Baghy, Kornelia			The Protective Role of Decorin in Hepatic Metastasis of Colorectal Carcinoma	BIOMOLECULES			English	Article						decorin; ECM; colorectal carcinoma; RTK; signaling; liver metastasis	GROWTH-FACTOR RECEPTOR; EXTRACELLULAR-MATRIX; EXPRESSING DECORIN; SIGNALING PATHWAY; TUMOR-GROWTH; IN-VIVO; AUTOPHAGY; LIVER; AMPK; PROTEOGLYCANS	Decorin, the prototype member of the small leucine-rich proteoglycan gene family of extracellular matrix (ECM) proteins, acts as a powerful tumor suppressor by inducing the p21(Waf1/Cip1)cyclin-dependent kinase inhibitor, as well as through its ability to directly bind and block the action of several tyrosine kinase receptors. Our previous studies suggested that the lack of decorin promotes hepatic carcinogenesis in mice. Based on this, we set out to investigate whether excess decorin may protect against the liver metastases of colon carcinoma. We also analyzed the effect of decorin in tissue microarrays of human colon carcinoma liver metastasis and examined whether the tumor cells can directly influence the decorin production of myofibroblasts. In humans, low levels of decorin in the liver facilitated the development of colon carcinoma metastases in proportion with more aggressive phenotypes, indicating a possible antitumor action of the proteoglycan. In vitro, colon carcinoma cells inhibited decorin expression in LX2 hepatic stellate cells. Moreover, liver-targeted decorin delivery in mice effectively attenuated metastasis formation of colon cancer. Overexpressed decorin reduced the activity of multiple receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR), an important player in colorectal cancer (CRC) pathogenesis. Downstream of that, we observed weakened signaling of ERK1/2, PLC gamma, Akt/mTOR, STAT and c-Jun pathways, while p38 MAPK/MSK/CREB and AMPK were upregulated culminating in enhanced p53 function. In conclusion, decorin may effectively inhibit metastatic tumor formation in the liver.	[Reszegi, Andrea; Horvath, Zsolt; Karaszi, Katalin; Regos, Eszter; Postnikova, Victoria; Kovalszky, Ilona; Baghy, Kornelia] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, Ulloi St 26, H-1085 Budapest, Hungary; [Tatrai, Peter] Solvo Biotechnol, H-1117 Budapest, Hungary; [Kiss, Andras; Schaff, Zsuzsa] Semmelweis Univ, Dept Pathol 2, H-1091 Budapest, Hungary		Baghy, K (corresponding author), Semmelweis Univ, Dept Pathol & Expt Canc Res 1, Ulloi St 26, H-1085 Budapest, Hungary.	areszegi2@gmail.com; opponent01@gmail.com; tika0604@gmail.com; eszter.regos.88@gmail.com; postnikova.victoria@gmail.com; tatrai@solvo.com; kiss.andras@med.semmelweis-univ.hu; schaff.zsuzsa@med.semmelweis-univ.hu; kovalszky.ilona@med.semmelweis-univ.hu; baghy.kornelia@med.semmelweis-univ.hu	Tatrai, Peter/AAR-6014-2020; Kovalszky, Ilona/ABH-2832-2020; Baghy, Kornélia/ABH-2549-2020	Tatrai, Peter/0000-0001-9726-1992; Kovalszky, Ilona/0000-0002-0179-3378; Baghy, Kornélia/0000-0002-5323-2775; Regos, Eszter/0000-0002-1707-1943; Karaszi, Katalin/0000-0002-9188-1987; Reszegi, Andrea/0000-0001-6902-7883	HUNGARIAN SCIENTIFIC RESEARCH FUNDOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [105763, 100904, 119283, 128881]; Scholarship For The Young Talents Of The Nation (NFTO) [NTP-NFTO-19-B-0037, NTP-NFTO-18-B-0165]; EUH2020 MSCA-RISE project [645756]; Hungarian National Research, Development and Innovation Office (NKFIH) [NVKP_16-1-2016-0004]	This research was funded by the HUNGARIAN SCIENTIFIC RESEARCH FUND grant number 105763 (to KB), 100904, 119283 (to IK), 128881 (to AK), by Scholarship For The Young Talents Of The Nation (NFTO NTP-NFTO-19-B-0037 and NTP-NFTO-18-B-0165 to AR) and by EUH2020 MSCA-RISE project #645756 "GLYCANC" (to IK). The study and publishing of the article was also supported by NVKP_16-1-2016-0004 grant of the Hungarian National Research, Development and Innovation Office (NKFIH).	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Xu W, 2015, GENE THER, V22, P247, DOI 10.1038/gt.2014.110; Yang YF, 2015, HUM GENE THER, V26, P813, DOI 10.1089/hum.2015.098	73	2	2	3	8	MDPI	BASEL	ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND		2218-273X		BIOMOLECULES	Biomolecules	AUG	2020	10	8							1199	10.3390/biom10081199			17	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	OC0IB	WOS:000578845700001	32824864	Green Published, gold			2022-04-25	
J	Lyu, Q; Tou, FF; Su, H; Wu, XY; Chen, XY; Zheng, Z				Lyu, Qing; Tou, Fangfang; Su, Hong; Wu, Xiaoyong; Chen, Xinyi; Zheng, Zhi			The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Peiminine; Autophagy; Natural product; Autophagic cell death	CANCER; DISEASE; ULK1; AMPK; ADIPOGENESIS; CONTRIBUTES; DYSFUNCTION; SUPPRESSES; ACTIVATION; STARVATION	Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. (C) 2015 Elsevier Inc. All rights reserved.	[Lyu, Qing] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China; [Lyu, Qing] Tsinghua Univ, Grad Sch Shenzhen, Div Life Sci, Key Lab Hlth Sci & Technol, Shenzhen 518055, Peoples R China; [Tou, Fangfang; Zheng, Zhi] Jiangxi Canc Hosp, Jiangxi Prov Key Lab Oncol Translat Med, Nanchang 330029, Peoples R China; [Su, Hong; Wu, Xiaoyong] Guiyang Coll Tradit Chinese Med, Affiliated Hosp 1, Guiyang 550002, Peoples R China; [Chen, Xinyi] Beijing Univ Chinese Med, Dept Hematol & Oncol, Beijing 100029, Peoples R China		Chen, XY (corresponding author), Beijing Univ Chinese Med, Dept Hematol & Oncol, Beijing 100029, Peoples R China.	zheng_sheva@hotmail.com	Lyu, Qing/AAF-5181-2021	Lyu, Qing/0000-0002-1325-6828	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81260592]	This work was supported by the National Natural Science Foundation of China (No. 81260592). The funding institute had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.	Baerga R, 2009, AUTOPHAGY, V5, P1118, DOI 10.4161/auto.5.8.9991; Esposti MD, 2003, BIOCHEM BIOPH RES CO, V304, P455, DOI 10.1016/S0006-291X(03)00617-X; Gozuacik D, 2007, CURR TOP DEV BIOL, V78, P217, DOI 10.1016/S0070-2153(06)78006-1; Kang C, 2007, GENE DEV, V21, P2161, DOI 10.1101/gad.1573107; Kim J, 2011, NAT CELL BIOL, V13, P132, DOI 10.1038/ncb2152; Klionsky DJ, 2005, J CELL SCI, V118, P7, DOI 10.1242/jcs.01620; Ko H, 2011, J CELL BIOCHEM, V112, P2471, DOI 10.1002/jcb.23171; Kristensen AR, 2008, MOL CELL PROTEOMICS, V7, P2419, DOI 10.1074/mcp.M800184-MCP200; Lai K, 2014, J CLIN PATHOL, V67, P854, DOI 10.1136/jclinpath-2014-202529; Lee S, 2005, GYNECOL ONCOL, V97, P26, DOI 10.1016/j.ygyno.2004.11.051; Massey AC, 2006, CURR TOP DEV BIOL, V73, P205, DOI 10.1016/S0070-2153(05)73007-6; Meijer A.J., 2014, AMINO ACIDS; Meijer Alfred J., 2006, Molecular Aspects of Medicine, V27, P411, DOI 10.1016/j.mam.2006.08.002; Meijer AJ, 2011, CURR BIOL, V21, pR227, DOI 10.1016/j.cub.2011.02.007; Mizushima N, 2007, ANNU REV NUTR, V27, P19, DOI 10.1146/annurev.nutr.27.061406.093749; Nazio F, 2013, NAT CELL BIOL, V15, P406, DOI 10.1038/ncb2708; Pivtoraiko VN, 2010, J NEUROCHEM, V114, P1193, DOI 10.1111/j.1471-4159.2010.06838.x; Ravikumar B, 2004, NAT GENET, V36, P585, DOI 10.1038/ng1362; Sato K, 2007, CANCER RES, V67, P9677, DOI 10.1158/0008-5472.CAN-07-1462; Shang LB, 2011, AUTOPHAGY, V7, P924, DOI 10.4161/auto.7.8.15860; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Shimizu S, 2014, INT J MOL SCI, V15, P3145, DOI 10.3390/ijms15023145; Tachibana Ken, 2006, Tanpakushitsu Kakusan Koso, V51, P1519; Takahashi Y, 2005, MOL CELL BIOL, V25, P9369, DOI 10.1128/MCB.25.21.9369-9382.2005; Tsujimoto Y, 2003, J CELL PHYSIOL, V195, P158, DOI 10.1002/jcp.10254; Wei MC, 2001, SCIENCE, V292, P727, DOI 10.1126/science.1059108; Xie ZP, 2007, NAT CELL BIOL, V9, P1102, DOI 10.1038/ncb1007-1102; Xue Yan, 2005, Yaoxue Xuebao, V40, P550; Zhao L, 2014, MOL NUTR FOOD RES, V58, P569, DOI 10.1002/mnfr.201300157	29	27	29	4	25	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	JUN 19	2015	462	1					38	45		10.1016/j.bbrc.2015.04.102			8	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	CJ6XL	WOS:000355638400007	25935480				2022-04-25	
J	Lv, YZ; Li, B; Han, KN; Xiao, Y; Yu, XJ; Ma, Y; Jiao, Z; Gao, JJ				Lv, Yongzhu; Li, Bing; Han, Kunna; Xiao, Yang; Yu, Xianjun; Ma, Yong; Jiao, Zhan; Gao, Jianjun			The Nedd8-activating enzyme inhibitor MLN4924 suppresses colon cancer cell growth via triggering autophagy	KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY			English	Article						Autophagy; Cell growth; Colon cancer; MLN4924; Neddylation	COLORECTAL-CANCER; E3 LIGASE; NEDDYLATION; APOPTOSIS; PATHWAYS; PROTEIN; DEATH; SENESCENCE; MATURATION; SURVIVAL	Neddylation is a post-translational protein modification process. MLN4924 is a newly discovered pharmaceutical neddylation inhibitor that suppresses cancer growth with several cancer types. in our study, we first investigated the effect of MLN4924 on colon cancer cells (HCT116 and HT29). MLN4924 significantly inhibited the neddylation of cullin-1 and colon cancer cell growth in a time and dose-dependent manner. MLN4924 induced 62/M cell cycle arrest and apoptosis in HCT116 and HT29 cells. Moreover, MLN4924 also triggered autophagy in HCT116 and HT29 cells via suppressing the PI3K/AKT/mTOR pathway. Inhibiting autophagy by autophagy inhibitor 3-MA or ATGS knockdown reversed the function of MLN4924 in suppressing colon cancer cell growth and cell death. Interestingly, MLN4924 suppresses colon cell growth in a xenograft model. Together, our finding revealed that blocking neddylation is an attractive colon cancer therapy strategy, and autophagy might act as a novel anti-cancer mechanism for the treatment of colon cancer by MLN4924.	[Lv, Yongzhu; Li, Bing; Han, Kunna; Yu, Xianjun; Ma, Yong; Jiao, Zhan; Gao, Jianjun] 210 Hosp Chinese Peoples Liberat Army, Dept Gen Surg, Dalian 116021, Peoples R China; [Xiao, Yang] Dalian Univ, Affiliated Zhongshan Hosp, Dept Gynecol & Obstet, Dalian 116001, Peoples R China		Gao, JJ (corresponding author), 210 Hosp Chinese Peoples Liberat Army, Dept Gen Surg, Dalian 116021, Peoples R China.	gaojianjun210@163.com					Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; Deegan S, 2012, THESIS; Deng SJ, 2015, FOOD CHEM TOXICOL, V75, P173, DOI 10.1016/j.fct.2014.11.019; Gil J, 2016, BIOMARK MED, V10, P1081, DOI 10.2217/bmm-2016-0083; Heerva E, 2018, J GASTROINTEST CANC, V49, P245, DOI 10.1007/s12029-017-9927-8; Heras-Sandoval D, 2014, CELL SIGNAL, V26, P2694, DOI 10.1016/j.cellsig.2014.08.019; Jia LJ, 2011, NEOPLASIA, V13, P561, DOI 10.1593/neo.11420; Jiang K, 2016, ONCOTARGET, V7, P25652, DOI 10.18632/oncotarget.8357; Kelekar A, 2005, ANN NY ACAD SCI, V1066, P259, DOI 10.1196/annals.1363.015; Kenific CM, 2015, TRENDS CELL BIOL, V25, P37, DOI 10.1016/j.tcb.2014.09.001; Kim JH, 2015, BMB REP, V48, P129, DOI 10.5483/BMBRep.2015.48.3.048; Kimura S, 2007, AUTOPHAGY, V3, P452, DOI 10.4161/auto.4451; Klionsky DJ, 2008, AUTOPHAGY, V4, P151, DOI 10.4161/auto.5338; Koskela A, 2016, ACTA OPHTHALMOL, V94, pS256; Lan HY, 2016, SCI REP-UK, V6, DOI 10.1038/srep24218; Maxwell PJ, 2016, CURRENT CONTROVERSIE; Merlet J, 2009, CELL MOL LIFE SCI, V66, P1924, DOI 10.1007/s00018-009-8712-7; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Nawrocki ST, 2012, EXPERT OPIN INV DRUG, V21, P1563, DOI 10.1517/13543784.2012.707192; Ouyang L, 2012, CELL PROLIFERAT, V45, P487, DOI 10.1111/j.1365-2184.2012.00845.x; Petrelli F, 2013, ANN ONCOL, V24, P186, DOI 10.1093/annonc/mds289; Ryabaya OO, 2015, BIOL B REV, V5, P579; Shen HM, 2011, AUTOPHAGY, V7, P457, DOI 10.4161/auto.7.5.14226; Song Lele, 2016, Zhong Nan Da Xue Xue Bao Yi Xue Ban, V41, P9, DOI 10.11817/j.issn.1672-7347.2016.01.002; Sui YY, 2015, BIOCHEM BIOPH RES CO, V461, P653, DOI 10.1016/j.bbrc.2015.04.085; Tanida I, 2011, ANTIOXID REDOX SIGN, V14, P2201, DOI 10.1089/ars.2010.3482; Wan JF, 2016, TECHNOL CANCER RES T, V15, P527, DOI 10.1177/1533034615588197; Wang YC, 2015, CANCER BIOL THER, V16, P420, DOI 10.1080/15384047.2014.1003003; Watson IR, 2011, CANCER CELL, V19, P168, DOI 10.1016/j.ccr.2011.01.002; Xu JF, 2015, MOL CELL PROTEOMICS, V14, P499, DOI 10.1074/mcp.M114.045211; Zhang Y, 2016, ONCOTARGET, V7, P45263, DOI 10.18632/oncotarget.9481; Zhao Y, 2012, CELL DEATH DIS, V3, DOI 10.1038/cddis.2012.125; Zhao YC, 2014, ANTIOXID REDOX SIGN, V21, P2383, DOI 10.1089/ars.2013.5795; Zheng WW, 2017, MOL MED REP, V15, P2795, DOI 10.3892/mmr.2017.6305	34	6	7	1	7	KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY	SEOUL	C/O EDITORIAL OFFICE, 448-13 SEOKYO-DONG, SEOUL, SOUTH KOREA	1226-4512	2093-3827		KOREAN J PHYSIOL PHA	KOREAN J. PHYSIOL. PHARMACOL.	NOV	2018	22	6					617	625		10.4196/kjpp.2018.22.6.617			9	Pharmacology & Pharmacy; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Physiology	GY0IP	WOS:000448200000002	30402022	Green Published, gold, Green Submitted			2022-04-25	
J	Wei, MF; Chen, MW; Chen, KC; Lou, PJ; Lin, SYF; Hung, SC; Hsiao, M; Yao, CJ; Shieh, MJ				Wei, Ming-Feng; Chen, Min-Wei; Chen, Ke-Cheng; Lou, Pei-Jen; Lin, Susan Yun-Fan; Hung, Shih-Chieh; Hsiao, Michael; Yao, Cheng-Jung; Shieh, Ming-Jium			Autophagy promotes resistance to photodynamic therapy-induced apoptosis selectively in colorectal cancer stem-like cells	AUTOPHAGY			English	Article						apoptosis; autophagy; autophagy-related proteins; cancer stem-like cells; colonosphere; colorectal cancer; photodynamic therapy; prominin 1 (PROM1)/CD133; tumorigenicity	IN-VITRO; INHIBITION; DEATH; GLIOBLASTOMA; PROTEIN; COLON; PHOTOSENSITIZERS; MACROAUTOPHAGY; OXYGENATION; MECHANISMS	Recent studies have indicated that cancer stem-like cells (CSCs) exhibit a high resistance to current therapeutic strategies, including photodynamic therapy (PDT), leading to the recurrence and progression of colorectal cancer (CRC). In cancer, autophagy acts as both a tumor suppressor and a tumor promoter. However, the role of autophagy in the resistance of CSCs to PDT has not been reported. In this study, CSCs were isolated from colorectal cancer cells using PROM1/CD133 (prominin 1) expression, which is a surface marker commonly found on stem cells of various tissues. We demonstrated that PpIX-mediated PDT induced the formation of autophagosomes in PROM1/CD133(+) cells, accompanied by the upregulation of autophagy-related proteins ATG3, ATG5, ATG7, and ATG12. The inhibition of PDT-induced autophagy by pharmacological inhibitors and silencing of the ATG5 gene substantially triggered apoptosis of PROM1/CD133(+) cells and decreased the ability of colonosphere formation in vitro and tumorigenicity in vivo. In conclusion, our results revealed a protective role played by autophagy against PDT in CSCs and indicated that targeting autophagy could be used to elevate the PDT sensitivity of CSCs. These findings would aid in the development of novel therapeutic approaches for CSC treatment.	[Wei, Ming-Feng; Chen, Ke-Cheng; Lin, Susan Yun-Fan; Shieh, Ming-Jium] Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan; [Chen, Min-Wei; Shieh, Ming-Jium] Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan; [Chen, Ke-Cheng] Natl Taiwan Univ Hosp, Dept Surg, Taipei, Taiwan; [Lou, Pei-Jen] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan; [Hung, Shih-Chieh] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan; [Hsiao, Michael] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan; [Yao, Cheng-Jung] Taipei Med Univ, Municipal Wan Fang Hosp, Taipei, Taiwan		Shieh, MJ (corresponding author), Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan.	soloman@ntu.edu.tw	Hsiao, Michael/U-6238-2019	Hsiao, Michael/0000-0001-8529-9213; LOU, PEI-JEN/0000-0002-3383-8593	National Science Council, ROCMinistry of Science and Technology, Taiwan [NSC 100-2218-E-002-002]; Ministry of Health and Welfare, ROC [MOHW103-TDU-N-211-133006]	This research was funded by the National Science Council, ROC (NSC 100-2218-E-002-002) and the Ministry of Health and Welfare, ROC (MOHW103-TDU-N-211-133006).	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J	Goulielmaki, M; Koustas, E; Moysidou, E; Vlassi, M; Sasazuki, T; Shirasawa, S; Zografos, G; Oikonomou, E; Pintzas, A				Goulielmaki, Maria; Koustas, Evangelos; Moysidou, Eirini; Vlassi, Margarita; Sasazuki, Takehiko; Shirasawa, Senji; Zografos, George; Oikonomou, Eftychia; Pintzas, Alexander			BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells	ONCOTARGET			English	Article						colorectal cancer; BRAF inhibitors; autophagy inhibitors; synergistic treatments	COLON-CANCER; RAS ONCOGENES; BRAF(V600E); MELANOMA; TUMORIGENESIS; INDUCTION; PATHWAY; TRANSFORMATION; VEMURAFENIB; SENSITIVITY	Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has a controversial role in cancer - both in protecting against tumor progression by isolation of damaged organelles, or by potentially contributing to cancer growth. The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context. In the present study, the effect of KRAS/BRAF/PIK3CA oncogenic pathways on the autophagic cell properties and on main components of the autophagic machinery like p62 (SQSTM1), Beclin-1 (BECN1) and MAP1LC3 (LC3) in colon cancer cells was investigated. This study provides evidence that BRAF oncogene induces the expression of key autophagic markers, like LC3 and BECN1 in colorectal tumor cells. Herein, PI3K/AKT/MTOR inhibitors induce autophagic tumor properties, whereas RAF/MEK/ERK signalling inhibitors reduce expression of autophagic markers. Based on the ineffectiveness of BRAFV600E inhibitors in BRAFV600E bearing colorectal tumors, the BRAF related autophagic properties in colorectal cancer cells are further exploited, by novel combinatorial anti-cancer protocols. Strong evidence is provided here that pre-treatment of autophagy inhibitor 3-MA followed by its combination with BRAFV600E targeting drug PLX4720 can synergistically sensitize resistant colorectal tumors. Notably, colorectal cancer cells are very sensitive to mono-treatments of another autophagy inhibitor, Bafilomycin A1. The findings of this study are expected to provide novel efficient protocols for treatment of otherwise resistant colorectal tumors bearing BRAFV600E, by exploiting the autophagic properties induced by BRAF oncogene.	[Goulielmaki, Maria; Koustas, Evangelos; Moysidou, Eirini; Vlassi, Margarita; Oikonomou, Eftychia; Pintzas, Alexander] Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Lab Signal Mediated Gene Express, Athens, Greece; [Sasazuki, Takehiko] Kyushu Univ, Inst Adv Study, Fukuoka 812, Japan; [Shirasawa, Senji] Kyushu Univ, Fac Med, Dept Cell Biol, Fukuoka 812, Japan; [Zografos, George] Gen Hosp Athens G Gennimatas, Dept Surg 3, Athens, Greece		Pintzas, A (corresponding author), Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Lab Signal Mediated Gene Express, Athens, Greece.	apint@eie.gr	Koustas, Evangelos/ABE-9336-2020	Moysidou, Eirini/0000-0002-3182-9159	European UnionEuropean Commission; General Secretariat of Research and Technology (GSRT) SINERGASIA "POM" [09SYN-11-675]; General Secretariat of Research and Technology (GSRT) KRIPIS "STHENOS" [MIS 447985]	This work was supported by FP6 and FP7 European Union grants, as well as by grants from the General Secretariat of Research and Technology (GSRT) SINERGASIA "POM" 09SYN-11-675 and KRIPIS "STHENOS" MIS 447985.	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J	Mishra, SK; Kang, JH; Song, KH; Park, MS; Kim, DK; Park, YJ; Choi, C; Kim, HM; Kim, MK; Oh, SH				Mishra, S. K.; Kang, J. -H.; Song, K. -H.; Park, M. S.; Kim, D. -K.; Park, Y. -J.; Choi, C.; Kim, H. M.; Kim, M. K.; Oh, S. H.			INONOTUS OBLIQUUS SUPPRESSES PROLIFERATION OF COLORECTAL CANCER CELLS AND TUMOR GROWTH IN MICE MODELS BY DOWNREGULATION OF beta-CATENIN/NF-kappa B-SIGNALING PATHWAYS	EUROPEAN JOURNAL OF INFLAMMATION			English	Article						anti-inflammation; colorectal carcinoma; Inonotus obliquus: natural product; Wnt/beta-catenin	INFLAMMATORY-BOWEL-DISEASE; COLON-CANCER; RECEPTOR ANTAGONIST; ULCERATIVE-COLITIS; WATER EXTRACT; APOPTOSIS; MUSHROOM; INDUCTION	Chaga mushroom (Inonotus obliquus) has been used as a folk remedy for several illnesses including gastrointestinal disorders. We recently reported the potent anti-inflammatory effect of chaga extract in experimental colitis. However, its effects on colorectal cancer (CRC) have not been clearly elucidated. We investigated the effects of an aqueous extract of Inonotus obliquus (IOAE) in vitro in HCT116 and DLD1 cell lines and in vivo for adenoma in APC(Min/+) mice and colitis-associated colon cancer in AOM/DSS-treated mice. Results show that IOAE suppressed the proliferation of both cell lines, and inhibited the growth of intestinal polyps in APC(Min/+) and colon tumors in AOM/DSS-treated mice. IOAE induced mitochondrial intrinsic pathway of apoptosis, autophagy, and S phase cell cycle arrest. IOAE suppressed the expression levels of iNOS and Cox-2 and mRNA levels of pro-inflammatory cytokines (IL-6, IL-1 beta, TNF-alpha and IFN-gamma) in the intestine of mice models. IOAE suppressed the nuclear levels of P-catenin and inhibited its downstream targets (cyclin D1 and c-Myc) along with CRC oncogene CDK8. IOAE inhibited the expression of NF-kappa B at cytoplasmic and nuclear levels. Our results demonstrate that IOAE possess potent anti-inflammatory and anti-proliferative properties through downregulation of Wnt/beta-catenin and NF-kappa B pathways. Considering recent anticancer approaches involving natural products with minimal side effects, we advocate that Inonotus obliquus could be a beneficial supplement in prevention of colorectal cancer.	[Kang, J. -H.; Choi, C.] Chung Ang Univ, Dept Food & Nutr, Div Nat Sci, Ansung, South Korea; [Kang, J. -H.; Song, K. -H.] Natl Canc Ctr, Div Canc Biol, Goyang Si, South Korea; [Park, M. S.; Kim, D. -K.; Park, Y. -J.] Natl Canc Ctr, Anim Sci Branch, Goyang Si, South Korea; [Kim, M. K.] Natl Canc Ctr, Div Canc Epidemiol & Prevent, Carcinogenesis Branch, Goyang Si, South Korea		Oh, SH (corresponding author), Gachon Univ, Gachon Inst Pharmaceut Sci, 7-45 Songdo Dong, Inchon 406840, South Korea.	alrud@ncc.re.kr; eyeball@gachon.ac.kr	Oh, Seung/AAN-6744-2021		Global Core Research Center (GCRC) from the National Research Foundation (NRF), Ministry of Education, Science and Technology (MEST), Republic of Korea [20110030678]; Korean Health Industry Development Industries (KHIDI); National Center for Efficacy Evaluation for the Development of Health Products Targeting Digestive Diseases	This work was financially supported by the Global Core Research Center (GCRC) Grant (No. 20110030678) from the National Research Foundation (NRF), Ministry of Education, Science and Technology (MEST), Republic of Korea and was also supported by the grant from Korean Health Industry Development Industries (KHIDI) and National Center for Efficacy Evaluation for the Development of Health Products Targeting Digestive Diseases.	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J. Inflamm.	SEP-DEC	2013	11	3					615	629		10.1177/1721727X1301100306			15	Immunology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology	287HS	WOS:000329533300006		Bronze			2022-04-25	
J	Luan, YP; Li, YM; Zhu, LN; Zheng, SQ; Mao, DC; Chen, ZX; Cao, Y				Luan, Yunpeng; Li, Yanmei; Zhu, Lina; Zheng, Shuangqing; Mao, Dechang; Chen, Zhuxue; Cao, Yong			Codonopis bulleynana Forest ex Diels inhibits autophagy and induces apoptosis of colon cancer cells by activating the NF-kappa B signaling pathway	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE			English	Article						Codonopis bulleynana Forest ex Diels; oxaliplatin; autophagy; nuclear factor-kappa B pathway; pyrrolidine dithiocarbamate	COLORECTAL-CANCER; MECHANISMS; RADIATION; MEDICINE; DEATH	Despite its favorable clinical efficacy, oxaliplatin-based chemotherapy frequently results in treatment withdrawal and induces liver damage in colon cancer. Therefore, it is important to develop novel drugs, which can safely and effectively complement or replace the therapeutic effects of oxaliplatin. Codonopis bulleynana Forest ex Diels (cbFeD) has wide range of pharmacological effects, including anticancer effects. In the present study, the anticancer activity of cbFeD and its potential molecular mechanisms were investigated. In vitro, cell counting kit-8 assays and flow cytometry were used to assess the anti-proliferation and apoptosis-promoting activities of cbFeD. Transmission electron microscopy was used to monitor the autophagic vesicles. Immunofluorescence staining was performed to observe the nuclear translocation of p65 and the fluorescence of microtubule-associated protein 1 light chain 3 (LC3) B-II. The protein expression levels of p65, inhibitor of nuclear factor (NF)-kappa B (I kappa B) a, LC3B-I, LC3B-II and Beclin-1 were detected using western blot analysis. In vivo, the antitumor effect of cbFeD was assessed in colon cancer-bearing nude mice as a model. H&E staining and immunohistochemistry (IHC) were performed, with oxaliplatin set as a positive control. The results showed that cbFeD inhibited cell proliferation and promoted cell apoptosis in a dose-dependent manner. The effects of a high dose of cbFeD on colon cancer cells were similar to those of oxaliplatin. In HCT116 and SW480 cells, cbFeD inhibited the expression of I kappa B alpha, LC3B-I/II and Beclin-1, and the results of western blot analysis and immunofluorescence showed that, in the cells treated with cbFeD, p65 gradually entered nuclei in a dose-dependent manner, and the expression of LC3B-II was gradually reduced. The results of the acridine orangestaining and electron microscopy demonstrated fewer autophagic vesicles in the high-dose cbFeD group and the oxaliplatin group. The high dose of cbFeD reversed the effect of pyrrolidine dithiocarbamate, a p65-inhibitor, on the expression of p65, LC3B-I, LC3B-II and Beclin-1, and on the production of autophagic vacuoles. The high dose of cbFeD and oxaliplatin also suppressed tumorigenicity in vivo. The results of the H&E and IHC staining confirmed the inhibition of autophagy (LC3 and Beclin-1) and activation of p65 by treatment with the high dose of cbFeD and oxaliplatin. Taken together, cbFeD exhibited an antitumor effect in colon cancer cells by inhibiting autophagy through activation of the NF-kappa B pathway. Therefore, cbFeD may be a promising Chinese herbal compound for development for use in cancer therapy.	[Luan, Yunpeng; Li, Yanmei; Zhu, Lina; Mao, Dechang; Chen, Zhuxue; Cao, Yong] Southwest Forestry Univ, Sch Life Sci, Dept Life Technol Teaching & Res, 300 Bailong Temple, Kunming 652400, Yunnan, Peoples R China; [Zheng, Shuangqing] Kunming Pharmaceut Corp, Kunming 652400, Yunnan, Peoples R China		Cao, Y (corresponding author), Southwest Forestry Univ, Sch Life Sci, Dept Life Technol Teaching & Res, 300 Bailong Temple, Kunming 652400, Yunnan, Peoples R China.	1820059756@qq.com		Luan, Yunpeng/0000-0002-6627-0906	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [61363061]	The study was supported by the National Natural Science Foundation of China (grant no. 61363061).	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J. Mol. Med.	MAR	2018	41	3					1305	1314		10.3892/ijmm.2017.3337			10	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	FV9ON	WOS:000424918000013	29286074	Green Published, hybrid, Green Submitted			2022-04-25	
J	Saint-Martin, A; Martinez-Rios, J; Castaneda-Patlan, MC; Sarabia-Sanchez, MA; Tejeda-Munoz, N; Chinney-Herrera, A; Soldevila, G; Benelli, R; Santoyo-Ramos, P; Poggi, A; Robles-Flores, M				Saint-Martin, Abril; Martinez-Rios, Jacobo; Cristina Castaneda-Patlan, M.; Angel Sarabia-Sanchez, Miguel; Tejeda-Munoz, Nydia; Chinney-Herrera, Alberto; Soldevila, Gloria; Benelli, Roberto; Santoyo-Ramos, Paula; Poggi, Alessandro; Robles-Flores, Martha			Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells	CANCERS			English	Article						colon cancer; hypoxia-inducible factors; drug resistance; autophagy	HIF-2-ALPHA; HIF-1-ALPHA; INHIBITION; RADIORESISTANCE; 5-FLUOROURACIL; HIF2-ALPHA; ANTAGONIST; EXPRESSION; GENES; ROLES	Hypoxia and the accumulation of hypoxia-inducible factors (HIFs) in tumors have been associated with therapeutic resistance and with autophagy establishment. We examined the effects of stable knockdown of HIF-1 alpha or HIF-2 alpha expression on autophagy and drug resistance in colon cancer cells. We found that under normoxic conditions, malignant cells exhibit increased basal levels of autophagy, compared with non-malignant cells, in addition to the previously reported coexpression of HIF-1 alpha and HIF-2 alpha. Knockdown of HIF-1 alpha or HIF-2 alpha expression resulted in increased autophagic and apoptotic cell death, indicating that the survival of cells is HIF-dependent. Cytotoxic-induced cell death was significantly increased by knockdown of HIFs but not by autophagy inhibition. Strikingly, although malignancy-resistant cells were sensitized to death by nutrient stress, the combination with HIF-2 alpha, depletion, but not with HIF-1 alpha depletion, induced severe cell death. Oxidative stress levels were significantly increased as a result of HIF-2 alpha specific inhibition or silencing suggesting that this may contribute to sensitize cells to death. The in vitro results were confirmed in vivo using a xenograft mouse model. We found that coordinated autophagy and mTOR inhibition enhanced cell death and induced tumor remission only in HIF-2 alpha-silenced cells. Finally, using a specific HIF-2 alpha inhibitor alone or in combination with drugs in patient-derived primary colon cancer cells, overcame their resistance to 5-FU or CCI-779, thus emphasizing the crucial role played by HIF-2 alpha in promoting resistance and cell survival.	[Saint-Martin, Abril; Cristina Castaneda-Patlan, M.; Angel Sarabia-Sanchez, Miguel; Tejeda-Munoz, Nydia; Santoyo-Ramos, Paula; Robles-Flores, Martha] Univ Nacl Autonoma Mexico, Fac Med, Dept Biochem, Mexico City 04510, DF, Mexico; [Martinez-Rios, Jacobo; Chinney-Herrera, Alberto; Soldevila, Gloria] Univ Nacl Autonoma Mexico, Inst Invest Biomed, Dept Immunol, Mexico City 04510, DF, Mexico; [Benelli, Roberto] IRCCS Osped Policlin San Martino, Immunol Unit, I-16132 Genoa, Italy; [Santoyo-Ramos, Paula; Poggi, Alessandro] IRCCS Osped Policlin San Martino, Mol Oncol & Angiogenesis Unit, I-16132 Genoa, Italy		Robles-Flores, M (corresponding author), Univ Nacl Autonoma Mexico, Fac Med, Dept Biochem, Mexico City 04510, DF, Mexico.	abrilsaint@hotmail.com; jacobomartinezrios@yahoo.com.mx; cristi_ccp@yahoo.com; mike_sarabia@hotmail.com; nydia.tejeda@gmail.com; alder_30@hotmail.com; soldevi@unam.mx; roberto.benelli@hsanmartino.it; paula_ab@yahoo.com; alessandro.poggi@hsanmartino.it; rmartha@unam.mx	Munoz, Nydia Tejeda/ABF-3038-2020; Benelli, Roberto/AAF-3143-2019; Poggi, Alessandro/K-6664-2016	Munoz, Nydia Tejeda/0000-0001-8314-412X; Benelli, Roberto/0000-0002-9769-0954; Poggi, Alessandro/0000-0002-1860-430X; Castaneda-Patlan, Maria Cristina/0000-0002-2551-4847; Soldevila, Gloria/0000-0003-1539-2548; Saint Martin, Abril/0000-0003-3294-1879	Universidad Nacional Autonoma de Mexico (DGAPA-UNAM)Universidad Nacional Autonoma de Mexico [IN215514, IN225717]; CONACYTConsejo Nacional de Ciencia y Tecnologia (CONACyT) [FOSSIS 2017-289600]	This research was supported by grants from Universidad Nacional Autonoma de Mexico (DGAPA-UNAM IN215514 and IN225717) and from CONACYT (FOSSIS 2017-289600).	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J	Gao, GY; Ma, J; Lu, P; Jiang, X; Chang, C				Gao, Guang-Yi; Ma, Jun; Lu, Peng; Jiang, Xuan; Chang, Cheng			Ophiopogonin B induces the autophagy and apoptosis of colon cancer cells by activating JNK/c-Jun signaling pathway	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Colon cancer; Ophiopogonin B; JNK/c-Jun; Autophagy; Apoptosis	COLORECTAL-CANCER; GASTRIC-CANCER; BECLIN 1; EXPRESSION; CARCINOMA; DEATH; BCL-2; PROLIFERATION; DEGRADATION; P62/SQSTM1	Objective: To investigate the effect of Ophiopogonin B (OP-B) on the autophagy and apoptosis of colon cancer cells via the regulation of JNK/c-Jun signaling pathway. Methods: Colon cancer cell lines (HT-29 and HCT-116) were treated with various concentrations of OP-B (0, 5, 10and 20 mu mol/l) and JNK inhibitor SP600125. MTT assay, flow cytometry, immunofluorescence staining were used to detect the biological function ofHT-29 and HCT-116 cells, and expressions of autophagy-, apoptotic-and pathway-related proteins were measured by Western Blot. Moreover, a nude mice model with transplanted tumor was used to observe the effect of OP-B on the growth, autophagy and apoptosis of the transplanted tumor of colon cancer. Results: The results demonstrated that OP-B suppressed the proliferation of HT-29 and HCT-116 cell lines through the G0/G1 phase cell cycle arrest. Moreover, OP-B induced apoptosis by inhibiting the expression of Bax and cleaved caspase 3 and promoting the expression of Bcl-2. Treatment with OP-B also increased the expression of Beclin 1 and the conversion of LC3I to LC3II with the activation of JNK/c-Jun signaling pathway, but reduced the expression of P62, whereas SP600125 (an inhibitor of JNK) reversed these process. In addition, the xenograft model using HCT-116 cells provided further evidence of the inhibition of OP-B on tumor proliferation. Immunohistochemistry detection verified that OP-B enhance the positive expression rate of LC3, and increase the apoptosis index of tumor cells in vivo. Importantly, all these changes induced by OP-B were clearly in a dosedependent manner. Conclusion: OP-B may induce cell autophagy, apoptosis and cell cycle arrest by activating the JNK/c-Jun signaling pathway, thereby inhibiting the growth of colon cancer.	[Gao, Guang-Yi] Xuzhou Med Univ, Affiliated Huaian Hosp, Huaian Peoples Hosp 2, Dept Tradit Chinese Med, 62 Huaihai South Rd, Huaian 223002, Jiangsu, Peoples R China; [Ma, Jun] Nanjing Univ Chinese Med, Affiliated Huaian Hosp, Huaian Hosp Chinese Med, Dept Oncol, Nanjing, Jiangsu, Peoples R China; [Lu, Peng] Yangzhou Univ, Med Acad, Huaian Matern & Child Healthcare Hosp, Dept Pharm, Huaian, Jiangsu, Peoples R China; [Jiang, Xuan] Xuzhou Med Univ, Affiliated Huaian Hosp, Huaian Peoples Hosp 2, Dept Oncol, Huaian, Jiangsu, Peoples R China; [Chang, Cheng] Nanjing Jianzhong Hosp Tradit Chinese Med, Internal Med Tradit Chinese Med, Nanjing, Jiangsu, Peoples R China		Gao, GY (corresponding author), Xuzhou Med Univ, Affiliated Huaian Hosp, Huaian Peoples Hosp 2, Dept Tradit Chinese Med, 62 Huaihai South Rd, Huaian 223002, Jiangsu, Peoples R China.	guangyi_gg@sina.com					Ahmed FE, 2003, J ENVIRON SCI HEAL C, V21, P65, DOI 10.1081/GNC-120026233; Alirezaei M, 2015, AUTOPHAGY, V11, P1389, DOI 10.1080/15548627.2015.1063769; Bayne K, 1996, Physiologist, V39, P208; Bayne K, 1996, PHYSIOLOGIST, V39, P208; Bjorkoy G, 2009, METHOD ENZYMOL, V452, P181, DOI 10.1016/S0076-6879(08)03612-4; Chen MJ, 2016, INT J ONCOL, V49, P316, DOI 10.3892/ijo.2016.3514; Chen MJ, 2013, ONCOL REP, V29, P430, DOI 10.3892/or.2012.2131; Chen MC, 2015, J AGR FOOD CHEM, V63, P1540, DOI 10.1021/jf5054063; Cunningham D, 2010, LANCET, V375, P1030, DOI 10.1016/S0140-6736(10)60353-4; Eimani BG, 2014, CELL J, V15, P356; Guo JL, 2008, J HUAZHONG U SCI-MED, V28, P281, DOI 10.1007/s11596-008-0311-6; Holt SV, 2011, TOXICOL PATHOL, V39, P516, DOI 10.1177/0192623310396903; Jiang QG, 2014, MOL BIOL REP, V41, P3359, DOI 10.1007/s11033-014-3198-2; Jing Z, 2016, ONCOTARGET, V7, P61509, DOI 10.18632/oncotarget.11385; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Kantara C, 2014, CANCER RES, V74, P2487, DOI 10.1158/0008-5472.CAN-13-3536; Kim YJ, 2015, BIOORG MED CHEM LETT, V25, P2559, DOI 10.1016/j.bmcl.2015.04.054; Kitanaka Chifumi, 2013, Genes Cancer, V4, P388, DOI 10.1177/1947601912474892; Li DD, 2009, ONCOGENE, V28, P886, DOI 10.1038/onc.2008.441; Lorin S, 2010, AUTOPHAGY, V6, P153, DOI 10.4161/auto.6.1.10537; Masuda G, 2016, ANTICANCER RES, V36, P129; Mehan S, 2011, J MOL NEUROSCI, V43, P376, DOI 10.1007/s12031-010-9454-6; Odonkor CA, 2009, CANCER INVEST, V27, P417, DOI 10.1080/07357900802438585; Pankiv S, 2007, J BIOL CHEM, V282, P24131, DOI 10.1074/jbc.M702824200; Prizment AE, 2010, CANCER EPIDEM BIOMAR, V19, P2229, DOI 10.1158/1055-9965.EPI-10-0522; Qi FH, 2015, BIOSCI TRENDS, V9, P16, DOI 10.5582/bst.2015.01019; Raychaudhuri S, 2013, J HEALTHC ENG, V4, P47, DOI 10.1260/2040-2295.4.1.47; Scorrano L, 2003, BIOCHEM BIOPH RES CO, V304, P437, DOI 10.1016/S0006-291X(03)00615-6; Su CC, 2012, EXP THER MED, V3, P555, DOI 10.3892/etm.2011.441; Sui XB, 2014, CANCER LETT, V344, P174, DOI 10.1016/j.canlet.2013.11.019; Tsukahara S, 2006, NEUROIMMUNOMODULAT, V13, P63, DOI 10.1159/000094829; Uen YH, 2015, SCI REP-UK, V5, DOI 10.1038/srep09360; Wei YJ, 2008, MOL CELL, V30, P678, DOI 10.1016/j.molcel.2008.06.001; Wu CX, 2015, OPEN BIOL, V5, DOI 10.1098/rsob.140171; Xavier CPR, 2013, J NUTR BIOCHEM, V24, P706, DOI 10.1016/j.jnutbio.2012.04.004; Xie CM, 2011, FREE RADICAL BIO MED, V51, P1365, DOI 10.1016/j.freeradbiomed.2011.06.016; Zamora-Ros R, 2015, GENES NUTR, V10, DOI 10.1007/s12263-014-0447-x; Zang QQ, 2016, J INTEGR MED-JIM, V14, P51, DOI 10.1016/S2095-4964(16)60238-8; Zhang WY, 2016, MOL MED REP, V13, P4981, DOI 10.3892/mmr.2016.5198	39	21	24	3	15	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER	ISSY-LES-MOULINEAUX	65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE	0753-3322	1950-6007		BIOMED PHARMACOTHER	Biomed. Pharmacother.	DEC	2018	108						1208	1215		10.1016/j.biopha.2018.06.172			8	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	HA2UZ	WOS:000450101800135	30372822	hybrid			2022-04-25	
J	Chen, ST; Lee, TY; Tsai, TH; Lin, YC; Lin, CP; Shieh, HR; Hsu, ML; Chi, CW; Lee, MC; Chang, HH; Chen, YJ				Chen, Shun-Ting; Lee, Tzung-Yan; Tsai, Tung-Hu; Lin, Yin-Cheng; Lin, Chin-Ping; Shieh, Hui-Ru; Hsu, Ming-Ling; Chi, Chih-Wen; Lee, Ming-Cheng; Chang, Hen-Hong; Chen, Yu-Jen			The Traditional Chinese Medicine DangguiBuxue Tang Sensitizes Colorectal Cancer Cells to Chemoradiotherapy	MOLECULES			English	Article						DangguiBuxue Tang; colorectal cancer; chemotherapy; radiotherapy	RADIX-ANGELICAE-SINENSIS; SIGNAL-REGULATED KINASE; HERBAL DECOCTION; BUXUE-TANG; AUTOPHAGY; ASTRAGALI; STATISTICS; TOXICITY; SURVIVAL	Chemotherapy is an important treatment modality for colon cancer, and concurrent chemoradiation therapy (CCRT) is the preferred treatment route for patients with stage II and III rectal cancer. We examined whether DangguiBuxue Tang (DBT), a traditional Chinese herbal extract, sensitizes colorectal cancer cells to anticancer treatments. The polysaccharide-depleted fraction of DBT (DBT-PD) contains greater amounts of astragaloside IV (312.626 mu g/g) and ferulic acid (1.404 mu g/g) than does the original formula. Treatment of the murine colon carcinoma cell line (CT26) with DBT-PD inhibits growth, whereas treatment with comparable amounts of purified astragaloside IV and ferulic acid showed no significant effect. Concurrent treatment with DBT-PD increases the growth inhibitory effect of 5-fluorouracil up to 4.39-fold. DBT-PD enhances the effect of radiation therapy (RT) with a sensitizer enhancement ratio (SER) of up to 1.3. It also increases the therapeutic effect of CCRT on CT26 cells. Cells treated with DBP-PD showed ultrastructural changes characteristic of autophagy, including multiple cytoplasmic vacuoles with double-layered membranes, vacuoles containing remnants of degraded organelles, marked swelling and vacuolization of mitochondria, and autolysosome-like vacuoles. We conclude that DBT-PD induces autophagy-associated cell death in CT26 cells, and may have potential as a chemotherapy or radiotherapy sensitizer in colorectal cancer treatment.	[Chen, Shun-Ting] Buddhist Tzu Chi Gen Hosp, Taipei Branch, Dept Chinese Med, New Taipei 23142, Taiwan; [Chen, Shun-Ting; Lee, Tzung-Yan] Chang Gung Univ, Grad Inst Tradit Chinese Med, Sch Chinese Med, Coll Med, Taoyuan 33302, Taiwan; [Chen, Shun-Ting] Chang Gung Univ, Grad Inst Clin Med Sci, Coll Med, Taoyuan 33302, Taiwan; [Tsai, Tung-Hu] Natl Yang Ming Univ, Inst Tradit Med, Sch Med, Taipei 11221, Taiwan; [Lin, Yin-Cheng; Lin, Chin-Ping; Shieh, Hui-Ru; Hsu, Ming-Ling; Chi, Chih-Wen; Chen, Yu-Jen] Mackay Mem Hosp, Dept Med Res, Taipei 25160, Taiwan; [Lee, Ming-Cheng] Buddhist Tzu Chi Gen Hosp, Taipei Branch, Dept Res, New Taipei 23141, Taiwan; [Chang, Hen-Hong] China Med Univ, Sch Postbaccalaureate Chinese Med, Taichung 40402, Taiwan; [Chang, Hen-Hong] China Med Univ, Res Ctr Chinese Med & Acupuncture, Taichung 40402, Taiwan; [Chang, Hen-Hong; Chen, Yu-Jen] China Med Univ Hosp, Dept Chinese Med, Taichung 40402, Taiwan; [Chen, Yu-Jen] Mackay Mem Hosp, Dept Radiat Oncol, Taipei 25160, Taiwan		Chen, YJ (corresponding author), Mackay Mem Hosp, Dept Med Res, Taipei 25160, Taiwan.; Chang, HH (corresponding author), China Med Univ, Sch Postbaccalaureate Chinese Med, Taichung 40402, Taiwan.; Chang, HH (corresponding author), China Med Univ, Res Ctr Chinese Med & Acupuncture, Taichung 40402, Taiwan.; Chang, HH; Chen, YJ (corresponding author), China Med Univ Hosp, Dept Chinese Med, Taichung 40402, Taiwan.; Chen, YJ (corresponding author), Mackay Mem Hosp, Dept Radiat Oncol, Taipei 25160, Taiwan.	cst.tp.tw@gmail.com; joejoylee@gmail.com; thtsai@ym.edu.tw; eric7772330@gmail.com; cplin66@gmail.com; ru123@ms1.mmh.org.tw; sabinehsu@gmail.com; cwchid48906003@gmail.com; sardorna@yahoo.com.tw; tcmchh55@mail.cmu.edu.tw; chenmdphd@gmail.com	Tsai, Tung-Hu/AAG-4558-2021	Tsai, Tung-Hu/0000-0002-9007-2547	Mackay Memorial Hospital [MMH-E-105-13, MMH-E-104-13]; China Medical University under the Aim of Top University Plan of Ministry of Education, Taiwan	This study was supported by Mackay Memorial Hospital (grant numbers MMH-E-105-13 and MMH-E-104-13) and China Medical University under the Aim of Top University Plan of Ministry of Education, Taiwan.	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J	Kosumi, K; Masugi, Y; Yang, JH; Qian, ZR; Kim, SA; Li, WW; Shi, Y; da Silva, A; Hamada, T; Liu, L; Gu, M; Twombly, TS; Cao, Y; Barbie, DA; Nosho, K; Baba, H; Garrett, WS; Meyerhardt, JA; Giovannucci, EL; Chan, AT; Fuchs, CS; Ogino, S; Nishihara, R				Kosumi, Keisuke; Masugi, Yohei; Yang, Juhong; Qian, Zhi Rong; Kim, Sun A.; Li, Wanwan; Shi, Yan; da Silva, Annacarolina; Hamada, Tsuyoshi; Liu, Li; Gu, Mancang; Twombly, Tyler S.; Cao, Yin; Barbie, David A.; Nosho, Katsuhiko; Baba, Hideo; Garrett, Wendy S.; Meyerhardt, Jeffery A.; Giovannucci, Edward L.; Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji; Nishihara, Reiko			Tumor SQSTM1 (p62) expression and T cells in colorectal cancer	ONCOIMMUNOLOGY			English	Article						Adenocarcinoma; colorectum; immunoprevention; immunotherapy; molecular pathology	ISLAND METHYLATOR PHENOTYPE; IMMUNE-RESPONSES; MICROSATELLITE INSTABILITY; MOLECULAR SUBTYPES; P62/SEQUESTOSOME 1; CROSS-PRESENTATION; PIK3CA MUTATION; BRAF MUTATION; ASPIRIN USE; AUTOPHAGY	Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3(+), CD8(+), CD45RO (PTPRC)(+), or FOXP3(+) cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3(+) cell density (p(trend) = 0.006), but not with CD3(+), CD8(+), or CD45RO(+) cell density (with the adjusted a level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3(+) cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45-0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36- 0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3(+) cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.	[Kosumi, Keisuke; Masugi, Yohei; Qian, Zhi Rong; Li, Wanwan; Shi, Yan; da Silva, Annacarolina; Hamada, Tsuyoshi; Liu, Li; Gu, Mancang; Twombly, Tyler S.; Barbie, David A.; Garrett, Wendy S.; Meyerhardt, Jeffery A.; Fuchs, Charles S.; Ogino, Shuji; Nishihara, Reiko] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA; [Kosumi, Keisuke; Masugi, Yohei; Qian, Zhi Rong; Li, Wanwan; Shi, Yan; da Silva, Annacarolina; Hamada, Tsuyoshi; Liu, Li; Gu, Mancang; Twombly, Tyler S.; Cao, Yin; Barbie, David A.; Garrett, Wendy S.; Meyerhardt, Jeffery A.; Giovannucci, Edward L.; Fuchs, Charles S.; Ogino, Shuji; Nishihara, Reiko] Harvard Med Sch, Boston, MA USA; [Yang, Juhong] Tianjin Med Univ, Collaborat Innovat Ctr Tianjin Med Epigenet, Key Lab Hormone & Dev, Minist Hlth,Metab Dis Hosp, Tianjin, Peoples R China; [Yang, Juhong] Tianjin Med Univ, Tianjin Inst Endocrinol, Tianjin, Peoples R China; [Kim, Sun A.] NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA; [Liu, Li; Cao, Yin; Giovannucci, Edward L.; Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA; [Cao, Yin; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA; [Cao, Yin; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA; [Nosho, Katsuhiko] Sapporo Med Univ, Sch Med, Dept Gastroenterol Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan; [Baba, Hideo] Kumamoto Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kumamoto, Japan; [Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA; [Giovannucci, Edward L.; Chan, Andrew T.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA; [Giovannucci, Edward L.; Ogino, Shuji; Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA; [Chan, Andrew T.] Broad Inst MIT & Harvard, Cambridge, MA USA; [Ogino, Shuji; Nishihara, Reiko] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 450 Brookline Ave,DFCI Room SM1036, Boston, MA 02215 USA; [Ogino, Shuji] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA; [Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA		Ogino, S; Nishihara, R (corresponding author), Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 450 Brookline Ave,DFCI Room SM1036, Boston, MA 02215 USA.	shuji_ogino@dfci.harvard.edu; rnishihara@hsph.harvard.edu	Masugi, Yohei/E-6980-2014; Masugi, Yohei/W-8215-2019; Cao, Yin/ABE-2332-2021	Masugi, Yohei/0000-0002-6952-4043; Masugi, Yohei/0000-0002-6952-4043; Cao, Yin/0000-0001-9835-7662; Garrett, Wendy/0000-0002-5092-0150; Ogino, Shuji/0000-0002-3909-2323; Shi, Yan/0000-0001-9777-8836	U.S. National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, P50 CA127003, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673]; Dana-Farber Harvard Cancer Center; Project P Fund; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81200612]; Tianjin City High School Science & Technology Fund Planning Project [20102217]; Japanese Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science; Keio Gijuku Fukuzawa Memorial Fund; Uehara Memorial FoundationUehara Memorial Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA169141, R35CA197735, R01CA118553, K07CA190673] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30DK043351] Funding Source: NIH RePORTER	This work was supported by U.S. National Institutes of Health (NIH) grants [P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S.F.; R01 CA137178 to A.T.C.; R01 CA151993 to S.O.; R35 CA197735 to S.O.; and K07 CA190673 to R.N.]; Nodal Award (to S.O.) from the Dana-Farber Harvard Cancer Center; and by grants from the Project P Fund, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. J. Y is supported by National Natural Science Foundation of China (81200612); Tianjin City High School Science & Technology Fund Planning Project (20102217). K.K. is supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japanese Society for the Promotion of Science. Y.M. is supported by a fellowship grant of the Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research. T.H. was supported by a fellowship grant from the Uehara Memorial Foundation and by a grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research.	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Yamauchi M, 2012, GUT, V61, P794, DOI 10.1136/gutjnl-2012-302014; Zhong ZY, 2016, CELL, V166, P288, DOI 10.1016/j.cell.2016.05.051	76	8	8	0	7	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	2162-402X			ONCOIMMUNOLOGY	OncoImmunology		2017	6	3							e1284720	10.1080/2162402X.2017.1284720			9	Oncology; Immunology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Immunology	EQ3QV	WOS:000397988500022	28405513	gold, Green Published			2022-04-25	
J	Du, CZ; Huang, DD; Peng, YF; Yao, YF; Zhao, Y; Yang, Y; Wang, HY; Cao, LL; Zhu, WG; Gu, J				Du, Changzheng; Huang, Dandan; Peng, Yifan; Yao, Yunfeng; Zhao, Ying; Yang, Yang; Wang, Haiying; Cao, Linlin; Zhu, Wei-Guo; Gu, Jin			5-Fluorouracil targets histone acetyltransferases p300/CBP in the treatment of colorectal cancer	CANCER LETTERS			English	Article						Colorectal cancer; 5-Fluorouracil; Histone acetyltransferases; Chemotherapy; Prognosis	CHAPERONE-MEDIATED AUTOPHAGY; TUMOR-SUPPRESSOR GENE; SURVIVAL FACTOR MEF2D; THYMIDYLATE SYNTHASE; COLON-CANCER; ACETYLATION; INHIBITOR; EXPRESSION; CELLS; PROGNOSIS	Although 5-fluorouracil (5-FU) is known to interfere with the synthesis of ribonucleic acid and deoxyribonucleic acid, the mechanism underlying its therapeutic efficacy in colorectal cancer (CRC) has not been fully elucidated. We aimed to investigate the influence of 5-FU on histone acetylation, a well-established anti-cancer target, to reveal novel pharmacological effects of 5-FU and their significance for CRC therapy. Results demonstrated that 5-FU induces global histone de-acetylation in multiple CRC cell lines. We identified that 5-FU reduces the binding ability of histone acetyltransferases p300 and CBP to chromatin, and induces their degradation through lysosome. Further work revealed that the degradation of p300/CBP induced by 5-FU was dependent on chaperone-mediated autophagy, mediated by heat-shock cognate protein 70 kDa (hsc70) and lysosomal-associated membrane protein 2A (LAMP2A). Moreover, the degradation of p300/CBP is relevant to cellular resistance to 5-FU, since blocking the degradation enhances 5-FU's cytotoxicity in CRC cells. From clinical data, we demonstrated that low expression of p300/CBP in CRC tissue was closely associated with poor clinical response to 5-FU based-chemotherapy, based on the analysis of 262 colorectal samples from the patients receiving 5-FU treatment: compared to cases with high expression of p300/CBP, those with low expression had lower long-term disease-free survival rate and increased early-progression. These results elucidate a novel pharmacological effect of 5-FU involving global histone de-acetylation by promoting the degradation of p300/CBP, and highlights p300 and CBP as promising predictors of chemo-sensitivity to 5-FU treatment. (C) 2017 Elsevier B.V. All rights reserved.	[Du, Changzheng; Huang, Dandan; Peng, Yifan; Yao, Yunfeng; Gu, Jin] Peking Univ, Canc Hosp, Gastrointestinal Canc Ctr, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing, Peoples R China; [Zhao, Ying; Yang, Yang; Wang, Haiying; Cao, Linlin; Zhu, Wei-Guo] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing, Peoples R China; [Zhu, Wei-Guo] Shenzhen Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, 3688 Nanhai Rd, Shenzhen 518060, Guangdong, Peoples R China; [Gu, Jin] Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China; [Gu, Jin] Peking Univ, Shougang Hosp, Beijing, Peoples R China		Zhu, WG (corresponding author), Shenzhen Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, 3688 Nanhai Rd, Shenzhen 518060, Guangdong, Peoples R China.; Gu, J (corresponding author), Peking Univ, Canc Hosp, Gastrointestinal Canc Ctr, 52 Fu Cheng Rd, Beijing 100142, Peoples R China.	zhuweiguo@szu.edu.cn; zIgujin@126.com	Du, Chang-Zheng/I-9784-2019	Du, Chang-Zheng/0000-0001-9016-4401; Zhu, Wei-Guo/0000-0001-8385-6581; Wang, Haiying/0000-0001-7729-0649; Yang, Yang/0000-0002-8737-590X	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [NSFC91319302]; Beijing Municipal Administration of Hospitals' Youth Program [QML20161105]; Discipline Construction Funding of Shenzhen; Shenzhen Municipal Commission of Science and Technology Innovation [JCYJ20160427104855100]	This work was supported by National Natural Science Foundation of China grants NSFC91319302; Beijing Municipal Administration of Hospitals' Youth Program QML20161105; Discipline Construction Funding of Shenzhen (2016) and Shenzhen Municipal Commission of Science and Technology Innovation grants JCYJ20160427104855100.	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AUG 1	2017	400						183	193		10.1016/j.canlet.2017.04.033			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EY0NO	WOS:000403655200019	28465257				2022-04-25	
J	Nozaki, R; Kono, T; Bochimoto, H; Watanabe, T; Oketani, K; Sakamaki, Y; Okubo, N; Nakagawa, K; Takeda, H				Nozaki, Reo; Kono, Toru; Bochimoto, Hiroki; Watanabe, Tsuyoshi; Oketani, Kaori; Sakamaki, Yuichi; Okubo, Naoto; Nakagawa, Koji; Takeda, Hiroshi			Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells	ONCOTARGET			English	Article						autophagy; autophagic cell death; vacuolization; colon cancer; zanthoxylum fruit	JNK; PIPERITUM; INVOLVEMENT; SUPPRESSES; GROWTH; COLON	Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) have multiple physiological activities (e.g., antiviral activity). However, the potential anticancer activity of ZFE has not been fully examined. In this study, we investigated the ability of ZFE to induce autophagic cell death (ACD). ZFE caused remarkable autophagy-like cytoplasmic vacuolization, inhibited cell proliferation, and ultimately induced cell death in the human cancer cell lines DLD-1, HepG2, and Caco-2, but not in A549, MCF7, or WiDr cells. ZFE increased the level of LC3-II protein, a marker of autophagy. Knockdown of ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, in cancer cells that could be induced to undergo cell death by ZFE, the extract increased the phosphorylation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 attenuated both vacuolization and cell death. Based on morphology and expression of marker proteins, ZFE-induced cell death was neither apoptosis nor necrosis. Normal intestinal cells were not affected by ZFE. Taken together, our findings show that ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.	[Nozaki, Reo; Kono, Toru; Oketani, Kaori; Sakamaki, Yuichi; Okubo, Naoto; Nakagawa, Koji; Takeda, Hiroshi] Hokkaido Univ, Fac Pharmaceut Sci, Pathophysiol & Therapeut, Sapporo, Hokkaido, Japan; [Kono, Toru] Sapporo Higashi Tokushukai Hosp, Ctr Clin & Biomed Res, Sapporo, Hokkaido, Japan; [Bochimoto, Hiroki; Watanabe, Tsuyoshi] Asahikawa Med Univ, Dept Microscop Anat & Cell Biol, Asahikawa, Hokkaido, Japan		Kono, T (corresponding author), Hokkaido Univ, Fac Pharmaceut Sci, Pathophysiol & Therapeut, Sapporo, Hokkaido, Japan.; Kono, T (corresponding author), Sapporo Higashi Tokushukai Hosp, Ctr Clin & Biomed Res, Sapporo, Hokkaido, Japan.	kono@toru-kono.com		Bochimoto, Hiroki/0000-0002-1708-0348	Grants-in-Aid for Scientific ResearchMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) [15K18951] Funding Source: KAKEN		Aoki H, 2007, MOL PHARMACOL, V72, P29, DOI 10.1124/mol.106.033167; Chen N, 2011, CANCER BIOL THER, V11, P157, DOI 10.4161/cbt.11.2.14622; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; Dhanasekaran DN, 2008, ONCOGENE, V27, P6245, DOI 10.1038/onc.2008.301; Fulda S, 2015, ONCOGENE, V34, P5105, DOI 10.1038/onc.2014.458; Galluzzi L, 2012, CELL DEATH DIFFER, V19, P107, DOI 10.1038/cdd.2011.96; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Gwon SY, 2012, J NUTR SCI VITAMINOL, V58, P393, DOI 10.3177/jnsv.58.393; Ha SY, 2014, J MICROBIOL, V52, P340, DOI 10.1007/s12275-014-4073-5; Harvey AL, 2015, NAT REV DRUG DISCOV, V14, P111, DOI 10.1038/nrd4510; Hirokawa Y, 2006, CANCER BIOL THER, V5, P305, DOI 10.4161/cbt.5.3.2404; Jeong CH, 2004, BIOSCI BIOTECH BIOCH, V68, P1984, DOI 10.1271/bbb.68.1984; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kimura T, 2013, CANCER RES, V73, P3, DOI 10.1158/0008-5472.CAN-12-2464; Kono T, 2015, FRONT PHARMACOL, V6, DOI 10.3389/fphar.2015.00159; Kono T, 2011, J GASTROENTEROL, V46, P1187, DOI 10.1007/s00535-011-0438-2; Kono T, 2009, SURGERY, V146, P837, DOI 10.1016/j.surg.2009.06.012; Kubota K, 2015, AM J PHYSIOL-GASTR L, V308, pG579, DOI 10.1152/ajpgi.00114.2014; Lee J, 2011, J PHARM PHARMACOL, V63, P840, DOI 10.1111/j.2042-7158.2011.01277.x; Li X, 2010, J ETHNOPHARMACOL, V129, P197, DOI 10.1016/j.jep.2010.03.003; Liu Y, 2015, CELL DEATH DIFFER, V22, P367, DOI 10.1038/cdd.2014.143; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; Mizushima N, 2004, INT J BIOCHEM CELL B, V36, P2491, DOI 10.1016/j.biocel.2004.02.005; Ohsumi Y, 2001, NAT REV MOL CELL BIO, V2, P211, DOI 10.1038/35056522; Opipari AW, 2004, CANCER RES, V64, P696, DOI 10.1158/0008-5472.CAN-03-2404; Pan HM, 2016, ONCOTARGET, V7, P21235, DOI 10.18632/oncotarget.6908; Park YD, 2007, BIOL PHARM BULL, V30, P205, DOI 10.1248/bpb.30.205; Puissant A, 2010, CANCER RES, V70, P1042, DOI 10.1158/0008-5472.CAN-09-3537; Shen HM, 2011, AUTOPHAGY, V7, P457, DOI 10.4161/auto.7.5.14226; Shimizu S, 2010, ONCOGENE, V29, P2070, DOI 10.1038/onc.2009.487; Surh YJ, 2003, NAT REV CANCER, V3, P768, DOI 10.1038/nrc1189; Vegliante R, 2016, CARCINOGENESIS, V37, P233, DOI 10.1093/carcin/bgw003; Wei YJ, 2008, MOL CELL, V30, P678, DOI 10.1016/j.molcel.2008.06.001; White E, 2015, J CLIN INVEST, V125, P42, DOI 10.1172/JCI73941; Yang ZNJ, 2011, CANCER BIOL THER, V11, P169, DOI 10.4161/cbt.11.2.14663; Yu L, 2006, P NATL ACAD SCI USA, V103, P4952, DOI 10.1073/pnas.0511288103; Zhang C, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0147405; Zhou Y.Y., 2015, BIOSCIENCE REP, P35	38	7	7	2	10	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	OCT 25	2016	7	43					70437	70446		10.18632/oncotarget.11926			10	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	EB5VI	WOS:000387448300102	27626481	gold, Green Submitted, Green Published			2022-04-25	
J	Lee, YJ; Cho, JM; Sai, S; Oh, JY; Park, JA; Oh, SJ; Park, M; Kwon, J; Shin, US; Baek, JH; Lim, SH; Song, JY; Hwang, SG; Kim, EH				Lee, Yeon-Joo; Cho, Jae-Min; Sai, Sei; Oh, Ju Yeon; Park, Ji-Ae; Oh, Se Jong; Park, Misun; Kwon, Junhye; Shin, Ui Sup; Baek, Jeong-Hwa; Lim, Sun Ha; Song, Jie-Young; Hwang, Sang-Gu; Kim, Eun Ho			5-Fluorouracil as a Tumor-Treating Field-Sensitizer in Colon Cancer Therapy	CANCERS			English	Article						tumor-treating fields; colon cancer; 5-fluorouracil	CELLS IN-VITRO; ADJUVANT THERAPY; CHEMOTHERAPY; GLIOBLASTOMA; COMBINATION; MECHANISMS; TTFIELDS; TRIAL; LINES	Colorectal cancer (CRC) is a major cause of mortality that can be treated effectively with chemotherapy and radiotherapy, although resistance to these therapeutic modalities often occurs. Tumor-treating fields (TTFields) can block tumor growth by selectively impairing tumor cell division. In this study, we investigated the mechanism by which 5-fluorouracil (5-FU) sensitizes tumor cells to TTFields. Human HCT116 and SW480 CRC cells were treated with 5-FU and/or TTFields, and characterized in vitro in terms of cell viability, apoptosis through reactive oxygen species production, autophagy, and metastatic potentials. The biological effects of 5-FU and/or TTFields were studied via positron emission tomography and computed tomography on xenograft tumor growth and were confirmed with organoid models of patients. Our results revealed that combination treatment with 5-FU and TTFields increased the efficiency of TTFields therapy in colon cancer cells by downregulating signaling pathways associated with cell proliferation, survival, cell invasion, and migration while upregulating pathways mediating apoptosis and autophagic cell death. The novel mechanistic insights gleaned in this study suggest that combination therapy with TTFields and 5-FU may be effective in treating CRC, although safety and efficacy testing in patients with CRC will need to be performed before this strategy can be implemented clinically for TTF-sensitization.	[Lee, Yeon-Joo; Cho, Jae-Min; Song, Jie-Young; Hwang, Sang-Gu] Korea Inst Radiol & Med Sci, Div Radiat Biomed Res, Seoul 01812, South Korea; [Sai, Sei] Natl Inst Radiol Sci, Dept Basic Med Sci Radiat Damages, Chiba 2638555, Japan; [Oh, Ju Yeon] Korea Univ, Sch Life Sci & Biotechnol, Lab Biochem, Anam Ro 145, Seoul 136701, South Korea; [Park, Ji-Ae; Oh, Se Jong] Korea Inst Radiol & Med Sci, Div Appl RI, Seoul 01812, South Korea; [Park, Misun; Kwon, Junhye] Korea Inst Radiol & Med Sci, Korea Canc Ctr Hosp, Dept Radiol & Clin Res, Seoul 01812, South Korea; [Shin, Ui Sup] Korea Inst Radiol & Med Sci, Dept Surg, Seoul 01812, South Korea; [Baek, Jeong-Hwa] Dongnam Inst Radiol & Med Sci, Res Ctr, Radiat Biol Res Team, Busan 46033, South Korea; [Lim, Sun Ha; Kim, Eun Ho] Daegu Catholic Univ, Sch Med, Dept Biochem, 33,17 Gil, Daegu 42472, South Korea		Hwang, SG (corresponding author), Korea Inst Radiol & Med Sci, Div Radiat Biomed Res, Seoul 01812, South Korea.; Kim, EH (corresponding author), Daegu Catholic Univ, Sch Med, Dept Biochem, 33,17 Gil, Daegu 42472, South Korea.	eyeonjoo@kirams.re.kr; chojaemin09@yuhs.ac; sai.sei@qst.go.jp; songoh10@korea.ac.kr; jpark@kirams.re.kr; osj5353@kirams.re.kr; usre@kirams.re.kr; jhkwon@kirams.re.kr; uisupshin@kirams.re.kr; jihan918@dirams.re.kr; sunhalimha@gmail.com; immu@kirams.re.kr; sgh63@kcch.re.kr; eh140149@cu.ac.kr		Lee, Yeon-Joo/0000-0002-6605-8761; Park, Ji Ae/0000-0001-6109-802X; baeg, jeonghwa/0000-0001-5364-0026; Song, Jie-Young/0000-0002-5769-3886; Oh, Se Jong/0000-0002-9688-1425	National Research Foundation of Korea (NRF)National Research Foundation of Korea [2017K2A9A2A08000212]; KIRAMS - Ministry of Science, ICT (MSIP) Republic of Korea [50531-2019, 50538-2019]; Creative Allied Project of the National Research Council of Science and Technology [CAP-15-06-ETRI]	This work was supported by a National Research Foundation of Korea (NRF) grant (2017K2A9A2A08000212) and a grant from the KIRAMS, which was funded by the Ministry of Science, ICT (MSIP) Republic of Korea (50531-2019, 50538-2019) and the Creative Allied Project (CAP-15-06-ETRI) of the National Research Council of Science and Technology.	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J	Tsukahara, T; Matsuda, Y; Haniu, H				Tsukahara, Tamotsu; Matsuda, Yoshikazu; Haniu, Hisao			PSF Knockdown Enhances Apoptosis via Downregulation of LC3B in Human Colon Cancer Cells	BIOMED RESEARCH INTERNATIONAL			English	Article							AUTOPHAGY; PROTEIN; RNA; MUTATIONS; BINDING; GENES	Our previous study demonstrated that PTB-associated splicing factor (PSF) is an important regulator of cell death and plays critical roles in the survival and growth of colon cancer cells. However, the molecular mechanism that activates these downstream signaling events remains unknown. To address this issue, we investigated the effects of PSF knockdown in two different colon cancer cell lines, DLD-1 and HT-29. We found that knockdown of PSF markedly decreased the autophagic molecule LC3B in DLD-1 cells but not in HT-29 cells. Furthermore, DLD-1 cells were more susceptible to PSF knockdown-induced cell growth inhibition and apoptosis than HT-29 cells. This susceptibility is probably a result of LC3B inhibition, given the known relationship between autophagy and apoptosis. C3B is associated with a number of physiological processes, including cell growth and apoptotic cell death. Our results suggest that autophagy is inhibited by PSF knockdown and that apoptosis and cell growth inhibition may act together to mediate the PSF-LC3B signaling pathway. Furthermore, we found that the peroxisome proliferator-activated receptor gamma (PPAR gamma)-PSF complex induced LC3B downregulation in DLD-1 cells. The results of this study identify a new physiological role for the PSF-LC3B axis as a potential endogenous modulator of colon cancer treatment.	[Tsukahara, Tamotsu] Kanazawa Med Univ, Dept Hematol & Immunol, Uchinada, Ishikawa 9200293, Japan; [Matsuda, Yoshikazu] Nihon Pharmaceut Univ, Clin Pharmacol Educ Ctr, Ina, Saitama 3620806, Japan; [Haniu, Hisao] Shinshu Univ, Dept Orthopaed Surg, Sch Med, Matsumoto, Nagano 3908621, Japan		Haniu, H (corresponding author), Shinshu Univ, Dept Orthopaed Surg, Sch Med, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan.	wadia781@yahoo.co.jp	Tsukahara, Tamotsu/ABB-3631-2021	Tsukahara, Tamotsu/0000-0001-6469-920X	Astellas Foundation for Research on Metabolic Disorders	This work was supported by research grants from the Astellas Foundation for Research on Metabolic Disorders (to Tamotsu Tsukahara) and a Grant-in-Aid for Takeda Science Foundation (to Tamotsu Tsukahara).	Altman BJ, 2012, CSH PERSPECT BIOL, V4, DOI 10.1101/cshperspect.a008763; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; DE DUVE CHRISTIAN, 1963, SCI AMER, V208, P64; Eskelinen EL, 2009, BBA-MOL CELL RES, V1793, P664, DOI 10.1016/j.bbamcr.2008.07.014; Ghavami S, 2009, J MED GENET, V46, P497, DOI 10.1136/jmg.2009.066944; Ghobrial IM, 2005, CA-CANCER J CLIN, V55, P178, DOI 10.3322/canjclin.55.3.178; Gupta RA, 2001, J BIOL CHEM, V276, P29681, DOI 10.1074/jbc.M103779200; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kimmelman AC, 2011, GENE DEV, V25, P1999, DOI 10.1101/gad.17558811; Kondo Y, 2006, AUTOPHAGY, V2, P85, DOI 10.4161/auto.2.2.2463; Lengauer C, 1998, NATURE, V396, P643, DOI 10.1038/25292; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Li BX, 2009, AUTOPHAGY, V5, P303, DOI 10.4161/auto.5.3.7491; Loeb LA, 2003, P NATL ACAD SCI USA, V100, P776, DOI 10.1073/pnas.0334858100; MANN SS, 1994, J BIOL CHEM, V269, P11492; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Munafo DB, 2001, J CELL SCI, V114, P3619; O'Malley BW, 2009, CANCER RES, V69, P8217, DOI 10.1158/0008-5472.CAN-09-2223; PATTON JG, 1993, GENE DEV, V7, P393, DOI 10.1101/gad.7.3.393; Reggiori F, 2002, EUKARYOT CELL, V1, P11, DOI 10.1128/EC.01.1.11-21.2002; Song X, 2005, P NATL ACAD SCI USA, V102, P12189, DOI 10.1073/pnas.0505179102; Song X, 2004, P NATL ACAD SCI USA, V101, P621, DOI 10.1073/pnas.0307794100; Tanida I, 2004, J BIOL CHEM, V279, P47704, DOI 10.1074/jbc.M407016200; Tsukahara T, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0058749; Wang G, 2009, P NATL ACAD SCI USA, V106, P16794, DOI 10.1073/pnas.0909022106; Wu JR, 2006, EMERGING THERAPEUTIC ULTRASOUND, P1, DOI 10.1142/9789812774125_0001	27	9	10	0	0	HINDAWI LTD	LONDON	ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND	2314-6133	2314-6141		BIOMED RES INT	Biomed Res. Int.		2013	2013								204973	10.1155/2013/204973			8	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	249PB	WOS:000326788000001	24288667	Green Submitted, Green Published, gold			2022-04-25	
J	Kim, Y; Kim, YS; Kim, DE; Lee, JS; Song, JH; Kim, HG; Cho, DH; Jeong, SY; Jin, DH; Jang, SJ; Seol, HS; Suh, YA; Lee, SJ; Kim, CS; Koh, JY; Hwang, JJ				Kim, Yunha; Kim, Yong-Sook; Kim, Dong Eun; Lee, Jee Suk; Song, Ji Hoon; Kim, Ha-Gyeong; Cho, Dong-Hyung; Jeong, Seong-Yun; Jin, Dong-Hoon; Jang, Se Jin; Seol, Hyang-Sook; Suh, Young-Ah; Lee, Seung Jin; Kim, Choung-Soo; Koh, Jae-Young; Hwang, Jung Jin			BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production	AUTOPHAGY			English	Article						autophagy; BIX-01294; EHMT2; G9a; histone methyltransferase; ROS	HISTONE LYSINE METHYLATION; GLIOMA-CELLS; CANCER; METHYLTRANSFERASE; G9A; CHLOROQUINE; CHAETOCIN; TUMORIGENESIS; DISRUPTION; INHIBITION	We screened a chemical library in MCF-7 cells stably expressing green fluorescent protein (GFP)-conjugated microtubule-associated protein 1 light chain 3 (LC3) (GFP-LC3-MCF-7) using cell-based assay, and identified BIX-01294 (BIX), a selective inhibitor of euchromatic histone-lysine N-methyltransferase 2 (EHMT2), as a strong autophagy inducer. BIX enhanced formation of GFP-LC3 puncta, LC3-II, and free GFP, signifying autophagic activation. Inhibition of these phenomena with chloroquine and increasement in punctate dKeima ratio (550/438) signal indicated that BIX activated autophagic flux. BIX-induced cell death was suppressed by the autophagy inhibitor, 3-methyladenine, or siRNA against BECN1 (VPS30/ATG6), ATG5, and ATG7, but not by caspase inhibitors. Moreover, EHMT2 siRNA augmented GFP-LC3 puncta, LC3-II, free GFP, and cell death, implying that inhibition of EHMT2 caused autophagy-mediated cell death. Treatment with EHMT2 siRNA and BIX accumulated intracellular reactive oxygen species (ROS). BIX augmented mitochondrial superoxide via NADPH oxidase activation. In addition, BIX increased hydrogen peroxide and glutathione redox potential in both cytosol and mitochondria. Treatment with N-acetyl-L-cysteine (NAC) or diphenyleneiodonium chloride (DPI) decreased BIX-induced LC3-II, GFP-LC3 puncta, and cell death, indicating that ROS instigated autophagy-dependent cell death triggered by BIX. We observed that BIX potentiated autophagy-dependent and caspase-independent cell death in estrogen receptor (ESR)-negative SKBr3 and ESR-positive MCF-7 breast cancer cells, HCT116 colon cancer cells, and importantly, in primary human breast and colon cancer cells. Together, the results suggest that BIX induces autophagy-dependent cell death via EHMT2 dysfunction and intracellular ROS accumulation in breast and colon cancer cells, therefore EHMT2 inhibition can be an effective therapeutic strategy for cancer treatment.	[Kim, Yunha; Kim, Yong-Sook; Kim, Dong Eun; Lee, Jee Suk; Song, Ji Hoon; Kim, Ha-Gyeong; Jeong, Seong-Yun; Jin, Dong-Hoon; Suh, Young-Ah; Lee, Seung Jin; Kim, Choung-Soo; Hwang, Jung Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Inst Innovat Canc Res, Seoul, South Korea; [Cho, Dong-Hyung] Kyung Hee Univ, Grad Sch East West Med Sci, Gyeonggi Do, South Korea; [Jang, Se Jin; Seol, Hyang-Sook] Asan Med Ctr, Dept Pathol, Seoul, South Korea; [Kim, Choung-Soo] Asan Med Ctr, Dept Urol, Seoul, South Korea; [Koh, Jae-Young] Univ Ulsan, Coll Med, Asan Med Ctr, Neural Injury Res Lab,Dept Neurol, Seoul, South Korea; [Hwang, Jung Jin] Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea		Hwang, JJ (corresponding author), Univ Ulsan, Coll Med, Asan Med Ctr, Inst Innovat Canc Res, Seoul, South Korea.	jjhwang@amc.seoul.kr	KIM, Yunha/J-4698-2019; Hwang, Jung Jin/F-3424-2014; Koh, Jae-Young/C-9014-2011	Koh, Jae-Young/0000-0002-4318-495X; Lee, Seung Jin/0000-0003-0625-7774	Korea Health Technology R&D Project, Ministry of Health Welfare [A062254, A092042]; Basic Science Research Program through the National Research Foundation of Korea (NRF); Ministry of Education, Science and TechnologyMinistry of Education, Science and Technology, Republic of Korea [2012R1A1A2007337]; Asan Institute for Life Sciences, Republic of Korea [2011-450]	This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare (A062254 and A092042), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2007337), and the Asan Institute for Life Sciences (2011-450), Republic of Korea.	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J	Cao, HH; Zhang, W; Liang, JL				Cao, Honghua; Zhang, Wei; Liang, Junlin			Inhibition of IL17A promotes bufalin-induced apoptosis in colon cancer cells via miR-96/DDIT3	INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY			English	Article						Bufalin; IL17A; DDIT3; colon cancer; miR-96	INFLAMMATORY-BOWEL-DISEASE; COLORECTAL-CANCER; NUCLEAR-PROTEIN; PROLIFERATION; CHOP; RECK; CHOP/GADD153; EXPRESSION; AUTOPHAGY; ROLES	Bufalin is used clinically to treat patients with many solid malignant tumors. However, the mechanisms remain to be further elucidated. Our study focused on IL17A involved in bufacin inducing apoptosis of colon cancer cells. The data showed that bufalin could induce colon cancer cell apoptosis via inhibiting IL17A. Ectopic expression of IL17A promoted the proliferation and induced anti-apoptosis of colon cancer cells by MTT and flow cytometry analysis. Further study verified bufalin inhibiting IL17A induced apoptosis was through miR-96-DDIT3, our study demonstrated that bufalin may inhibit the proliferation and promote the apoptosis of colon cancer cells. Bufalin-associated IL-17A inhibition may indirectly be involved in cell proliferation and apoptosis by miR-96 targeting DDIT3, pointing to use as a potential molecular target of bufacin in colon cancer therapy.	[Cao, Honghua; Zhang, Wei] Guigang City Peoples Hosp, Dept Gastrointestinal Surg, Guigang, Guangxi, Peoples R China; [Liang, Junlin] Guangxi Med Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, 6 Shuangyong Rd, Nanning 53000, Guangxi, Peoples R China		Liang, JL (corresponding author), Guangxi Med Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, 6 Shuangyong Rd, Nanning 53000, Guangxi, Peoples R China.	ljunlin15@sina.com					Chiba T, 2012, GASTROENTEROLOGY, V143, P550, DOI 10.1053/j.gastro.2012.07.009; Chin CC, 2015, J CELL PHYSIOL, V230, P1430, DOI 10.1002/jcp.24796; Chung AS, 2013, NAT MED, V19, P1114, DOI 10.1038/nm.3291; Fendler A, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0080807; Feng J, 2014, ONCOTARGET, V5, P5832, DOI 10.18632/oncotarget.2200; Gao F, 2015, MOL MED REP, V11, P1200, DOI 10.3892/mmr.2014.2854; Giovannucci E, 2002, GASTROENTEROL CLIN N, V31, P925, DOI 10.1016/S0889-8553(02)00057-2; Guo HZ, 2014, MOL CELL BIOCHEM, V390, P155, DOI 10.1007/s11010-014-1966-x; Haflidadottir BS, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0072400; Hu Q, 2014, INT J NANOMED, V9, P4035, DOI 10.2147/IJN.S64708; Huang X, 2014, INT J MOL MED, V34, P1599, DOI 10.3892/ijmm.2014.1940; Itzkowitz SH, 2004, AM J PHYSIOL-GASTR L, V287, pG7, DOI 10.1152/ajpgi.00079.2004; Li LQ, 2013, CLIN IMMUNOL, V148, P246, DOI 10.1016/j.clim.2013.05.003; Lin HX, 2010, PLOS ONE, V5, DOI 10.1371/journal.pone.0015797; Ma Y, 2014, ONCOTARGET, V5, P9169, DOI 10.18632/oncotarget.2396; Matsumoto M, 1996, FEBS LETT, V395, P143, DOI 10.1016/0014-5793(96)01016-2; Maytin EV, 2001, EXP CELL RES, V267, P193, DOI 10.1006/excr.2001.5248; Omrane I, 2014, TUMOR BIOL, V35, P6627, DOI 10.1007/s13277-014-1890-4; Oyadomari S, 2004, CELL DEATH DIFFER, V11, P381, DOI 10.1038/sj.cdd.4401373; RON D, 1992, GENE DEV, V6, P439, DOI 10.1101/gad.6.3.439; Siegel RL, 2015, CA-CANCER J CLIN, V65, P5, DOI [10.3322/caac.21254, 10.3322/caac.21208, 10.1001/jamaoto.2014.2530, 10.1136/bmj.g1502]; Ubeda M, 1996, MOL CELL BIOL, V16, P1479; Wang KP, 2014, IMMUNITY, V41, P1052, DOI 10.1016/j.immuni.2014.11.009; Wang YM, 2012, CANCER RES, V72, P4037, DOI 10.1158/0008-5472.CAN-12-0103; Xia HF, 2014, BIOMED PHARMACOTHER, V68, P951, DOI 10.1016/j.biopha.2014.10.023; Xie CM, 2011, FREE RADICAL BIO MED, V51, P1365, DOI 10.1016/j.freeradbiomed.2011.06.016; Xu XM, 2012, ONCOL LETT, V4, P339, DOI 10.3892/ol.2012.714; Yan ZY, 2014, FEBS LETT, V588, P3038, DOI 10.1016/j.febslet.2014.06.017; Yu JJ, 2014, MED ONCOL, V31, DOI 10.1007/s12032-014-0910-y; Zhang JF, 2014, ONCOL REP, V31, P1357, DOI 10.3892/or.2013.2934; Zhu ZT, 2012, WORLD J SURG ONCOL, V10, DOI 10.1186/1477-7819-10-228	31	2	2	0	3	E-CENTURY PUBLISHING CORP	MADISON	40 WHITE OAKS LN, MADISON, WI 53711 USA	1936-2625			INT J CLIN EXP PATHO	Int. J. Clin. Exp. Pathol.		2016	9	4					4360	4367					8	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	DO2HZ	WOS:000377601900007					2022-04-25	
J	Fu, CH; Tian, G; Duan, JY; Liu, K; Zhang, C; Yan, WQ; Wang, Y				Fu, Changhao; Tian, Geer; Duan, Jinyue; Liu, Kun; Zhang, Chen; Yan, Weiqun; Wang, Yi			Therapeutic Antitumor Efficacy of Cancer Stem Cell-Derived DRibble Vaccine on Colorectal Carcinoma	INTERNATIONAL JOURNAL OF MEDICAL SCIENCES			English	Article						DRips-Containing Blebs (DRibbles); Dendritic Cells; Cancer Stem Cells; Autophagosome; Colorectal Cancer	DENDRITIC CELLS; CROSS-PRESENTATION; IMMUNE-RESPONSES; TUMOR LYSATE; IN-VITRO; AUTOPHAGOSOME VACCINE; ANTIGEN; MECHANISM; PEPTIDE; CD86	Dendritic cell (DC)-based immunotherapy has been a promising strategy for colon cancer therapy, but the efficacy of dendritic cell vaccines is in part limited by immunogenicity of loaded antigens. In this study, we aimed to identify a putative tumor antigen that can generate or enhance anti-tumor immune responses against colon cancer. CD44+ colon cancer stem cells (CCSCs) were isolated from mouse colorectal carcinoma CT-26 cell cultures and induced to form defective ribosomal products-containing autophagosome-rich blebs (DRibbles) by treatment with rapamycin, bortezomib, and ammonium chloride. DRibbles were characterized by western blot and transmission electron microscopy. DCs generated from the mice bone marrow monocytes were cocultured with DRibbles, then surface markers of DCs were analyzed by flow cytometry. Meanwhile, the efficacy of DRibble-DCs was examined in vivo. Our results showed that CCSC-derived DRibbles upregulated CD80, CD86, major histocompatibility complex (MHC)-I, and MHC-II on DCs and induced proliferation of mouse splenic lymphocytes and CD8+ T cells. In a model of colorectal carcinoma using BALB/c mice with robust tumor growth and mortality, DC vaccine pulsed with CCSC-derived DRibbles suppressed tumor growth and extended survival. A lactate dehydrogenase test indicated a strong cytolytic activity of cytotoxic T-cells derived from mice vaccinated with CCSC-derived DRibbles against CT-26 cells. Furthermore, flow cytometry analyses showed that the percentages of IFN-gamma-producing CD8+ T-cells were increased in SD-DC group compare with the other groups. These findings provide a rationale for novel immunotherapeutic anti-tumor approaches based on DRibbles derived from colon cancer stem cells.	[Fu, Changhao; Tian, Geer; Duan, Jinyue; Liu, Kun; Wang, Yi] Jilin Univ, Sch Pharmaceut Sci, Dept Regenerat Med, Changchun 130021, Jilin, Peoples R China; [Fu, Changhao] Stanford Univ Med Sch, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA; [Zhang, Chen] Minjiang Univ, Inst Oceanog, Fuzhou 350108, Fujian, Peoples R China; [Yan, Weiqun] Jilin Univ, Med Inst Regenerat Sci, Changchun 130021, Jilin, Peoples R China		Wang, Y (corresponding author), Jilin Univ, Sch Pharmaceut Sci, Dept Regenerat Med, Changchun 130021, Jilin, Peoples R China.	wangyi@jlu.edu.cn			Jilin Province Science and Technology Support Program [20200404121YY]; Education Department of Jilin Province [JJKH20201122KJ]; Jilin Province Health Technology Innovation Project [2017J062]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801849]	Funding source This work was supported by Jilin Province Science and Technology Support Program [Grant number 20200404121YY] ; Education Department of Jilin Province [Grant number JJKH20201122KJ] ; Jilin Province Health Technology Innovation Project [Grant number 2017J062] ; and National Natural Science Foundation of China [Grant number 81801849] .	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J. Med. Sci.		2021	18	14					3249	3260		10.7150/ijms.61510			12	Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	General & Internal Medicine	TX7YM	WOS:000683304200020	34400894	Green Published, gold			2022-04-25	
J	Zhao, YL; Hu, XQ; Zuo, XY; Wang, MF				Zhao, Yueliang; Hu, Xiaoqian; Zuo, Xinyuan; Wang, Mingfu			Chemopreventive effects of some popular phytochemicals on human colon cancer: a review	FOOD & FUNCTION			English	Review							CELL-CYCLE ARREST; NF-KAPPA-B; GRAPE SEED PROANTHOCYANIDINS; COLORECTAL-CARCINOMA CELLS; SWEET-POTATO PROTEIN; IN-VITRO; (-)-EPIGALLOCATECHIN GALLATE; INHIBITS PROLIFERATION; DIETARY POLYPHENOLS; MOLECULAR TARGETS	Colon cancer is one of the major causes of morbidity and mortality worldwide. Dietary phytochemicals have been drawing increasing attention for colon cancer prevention and treatment due to their chemical diversity, biological activity, easy availability, lack of toxic effects, and ability to modulate various signal transduction pathways and cell processes. The chemoprotective effects elicited by phytochemicals include antioxidative and anti-inflammatory activities, induction of phase II enzymes, cell cycle arrest, apoptosis, autophagy, and changes in gut microbiota. The present review summarizes the main chemopreventive properties of selected phytochemicals (carotenoids, flavonoids, flavonolignan, proanthocyanidin, isothiocyanates, terpenoids, peptides, and medicinal plant extracts) against colon cancer. It is found that these phytochemicals exhibit their anti-colon cancer activity through the modulation of various signaling pathways involved in the regulation of chronic inflammation, cell cycle, autophagy, apoptosis, metastasis, and angiogenesis. These phytochemicals could be helpful starting points in the design and development of novel colon cancer chemopreventive agents.	[Zhao, Yueliang; Hu, Xiaoqian; Wang, Mingfu] Shanghai Ocean Univ, Coll Food Sci & Technol, Shanghai 201306, Peoples R China; [Zhao, Yueliang; Hu, Xiaoqian; Wang, Mingfu] Minist Agr, Lab Qual & Safety Risk Assessment Aquat Prod Stor, Shanghai 201306, Peoples R China; [Zuo, Xinyuan] Dalian Univ Technol, Sch Petr & Chem Engn, 2 Dagong Rd, Panjin City, Liaoning, Peoples R China; [Wang, Mingfu] Univ Hong Kong, Sch Biol Sci, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China		Wang, MF (corresponding author), Shanghai Ocean Univ, Coll Food Sci & Technol, Shanghai 201306, Peoples R China.; Wang, MF (corresponding author), Minist Agr, Lab Qual & Safety Risk Assessment Aquat Prod Stor, Shanghai 201306, Peoples R China.; Wang, MF (corresponding author), Univ Hong Kong, Sch Biol Sci, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China.	mfwang@hku.hk	Wang, Mingfu/AAT-3292-2021; Wang, Mingfu/D-3136-2009	Wang, Mingfu/0000-0003-1469-3963	National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31671821]	This research work is partially supported by the general research project of the National Science Foundation of China (grant no. 31671821).	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SEP 1	2018	9	9					4548	4568		10.1039/c8fo00850g			21	Biochemistry & Molecular Biology; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Food Science & Technology	GU3YO	WOS:000445216900002	30118121				2022-04-25	
J	Koneri, K; Goi, T; Hirono, Y; Katayama, K; Yamaguchi, A				Koneri, Kenji; Goi, Takanori; Hirono, Yasuo; Katayama, Kanji; Yamaguchi, Akio			Beclin 1 gene inhibits tumor growth in colon cancer cell lines	ANTICANCER RESEARCH			English	Article						colon cancer; Beclin 1 gene; cell cycle	MAMMALIAN-CELLS; AUTOPHAGY GENE; PROTEIN; CYCLE; SUPPRESSOR; COMPLEX; KINASE; TUMORIGENESIS; TRANSITION; RECEPTOR	Background: The Beclin 1 gene binds to the apoptosis-inhibiting protein Bcl-2. The expression and function of the Beclin 1 gene in four colorectal cancer cell lines (HT29, DLD-1, SW480, SW620) was investigated. Materials and Methods: The expression of Beclin 1 mRNA was examined by reverse transcription-polymerase chain reaction (RT-PCR), the cell growth rate of a stable cell line established after transfection of the Beclin 1 gene into low Beclin 1-expressing HT29 colon cancer cells. In addition, changes in cell cycle were investigated by flow cytometry, and the expression levels of cell cycle related proteins in the Beclin 1 transfected colon cancer cell line were assessed. Results: The expression level of Beclin 1 mRNA in the colon cancer cell lines was variable. Transfection of the low Beclin 1 gene-expressing colon cancer cell line with the Beclin 1 gene resulted in cell growth inhibition. The cell cycle analysis showed that the percentage of G1-phase cells was significantly higher in Beclin 1 transfectants than in mock transfected cells. The expression levels of cyclin E and phosphorylated Rb were decreased. Conclusion: These results indicate that Beclin 1 can inhibit the growth of colorectal cancer cells.	Univ Fukui, Fac Med, Dept Surg Gastroenterol, Matsuoka, Fukui 9101193, Japan		Yamaguchi, A (corresponding author), Univ Fukui, Dept Surg 1, 23-3,Eiheiji Cho, Matsuoka, Fukui 9101193, Japan.	akio@fmsrsa.fukui-med.ac.jp	Hirono, Yasuo/E-9383-2011				Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; BALDIN V, 1993, GENE DEV, V7, P812, DOI 10.1101/gad.7.5.812; Goi T, 2004, CANCER RES, V64, P1906, DOI 10.1158/0008-5472.CAN-3696-2; Goi T, 1998, BRIT J CANCER, V77, P466, DOI 10.1038/bjc.1998.74; GRANA X, 1995, ONCOGENE, V11, P211; HOROWITZ JM, 1990, P NATL ACAD SCI USA, V87, P2775, DOI 10.1073/pnas.87.7.2775; Kametaka S, 1998, J BIOL CHEM, V273, P22284, DOI 10.1074/jbc.273.35.22284; KOFF A, 1992, SCIENCE, V257, P1689, DOI 10.1126/science.1388288; Liang XH, 1998, J VIROL, V72, P8586, DOI 10.1128/JVI.72.11.8586-8596.1998; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Masciullo V, 2000, INT J ONCOL, V17, P897; Melendez A, 2003, SCIENCE, V301, P1387, DOI 10.1126/science.1087782; OHTSUBO M, 1995, MOL CELL BIOL, V15, P2612; PAGANO M, 1993, J CELL BIOL, V121, P101, DOI 10.1083/jcb.121.1.101; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Seaman MNJ, 1997, J CELL BIOL, V137, P79, DOI 10.1083/jcb.137.1.79; TSAI LH, 1993, ONCOGENE, V8, P1593; Yue ZY, 2002, NEURON, V35, P921, DOI 10.1016/S0896-6273(02)00861-9; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	19	68	77	0	3	INT INST ANTICANCER RESEARCH	ATHENS	EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE	0250-7005	1791-7530		ANTICANCER RES	Anticancer Res.	MAY-JUN	2007	27	3B					1453	1457					5	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	170GL	WOS:000246650700010	17595761				2022-04-25	
J	Zhang, YL; Li, C; Liu, XF; Wang, YL; Zhao, R; Yang, YM; Zheng, X; Zhang, Y; Zhang, X				Zhang, Yanli; Li, Chen; Liu, Xinfeng; Wang, Yanlei; Zhao, Rui; Yang, Yongmei; Zheng, Xin; Zhang, Yi; Zhang, Xin			circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637	EBIOMEDICINE			English	Article						Colorectal cancer; Chemoresistance; circHIPK3; Autophagy; miR-637; STAT3	COLON-CANCER; CIRCULAR RNAS; CELL-GROWTH; IN-VITRO; TUMORIGENESIS; CARCINOMA; SURVIVAL; MACROAUTOPHAGY; FLUOROURACIL; COMBINATION	Background: Resistance to oxaliplatin-based chemotherapy is a major cause of recurrence in colorectal cancer (CRC) patients. There is increasing evidence indicating that circHIPK3 is involved in the development and progression of tumours. However, little is known about the potential role of circHIPK3 in CRC chemotherapy and its molecular mechanisms in chemoresistance also remain unclear. Methods: Quantitative real-time PCR was performed to detect circHIPK3 expression in tissues of 2 cohorts of CRC patients who received oxaliplatin-based chemotherapy. The chemoresistant effects of circHIPK3 were assessed by cell viability, apoptosis, and autophagy assays. The relationship between circHIPK3, miR-637, and STAT3 mRNA was confirmed by biotinylated RNA pull-down, luciferase reporter, and western blot assays. Findings: In the pilot study, increased circHIPK3 expression was observed in chemoresistant CRC patients. Functional assays showed that circHIPK3 promoted oxaliplatin resistance, which was dependent on inhibition of autophagy. Mechanistically, circHIPK3 sponged miR-637 to promote STAT3 expression, thereby activating the downstream Bcl-2/beclinl signalling pathway. A clinical cohort study showed that circHIPK3 was upregulated in tissues from recurrent CRC patients and correlated with tumour size, regional lymph node metastasis, distant metastasis, and survival. Interpretation: circHIPK3 functions as a chemoresistant gene in CRC cells by targeting the miR-637/STAT3/Bcl-2/beclinl axis and might be a prognostic predictor for CRC patients who receive oxaliplatin-based chemotherapy. (C) 2019 The Author(s). Published by Elsevier B.V.	[Li, Chen; Zhao, Rui; Yang, Yongmei; Zheng, Xin; Zhang, Yi; Zhang, Xin] Shandong Univ, Dept Clin Lab, Qilu Hosp, 107 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China; [Zhang, Yanli; Liu, Xinfeng] Shandong Prov Third Hosp, Dept Clin Lab, Jinan 250031, Shandong, Peoples R China; [Wang, Yanlei] Shandong Univ, Dept Gen Surg, Qilu Hosp, Jinan 250012, Shandong, Peoples R China		Zhang, X (corresponding author), Shandong Univ, Dept Clin Lab, Qilu Hosp, 107 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China.	xinzhang@sdu.edu.cn		Zhang, Xin/0000-0003-2138-5600	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81301506]; Shandong Medical and Health Technology Development Project [2018WSB20002]; Shandong Key Research and Development Program [2016CSF201122]; Natural Science Foundation of Shandong ProvinceNatural Science Foundation of Shandong Province [ZR2017MH044]; Jinan Science and Technology Development Plan [201805084, 201805003]	This study was supported by National Natural Science Foundation of China (81301506), Shandong Medical and Health Technology Development Project(2018WSB20002), Shandong Key Research and Development Program (2016CSF201122), Natural Science Foundation of Shandong Province (ZR2017MH044), Jinan Science and Technology Development Plan(201805084, 201805003). The funders had no role in study design, data collection, data analysis, interpretation, and writing of the manuscript.	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J	Koehler, BC; Jager, D; Schulze-Bergkamen, H				Koehler, Bruno Christian; Jaeger, Dirk; Schulze-Bergkamen, Henning			Targeting cell death signaling in colorectal cancer: Current strategies and future perspectives	WORLD JOURNAL OF GASTROENTEROLOGY			English	Article						Colorectal cancer; Apoptosis; Necroptosis; Autophagy; Clinical trial; Bcl-2 proteins; BH-3 mimetics; Inflammatory bowel disease	APOPTOSIS-INDUCING LIGAND; TRAIL-INDUCED APOPTOSIS; X-LINKED INHIBITOR; PHASE-I TRIAL; FAS-MEDIATED APOPTOSIS; COLON-CARCINOMA CELLS; TUMOR-GROWTH; RECEPTOR 5; PHARMACODYNAMIC BIOMARKERS; OBLIMERSEN SODIUM	The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the "druggability" of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.	[Koehler, Bruno Christian; Jaeger, Dirk; Schulze-Bergkamen, Henning] Univ Heidelberg Hosp, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany		Schulze-Bergkamen, H (corresponding author), Univ Heidelberg Hosp, Natl Ctr Tumor Dis, Neuenheimer Feld 460, D-69120 Heidelberg, Germany.	henning.schulze@med.uni-heidelberg.de			Medical Faculty of the University of Heidelberg, Germany; German Research FoundationGerman Research Foundation (DFG) [DFG SCHU 1443/4-1]	BCK holds a Postdoctoral-Fellowship from the Medical Faculty of the University of Heidelberg, Germany. HSB receives grants from the German Research Foundation (DFG SCHU 1443/4-1). All authors are members of the colorectal cancer clinical research unit at the University Hospital Heidelberg, Germany (KFO227).	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Gastroenterol.	FEB 28	2014	20	8					1923	1934		10.3748/wjg.v20.i8.1923			12	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	AB7GP	WOS:000331957900004	24587670	Green Published, hybrid			2022-04-25	
J	Grossi, V; Liuzzi, M; Murzilli, S; Martelli, N; Napoli, A; Ingravallo, G; Del Rio, A; Simone, C				Grossi, Valentina; Liuzzi, Micaela; Murzilli, Stefania; Martelli, Nicola; Napoli, Anna; Ingravallo, Giuseppe; Del Rio, Alberto; Simone, Cristiano			Sorafenib inhibits p38 alpha activity in colorectal cancer cells and synergizes with the DFG-in inhibitor SB202190 to increase apoptotic response	CANCER BIOLOGY & THERAPY			English	Article						protein kinase; DFG-in and DFG-out; conformations; sorafenib; type-I and type-II inhibitors; colorectal cancer; p38 alpha; BRAF; MEK/ERK; apoptosis	MULTIKINASE INHIBITOR; AMPK-FOXO3A AXIS; PATHWAY; GROWTH; AUTOPHAGY; TARGETS; COLON; RAF; DISCOVERY; BLOCKADE	In the search for new strategies to efficiently fight colorectal cancer, efforts are being increasingly focused on targeting regulatory signaling pathways involved in cancer-specific features. As a result, several studies have recently addressed the therapeutic potential of molecularly-targeted drugs capable of inhibiting the activity of protein kinases involved in relevant signaling cascades. Here we show that simultaneous inhibition of the DFG-in and DFG-out conformations of p38 alpha by means of type-I and type-II inhibitors is beneficial to impair more efficiently its kinase activity. Moreover, we found that SB202190 (type-I) and sorafenib (type-II) synergize at the molecular and biological level, as co-treatment with these compounds enhances tumor growth inhibition and induction of apoptosis both in colorectal cancer cell lines and animal models. These results support the need to reconsider sorafenib as a therapeutic agent against colorectal cancer and provide new insights that underline the importance to elucidate the activity of protein kinase inhibitors for the treatment of colorectal carcinoma.	[Del Rio, Alberto] Alma Mater Studiorum Univ Bologna, Dept Expt Pathol, Lab Biochemoinformat, Bologna, Italy; [Grossi, Valentina] IRCCS S Bellis, Canc Genet Lab, Castellana Grotte, Italy; [Liuzzi, Micaela; Napoli, Anna; Ingravallo, Giuseppe] Univ Bari, DIM, Div Anat Pathol, Bari, Italy; [Murzilli, Stefania; Martelli, Nicola] Consorzio Mario NegriSud, Dept Translat Pharmacol, Lab Lipid Metab & Canc, Santa Maria Imbaro, Italy; [Murzilli, Stefania] Consorzio Mario NegriSud, Dept Translat Pharmacol, Anim Care Facil, Santa Maria Imbaro, Italy; [Martelli, Nicola] Consorzio Mario NegriSud, Dept Translat Pharmacol, Flow Cytometry Facil, Santa Maria Imbaro, Italy; [Simone, Cristiano] Univ Bari, Div Med Genet, Bari, Italy; [Simone, Cristiano] Consorzio Mario NegriSud, Dept Translat Pharmacol, Lab Signal Dependent Transcript, Santa Maria Imbaro, Italy		Del Rio, A (corresponding author), Alma Mater Studiorum Univ Bologna, Dept Expt Pathol, Lab Biochemoinformat, Bologna, Italy.	alberto.delrio@gmail.com; cristiano.simone@uniba.it	Ingravallo, Giuseppe/Q-1477-2016; INGRAVALLO, Giuseppe/N-2466-2019; Del Rio, Alberto/F-5230-2010; Simone, Cristiano/K-3452-2018; GROSSI, Valentina/O-6546-2019; Grossi, Valentina/K-9821-2016	Ingravallo, Giuseppe/0000-0002-4792-3545; INGRAVALLO, Giuseppe/0000-0002-4792-3545; Del Rio, Alberto/0000-0002-1890-6797; Simone, Cristiano/0000-0002-2628-7658; GROSSI, Valentina/0000-0003-3843-1618; Grossi, Valentina/0000-0003-3843-1618	Italian Association for Cancer Research (AIRC)Fondazione AIRC per la ricerca sul cancro [IG10177, 6266]	This article is dedicated to the memory of Margherita D'Aprile and Gianni Iannuzzi. We thank Dr Francesco Paolo Jori for his helpful discussion during the preparation of the manuscript and editorial assistance, and Dr Giovanna Forte for contribution in preparing the illustrations. This work was partially supported by an Investigator Grant 2010 (IG10177) (to C.S.) and by the Start-Up Grant (no. 6266 to A.D.R) from the Italian Association for Cancer Research (AIRC). Bayer Italia is gratefully acknowledged for providing Sorafenib.	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Ther.	DEC	2012	13	14					1471	1481		10.4161/cbt.22254			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	052QD	WOS:000312212200016	22986232	Bronze, Green Published			2022-04-25	
J	Tai, CJ; Wang, CK; Tai, CJ; Lin, YF; Lin, CS; Jian, JY; Chang, YJ; Chang, CC				Tai, Chen-Jei; Wang, Chien-Kai; Tai, Cheng-Jeng; Lin, Yi-Feng; Lin, Chi-Shian; Jian, Jiun-Yu; Chang, Yu-Jia; Chang, Chun-Chao			Aqueous Extract of Solanum nigrum Leaves Induces Autophagy and Enhances Cytotoxicity of Cisplatin, Doxorubicin, Docetaxel, and 5-Fluorouracil in Human Colorectal Carcinoma Cells	EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article							COLON-CANCER; COMPLEMENTARY/ALTERNATIVE MEDICINE; ADJUVANT THERAPY; APOPTOSIS; CHEMOTHERAPY; INDUCTION; HEPG2; ACTIVATION; CASPASE-3; PATHWAYS	Colorectal cancer is a common cancer worldwide, and chemotherapy is a mainstream approach for advanced and recurrent cases. Development of effective complementary drugs could help improve tumor suppression efficiency and control adverse effects from chemotherapy. The aqueous extract of Solanum nigrum leaves (AE-SN) is an essential component in many traditional Chinese medicine formulas for treating cancer, but there is a lack of evidence verifying its tumor suppression efficacy in colorectal cancer. The purpose of this study is to evaluate the tumor suppression efficacy of AE-SN using DLD-1 and HT-29 human colorectal carcinoma cells and examine the combined drug effect when combined with the chemotherapeutic drugs cisplatin, doxorubicin, docetaxel, and 5-fluorouracil. The results indicated that AE-SN induced autophagy via microtubule-associated protein 1 light chain 3 A/B II accumulation but not caspase-3-dependent apoptosis in both cell lines. The IC(50)s after 48 hours of treatment were 0.541 and 0.948 mg/ml AE-SN in DLD-1 and HT-29, respectively. AE-SN also demonstrated a combined drug effect with all tested drugs by enhancing cytotoxicity in tumor cells. Our results suggest that AE-SN has potential in the development of complementary chemotherapy for colorectal cancer.	[Tai, Chen-Jei; Wang, Chien-Kai] Taipei Med Univ Hosp, Dept Chinese Med, Taipei 11031, Taiwan; [Tai, Chen-Jei; Wang, Chien-Kai; Jian, Jiun-Yu] Taipei Med Univ, Coll Med, Sch Med, Dept Obstet & Gynecol, Taipei 11031, Taiwan; [Wang, Chien-Kai; Tai, Cheng-Jeng] Taipei Med Univ Hosp, Dept Internal Med, Div Hematol & Oncol, Taipei 11031, Taiwan; [Wang, Chien-Kai; Tai, Cheng-Jeng; Chang, Chun-Chao] Taipei Med Univ, Coll Med, Sch Med, Dept Internal Med, Taipei 11031, Taiwan; [Lin, Yi-Feng] Chi Mei Hosp Chiali, Dept Surg, Div Gen Surg, Tainan 72263, Taiwan; [Lin, Chi-Shian] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 11031, Taiwan; [Chang, Yu-Jia] Taipei Med Univ, Coll Med, Grad Inst Clin Med, Taipei 11031, Taiwan; [Chang, Yu-Jia] Taipei Med Univ & Hosp, Dept Surg, Taipei 11031, Taiwan; [Chang, Yu-Jia] Taipei Med Univ, Taipei Med Univ Hosp, Dept Surg, Div Gen Surg, Taipei 11031, Taiwan; [Chang, Chun-Chao] Taipei Med Univ Hosp, Dept Internal Med, Div Gastroenterol & Hepatol, Taipei 11031, Taiwan		Chang, CC (corresponding author), Taipei Med Univ, Coll Med, Sch Med, Dept Internal Med, Taipei 11031, Taiwan.	chunchao@tmu.edu.tw	Jian, Jiun-Yu/E-8605-2014	Jian, Jiun-Yu/0000-0002-5767-8803; Wang, Chien-Kai/0000-0002-9162-6820; Chang, Yu-Jia/0000-0003-3978-3244	Chi Mei Medical Center [101CM-TMU-12-3]	This work was supported by Chi Mei Medical Center (101CM-TMU-12-3).	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Med.		2013	2013								514719	10.1155/2013/514719			12	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	177SE	WOS:000321394900001	23843876	Green Submitted, gold, Green Published			2022-04-25	
J	Wu, WKK; Wu, YC; Yu, L; Li, ZJ; Sung, JJY; Cho, CH				Wu, William Ka Kei; Wu, Ya Chun; Yu, Le; Li, Zhi Jie; Sung, Joseph Jao Yiu; Cho, Chi Hin			Induction of autophagy by proteasome inhibitor is associated with proliferative arrest in colon cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						proteasome inhibitor; colon cancer; proliferation; autophagy; LC3	PROTEIN-DEGRADATION; BORTEZOMIB; PATHWAYS; UBIQUITINATION; MACROAUTOPHAGY; MG-132; ROLES; LINK; LC3	The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Blockade of UPS by proteasome inhibitors has been shown to activate autophagy. Recent evidence also suggests that proteasome inhibitors may inhibit cancer growth. In this study, the effect of a proteasome inhibitor MG-132 on the proliferation and autophagy of cultured colon cancer cells (HT-29) was elucidated. Results showed that MG-132 inhibited HT-29 cell proliferation and induced G(2)/M cell cycle arrest which was associated with the formation of LC3(+) autophagic vacuoles and the accumulation of acidic vesicular organelles. MG-132 also increased the protein expression of LC3-I and -II in a time-dependent manner. In this connection, 3-methyladenine, a Class III phosphoinositide 3-kinase inhibitor, significantly abolished the formation of LC3(+) autophagic vacuoles and the expression of LC3-II but not LC3-I induced by MG-132. Taken together, this study demonstrates that inhibition of proteasome in colon cancer cells lowers cell proliferation and activates autophagy. This discovery may shed a new light on the novel function of proteasome in the regulation of autophagy and proliferation in colon cancer cells. (C) 2008 Elsevier Inc. All rights reserved.	[Wu, William Ka Kei; Wu, Ya Chun; Yu, Le; Li, Zhi Jie; Cho, Chi Hin] Chinese Univ Hong Kong, Dept Pharmacol, Shatin, Hong Kong, Peoples R China; [Wu, William Ka Kei; Sung, Joseph Jao Yiu] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China; [Wu, William Ka Kei; Sung, Joseph Jao Yiu; Cho, Chi Hin] Chinese Univ Hong Kong, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China; [Wu, Ya Chun] Zhejiang Univ, Dept Med, Affiliated Hosp 1, Coll Med, Hangzhou 310003, Zhejiang, Peoples R China		Cho, CH (corresponding author), Chinese Univ Hong Kong, Dept Pharmacol, Basic Med Sci Bldg, Shatin, Hong Kong, Peoples R China.	wukakei@cuhk.edu.hk; chcho@cuhk.edu.hk	Cho, Chi Hin/C-6543-2014; Wu, William K.K./A-3277-2009; Sung, Joseph J. Y./R-3203-2018	Cho, Chi Hin/0000-0002-7658-3260; Wu, William K.K./0000-0002-5662-5240; Sung, Joseph J. Y./0000-0003-3125-5199	Hong Kong Research Grants CouncilHong Kong Research Grants Council [CUHK 7499/05M]	This work is supported by the Hong Kong Research Grants Council (CUHK 7499/05M).	Backer JM, 2008, BIOCHEM J, V410, P1, DOI 10.1042/BJ20071427; Bialik S, 2008, ADV EXP MED BIOL, V615, P177, DOI 10.1007/978-1-4020-6554-5_9; Blagosklonny MV, 1996, BIOCHEM BIOPH RES CO, V227, P564, DOI 10.1006/bbrc.1996.1546; Chang YC, 1998, CELL GROWTH DIFFER, V9, P79; Davies AM, 2007, CLIN CANCER RES, V13, p4647S, DOI 10.1158/1078-0432.CCR-07-0334; Ding WX, 2007, AM J PATHOL, V171, P513, DOI 10.2353/ajpath.2007.070188; Ellington AA, 2005, CARCINOGENESIS, V26, P159, DOI 10.1093/carcin/bgh297; Goldberg AL, 2003, NATURE, V426, P895, DOI 10.1038/nature02263; Hansen K, 2007, J NEUROCHEM, V103, P259, DOI 10.1111/j.1471-4159.2007.04753.x; Ito S, 2007, INT J ONCOL, V31, P261; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kanzawa T, 2004, CELL DEATH DIFFER, V11, P448, DOI 10.1038/sj.cdd.4401359; Komata T, 2004, J NEURO-ONCOL, V68, P101, DOI 10.1023/B:NEON.0000027739.33842.6c; Kumar A, 2007, CELL CYCLE, V6, P1696, DOI 10.4161/cc.6.14.4492; Kuo PL, 2006, MOL CANCER THER, V5, P3209, DOI 10.1158/1535-7163.MCT-06-0478; Liang C, 2006, NAT CELL BIOL, V8, P688, DOI 10.1038/ncb1426; Maki CG, 1996, CANCER RES, V56, P2649; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Mizushima N, 2007, AUTOPHAGY, V3, P542, DOI 10.4161/auto.4600; PAGANO M, 1995, SCIENCE, V269, P682, DOI 10.1126/science.7624798; Paglin S, 2001, CANCER RES, V61, P439; Pandey UB, 2007, NATURE, V447, P859, DOI 10.1038/nature05853; Pankiv S, 2007, J BIOL CHEM, V282, P24131, DOI 10.1074/jbc.M702824200; Papandreou CN, 2004, J CLIN ONCOL, V22, P2108, DOI 10.1200/JCO.2004.02.106; Petiot A, 2000, J BIOL CHEM, V275, P992, DOI 10.1074/jbc.275.2.992; Pisani P, 1999, INT J CANCER, V83, P18, DOI 10.1002/(SICI)1097-0215(19990924)83:1&lt;18::AID-IJC5&gt;3.0.CO;2-M; Richardson PG, 2006, ANNU REV MED, V57, P33, DOI 10.1146/annurev.med.57.042905.122625; Rodriguez MS, 1996, ONCOGENE, V12, P2425; Rubinsztein DC, 2006, NATURE, V443, P780, DOI 10.1038/nature05291; Tobinai K, 2007, INT J CLIN ONCOL, V12, P318, DOI 10.1007/s10147-007-0695-5; Wu WKK, 2008, BRIT J PHARMACOL, V154, P632, DOI 10.1038/bjp.2008.115; Wu WKK, 2008, BIOCHEM BIOPH RES CO, V371, P209, DOI 10.1016/j.bbrc.2008.04.059	32	65	67	0	11	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	SEP 19	2008	374	2					258	263		10.1016/j.bbrc.2008.07.031			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	339TL	WOS:000258600100016	18638451				2022-04-25	
J	Xia, YH; Cheng, CR; Yao, SY; Zhang, Q; Wang, Y; Ji, ZN				Xia, Yong-hui; Cheng, Chuan-rong; Yao, Shu-yan; Zhang, Qing; Wang, Ying; Ji, Zhao-ning			L-Securinine induced the human colon cancer SW480 cell autophagy and its molecular mechanism	FITOTERAPIA			English	Article						L-Securinine; Autophagy; SW480 cell; Colon cancer	APOPTOSIS; INHIBITION; TUMORIGENESIS; RESISTANCE; INDUCTION; INCREASES; BECLIN-1; RECEPTOR; DEATH	Aims: To investigate the anti-tumor effects of L-securinine inducing colon cancer SW480 cell autophagy and explore its potential molecular mechanism. Main methods: MTT method was used to detect the antitumor effect of SW480 cells cultured with L-securinine in vitro. Light and electron microscopy were used to observe SW480 cells treated with L-securinine morphological changes. Flow cytometry was used to observe the apoptotic ratio and cell cycle inducing with the L-securinine in SW480 cells, and the autophagic apoptosis ratio was determined by FITC-conjugated annexin V by flow cytometry (FCM). FCM was applied to analysis cell cycle: the expression of autophagy gene Beclin-1 was examined by reverse transcriptase polymerase chain reaction (RT-PCR). Key findings: The generation depression effects of SW480 cells cultured in vitro were detected by MU method (P<0.05), and there were dosage-time dependent relationships. Numerous autophagic vacuoles and empty vacuoles were observed in SW480 cells treated with 2.5 mu ML-securinine for 48 h by electron microscopy, and the process of cell division that got less was observed. Through flow cytometry. a number of observed autophagic cells were obviously increased, and G1/S phase was retarded. L-Securinine tended to arrest cells at the G1 phase of the cell cycle. The percentage of the apoptotic cells increased as treatment duration and concentrations increased. Beclin-1 expression enhanced with L-securinine concentration increased. Significance: L-Securinine has an anti-tumor effect against colon cancer SW480 cell. The L-securinine can induce striking autophagy in SW480 cell in vitro. The autophagy induced by L-securinine is related with upregulating the expression of autophagy gene Beclin-1. (C) 2011 Elsevier B.V. All rights reserved.	[Ji, Zhao-ning] Yijishan Hosp, Ctr Canc, Wannan Med Coll, Wuhu 241001, Peoples R China; [Xia, Yong-hui; Cheng, Chuan-rong; Yao, Shu-yan; Zhang, Qing] Wannan Med Coll, Dept Oncol, Wuhu 241001, Peoples R China; [Wang, Ying] JiNan Univ, Inst Tradit Chinese Med & Nat Prod, Guangzhou 510632, Guangdong, Peoples R China		Ji, ZN (corresponding author), Yijishan Hosp, Ctr Canc, Wannan Med Coll, Wuhu 241001, Peoples R China.	jzning@163.com			Natural Science Foundation of AnHui ProvinceNatural Science Foundation of Anhui Province [090413123]	This work was supported by the Fund of Natural Science Foundation of AnHui Province (Grant No. 090413123).We would particularly like to thank Institute of Traditional Chinese Medicine & Natural Products, JiNan University for providing pure sample of L-securinine.	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J	Gu, XY; Jiang, Y; Li, MQ; Han, P; Liu, YL; Cui, BB				Gu, Xin-Yue; Jiang, Yang; Li, Ming-Qi; Han, Peng; Liu, Yan-Long; Cui, Bin-Bin			Over-expression of EGFR regulated by RARA contributes to 5-FU resistance in colon cancer	AGING-US			English	Article						autophagy; drug sensitivity; EGFR; 5-fluorouracil	AUTOPHAGY INHIBITOR; THERAPEUTIC TARGET; GROWTH; OVEREXPRESSION; TUMORIGENESIS; INDUCTION; RECEPTOR; GENE	A promising new strategy for cancer therapy is to target the autophagic pathway. However, comprehensive characterization of autophagy genes and their clinical relevance in cancer is still lacking. Here, we systematically characterized alterations of autophagy genes in multiple cancer lines by analyzing data from The Cancer Genome Atlas and CellMiner database. Interactions between autophagy genes and clinically actionable genes (CAGs) were identified by analyzing co-expression, protein-protein interactions (PPIs) and transcription factor (TF) data. A key subnetwork was identified that included 18 autophagy genes and 22 CAGs linked by 28 PPI pairs and 1 TF-target pair, which was EGFR targeted by RARA. Alterations in the expression of autophagy genes were associated with patient survival in multiple cancer types. RARA and EGFR were associated with worse survival in colorectal cancer patients. The regulatory role of EGFR in 5-FU resistance was validated in colon cancer cells in vivo and in vitro. EGFR contributed to 5-FU resistance in colon cancer cells through autophagy induction, and EGFR overexpression in 5-FU resistant colon cancer was regulated by RARA. The present study provides a comprehensive analysis of autophagy in different cancer cell lines and highlights the potential clinical utility of targeting autophagy genes.	[Gu, Xin-Yue; Li, Ming-Qi; Han, Peng; Liu, Yan-Long; Cui, Bin-Bin] Harbin Med Univ, Dept Colorectal Surg, Canc Hosp, Harbin 150040, Peoples R China; [Jiang, Yang] Harbin Med Univ, Dept Pathol, Canc Hosp, Harbin 150040, Peoples R China		Cui, BB (corresponding author), Harbin Med Univ, Dept Colorectal Surg, Canc Hosp, Harbin 150040, Peoples R China.	cbb2888@163.com	Liu, Yanlong/AAL-3503-2021		Nn10 program of Harbin Medical University Cancer Hospital; Natural Science Foundation of Heilongjiang Province of ChinaNatural Science Foundation of Heilongjiang Province [ZD2017019]	This work was supported by grants from Nn10 program of Harbin Medical University Cancer Hospital and Natural Science Foundation of Heilongjiang Province of China (ZD2017019).	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J	Mori, S; Sawada, T; Okada, T; Ohsawa, T; Adachi, M; Keiichi, K				Mori, Shozo; Sawada, Tokihiko; Okada, Toshie; Ohsawa, Tatsushi; Adachi, Masakazu; Keiichi, Kubota			New anti-proliferative agent, MK615, from Japanese apricot "Prunus mume" induces striking autophagy in colon cancer cells in vitro	WORLD JOURNAL OF GASTROENTEROLOGY			English	Article						colon cancer; Japanese apricot; Prunus mume; autophagy; apoptosis; MK615	MOLECULAR MACHINERY; COLORECTAL-CANCER; THERAPY; DEATH; MECHANISM; APOPTOSIS; MACROAUTOPHAGY; DEGRADATION; INHIBITION; RADIATION	AIM: To investigate the anti-neoplastic effects of MK615, an extract from the Japanese apricot (Prunus mume), against colon cancer cells. METHODS: Three colon cancer cell lines, SW480, COLO, and WiDr, were cultured with MK615. Growth inhibition was evaluated by cell proliferation assay and killing activity was determined by lactate dehydrogenase assay. Induction of apoptosis was evaluated by annexin V flow cytometry. Morphological changes were studied by light and electron microscopy, and immunofluorescence staining with Atg8. RESULTS: MK615 inhibited growth and lysed SW480, COLO and WiDr cells in a dose-dependent manner. Annexin V flow cytometry showed that MK615 induced apoptosis after 6 h incubation, at which point the occurrence of apoptotic cells was 68.0%, 65.7% and 64.7% for SW480, COLO, and WiDr cells, respectively. Light and electron microscopy, and immunofluorescence staining with Atg8 revealed that MK615 induced massive cytoplasmic vacuoles (autophagosomes) in all three cell lines. CONCLUSION: MK615 has an anti-neoplastic effect against colon cancer cells. The effect may be exerted by induction of apoptosis and autophagy. (C) 2007 WJG. All rights reserved.	[Mori, Shozo; Sawada, Tokihiko; Okada, Toshie; Keiichi, Kubota] Dokkyo Univ, Sch Med, Dept Surg 2, Shimotsuga, Tochigi 3210293, Japan; [Ohsawa, Tatsushi; Adachi, Masakazu] Japan Apricot Co Ltd, Gunma 3700073, Japan		Sawada, T (corresponding author), Dokkyo Univ, Sch Med, Dept Surg 2, Kitakobayashi 880, Shimotsuga, Tochigi 3210293, Japan.	tsawada@dokkyomed.ac.jp					Adachi M, 2007, INT J FOOD PROP, V10, P375, DOI 10.1080/10942910600547624; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Bursch W, 2000, J CELL SCI, V113, P1189; Bursch W, 2000, ANN NY ACAD SCI, V926, P1, DOI 10.1111/j.1749-6632.2000.tb05594.x; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; Corcelle E, 2006, CANCER RES, V66, P6861, DOI 10.1158/0008-5472.CAN-05-3557; Ellington AA, 2005, CARCINOGENESIS, V26, P159, DOI 10.1093/carcin/bgh297; Gewirtz DA, 2007, AUTOPHAGY, V3, P249, DOI 10.4161/auto.3723; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Huang WP, 2002, CELL STRUCT FUNCT, V27, P409, DOI 10.1247/csf.27.409; Hunter AM, 2007, APOPTOSIS, V12, P1543, DOI 10.1007/s10495-007-0087-3; Kabore AF, 2004, CURR CANCER DRUG TAR, V4, P147, DOI 10.2174/1568009043481551; Kim KW, 2006, J BIOL CHEM, V281, P36883, DOI 10.1074/jbc.M607094200; Kirisako T, 2000, J CELL BIOL, V151, P263, DOI 10.1083/jcb.151.2.263; Kirkegaard K, 2004, NAT REV MICROBIOL, V2, P301, DOI 10.1038/nrmicro865; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Meiler J, 2006, CURR DRUG TARGETS, V7, P1361, DOI 10.2174/138945006778559175; Monga DK, 2006, ANN SURG ONCOL, V13, P1021, DOI 10.1245/ASO.2006.08.015; Nakagawa A, 2007, BREAST J, V13, P44, DOI 10.1111/j.1524-4741.2006.00361.x; Ogier-Denis E, 2003, BBA-REV CANCER, V1603, P113, DOI 10.1016/S0304-419X(03)00004-0; OTSUKA H, 1978, EXP CELL RES, V112, P127, DOI 10.1016/0014-4827(78)90533-5; Penn L Z, 2001, Curr Opin Investig Drugs, V2, P684; Ravikumar B, 2005, NAT GENET, V37, P771, DOI 10.1038/ng1591; Takeuchi H, 2004, INT J ONCOL, V25, P57; Tanida I, 2005, AUTOPHAGY, V1, P84, DOI 10.4161/auto.1.2.1697; Terstriep S, 2006, EXPERT REV ANTICANC, V6, P921, DOI 10.1586/14737140.6.6.921; Wang CW, 2003, MOL MED, V9, P65, DOI 10.1007/BF03402040; Yao KC, 2003, J NEUROSURG, V98, P378, DOI 10.3171/jns.2003.98.2.0378; Yorimitsu T, 2005, CELL DEATH DIFFER, V12, P1542, DOI 10.1038/sj.cdd.4401765; Yoshimori T, 2004, BIOCHEM BIOPH RES CO, V313, P453, DOI 10.1016/j.bbrc.2003.07.023	30	34	34	0	7	W J G PRESS	BEIJING	APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA	1007-9327			WORLD J GASTROENTERO	World J. Gastroenterol.	DEC 28	2007	13	48					6512	6517		10.3748/wjg.13.6512			6	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	247AH	WOS:000252049000009	18161921	Green Published			2022-04-25	
J	Kim, Y; Oh, S; Yun, HS; Oh, S; Kim, SH				Kim, Y.; Oh, S.; Yun, H. S.; Oh, S.; Kim, S. H.			Cell-bound exopolysaccharide from probiotic bacteria induces autophagic cell death of tumour cells	LETTERS IN APPLIED MICROBIOLOGY			English	Article						antitumour activity; autophagy; cb-EPS; two-dimensional polyacrylamide gel electrophoresis (2D-PAGE)	ESCHERICHIA-COLI O157-H7; STRESS-INDUCED AUTOPHAGY; EXPRESSION; INHIBITION; TUMORIGENESIS; PROTEINS; STRAINS; ACID	Aim: Lactic acid bacteria (LAB) are beneficial micro-organisms that have been associated with several probiotic effects in both humans and animals. Here, using proteome analysis, we investigate the antitumour effects of cell-bound exopolysaccharides (cb-EPS) isolated from Lactobacillus acidophilus 606 on colon cancer cells and explore the proteins critical for their antitumour activity. Methods and Results: cb-EPS inhibited the proliferation of HT-29 colon cancer cells by directly affecting cell morphology and not the cell cycle. Using two-dimensional polyacrylamide gel electrophoresis coupled with matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF/MS) and immunoblot analysis, we found that cb-EPS dramatically induced Beclin-1 and GRP78, and affected Bcl-2 and Bak regulation. Conclusions: The results of this study indicate that cb-EPS are antitumourigenic against HT-29 colon cancer cells and that this activity is because of the activation of autophagic cell death promoted directly by the induction of Beclin-1 and GRP78, as well as indirectly through the induction of Bcl-2 and Bak. Significance and Impact of the Study: These results may contribute to understanding the novel mechanisms by which probiotic bacteria induce tumour cell death via autophagy.	[Yun, H. S.; Kim, S. H.] Korea Univ, Div Food Biosci & Technol, Seoul 136701, South Korea; [Kim, Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA; [Oh, S.] Korea Univ, Div Cellular & Dev Biol, Brain Korea Program Biomed Sci 21, Seoul 136701, South Korea; [Oh, S.] Chonnam Natl Univ, Dept Anim Sci, Kwangju, South Korea		Kim, SH (corresponding author), Korea Univ, Div Food Biosci & Technol, 1,5 Ka Anam Dong, Seoul 136701, South Korea.	saehkim@korea.ac.kr			Korea government (MEST)Ministry of Education, Science and Technology, Republic of KoreaKorean Government [R01-2008-000-20593-0]; Korean Government (MOEHRD)Ministry of Education & Human Resources Development (MOEHRD), Republic of KoreaKorean Government [KRF-F00025]	This study was supported by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (R01-2008-000-20593-0). Y. Kim was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-F00025).	Arlorio M, 2009, J AGR FOOD CHEM, V57, P10612, DOI 10.1021/jf902419t; Belury MA, 2002, J NUTR, V132, P2995, DOI 10.1093/jn/131.10.2995; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; Choi SS, 2006, LETT APPL MICROBIOL, V42, P452, DOI 10.1111/j.1472-765X.2006.01913.x; Di Marzio L, 2001, NUTR CANCER, V40, P185, DOI 10.1207/S15327914NC402_16; Ding WX, 2007, J BIOL CHEM, V282, P4702, DOI 10.1074/jbc.M609267200; Ertmer A, 2007, LEUKEMIA, V21, P936, DOI 10.1038/sj.leu.2404606; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; KATO I, 1994, INT J IMMUNOPHARMACO, V16, P29, DOI 10.1016/0192-0561(94)90116-3; Kim JU, 2006, J MICROBIOL BIOTECHN, V16, P939; Kim YH, 2006, PROTEOMICS, V6, P6181, DOI 10.1002/pmic.200600320; Kim Y, 2008, FOOD CONTROL, V19, P1042, DOI 10.1016/j.foodcont.2007.10.014; Kim Y, 2009, BIOCHEM BIOPH RES CO, V379, P324, DOI 10.1016/j.bbrc.2008.12.053; Kondo Y, 2006, AUTOPHAGY, V2, P85, DOI 10.4161/auto.2.2.2463; Lee YH, 2008, TOXICOL APPL PHARM, V231, P43, DOI 10.1016/j.taap.2008.03.025; Li DD, 2009, ONCOGENE, V28, P886, DOI 10.1038/onc.2008.441; Li J, 2008, CELL DEATH DIFFER, V15, P1460, DOI 10.1038/cdd.2008.81; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Moretti L, 2007, AUTOPHAGY, V3, P142, DOI 10.4161/auto.3607; Pattingre S, 2005, CELL, V122, P927, DOI 10.1016/j.cell.2005.07.002; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Scarlatti F, 2004, J BIOL CHEM, V279, P18384, DOI 10.1074/jbc.M313561200; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Sun Y, 2010, CANCER LETT, V294, P204, DOI 10.1016/j.canlet.2010.02.001; Szczesna-Skorupa E, 2004, J BIOL CHEM, V279, P13953, DOI 10.1074/jbc.M312170200; YUE Z, 1999, P NATL ACAD SCI USA, V100, P15077	26	82	86	3	28	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0266-8254	1472-765X		LETT APPL MICROBIOL	Lett. Appl. Microbiol.	AUG	2010	51	2					123	130		10.1111/j.1472-765X.2010.02859.x			8	Biotechnology & Applied Microbiology; Microbiology	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Microbiology	623OB	WOS:000279750600001	20536712	Bronze			2022-04-25	
J	Park, JM; Huang, SB; Wu, TT; Foster, NR; Sinicrope, FA				Park, Jae Myung; Huang, Shengbing; Wu, Tsung-Teh; Foster, Nathan R.; Sinicrope, Frank A.			Prognostic impact of Beclin 1, p62/sequestosome 1 and LC3 protein expression in colon carcinomas from patients receiving 5-fluorouracil as adjuvant chemotherapy	CANCER BIOLOGY & THERAPY			English	Article						autophagy; Beclin 1; p62/sequestosome 1; LC3; colon cancer; 5-fluorouracil	TUMOR-SUPPRESSOR GENE; INDUCED CELL-DEATH; COLORECTAL-CANCER; AUTOPHAGY GENE; REGULATES AUTOPHAGY; INDUCED APOPTOSIS; DRUG-RESISTANCE; POOR-PROGNOSIS; P62; INHIBITION	Autophagy is a cellular degradation process that can be activated in tumor cells to confer stress tolerance. During autophagy initiation and autophagosome formation, Beclin 1 binds microtubule-associated protein-1 light chain 3 (LC3I) that is converted to its membrane-bound form (LC3II) and interacts with the ubiquitin-binding protein p62/sequestosome 1 (SQSTM1). We determined the association of Beclin 1, LC3 and p62 protein expression with clinical outcome in resected stage II and III colon carcinomas (n = 178) from participants in 5-fluororuacil (5-FU)-based adjuvant therapy trials. The immunopercentage for each marker was determined and dichotomized for analysis with overall survival (OS) using Cox models. We found that autophagy markers localized to the tumor cell cytoplasm and showed increased expression relative to normal epithelial cells. Overexpression of Beclin 1, LC3 and p62 proteins were detected in 69, 79 and 85% of tumors, respectively. Expression levels were not significantly associated with clinicopathological variables. In a multivariable analysis adjusting for tumor grade, stage and patient age, Beclin 1 overexpression was independently associated with worse OS [hazard ratio (HR), 1.82; 95% confidence interval (CI), 1.0-3.3; p = 0.042] in patients who received 5-FU-based adjuvant therapy. Neither LC3 nor p62 overexpression was prognostic. In conclusion, Beclin 1 overexpression was associated with reduced survival in colon cancer patients treated with adjuvant 5-FU. These data are consistent with preclinical evidence indicating that autophagy can protect colon cancer cells from 5-FU and support the targeting of autophagy for therapeutic advantage in this malignancy.	[Park, Jae Myung; Huang, Shengbing; Sinicrope, Frank A.] Mayo Clin, Dept Med, Rochester, MN 55905 USA; [Park, Jae Myung; Huang, Shengbing; Wu, Tsung-Teh; Foster, Nathan R.; Sinicrope, Frank A.] Mayo Canc Ctr, Rochester, MN USA; [Wu, Tsung-Teh] Mayo Clin, Dept Pathol & Lab Med, Rochester, MN USA; [Foster, Nathan R.] Mayo Clin, Dept Biomed Stat & Informat, Rochester, MN USA; [Sinicrope, Frank A.] Mayo Clin, Dept Oncol, Rochester, MN USA		Sinicrope, FA (corresponding author), Mayo Clin, Dept Med, Rochester, MN 55905 USA.	sinicrope.frank@mayo.edu			National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [5 K05 CA142885]; Mayo Clinic Center for Cell Signaling in Gastroenterology [NIDDK P30DK084567]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [K05CA142885] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30DK084567] Funding Source: NIH RePORTER	This work was supported, in part, by a grant from the National Cancer Institute 5 K05 CA142885 (FAS) and from the Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567).	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Ther.	FEB	2013	14	2					100	107		10.4161/cbt.22954			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	083MP	WOS:000314468700006	23192274	Green Published, Bronze			2022-04-25	
J	Hu, F; Wei, F; Wang, YL; Wu, BB; Fang, Y; Xiong, B				Hu, Fen; Wei, Fei; Wang, Yulei; Wu, Bibo; Fang, Yuan; Xiong, Bin			EGCG synergizes the therapeutic effect of cisplatin and oxaliplatin through autophagic pathway in human colorectal cancer cells	JOURNAL OF PHARMACOLOGICAL SCIENCES			English	Article						EGCG; Cisplatin; Oxaliplatin; Autophagic death	GREEN TEA POLYPHENOL; EPIGALLOCATECHIN GALLATE; PROSTATE-CANCER; COLON-CANCER; APOPTOSIS; DEATH; CHEMOTHERAPY; SUPEROXIDE; INHIBITORS	Application of the platinum-based chemotherapy for colorectal cancer is restricted due to its severe cytotoxic effects. In this study we used synergistic strategies by combining (-)-Epigallocatechin gallate (EGCG) with cisplatin or oxaliplatin to minimize the ill effects of platinum-based therapy. MTS assay was used to examine the effect of EGCG, cisplatin and oxaliplatin on the proliferation of human colorectal cancer DLD-1 and HT-29 cells. Autophagic process was evaluated by detection of LC3-II protein, auto-phagosome formation, and quantification of Acidic Vesicular. Treatment of DLD-1 and HT-29 cells with EGCG plus cisplatin or oxaliplatin showed a synergistic effect on inhibition of cell proliferation and induction of cell death. EGCG enhanced the effect of cisplatin and oxaliplatin-induced autophagy in DLD-1 and HT-29 cells, as characterized by the accumulation of LC3-II protein, the increase of acidic vesicular organelles (AVOs), and the formation of autophagosome. In addition, transfection of DLD-1 and HT-29 cells with siRNA against ATG genes reduced EGCG synergistic effect. Our findings suggest that combining EGCG with cisplatin or oxaliplatin could potentiate the cytotoxicity of cisplatin and oxaliplatin in colorectal cancer cells through autophagy related pathway. (C) 2015 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.	[Hu, Fen; Wang, Yulei; Wu, Bibo; Fang, Yuan; Xiong, Bin] Wuhan Univ, Zhongnan Hosp, Hubei Canc Clin Study Ctr, Dept Oncol,Hubei Key Lab Tumor Biol Behav, Wuhan 430071, Peoples R China; [Wei, Fei] Wuhan Univ, Sch Med, Res Ctr Food & Drug Evaluat,State Key Lab Virol, Inst Med Virol,Natl Lab Antiviral & Tumor Traditi, Wuhan 430071, Peoples R China		Xiong, B (corresponding author), Wuhan Univ, Zhongnan Hosp, Hubei Canc Clin Study Ctr, Dept Oncol,Hubei Key Lab Tumor Biol Behav, Wuhan 430071, Peoples R China.	hu.fen1989@163.com; fei.wei@qut.edu.au; whu_yuleiwang@qq.com; bibo2006@163.com; fy_whu@126.com; binxiong1961@whu.edu.cn		Wang, Yulei/0000-0002-6495-3391	National High Technology Research and Development Program of ChinaNational High Technology Research and Development Program of China [2012AA02A502, 2012AA02A506]	This work was supported by the grant from National High Technology Research and Development Program of China (Project No. 2012AA02A502, 2012AA02A506).	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Pharmacol. Sci.	MAY	2015	128	1					27	34		10.1016/j.jphs.2015.04.003			8	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	CJ5VE	WOS:000355559300004	26003085	gold			2022-04-25	
J	Wu, SB; Wang, XW; Chen, JX; Chen, YX				Wu, Shaobin; Wang, Xianwei; Chen, Jinxiang; Chen, Yuxiang			Autophagy of cancer stem cells is involved with chemoresistance of colon cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Colon cancer; Cancer stem cell; Chemoresistance; Cdx1; Paclitaxel	COLORECTAL-CANCER; TUMOR-CELLS; RESISTANCE; RADIATION; CDX2	Background: Chemoresistance is a major cause of treatment failure in colon cancer, and cancer stem cells have been found to be involved in the chemoresistance of colon cancer. However, the mechanisms driving the chemoresistance of colon cancer stem cells have not been addressed. Methods: In this study, we investigated the cytotoxicity of paclitaxel in CD44(+)CD24(+) SW1222 colon cancer cells expressing Cdx1 (CD44(+)CD24(+)Cdx1(+) stem cells) and CD44(+)CD24(+) HCf116 colon cancer cells expressing wild-type p53 (CD44(+)CD24(+)p53wt stem cells). Results: SW1222 cells were more resistant to paclitaxel-induced cytotoxicity than HCT116 cells. Conversely, HCT-116 cells had higher matrigel colony formation ability than SW1222 cells. The isolated CD44(+)CD24(+)Cdx1(+) cells showed higher resistance to paclitaxel-induced cytotoxicity than CD44(+)CD2ep53wt cells. The resistance of CD44(+)CD24(+)Cdx1(+) cells to paclitaxel is associated with upregulation of Cdx1 and Bcl-2 expression, caspase-3 activity, and the ratio of LC3-II/LC3-I. The sensitivity of CD44(+)CD24(+)p53wt cells to paclitaxel is associated with the downregulation of Bc1-2 expression, upregulation of Bax levels, and upregulation of caspase-3 activity. Silencing of Cdx1 expression and treatment with lysosomal inhibitor bafilomycin A increased paclitaxel-induced cytotoxicity in CD44(+)CD24(+)Cdx1(+) cells. Conversely, overexpression of Cdxl decreased cell death in CD44(+)CD24(+)p53wt cells. Intratumoral injection of Cdxl siRNA significantly inhibited tumor growth in a xenograft tumor model inoculated with CD44(+)CD24(+)Cdx1(+) cancer cells. Conclusion: Cdxl exerts a protective role in colon cancer stem cells, which play a crucial role in chemoresistance to paclitaxel through activation of autophagy. Autophagy is activated though the Cdx1-Bcl-2-LC3 pathway. In contrast, p53 exerts a major role in apoptosis and inhibits autophagy in colon cancer stem cells. (C) 2013 Elsevier Inc. All rights reserved.	[Wu, Shaobin; Wang, Xianwei; Chen, Jinxiang] Cent S Univ, Xiangya Hosp, Dept Gen Surg, Changsha 410008, Hunan, Peoples R China; [Chen, Yuxiang] Cent S Univ, Xiangya Hosp, Hepatobiliary & Enter Surg Res Ctr, Changsha 410008, Hunan, Peoples R China		Chen, YX (corresponding author), Cent S Univ, Xiangya Hosp, Hepatobiliary & Enter Surg Res Ctr, 87 Xiangya Rd, Changsha 410008, Hunan, Peoples R China.	chenyx008@yahoo.cn	Chen, Yu/Y-3292-2019				Ades S, 2009, ONCOLOGY-NY, V23, P162; Chaachouay H, 2011, RADIOTHER ONCOL, V99, P287, DOI 10.1016/j.radonc.2011.06.002; Dave B, 2009, J MAMMARY GLAND BIOL, V14, P79, DOI 10.1007/s10911-009-9117-9; Djeu JY, 2009, ADV CANCER RES, V105, P77, DOI 10.1016/S0065-230X(09)05005-2; Hemmati HD, 2003, P NATL ACAD SCI USA, V100, P15178, DOI 10.1073/pnas.2036535100; Koslowski M, 2009, MOL CANCER, V8, DOI 10.1186/1476-4598-8-77; Lara-Padilla E, 2012, CURR STEM CELL RES T, V7, P26, DOI 10.2174/157488812798483412; Li J, 2011, MOL CELL BIOCHEM, V357, P31, DOI 10.1007/s11010-011-0872-8; Lin HM, 2007, J AGR FOOD CHEM, V55, P3620, DOI 10.1021/jf062406m; Mallo GV, 1998, J BIOL CHEM, V273, P14030, DOI 10.1074/jbc.273.22.14030; Moucadel V, 2002, BIOCHEM BIOPH RES CO, V297, P607, DOI 10.1016/S0006-291X(02)02250-7; Ogata M, 2006, MOL CELL BIOL, V26, P9220, DOI 10.1128/MCB.01453-06; Russo A, 2005, J CLIN ONCOL, V23, P7518, DOI 10.1200/JCO.2005.00.471; Warr MR, 2013, NATURE, V494, P323, DOI 10.1038/nature11895; Xu AG, 2010, WORLD J GASTROENTERO, V16, P960, DOI 10.3748/wjg.v16.i8.960; Zhang XW, 2004, CANCER RES, V64, P8139, DOI 10.1158/0008-5472.CAN-03-2301; Zhang XW, 2003, CLIN CANCER RES, V9, P1155	17	49	55	0	29	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X			BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	MAY 17	2013	434	4					898	903		10.1016/j.bbrc.2013.04.053			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	161SI	WOS:000320213200033	23624503				2022-04-25	
J	Zhu, ML; Zhang, PM; Jiang, M; Yu, SW; Wang, L				Zhu, Ming-liang; Zhang, Pei-min; Jiang, Min; Yu, Shu-wen; Wang, Lu			Myricetin induces apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling in human colon cancer cells	BMC COMPLEMENTARY MEDICINE AND THERAPIES			English	Article						Myricetin; Autophagy; Apoptosis; Colon cancer; 3-MA	PROSTATE-CANCER; STEM-CELLS; DEATH; PROLIFERATION; STATISTICS; FLAVONOIDS; QUERCETIN; INDUCTION; PATHWAY	Background The compound 3,3 ',4 ',5,5 ',7-hexahydroxyflavone (myricetin) is a natural flavonoid with antitumour activity. Most of the studies on myricetin have focused on the induction of tumour cell apoptosis, and little is known about the regulatory effects of myricetin on autophagy in colorectal cancer. Methods Here, we studied the effects of myricetin on colon cancer cell proliferation, apoptosis and autophagy. We detected colon cancer cell apoptosis induced by myricetin via flow cytometry and Hoechst 33258 staining. Transmission electron microscopy was performed to observe the morphological changes associated with autophagy. The expression levels of apoptosis-, autophagy- and PI3K/Akt/mTOR signalling-related proteins were measured by Western blot analysis. Results This study confirmed that myricetin inhibits the proliferation of 4 kinds of colon cancer cell lines. Myricetin induced cell apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling pathway. In addition, the inhibition of autophagy with 3-methyladenine (3-MA) promoted the apoptosis of myricetin-treated colon cancer cells. Conclusions Considering that myricetin induces apoptosis and autophagy in colon cancer cells, myricetin may become a viable candidate for chemotherapy; it could be used to exert tumour inhibitory effects alone or as adjuvant chemotherapy to inhibit autophagy. These studies may provide further evidence for the potential use of myricetin in the treatment of colon cancer.	[Zhu, Ming-liang; Jiang, Min; Yu, Shu-wen; Wang, Lu] Shandong Univ, Sch Pharmaceut Sci, Cheeloo Coll Med, Jinan 250012, Peoples R China; [Zhang, Pei-min; Yu, Shu-wen; Wang, Lu] Shandong Univ, Jinan Cent Hosp, Dept Pharm, Cheeloo Coll Med, Jinan 250013, Peoples R China		Yu, SW; Wang, L (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Cheeloo Coll Med, Jinan 250012, Peoples R China.	yaoxuebu2012@163.com; lulucc@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81803570]; Postdoctoral Science Foundation of ChinaChina Postdoctoral Science Foundation [2019 M652411]; Postdoctoral Innovation Project of Shandong Province [201902044]; Jinan Science and Technology Bureau [201907111]	This work was supported by the National Natural Science Foundation of China (81803570), the Postdoctoral Science Foundation of China (2019 M652411), the Postdoctoral Innovation Project of Shandong Province (201902044) and the Jinan Science and Technology Bureau (201907111).	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Med. Ther.	JUL 6	2020	20	1							209	10.1186/s12906-020-02965-w			9	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	MM3MI	WOS:000550063300001	32631392	Green Published, gold			2022-04-25	
J	Emanuele, S; Notaro, A; Piccionello, AP; Maggio, A; Lauricella, M; D'Anneo, A; Cernigliaro, C; Calvaruso, G; Giuliano, M				Emanuele, Sonia; Notaro, Antonietta; Piccionello, Antonio Palumbo; Maggio, Antonella; Lauricella, Marianna; D'Anneo, Antonella; Cernigliaro, Cesare; Calvaruso, Giuseppe; Giuliano, Michela			Sicilian Litchi Fruit Extracts Induce Autophagy versus Apoptosis Switch in Human Colon Cancer Cells	NUTRIENTS			English	Article						Litchi chinensis; anti-tumor activity; autophagy; colon cancer	IN-VITRO; ANTIOXIDANT; CHINENSIS; TUMORIGENESIS; PERICARP; STRESS; PULP	Litchi chinensis Sonnerat is a tropical tree whose fruits contain significant amounts of bioactive polyphenols. Litchi cultivation has recently spread in Sicily where the climate conditions are particularly favorable for this crop. Recent findings have shown that Litchi extracts display anti-tumor and pro-apoptotic effects in vitro, but the precise underlying mechanisms have not been fully elucidated. In this study, we report for the first time the effects of Sicilian litchi fruit extracts on colon cancer cells. The results indicated that litchi exocarp, mesocarp and endocarp fractions reduce the viability and clonogenic growth of HT29 cells. These effects were due to cell cycle arrest in the G2/M phase followed by caspase-dependent cell death. Interestingly, litchi exocarp and endocarp triggered a precocious autophagic response (16-24 h), which was accompanied by an increase in the level of autophagy related 1/autophagy activating kinase 1 (ATG1/ULK1), beclin-1, microtubule associated protein 1 light chain 3 (LC3)-II and p62 proteins. Autophagy inhibition by bafilomycin A1 or beclin-1 silencing increased cell death, thus suggesting that autophagy was initially triggered as a pro-survival response. Significant effects of Litchi extracts were also observed in other colon cancer cells, including HCT116 and Caco-2 cells. On the other hand, differentiated Caco-2 cells, a model of human enterocytes, appeared to be insensitive to the extracts at the same treatment conditions. High-Performance Liquid Chromatography-Electrospray Ionization-Quadrupole-Time-Of-Flight HPLC/ESI/Q-TOF evidenced the presence of some polyphenolic compounds, specifically in exocarp and endocarp extracts, that can account for the observed biological effects. The results obtained suggest a potential therapeutic efficacy of polyphenolic compounds purified from Sicilian Litchi fractions for the treatment of colon cancer. Moreover, our findings indicate that modulation of autophagy can represent a tool to improve the effectiveness of these agents and potentiate the anti-tumor response of colon cancer cells.	[Emanuele, Sonia; Lauricella, Marianna; Cernigliaro, Cesare] Univ Palermo, Dept Expt Biomed & Clin Neurosci BIONEC, Lab Biochem, I-90127 Palermo, Italy; [Notaro, Antonietta; Piccionello, Antonio Palumbo; Maggio, Antonella; D'Anneo, Antonella; Calvaruso, Giuseppe; Giuliano, Michela] Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol STEBICE, I-90133 Palermo, Italy		Giuliano, M (corresponding author), Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol STEBICE, I-90133 Palermo, Italy.	sonia.emanuele@unipa.it; antonietta.notaro@unipa.it; antonio.palumbopiccionello@unipa.it; antonella.maggio@unipa.it; marianna.lauricella@unipa.it; antonella.danneo@unipa.it; cesare.cernigliaro@unipa.it; giuseppe.calvaruso@unipa.it; michela.giuliano@unipa.it	Piccionello, Antonio Palumbo/V-6634-2017; D’Anneo, Antonella/P-1064-2019; Lauricella, Marianna/ABD-1263-2020; Maggio, Antonella Maria/AAW-2804-2021	Piccionello, Antonio Palumbo/0000-0003-4402-5798; D’Anneo, Antonella/0000-0002-1785-8236; Maggio, Antonella Maria/0000-0002-0861-626X; GIULIANO, Michela/0000-0002-5114-6267; LAURICELLA, Marianna/0000-0002-0157-3834; CERNIGLIARO, Cesare/0000-0002-0264-4921	Gruppo Azione Locale (GAL) of Golfo di Castellammare, Italy [17/2015, 313B]	This research was funded by Gruppo Azione Locale (GAL) of Golfo di Castellammare, Italy (Progetto Operativo n. 17/2015, misura 313B).	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J	Shintani, M; Sangawa, A; Yamao, N; Kamoshida, S				Shintani, Michiko; Sangawa, Akiko; Yamao, Naoki; Kamoshida, Shingo			Smac/DIABLO expression in human gastrointestinal carcinoma: Association with clinicopathological parameters and survivin expression	ONCOLOGY LETTERS			English	Article						survivin; Smac/DIABLO; immunohistochemistry; apoptosis	APOPTOSIS PROTEIN FAMILY; COLORECTAL-CANCER; GASTRIC-CANCER; IMMUNOHISTOCHEMICAL ANALYSIS; CYTOPLASMIC SURVIVIN; CELL-DEATH; PROGNOSIS; ADENOCARCINOMA; INHIBITOR; THERAPY	Lack of apoptosis is a key factor in carcinogenesis and tumor progression. Survivin is a member of the inhibitor of apoptosis protein (IA P) family. Second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) is an antagonist of IAPs. Recently, Smac/DIABLO was identified as a potent therapeutic target. However, the clinical significance of Smac/DIABLO in gastrointestinal carcinomas remains unclear. In the present study, Smac/DIABLO expression was analyzed by immunohistochemistry in 72 gastric adenocarcinomas and 78 colorectal adenocarcinomas. The expression of Smac/DIABLO was significantly higher in colorectal carcinoma than in gastric carcinoma. Additionally, a correlation was found between the expression of Smac/DIABLO and nuclear survivin in well- to moderately-differentiated colorectal adenocarcinomas (r=0.245; P<0.01). Based on these results, it was hypothesized that gastric and colorectal carcinomas differ in the level of Smac/DIABLO expression. Our previous studies revealed that the expression of cleaved caspase-9 was significantly lower in colorectal carcinoma than in gastric carcinoma (P<0.0001). Conversely, the expression levels of microtubule-associated protein 1 light chain 3 (LC3), an autophagy marker, and survivin were significantly higher in colon cancer than in gastric cancer (P<0.0001 and P<0.01, respectively). Taken together, these results indicate that not only LC3 and survivin expression, but also Smac/DIABLO expression, are significantly higher in colorectal carcinoma than in gastric carcinoma. We hypothesize that the analysis of Smac/DIABLO, survivin and LC3 expression in colorectal carcinoma is likely to aid cancer therapy due to the involvement of these markers in apoptosis and/or autophagy.	[Shintani, Michiko; Sangawa, Akiko; Kamoshida, Shingo] Kobe Univ, Grad Sch Hlth Sci, Div Med Biophys, Pathol Lab, Kobe, Hyogo 6540142, Japan; [Sangawa, Akiko] Osaka Red Cross Hosp, Dept Diagnost Pathol, Osaka 5438555, Japan; [Yamao, Naoki] Kuma Hosp, Dept Clin Lab, Kobe, Hyogo 6500011, Japan		Shintani, M (corresponding author), Kobe Univ, Grad Sch Hlth Sci, Div Med Biophys, Pathol Lab, 7-10-2 Tomogaoka, Kobe, Hyogo 6540142, Japan.	mtshin@kobe-u.ac.jp		yamao, naoki/0000-0002-0999-7420	Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [23590396]	The authors would like to thank Dr Masayuki Shintaku and Dr Toshihiko Miyake for their kind support. This study was supported by a Grant-in-Aid for Scientific Research (grant no. 23590396) from the Japan Society for the Promotion of Science.	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Lett.	DEC	2014	8	6					2581	2586		10.3892/ol.2014.2598			6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AU9YT	WOS:000345948600044	25364431	Green Submitted, Green Published, gold			2022-04-25	
J	Groulx, JF; Khalfaoui, T; Benoit, YD; Bernatchez, G; Carrier, JC; Basora, N; Beaulieu, JF				Groulx, Jean-Francois; Khalfaoui, Taoufik; Benoit, Yannick D.; Bernatchez, Gerald; Carrier, Julie C.; Basora, Nuria; Beaulieu, Jean-Francois			Autophagy is active in normal colon mucosa	AUTOPHAGY			English	Article						BECN1; p62/SQSTM1; autophagy; colon; epithelium; cancer	STEM-CELLS; BECLIN 1; CANCER; DISEASE; TUMORIGENESIS; EXPRESSION; PROGNOSIS; PROTEIN; GENE; DEGRADATION	Recently, autophagy has been found to be strongly activated in colon cancer cells, but few studies have addressed the normal colon mucosa. The aim of this study was to characterize autophagy in normal human intestinal cells. We used the expression of LC3-II and BECN1 as well as SQSTM1 as markers of autophagy activity. Using the normal human intestinal epithelial crypt (HIEC) cell experimental model, we found that autophagy was much more active in undifferentiated cells than in differentiated cells. In the normal adult colonic mucosa, BECN1 was found in the proliferative epithelial cells of the lower part of the gland while SQSTM1 was predominantly found in the differentiated cells of the upper part of the gland and surface epithelium. Interestingly, the weak punctate pattern of SQSTM1 expression in the lower gland colocalized with BECN1-labeled autophagosomes. The usefulness of SQSTM1 as an active autophagy marker was confirmed in colon cancer specimens at the protein and transcript levels. In conclusion, our results show that autophagy is active in the colonic gland and is associated with the intestinal proliferative/undifferentiated and progenitor cell populations.	[Groulx, Jean-Francois; Khalfaoui, Taoufik; Benoit, Yannick D.; Bernatchez, Gerald; Carrier, Julie C.; Basora, Nuria; Beaulieu, Jean-Francois] Univ Sherbrooke, CIHR Team Digest Epithelium, Dept Anat & Cell Biol, Fac Med & Hlth Sci, Sherbrooke, PQ J1K 2R1, Canada		Beaulieu, JF (corresponding author), Univ Sherbrooke, CIHR Team Digest Epithelium, Dept Anat & Cell Biol, Fac Med & Hlth Sci, Sherbrooke, PQ J1K 2R1, Canada.	Jean-Francois.Beaulieu@USherbrooke.ca		Benoit, Yannick/0000-0002-6677-4020	Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [MOP-57727, MOP-97836]; Canadian Research Chair in Intestinal Physiopathology	The work was supported by the Canadian Institutes of Health Research Grants MOP-57727 and MOP-97836 (to J.F.B.). J.F.B. is the recipient of a Canadian Research Chair in Intestinal Physiopathology and is a member of the FRSQ-funded Centre de Recherche Clinique Etienne Lebel of the CHUS.	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J	Kim, AD; Kang, KA; Kim, HS; Kim, DH; Choi, YH; Lee, SJ; Kim, HS; Hyun, JW				Kim, A. D.; Kang, K. A.; Kim, H. S.; Kim, D. H.; Choi, Y. H.; Lee, S. J.; Kim, H. S.; Hyun, J. W.			A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells	CELL DEATH & DISEASE			English	Article						apoptosis; autophagy; compound K; reactive oxygen species; colon cancer	DEATH; PATHWAY; SAPONIN; LC3; CROSSTALK; PROTEINS; ASSAY	Compound K (20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol) is an active metabolite of ginsenosides and induces apoptosis in various types of cancer cells. This study investigated the role of autophagy in compound K-induced cell death of human HCT-116 colon cancer cells. Compound K activated an autophagy pathway characterized by the accumulation of vesicles, the increased positive acridine orange-stained cells, the accumulation of LC3-II, and the elevation of autophagic flux. Whereas blockade of compound K-induced autophagy by 3-methyladenein and bafilomycin A1 significantly increased cell viability. In addition, compound K augmented the time-dependent expression of the autophagy-related proteins Atg5, Atg6, and Atg7. However, knockdown of Atg5, Atg6, and Atg7 markedly inhibited the detrimental impact of compound K on LC3-II accumulation and cell vitality. Compound K-provoked autophagy was also linked to the generation of intracellular reactive oxygen species (ROS); both of these processes were mitigated by the pre-treatment of cells with the antioxidant N-acetylcysteine. Moreover, compound K activated the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas downregulation of JNK by its specific inhibitor SP600125 or by small interfering RNA against JNK attenuated autophagy-mediated cell death in response to compound K. Compound K also provoked apoptosis, as evidenced by an increased number of apoptotic bodies and sub-G(1) hypodiploid cells, enhanced activation of caspase-3 and caspase-9, and modulation of Bcl-2 and Bcl-2-associated X protein expression. Notably, compound K-stimulated autophagy as well as apoptosis was induced by disrupting the interaction between Atg6 and Bcl-2. Taken together, these results indicate that the induction of autophagy and apoptosis by compound K is mediated through ROS generation and JNK activation in human colon cancer cells.	[Kim, A. D.; Kang, K. A.; Hyun, J. W.] Jeju Natl Univ, Sch Med, Cheju 690756, South Korea; [Kim, A. D.; Kang, K. A.; Hyun, J. W.] Jeju Natl Univ, Inst Nucl Sci & Technol, Cheju 690756, South Korea; [Kim, H. S.] Ewha Womans Univ, Dept Neurosci, Coll Med, Seoul, South Korea; [Kim, D. H.] Kyung Hee Univ, Dept Microbial Chem, Coll Pharm, Seoul, South Korea; [Choi, Y. H.] Dong Eui Univ, Dept Biochem, Coll Oriental Med, Pusan, South Korea; [Choi, Y. H.] Dong Eui Univ, Res Inst Oriental Med, Pusan, South Korea; [Lee, S. J.] Hanyang Univ, Dept Chem, Res Inst Nat Sci, Seoul 133791, South Korea; [Kim, H. S.] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea		Hyun, JW (corresponding author), Jeju Natl Univ, Sch Med, Cheju 690756, South Korea.	jinwonh@jejunu.ac.kr			National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea [1120340]	This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1120340).	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AUG	2013	4								e750	10.1038/cddis.2013.273			11	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	214PK	WOS:000324146000007	23907464	gold, Green Published			2022-04-25	
J	Miki, H; Uehara, N; Kimura, A; Sasaki, T; Yuri, T; Yoshizawa, K; Tsubura, A				Miki, Hisanori; Uehara, Norihisa; Kimura, Ayako; Sasaki, Tomo; Yuri, Takashi; Yoshizawa, Katsuhiko; Tsubura, Airo			Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						resveratrol; reactive oxygen species; autophagy; apoptosis; caspase-8; colon cancer; HT-29; COLO 201	DEATH; MITOCHONDRIA; INHIBITION; MODULATION; EXPRESSION; PATHWAY; GROWTH; ACID	Resveratrol (Res; 3,41,5-trihydroxy-trans-stilbene), which is a polyphenol found in grapes, can block cell proliferation and induce growth arrest and/or cell death in several types of cancer cells. However, the precise mechanisms by which Res exerts anticancer effects remain poorly understood. Res blocked both anchorage-dependent and -independent growth of HT-29 and COLO 201 human colon cancer cells in a dose- and time-dependent manner. Annexin V staining and Western blot analysis revealed that Res induced apoptosis accompanied by an increase in Caspase-8 and Caspase-3 cleavage. In HT-29 cells, Res caused autophagy as characterized by the appearance of autophagic vacuoles by electron microscopy and elevation of microtubule-associated protein 1 light chain 3 (LC3)-II by immunoblotting, which was associated with the punctuate pattern of LC3 detected by fluorescein microscopy. Inhibition of Res-induced autophagy by the autophagy inhibitor 3-methyladenine caused a significant decrease in apoptosis accompanied by decreased cleavage of Casapse-8 and Caspase-3, indicating that Res-induced autophagy was cytotoxic. However, inhibition of Res-induced apoptosis by the pan-caspase inhibitor Z-VAD(OMe)-FMK did not decrease autophagy but elevated LC3-II levels. Interestingly, Res increased the intracellular reactive oxygen species (ROS) level, which correlated to the induction of Casapse-8 and Caspase-3 cleavage and the elevation of LC3-II; treatment with ROS scavenger N-acetyl cysteine diminished this effect. Therefore, the effect of Res on the induction of apoptosis via autophagy is mediated through ROS in human colon cancer cells.	[Miki, Hisanori; Uehara, Norihisa; Kimura, Ayako; Sasaki, Tomo; Yuri, Takashi; Yoshizawa, Katsuhiko; Tsubura, Airo] Kansai Med Univ, Dept Pathol 2, Moriguchi, Osaka 5708506, Japan		Tsubura, A (corresponding author), Kansai Med Univ, Dept Pathol 2, Moriguchi, Osaka 5708506, Japan.	tsubura@takii.kmu.ac.jp	Uehara, Norihisa/F-5933-2012; Uehara, Norihisa/ABB-8106-2020				Athar M, 2007, TOXICOL APPL PHARM, V224, P274, DOI 10.1016/j.taap.2006.12.025; Chau I, 2006, ANN ONCOL, V17, P1347, DOI 10.1093/annonc/mdl029; Chen Z, 2010, EUR J PHARMACOL, V643, P170, DOI 10.1016/j.ejphar.2010.06.025; Chen ZH, 2010, P NATL ACAD SCI USA, V107, P18880, DOI 10.1073/pnas.1005574107; Juan ME, 2008, J AGR FOOD CHEM, V56, P4813, DOI 10.1021/jf800175a; Fawcett H, 2005, INT J ONCOL, V27, P1717; Fulda S, 2006, CANCER DETECT PREV, V30, P217, DOI 10.1016/j.cdp.2006.03.007; Ganapathy S, 2010, PLOS ONE, V5, DOI 10.1371/journal.pone.0015627; Gozuacik D, 2007, CURR TOP DEV BIOL, V78, P217, DOI 10.1016/S0070-2153(06)78006-1; Huang CS, 1999, CARCINOGENESIS, V20, P237, DOI 10.1093/carcin/20.2.237; Huerta S, 2006, AM J SURG, V191, P517, DOI 10.1016/j.amjsurg.2005.11.009; Jang MS, 1997, SCIENCE, V275, P218, DOI 10.1126/science.275.5297.218; Johnson WD, 2011, FOOD CHEM TOXIC 0910; Kanematsu S, 2010, ANTICANCER RES, V30, P3381; Kim MY, 2009, ANTICANCER RES, V29, P3733; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Kondo Y, 2006, AUTOPHAGY, V2, P85, DOI 10.4161/auto.2.2.2463; Kroemer G, 2007, PHYSIOL REV, V87, P99, DOI 10.1152/physrev.00013.2006; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Liang YC, 2003, BIOCHEM PHARMACOL, V65, P1053, DOI 10.1016/S0006-2952(03)00011-X; Liao PC, 2010, J MED FOOD, V13, P1415, DOI 10.1089/jmf.2010.1126; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Nakagawa H, 2001, J CANCER RES CLIN, V127, P258, DOI 10.1007/s004320000190; Opipari AW, 2004, CANCER RES, V64, P696, DOI 10.1158/0008-5472.CAN-03-2404; Puissant A, 2010, CANCER RES, V70, P1042, DOI 10.1158/0008-5472.CAN-09-3537; Reis-Sobreiro M, 2009, ONCOGENE, V28, P3221, DOI 10.1038/onc.2009.183; Roig P, 1999, LIFE SCI, V64, P1517, DOI 10.1016/S0024-3205(99)00088-0; Scarlatti F, 2008, CELL DEATH DIFFER, V15, P1318, DOI 10.1038/cdd.2008.51; SCHATZKIN A, 1995, EUR J CANCER, V31A, P1198, DOI 10.1016/0959-8049(95)00138-9; Shankar S, 2007, MOL CELL BIOCHEM, V304, P273, DOI 10.1007/s11010-007-9510-x; Shih A, 2002, J CLIN ENDOCR METAB, V87, P1223, DOI 10.1210/jc.87.3.1223; Trincheri NF, 2008, CARCINOGENESIS, V29, P381, DOI 10.1093/carcin/bgm271; Uehara N, 2008, MOL CANCER RES, V6, P186, DOI 10.1158/1541-7786.MCR-07-0254; Wang QL, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0017234; Wenzel U, 2005, APOPTOSIS, V10, P359, DOI 10.1007/s10495-005-0810-x; White E, 2009, CLIN CANCER RES, V15, P5308, DOI 10.1158/1078-0432.CCR-07-5023; Wong CH, 2010, PLOS ONE, V5, DOI 10.1371/journal.pone.0009996; Xu R, 2006, HISTOL HISTOPATHOL, V21, P867, DOI 10.14670/HH-21.867	39	147	159	0	16	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1019-6439	1791-2423		INT J ONCOL	Int. J. Oncol.	APR	2012	40	4					1020	1028		10.3892/ijo.2012.1325			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	910LI	WOS:000301637800015	22218562	Green Submitted, Bronze, Green Published			2022-04-25	
J	Wu, HC; Liu, JQ; Yin, Y; Zhang, D; Xia, PP; Zhu, GQ				Wu, Hucong; Liu, Jiaqi; Yin, Yi; Zhang, Dong; Xia, Pengpeng; Zhu, Guoqiang			Therapeutic Opportunities in Colorectal Cancer: Focus on Melatonin Antioncogenic Action	BIOMED RESEARCH INTERNATIONAL			English	Review							COLON CARCINOGENESIS; PROLIFERATIVE ACTIVITY; AUTOPHAGY; CELLS; APOPTOSIS; EXPRESSION; ANGIOGENESIS; TUMORS; 1,2-DIMETHYLHYDRAZINE; SENESCENCE	Colorectal cancer (CRC) influences individual health worldwide with high morbidity and mortality. Melatonin, which shows multiple physiological functions (e.g., circadian rhythm, immune modulation, and antioncogenic action), can be present in almost all organisms and found in various tissues including gastrointestinal tract. Notably, melatonin disruption is closely associated with the elevation of CRC incidence, indicating that melatonin is effective in suppressing CRC development and progression. Mechanistically, melatonin favors in activating apoptosis and colon cancer immunity, while reducing proliferation, autophagy, metastasis, and angiogenesis, thereby exerting its anticarcinogenic effects.)is review highlights that melatonin can be an adjuvant therapy and be beneficial in treating patients suffering from CRC.	[Wu, Hucong; Liu, Jiaqi; Yin, Yi; Zhang, Dong; Xia, Pengpeng; Zhu, Guoqiang] Yangzhou Univ, Coll Vet Med, Yangzhou 225009, Jiangsu, Peoples R China; [Wu, Hucong; Liu, Jiaqi; Yin, Yi; Xia, Pengpeng; Zhu, Guoqiang] Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou 225009, Jiangsu, Peoples R China		Zhu, GQ (corresponding author), Yangzhou Univ, Coll Vet Med, Yangzhou 225009, Jiangsu, Peoples R China.; Zhu, GQ (corresponding author), Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou 225009, Jiangsu, Peoples R China.	yzgqzhu@yzu.edu.cn	Xia, pengpeng/AAR-1874-2020	Xia, pengpeng/0000-0002-3693-1312	National Key Research and Development Program of China [2017YFD0500203, 2017YFD 0500105, 2016YDF0500905]; Chinese National Science FoundationNational Natural Science Foundation of China (NSFC) [31672579, 30571374, 30771603, 31092136, 31270171]; Yangzhou Science and Technology Bureau International Cooperation Project [YZ2018154]; Priority Academic Program of Development Jiangsu High Education Institution	This work was partially supported by Grant nos. 2017YFD0500203, 2017YFD 0500105, and 2016YDF0500905 from the National Key Research and Development Program of China, grants from the Chinese National Science Foundation Grant (Nos. 31672579, 30571374, 30771603, 31092136, 31270171), and a project funded by the Priority Academic Program of Development Jiangsu High Education Institution and it grants from the Yangzhou Science and Technology Bureau International Cooperation Project (YZ2018154).	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Int.	SEP 17	2019	2019								9740568	10.1155/2019/9740568			6	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	JH7HM	WOS:000492938700003	31637261	Green Published, gold, Green Submitted			2022-04-25	
J	Huang, HL; Chen, WC; Hsu, HP; Cho, CY; Hung, YH; Wang, CY; Lai, MD				Huang, Hau-Lun; Chen, Wei-Ching; Hsu, Hui-Ping; Cho, Chien-Yu; Hung, Yu-Hsuan; Wang, Chih-Yang; Lai, Ming-Derg			Silencing of argininosuccinate lyase inhibits colorectal cancer formation	ONCOLOGY REPORTS			English	Article						argininosuccinate lyase; nitric oxide; autophagy; endoplasmic reticulum; cyclin A; colorectal cancer	NITRIC-OXIDE PRODUCTION; BODY-MASS INDEX; L-ARGININE; CELL-PROLIFERATION; SYNTHASE GENE; BREAST-CANCER; TUMOR-GROWTH; AUTOPHAGY; DEPRIVATION; EXPRESSION	Arginine and nitric oxide (NO) are important mediators of tumorigenesis in various types of cancer. Dysregulation of NO content by argininosuccinate lyase (ASL) has been previously demonstrated to inhibit the proliferation of liver and breast cancer cells. However, the function of ASL in colon cancer is not well defined. The present study aimed to determine the effect of ASL on colon cancer. Western blot analysis indicated that ASL expression was induced by endoplasmic reticulum stress in HCT116 and SW480 colon cancer cells. Additionally, the expression of ASL in colon cancer tissues was enhanced compared with that in the adjacent normal tissues, and the patients with colon cancer with higher ASL expression exhibited poorer survival rates. Transfection of ASL-targeting short hairpin RNA (shRNA) into HCT116 cells inhibited cell proliferation and decreased anchorage-independent growth in a soft agar assay. In addition, when injected subcutaneously into NOD/SCID mice, stable transfectant ASL-downregulated HCT116 cells exhibited decreased in vivo tumorigenic ability. Flow cytometric analysis of cell cycle progression indicated that ASL-targeting shRNA induced G2/M arrest, and western blot analysis showed that the inhibition of ASL was accompanied by cyclin A2 degradation. Furthermore, ASL-targeting shRNA resulted in increased autophagosomes and decreased NO levels. Inhibition of NO by the NO synthase inhibitor L-NMMA significantly reduced cell proliferation and colony formation. In summary, the results of the present study indicated that ASL-targeting shRNA-induced growth inhibition is associated with decreased cyclin A2 expression and NO content in colon cancer.	[Huang, Hau-Lun; Chen, Wei-Ching; Cho, Chien-Yu; Hung, Yu-Hsuan; Wang, Chih-Yang; Lai, Ming-Derg] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan, Taiwan; [Huang, Hau-Lun; Chen, Wei-Ching; Cho, Chien-Yu; Hung, Yu-Hsuan; Wang, Chih-Yang; Lai, Ming-Derg] Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, 1 Univ Rd, Tainan 701, Taiwan; [Hsu, Hui-Ping] Natl Cheng Kung Univ, Coll Med, Dept Surg, Tainan, Taiwan; [Lai, Ming-Derg] Natl Cheng Kung Univ, Coll Med, Ctr Infect Dis & Signaling Res, Tainan, Taiwan		Lai, MD (corresponding author), Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, 1 Univ Rd, Tainan 701, Taiwan.	a1211207@mail.ncku.edu.tw	Lai, Ming-Derg/M-8028-2014	Wang, Chih-Yang/0000-0002-4137-5074	National Science Council (Taiwan)Ministry of Science and Technology, Taiwan [NSC-100-2325-B-006-008]; National Health Research Institute, TaiwanNational Health Research Institutes - Taiwan [NHRI-EX100-9927B1]; Department of Health, Executive Yuan (Taiwan) [DOH101-TD-C-111-003]	The present study was supported by a grant to M.-D. Lai, (NSC-100-2325-B-006-008) from the National Science Council (Taiwan) and (NHRI-EX100-9927B1) from the National Health Research Institute, Taiwan to establish Centers of Excellence for Cancer Research in Taiwan, (DOH101-TD-C-111-003) Department of Health, Executive Yuan (Taiwan).	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Rep.	JAN	2017	37	1					163	170		10.3892/or.2016.5221			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EF9GX	WOS:000390639800020	27840980	Bronze			2022-04-25	
J	Yoo, HY; Park, SY; Chang, SY; Kim, SH				Yoo, Hee Young; Park, So Yeon; Chang, Sun-Young; Kim, So Hee			Regulation of Butyrate-Induced Resistance through AMPK Signaling Pathway in Human Colon Cancer Cells	BIOMEDICINES			English	Article						butyrate resistance; colon cancer; AMPK; autophagy; ACC; Akt; mTOR	COLORECTAL-CANCER; DRUG-RESISTANCE; AUTOPHAGY; METABOLISM; ACQUISITION; INHIBITION	Butyrates inhibit cell growth in colon cancer cells by inhibiting histone deacetylases. However, chronic exposure to butyrates induces butyrate resistance in colon cancer cells. The mechanism underlying the acquisition of resistance is not yet fully understood. Here, butyrate-resistant (BR) colon cancer cells were developed in HCT116, HT29, and SW480 human colon cancer cells and were confirmed by the increase in the inhibitory concentrations of cell growth by 50% (IC50) compared to their respective parental (PT) cells. Chronic exposure to butyrate induced autophagy via higher expression of Beclin-1 and LC3B-II. The AMP-activated protein kinase (AMPK) was downregulated along with the activation of Akt and mammalian target of rapamycin (mTOR) and decrease in acetyl-CoA carboxylase (ACC) in BR colon cancer cells compared to those in their respective PT cells. Activation of AMPK by AICAR treatment in BR colon cancer cells suppressed cell proliferation by inhibiting Akt and mTOR and activating ACC. Taken together, chronic exposure to butyrate increased butyrate resistance in human colon cancer by inducing protective autophagy through the downregulation of AMPK/ACC and activation of Akt/mTOR signaling. Activation of AMPK restored sensitivity to butyrate by the inhibition of Akt/mTOR, suggesting that AMPK could be a therapeutic target for BR colon cancers.	[Kim, So Hee] Ajou Univ, Coll Pharm, Suwon 16499, South Korea; Ajou Univ, Res Inst Pharmaceut Sci & Technol, Suwon 16499, South Korea		Kim, SH (corresponding author), Ajou Univ, Coll Pharm, Suwon 16499, South Korea.	yoo1454@ajou.ac.kr; qkrth0413@ajou.ac.kr; sychang@ajou.ac.kr; shkim67@ajou.ac.kr			Basic Science Research Program through the National Research Foundation of Korea (NRF) [NRF-2018R1A2B6004895, NRF-2021R1A2C1011142]	Funding This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) through the Ministry of Science, ICT, and Future Planning, NRF-2018R1A2B6004895 and NRF-2021R1A2C1011142.	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J	Zhang, X; Yang, H; Yue, SQ; He, GB; Qu, SB; Zhang, ZC; Ma, B; Ding, R; Peng, W; Zhang, HT; Yang, ZX; Dou, KF; Tao, KS; Li, X				Zhang, Xuan; Yang, Hua; Yue, Shuqiang; He, Guangbin; Qu, Shibin; Zhang, Zhuochao; Ma, Ben; Ding, Rui; Peng, Wei; Zhang, Hongtao; Yang, Zhaoxu; Dou, Kefeng; Tao, Kaishan; Li, Xiao			The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma	CANCER MEDICINE			English	Article						Autophagy; ERK1/2; glycyrrhizin; hepatocellular carcinoma; mTOR	ADENOCARCINOMA CELL-GROWTH; COLON-CANCER CELLS; PROMYELOTIC LEUKEMIA; PI3K/AKT PATHWAY; ACID; APOPTOSIS; DEATH; MACROAUTOPHAGY; INDUCTION; HEPATOMA	Autophagy is a life phenomenon in which autophagosomes remove damaged or aging organelles and long-lived circulating proteins to maintain the cell's stability. However, disorders of excessive autophagy are a response of cancer cells to a variety of anticancer treatments which lead to cancer cell death. The Akt/mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are both involved in nutrient-induced autophagic phenomenon and exhibit vital relevance to oncogenesis in various cancer cell types, including hepatocellular carcinoma (HCC). However, the influence of autophagy for cancer cell death remains controversial and few scientists have investigated the variation of these two signaling pathways in cancer cell autophagic phenomenon induced by anticancer treatment simultaneously. Here, we explored the anticancer efficacy and mechanisms of glycyrrhizin (GL), a bioactive compound of licorice with little toxicity in normal cells. It is interesting that inhibition of Akt/mTOR signaling in concurrence with enhanced ERK1/2 activity exists in GL-induced autophagy and cytotoxicity in HepG2 and MHCC97-H hepatocellular carcinoma cells. These results imply that the GL-related anticancer ability might correlate with the induction of autophagy. The influence of induced autophagic phenomenon on cell viability might depend on the severity of autophagy and be pathway specific. In the subsequent subcutaneous xenograft experiment in vivo with MHCC97-H cells, GL obviously exhibited its inhibitory efficacy in tumor growth via inducing excess autophagy in MHCC97-H cells (P<0.05). Our data prompt that GL possesses a property of excess autophagic phenomenon induction in HCC and exerts high anticancer efficacy in vitro and in vivo. This warrants further investigation toward possible clinical applications in patients with HCC.	[Zhang, Xuan; Qu, Shibin; Zhang, Zhuochao; Ma, Ben; Ding, Rui; Peng, Wei; Zhang, Hongtao; Yang, Zhaoxu; Dou, Kefeng; Tao, Kaishan; Li, Xiao] Fourth Mil Med Univ, Xijing Hosp, Dept Hepatobiliary Surg, Xian, Shaanxi, Peoples R China; [Yang, Hua] Xian 1 Hosp, Dept Geriatr, Xian, Shaanxi, Peoples R China; [Yue, Shuqiang] Fourth Mil Med Univ, Xijing Hosp, Dept Surg Oncol, Xian, Shaanxi, Peoples R China; [He, Guangbin] Fourth Mil Med Univ, Xijing Hosp, Dept Ultrasound Diag, Xian, Shaanxi, Peoples R China		Dou, KF; Tao, KS; Li, X (corresponding author), Fourth Mil Med Univ, Xijing Hosp, Dept Hepatobiliary Surg, Xian, Shaanxi, Peoples R China.	doukef@fmmu.edu.cn; taokaishan0686@163.com; lixiao0076@163.com	Zhang, Xuan/L-3020-2019	/0000-0002-6624-5532	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81272648, 81201926]; Shaanxi Resource-based Industry Key Technology [2015KTCL-03-011]	This study was supported by the National Natural Science Foundation of China (81272648 and 81201926) and Shaanxi Resource-based Industry Key Technology (2015KTCL-03-011).	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AUG	2017	6	8					1941	1951		10.1002/cam4.1127			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FD3JI	WOS:000407428900010	28675698	Green Published, gold			2022-04-25	
J	Kim, SY; Song, XX; Zhang, L; Bartlett, DL; Lee, YJ				Kim, Seog-Young; Song, Xinxin; Zhang, Lin; Bartlett, David L.; Lee, Yong J.			Role of Bcl-xL/Beclin-1 in interplay between apoptosis and autophagy in oxaliplatin and bortezomib-induced cell death	BIOCHEMICAL PHARMACOLOGY			English	Article						Oxaliplatin; Bortezomib; Mitochondria-dependent pathway; Bcl-xL; Beclin-1	ENDOPLASMIC-RETICULUM STRESS; CASPASE-MEDIATED CLEAVAGE; HUMAN COLON-CANCER; BCL-X-L; BECLIN 1; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEASOME INHIBITION; COLORECTAL-CANCER; JNK1-MEDIATED PHOSPHORYLATION; REGULATES AUTOPHAGY	Recent studies indicate that a complex relationship exists between autophagy and apoptosis. In this study we investigated a regulatory relationship between autophagy and apoptosis in colorectal cancer cells utilizing molecular and biochemical approaches. For this study, human colorectal carcinoma HCT116 and CX-1 cells were treated with two chemotherapeutic agents-oxaliplatin, which induces apoptosis, and bortezomib, which triggers both apoptosis and autophagy. A combinatorial treatment of oxaliplatin and bortezomib caused a synergistic induction of apoptosis which was mediated through an increase in caspase activation. The combinational treatment of oxaliplatin and bortezomib promoted the JNK-Bcl-xL-Bax pathway which modulated the synergistic effect through the mitochondria-dependent apoptotic pathway. JNK signaling led to Bcl-xL phosphorylation at serine 62, oligomerization of Bax, alteration of mitochondrial membrane potential, and subsequent cytochrome c release. Overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed cytochrome c release and synergistic death effect. Interestingly, Bcl-xL also affected autophagy through alteration of interaction with Beclin-1. Beclin-1 was dissociated from Bcl-xL and initiated autophagy during treatment with oxaliplatin and bortezomib. However, activated caspase 8 cleaved Beclin-1 and suppressed Beclin-1-associated autophagy and enhanced apoptosis. A combinatorial treatment of oxaliplatin and bortezomib-induced Beclin-1 cleavage was abolished in Beclin-1 double mutant (D133AA/D149A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. In addition, the combinatorial treatment significantly inhibited colorectal cancer xenografts' tumor growth. An understanding of the molecular mechanisms of crosstalk between apoptosis and autophagy will support the application of combinatorial treatment to colorectal cancer. (C) 2014 Elsevier Inc. All rights reserved.	[Kim, Seog-Young; Song, Xinxin; Bartlett, David L.; Lee, Yong J.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA; [Zhang, Lin; Lee, Yong J.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA		Lee, YJ (corresponding author), Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA.	leeyj@upmc.edu	Zhang, Lin/A-7389-2009	Zhang, Lin/0000-0003-0018-3903	NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA140554, R01CA106348, R01CA121105];  [P30CA047904]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA121105, R01CA140554, P30CA047904, R01CA106348] Funding Source: NIH RePORTER	This work was supported by the following grant: NCI grant R01CA140554 (Y.J.L.), R01CA106348 (L.Z.) and R01CA121105 (L.Z.) This project used the UPCI Core Facility and was supported in part by award P30CA047904.	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Pharmacol.	MAR 15	2014	88	2					178	188		10.1016/j.bcp.2014.01.027			11	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	AD0DC	WOS:000332903600006	24486574	Green Accepted			2022-04-25	
J	Wang, LJ; Zhu, YR; Wang, SW; Zhao, S				Wang, Lijun; Zhu, Yun-Rong; Wang, Shaowei; Zhao, Song			Autophagy inhibition sensitizes WYE-354-induced anti-colon cancer activity in vitro and in vivo	TUMOR BIOLOGY			English	Article						Colon cancer; mTORC1/2; WYE-354; Autophagy; Chemo-sensitization	COLORECTAL-CANCER; PRECLINICAL EVALUATION; INDUCED APOPTOSIS; MTOR; PROTEIN; PHOSPHORYLATION; CHEMOTHERAPY; STRATEGIES; THERAPY; TARGET	Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 are frequently dysregulated in human colon cancers. In the present study, we evaluated the potential anti-colon cancer cell activity by a novel mTORC1/2 dual inhibitor WYE-354. We showed that WYE-354 was anti-survival and anti-proliferative when adding to primary (patient-derived) and established (HCT-116, HT-29, Caco-2, LoVo, and DLD-1 lines) colon cancer cells. In addition, WYE-354 treatment activated caspase-dependent apoptosis in the colon cancer cells. Mechanistically, WYE-354 blocked mTORC1 and mTORC2 activation. Meanwhile, it also induced autophagy activation in the colon cancer cells. Autophagy inhibitors (bafilomycin A1 and 3-methyladenine), or shRNA-mediated knockdown of autophagy elements (Beclin-1 and ATG-5), remarkably sensitized WYE-354-mediated anti-colon cancer cell activity in vitro. Further studies showed that WYE-354 administration inhibited HT-29 xenograft growth in severe combined immunodeficient (SCID) mice. Importantly, its activity in vivo was further potentiated with co-administration of the autophagy inhibitor 3-MA. Phosphorylations of Akt (Ser-473) and S6 were also decreased in WYE-354-treated HT-29 xenografts. Together, these pre-clinical results demonstrate the potent anti-colon cancer cell activity by WYE-354, and its activity may be further augmented with autophagy inhibition.	[Wang, Lijun; Wang, Shaowei] Tianjin Hosp, Dept Gen Surg, 406 Jiefang South Rd, Tianjin 300211, Peoples R China; [Zhu, Yun-Rong] Southeast Univ, Affiliated Jiangyin Hosp, Dept Orthoped, Coll Med, Jiangyin City 214400, Peoples R China; [Zhao, Song] Hebei Med Univ, Dept Pathophysiol, Shijiazhuang, Peoples R China		Wang, SW (corresponding author), Tianjin Hosp, Dept Gen Surg, 406 Jiefang South Rd, Tianjin 300211, Peoples R China.	wangshaoweidr@sohu.com					Alcarraz-Vizan G, 2014, BBA-GEN SUBJECTS, V1840, P1634, DOI 10.1016/j.bbagen.2013.12.024; Chen B, 2015, DNA CELL BIOL; Chen MB, 2015, CARCINOGENESIS, V36, P1061, DOI 10.1093/carcin/bgv094; Chen MB, 2014, CELL SIGNAL, V26, P102, DOI 10.1016/j.cellsig.2013.07.017; Chen MB, 2013, CELL SIGNAL, V25, P1993, DOI 10.1016/j.cellsig.2013.05.026; Chen MB, 2011, J CELL PHYSIOL, V226, P1915, DOI 10.1002/jcp.22522; Chen XG, 2010, MOL CARCINOGEN, V49, P603, DOI 10.1002/mc.20628; Dancey J, 2010, NAT REV CLIN ONCOL, V7, P209, DOI 10.1038/nrclinonc.2010.21; Ekstrand AI, 2010, FAM CANCER, V9, P125, DOI 10.1007/s10689-009-9293-1; Francipane MG, 2014, ONCOTARGET, V5, P49, DOI 10.18632/oncotarget.1548; Fruman DA, 2014, NAT REV DRUG DISCOV, V13, P140, DOI 10.1038/nrd4204; Guertin DA, 2006, DEV CELL, V11, P859, DOI 10.1016/j.devcel.2006.10.007; Holohan C, 2013, NAT REV CANCER, V13, P714, DOI 10.1038/nrc3599; Hubbard JM, 2015, NAT REV CLIN ONCOL, V12, P73, DOI 10.1038/nrclinonc.2014.233; Jung CH, 2009, MOL BIOL CELL, V20, P1992, DOI 10.1091/mbc.E08-12-1249; Kerr D, 2003, NAT REV CANCER, V3, P615, DOI 10.1038/nrc1147; Kim J, 2011, NAT CELL BIOL, V13, P132, DOI 10.1038/ncb2152; Kim KH, 2014, NAT REV ENDOCRINOL; Kuipers EJ, 2013, NAT REV CLIN ONCOL, V10, P130, DOI 10.1038/nrclinonc.2013.12; Leake Isobel, 2014, Nat Rev Gastroenterol Hepatol, V11, P270, DOI 10.1038/nrgastro.2014.60; Li C, 2015, CANCER BIOL THER, V16, P34, DOI 10.4161/15384047.2014.972274; Li J, 2010, EUR J CANCER, V46, P1900, DOI 10.1016/j.ejca.2010.02.021; Li Q, 2013, BIOCHEM BIOPH RES CO, V440, P701, DOI 10.1016/j.bbrc.2013.09.130; Ma J, 2012, J BIOL CHEM, V287, P34149, DOI 10.1074/jbc.M112.382812; Mammucari C, 2007, CELL METAB, V6, P458, DOI 10.1016/j.cmet.2007.11.001; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; McCarthy N, 2013, NAT REV CANCER, V13, P297, DOI [10.1038/nrc3509, 10.1038/nrc3909]; Metzger-Filho O, 2010, CURR CLIN PHARMACOL, V5, P166, DOI 10.2174/157488410791498716; Moyer MP, 1996, IN VITRO CELL DEV-AN, V32, P315; Palta M, 2014, NAT REV CLIN ONCOL, V11, P182, DOI 10.1038/nrclinonc.2014.43; Pandurangan AK, 2013, ASIAN PAC J CANCER P, V14, P2201, DOI 10.7314/APJCP.2013.14.4.2201; Rubinsztein DC, 2012, NAT REV DRUG DISCOV, V11, P709, DOI 10.1038/nrd3802; Sabatini DM, 2006, NAT REV CANCER, V6, P729, DOI 10.1038/nrc1974; Schmoll HJ, 2014, NAT REV CLIN ONCOL, V11, P79, DOI 10.1038/nrclinonc.2013.254; SEGLEN PO, 1982, P NATL ACAD SCI-BIOL, V79, P1889, DOI 10.1073/pnas.79.6.1889; Shimobayashi M, 2014, NAT REV MOL CELL BIO, V15, P155, DOI 10.1038/nrm3757; Siegel RL, 2015, CA-CANCER J CLIN, V65, P5, DOI [10.3322/caac.21254, 10.3322/caac.21208, 10.1001/jamaoto.2014.2530, 10.1136/bmj.g1502]; Vilar E, 2011, MOL CANCER THER, V10, P395, DOI 10.1158/1535-7163.MCT-10-0905; Yu K, 2009, CANCER RES, V69, P6232, DOI 10.1158/0008-5472.CAN-09-0299; Zhang YJ, 2009, ANN SURG ONCOL, V16, P2617, DOI 10.1245/s10434-009-0555-9; Zheng B, 2015, CANCER LETT, V357, P468, DOI 10.1016/j.canlet.2014.11.012; Zhou HY, 2012, CHIN J CANCER, V31, P8, DOI 10.5732/cjc.011.10281; Zhu YR, 2014, BIOCHEM BIOPH RES CO, V451, P112, DOI 10.1016/j.bbrc.2014.07.077	43	10	11	0	5	SAGE PUBLICATIONS LTD	LONDON	1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND	1010-4283	1423-0380		TUMOR BIOL	Tumor Biol.	SEP	2016	37	9					11743	11752		10.1007/s13277-016-5018-x			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EB0ZJ	WOS:000387075400018	27020593				2022-04-25	
J	Bhardwaj, M; Cho, HJ; Paul, S; Jakhar, R; Khan, I; Lee, SJ; Kim, BY; Krishnan, M; Khaket, TP; Lee, HG; Kang, SC				Bhardwaj, Monika; Cho, Hee Jun; Paul, Souren; Jakhar, Rekha; Khan, Imran; Lee, Seon-Jin; Kim, Bo-Yeon; Krishnan, Manigandan; Khaket, Tejinder Pal; Lee, Hee Gu; Kang, Sun Chul			Vitexin induces apoptosis by suppressing autophagy in multi-drug resistant colorectal cancer cells	ONCOTARGET			English	Article						apoptosis; autophagy; colorectal cancer; multidrug resistance; vitexin	HEAT-SHOCK; CARCINOMA CELLS; MDR1 GENE; IN-VITRO; EXPRESSION; TRANSPORTERS; CHEMORESISTANCE; SURVIVAL; FACTOR-1; FAMILY	Cancer treatment is limited due to the diverse multidrug resistance acquired by cancer cells and the collateral damage caused to adjacent normal cells by chemotherapy. The flavonoid compound vitexin exhibits anti-oxidative, anti-inflammatory and anti-tumor activity. This study elucidated the antitumor effects of vitexin and its underlying mechanisms in a multi-drug resistant human colon cancer cell line (HCT-116DR), which exhibits higher levels of multidrug-resistant protein 1 (MDR1) expression as compared with its parental cell line (HCT-116). Here, we observed that vitexin suppressed MDR-1 expression and activity in HCT-116DR cells and showed cytotoxic effect in HCT-116DR cells by inhibiting autophagy and inducing apoptosis in a concentration-dependent manner. Additionally, vitexin treatment caused cleavage of caspase-9 and caspase-3, and upregulated the expression of the pro-apoptotic proteins, BID and Bax. Moreover, the expression of autophagy-related proteins, such as ATG5, Beclin-1 and LC3-II, was markedly reduced by vitexin treatment. Furthermore, in vivo experiments showed that vitexin induced apoptosis and suppressed tumor growth in HCT-116DR xenograft model. These results revealed that vitexin induced apoptosis through suppression of autophagy in vitro and in vivo and provide insight into the therapeutic potential of vitexin for the treatment of chemo-resistant colorectal cancer.	[Bhardwaj, Monika; Paul, Souren; Jakhar, Rekha; Khan, Imran; Krishnan, Manigandan; Khaket, Tejinder Pal; Kang, Sun Chul] Daegu Univ, Dept Biotechnol, Kyongsan, Kyoungbook, South Korea; [Cho, Hee Jun; Lee, Seon-Jin; Lee, Hee Gu] Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, Daejeon, South Korea; [Lee, Seon-Jin; Kim, Bo-Yeon; Lee, Hee Gu] Univ Sci & Technol, Dept Biomol Sci, Daejeon, South Korea; [Kim, Bo-Yeon] Korea Res Inst Biosci & Biotechnol, Anticanc Agents Res Ctr, World Class Inst, Ochang, Cheongwon, South Korea		Kang, SC (corresponding author), Daegu Univ, Dept Biotechnol, Kyongsan, Kyoungbook, South Korea.; Lee, HG (corresponding author), Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, Daejeon, South Korea.; Lee, HG (corresponding author), Univ Sci & Technol, Dept Biomol Sci, Daejeon, South Korea.	hglee@kribb.re.kr; sckang@daegu.ac.kr	Shubhakaran, Khichar/AAH-2454-2020; Lee, Seon-Jin/AAJ-8258-2020; Khaket, Tej/I-6260-2015	Shubhakaran, Khichar/0000-0001-5515-7572; Manigandan, Krishnan/0000-0002-4998-4405; Lee, Seon-Jin/0000-0001-7214-7536	National Research Foundation (NRF) of South Korea [2016R1A2B4009227, 2017R1A2B2005629, 2016H1D3A1938249, 2017R1D1A1B03036569]	This research was funded by the National Research Foundation (NRF) of South Korea (2016R1A2B4009227, 2017R1A2B2005629, 2016H1D3A1938249 and 2017R1D1A1B03036569).	Adams JM, 1998, SCIENCE, V281, P1322, DOI 10.1126/science.281.5381.1322; An F, 2012, NEURAL REGEN RES, V7, P2565, DOI 10.3969/j.issn.1673-5374.2012.33.001; AZZARIA M, 1989, MOL CELL BIOL, V9, P5289, DOI 10.1128/MCB.9.12.5289; Bhardwaj M, 2017, ONCOTARGET, V5; Burada F, 2015, WORLD J GASTRO ONCOL, V7, P271, DOI 10.4251/wjgo.v7.i11.271; CHIN KV, 1990, J BIOL CHEM, V265, P221; Dai C, 2007, CELL, V130, P1005, DOI 10.1016/j.cell.2007.07.020; de Grouw EPLM, 2006, LEUKEMIA, V20, P750, DOI 10.1038/sj.leu.2404131; de Thonel A, 2012, INT J BIOCHEM CELL B, V44, P1593, DOI 10.1016/j.biocel.2012.06.012; Evan G, 1998, SCIENCE, V281, P1317, DOI 10.1126/science.281.5381.1317; FOJO AT, 1987, P NATL ACAD SCI USA, V84, P265, DOI 10.1073/pnas.84.1.265; Fu T, 2016, ACTA PHARMACOL SIN, V37, P505, DOI 10.1038/aps.2015.148; GAITAN E, 1995, J CLIN ENDOCR METAB, V80, P1144, DOI 10.1210/jc.80.4.1144; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Halliwell B, 2008, ARCH BIOCHEM BIOPHYS, V476, P107, DOI 10.1016/j.abb.2008.01.028; Ismail Hassan Fahmi, 2017, J Tradit Complement Med, V7, P452, DOI 10.1016/j.jtcme.2016.12.006; KIOKA N, 1992, FEBS LETT, V301, P37, DOI 10.1016/0014-5793(92)80205-U; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Krishnamurthy K, 2012, P NATL ACAD SCI USA, V109, P9023, DOI 10.1073/pnas.1200731109; Kumar A, 2015, FUTURE MED CHEM, V7, P1535, DOI 10.4155/fmc.15.88; Lage H, 2016, RECENT RESULTS CANC, V209, P87, DOI 10.1007/978-3-319-42934-2_6; LOO TW, 1995, J BIOL CHEM, V270, P22957, DOI 10.1074/jbc.270.39.22957; Lorin S, 2013, SEMIN CANCER BIOL, V23, P361, DOI 10.1016/j.semcancer.2013.06.007; Meschini S, 2007, TOXICOL IN VITRO, V21, P197, DOI 10.1016/j.tiv.2006.09.007; Meschini S, 2000, INT J CANCER, V87, P615, DOI 10.1002/1097-0215(20000901)87:5<615::AID-IJC1>3.0.CO;2-4; Modok S, 2006, CURR OPIN PHARMACOL, V6, P350, DOI 10.1016/j.coph.2006.01.009; Roos WP, 2016, NAT REV CANCER, V16, P20, DOI 10.1038/nrc.2015.2; Schinkel AH, 2012, ADV DRUG DELIVER REV, V64, P138, DOI 10.1016/j.addr.2012.09.027; Song JR, 2009, AUTOPHAGY, V5, P1131, DOI 10.4161/auto.5.8.9996; Stein A, 2011, EUR J CANCER, V47, pS312, DOI 10.1016/S0959-8049(11)70183-6; Sun YL, 2012, CHIN J CANCER, V31, P51, DOI 10.5732/cjc.011.10466; Szakacs G, 2006, NAT REV DRUG DISCOV, V5, P219, DOI 10.1038/nrd1984; Thornberry NA, 1998, SCIENCE, V281, P1312, DOI 10.1126/science.281.5381.1312; Vilaboa NE, 2000, J BIOL CHEM, V275, P24970, DOI 10.1074/jbc.M909136199; Yorimitsu T, 2005, CELL DEATH DIFFER, V12, P1542, DOI 10.1038/sj.cdd.4401765; Zhou YJ, 2009, CLIN CANCER RES, V15, P5161, DOI 10.1158/1078-0432.CCR-09-0661; Zhu Q, 2016, SCI REP-UK, V6, DOI 10.1038/srep19266; Zou JY, 1998, CELL, V94, P471, DOI 10.1016/S0092-8674(00)81588-3	38	40	43	1	7	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	JAN 9	2018	9	3					3278	3291		10.18632/oncotarget.22890			14	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	FS3GU	WOS:000419669600027	29423046	Green Published, gold, Green Submitted			2022-04-25	
J	Chok, KC; Koh, RY; Ng, MG; Ng, PY; Chye, SM				Chok, Kian Chung; Koh, Rhun Yian; Ng, Ming Guan; Ng, Pei Ying; Chye, Soi Moi			Melatonin Induces Autophagy via Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress Pathway in Colorectal Cancer Cells	MOLECULES			English	Article						melatonin; autophagy; colorectal cancer cells; reactive oxygen species; endoplasmic reticulum stress	PROLIFERATION; APOPTOSIS; CHAPERONE; SYSTEM; AMPK; AKT	Even though an increasing number of anticancer treatments have been discovered, the mortality rates of colorectal cancer (CRC) have still been high in the past few years. It has been discovered that melatonin has pro-apoptotic properties and counteracts inflammation, proliferation, angiogenesis, cell invasion, and cell migration. In previous studies, melatonin has been shown to have an anticancer effect in multiple tumors, including CRC, but the underlying mechanisms of melatonin action on CRC have not been fully explored. Thus, in this study, we investigated the role of autophagy pathways in CRC cells treated with melatonin. In vitro CRC cell models, HT-29, SW48, and Caco-2, were treated with melatonin. CRC cell death, oxidative stress, and autophagic vacuoles formation were induced by melatonin in a dose-dependent manner. Several autophagy pathways were examined, including the endoplasmic reticulum (ER) stress, 5 '-adenosine monophosphate-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (Akt), and mammalian target of rapamycin (mTOR) signaling pathways. Our results showed that melatonin significantly induced autophagy via the ER stress pathway in CRC cells. In conclusion, melatonin demonstrated a potential as an anticancer drug for CRC.	[Chok, Kian Chung; Ng, Ming Guan] Int Med Univ, Sch Hlth Sci, Kuala Lumpur 57000, Malaysia; [Koh, Rhun Yian; Chye, Soi Moi] Int Med Univ, Sch Hlth Sci, Div Biomed Sci & Biotechnol, Kuala Lumpur 57000, Malaysia; [Ng, Pei Ying] Int Med Univ, Sch Postgrad, Kuala Lumpur 57000, Malaysia		Chye, SM (corresponding author), Int Med Univ, Sch Hlth Sci, Div Biomed Sci & Biotechnol, Kuala Lumpur 57000, Malaysia.	chok.kianchung@student.imu.edu.my; rhunyian_koh@imu.edu.my; NG.MINGGUAN@student.imu.edu.my; NG.PEIYING@student.imu.edu.my; chye_soimoi@imu.edu.my		Chok, Kian Chung/0000-0002-1440-4861	International Medical University [BMSc I-2020 (08), BMSc I-2019 (02), BMSc I-2018 (09)]	This research was funded by International Medical University, grant numbers are BMSc I-2020 (08), BMSc I-2019 (02) and BMSc I-2018 (09).	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J	Pandurangan, AK; Ismail, S; Esa, NM; Munusamy, MA				Pandurangan, Ashok Kumar; Ismail, Salmiah; Esa, Norhaizan Mohd; Munusamy, Murugan A.			Inositol-6 phosphate inhibits the mTOR pathway and induces autophagy-mediated death in HT-29 colon cancer cells	ARCHIVES OF MEDICAL SCIENCE			English	Article						inositol-6-phosphate; colorectal cancer; autophagy; mammalian target of rapamycin; apoptosis	COLORECTAL-CANCER; RICE-BRAN; PHYTIC ACID; SIGNALING PATHWAY; APOPTOSIS; PI3K/AKT/MTOR; INVOLVEMENT; ARREST; IP6	Introduction: Colorectal cancer (CRC) is common, with a worldwide incidence estimated at more than 1 million cases annually. Therefore, the search for agents for CRC treatment is highly warranted. Inosito1-6 phosphate (IP6) is enriched in rice bran and possesses many beneficial effects. In the present study the effect of IP6 on autophagy-mediated death by modulating the mTOR pathway in HT-29 colon cancer cells was studied. Material and methods: Autophagy was assessed by acridine orange (AO) staining, transmission electron microscopy, and western blotting to detect LC3-II and Beclin 1. Akt/mTOR signaling protein expression was also analyzed by western blotting. Apoptosis was analyzed by annexin V staining. Results: Incubation of cells with IP6 resulted in downregulation of the p-Akt at 3h. Along with that confocal microscopic analysis of p-AKT, IP6 administration resulted that a diminished expression of p-Akt. mTOR pathway regulates autophagy and incubation with IP6 to HT-29 cells showed decreased expression of p-70S6Kinase, 4-EBP-1 in a time-dependent manner. Inositol-6 phosphate (10 Ng/ml, 24 and 48 h) induced autophagic vesicles, as confirmed by AO staining and transmission electron microscopy. We also found increased expression of LC3-II and Beclin 1 in a time-dependent manner after incubation with IP6. Furthermore, IP6 induced apoptosis, as revealed by annexin V staining. Conclusions: Our results clearly indicate that IP6 induces autophagy by inhibiting the Akt/mTOR pathway.	[Pandurangan, Ashok Kumar] Univ Malaya, Fac Med, Dept Pharmacol, Kuala Lumpur, Malaysia; [Pandurangan, Ashok Kumar; Ismail, Salmiah; Esa, Norhaizan Mohd] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Nutr & Dietet, Serdang 43400, Selangor, Malaysia; [Munusamy, Murugan A.] King Saud Univ, Coll Sci, Dept Bot & Microbiol, Riyadh, Saudi Arabia		Esa, NM (corresponding author), Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Nutr & Dietet, Serdang 43400, Selangor, Malaysia.	nhaizan@upm.edu.my	Mohd.-Esa, Norhaizan/ABA-2783-2021; Pandurangan, Ashok Kumar/M-7335-2013	Pandurangan, Ashok Kumar/0000-0003-2824-1757	Fundamental Research Grant Scheme (FRGS), Malaysia [5524455]; Deanship of Scientific Research at King Saud UniversityKing Saud University [RG-1435-057]	Dr. Norhaizan greatly acknowledges the Fundamental Research Grant Scheme (FRGS), Malaysia (Grant Number: 5524455) for financial assistance. The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this work (Research Group No. RG-1435-057).	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J	Zhan, Y; Gong, K; Chen, C; Wang, HQ; Li, WH				Zhan, Yao; Gong, Ke; Chen, Chao; Wang, Haiqing; Li, Wenhua			P38 MAP kinase functions as a switch in MS-275-induced reactive oxygen species-dependent autophagy and apoptosis in Human colon Cancer cells	FREE RADICAL BIOLOGY AND MEDICINE			English	Article						MS-275; Reactive oxygen species; Autophagy; Apoptosis; p38; Free radicals	HISTONE DEACETYLASE INHIBITOR; VIVO ANTITUMOR-ACTIVITY; HEPATOCELLULAR-CARCINOMA; LEUKEMIA-CELLS; PROTEIN; MS-275; DEATH; GROWTH; DEGRADATION; ACTIVATION	MS-275 is a synthetic benzamide derivative of the histone deacetylase inhibitor and is currently in phase I/II clinical trials. Many reports have shown that the anti-tumor activity of MS-275 in several types of cancer is mainly attributable to its capacity to induce the apoptotic death of tumor cells. It remains unclear if autophagy is involved in MS-275 treatment of cancer cells. Here, we first show that MS-275 induces human colon cancer cell HCT116 autophagy as well as apoptosis. Short-term treatment (24 h) induced HCT116 cells to undergo autophagy with dependence on intracellular reactive oxygen species production and ERK activation. The activated reactive oxygen species/ERK signal promoted Atg7 protein expression, which triggered MS-275-induced cancer cell autophagy. However, after prolonged treatment with MS-275 (over 48 h), autophagic cells turned apoptotic, which was also dependent on reactive oxygen species generation. Interestingly, we found that p38 MAP kinase played a vital role in the switch from autophagy to apoptosis in MS-275-induced human colon cancer cells. High expression of p38 induced cell autophagy, but low expression resulted in apoptosis. In addition, observations in vivo are strongly consistent with the in vitro results. Therefore, these findings extend our understanding of the action of MS-275 in inducing cancer cell death and suggest that it may be a promising clinical chemotherapeutic agent with multiple effects. (C) 2012 Elsevier Inc. All rights reserved.	[Zhan, Yao; Gong, Ke; Chen, Chao; Wang, Haiqing; Li, Wenhua] Wuhan Univ, Coll Life Sci, Wuhan 430072, Peoples R China		Li, WH (corresponding author), Wuhan Univ, Coll Life Sci, Wuhan 430072, Peoples R China.	whli@whu.edu.cn			National Basic Research Program of ChinaNational Basic Research Program of China [2010CB529800]; National Nature Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81072151]; Chinese 111 ProjectMinistry of Education, China - 111 Project [B06018]; Major Scientific and Technological Special Project for the "Significant Creation of New Drugs" [2011ZX09102-001-32, 2010ZX09401]	This work was supported by the National Basic Research Program of China (2010CB529800), the National Nature Science Foundation of China (81072151), the Chinese 111 Project (B06018), and the Major Scientific and Technological Special Project for the "Significant Creation of New Drugs" (2011ZX09102-001-32, 2010ZX09401).	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J	Gil, J; Ramsey, D; Pawlowski, P; Szmida, E; Leszczynski, P; Bebenek, M; Sasiadek, MM				Gil, Justyna; Ramsey, David; Pawlowski, Pawel; Szmida, Elzbieta; Leszczynski, Przemyslaw; Bebenek, Marek; Sasiadek, Maria M.			The Influence of Tumor Microenvironment on ATG4D Gene Expression in Colorectal Cancer Patients	MEDICAL ONCOLOGY			English	Article						Colorectal cancer; Autophagy; ATG; LC3; GABARAP; Relative expression	DOWN-REGULATION; AUTOPHAGY; LC3; APOPTOSIS; EFFICACY; ROLES	Despite great progress in research on the subject, the involvement of autophagy in colorectal cancer (CRC) pathogenesis (initiation, progression, metastasis) remains obscure and controversial. Autophagy is a catabolic process, fundamental to cell viability and connected with degradation/recycling of proteins and organelles. In this study, we aimed at investigating the relative expression level of mRNA via Real-Time PCR of 16 chosen genes belonging to Atg8 mammalian orthologs and their conjugation system, comprising GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B, MAP1LC3C, ATG3, ATG7, ATG10, ATG4A, ATG4B, ATG4C, ATG4D, and three genes encoding proteins building the multimeric ATG16L1 complex, namely ATG5, ATG12, and ATG16L1, in 73 colorectal tumors and paired adjacent normal colon mucosa. Our study demonstrated the relative downregulation of all examined genes in CRC tissues in comparison to adjacent noncancerous mucosa, with the highest rate of expression in both tumor and non-tumor tissues observed for GAPARBPL2 and the lowest for MAP1LC3C. Moreover, in patients with advanced-stage tumors and high values of regional lymph nodes, statistically significant downregulation of ATG4D expression in adjacent normal cells was observed. Our study confirms the role of autophagy genes as cancer suppressors in colorectal carcinogenesis. Furthermore, in regard to the ATG4D gene, we observed the influence of tumor microenvironments on gene expression in adjacent colon mucosa.	[Gil, Justyna; Pawlowski, Pawel; Szmida, Elzbieta; Sasiadek, Maria M.] Wroclaw Med Univ, Dept Genet, PL-50368 Wroclaw, Poland; [Ramsey, David] Wroclaw Univ Technol, Dept Operat Res, PL-50372 Wroclaw, Poland; [Leszczynski, Przemyslaw] Wroclaw Med Univ, Dept Biol & Med Parasitol, PL-50345 Wroclaw, Poland; [Bebenek, Marek] Lower Silesian Oncol Ctr, Dept Surg Oncol 1, PL-53413 Wroclaw, Poland		Gil, J (corresponding author), Wroclaw Med Univ, Dept Genet, PL-50368 Wroclaw, Poland.	justyna.gil@umed.wroc.pl; david.ramsey@pwr.edu.pl; paweltoxic@tlen.pl; elzbieta.szmida@umed.wroc.pl; przemyslaw.leszczynski@umed.wroc.pl; marek.bebenek@onkomed.pl; maria.sasiadek@umed.wroc.pl	/L-5618-2019	/0000-0003-0991-7686; Sasiadek, Maria/0000-0002-7599-7074; Bebenek, Marek/0000-0001-7716-5960; Szmida, Elzbieta/0000-0003-3108-0165; Leszczynski, Przemyslaw/0000-0002-4181-4997; Ramsey, David/0000-0002-7186-1436	Narodowe Centrum NaukiNational Science Centre, Poland [DEC-2012/07/D/NZ5/04305] Funding Source: Medline		Arnold M, 2017, GUT, V66, P683, DOI 10.1136/gutjnl-2015-310912; Behrends C, 2010, NATURE, V466, P68, DOI 10.1038/nature09204; Betin VMS, 2009, J CELL SCI, V122, P2554, DOI 10.1242/jcs.046250; Bortnik S, 2017, INT J MOL SCI, V18, DOI 10.3390/ijms18071496; Chang YT, 2011, EUR J CLIN INVEST, V41, P84, DOI 10.1111/j.1365-2362.2010.02383.x; Chen ZH, 2013, DIGEST DIS SCI, V58, P2887, DOI 10.1007/s10620-013-2732-8; Cho DH, 2012, ANTICANCER RES, V32, P4091; Choi JH, 2014, GASTROENT RES PRACT, V2014, DOI 10.1155/2014/179586; Costa JR, 2016, ONCOTARGET, V7, P41203, DOI 10.18632/oncotarget.9754; Dower CM, 2018, AUTOPHAGY, V14, P1110, DOI 10.1080/15548627.2018.1450020; El Andaloussi A, 2017, CELL DEATH DISCOV, V3, DOI 10.1038/cddiscovery.2017.41; Galluzzi L, 2017, EMBO J, V36, P1811, DOI 10.15252/embj.201796697; Gil J, 2017, MED ONCOL, V34, DOI 10.1007/s12032-016-0869-y; Gil J, 2016, BIOMARK MED, V10, P1081, DOI 10.2217/bmm-2016-0083; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Guo GF, 2011, WORLD J GASTROENTERO, V17, P4779, DOI 10.3748/wjg.v17.i43.4779; Hervouet E, 2015, BMC CANCER, V15, DOI 10.1186/s12885-015-1761-4; Klionsky DJ, 2007, NAT REV MOL CELL BIO, V8, P931, DOI 10.1038/nrm2245; Klionsky DJ, 2010, AUTOPHAGY, V6, P438, DOI 10.4161/auto.6.4.12244; Le Grand JN, 2011, AUTOPHAGY, V7, P1098, DOI 10.4161/auto.7.10.15904; MIAO Y, HEPATOGASTROENTEROLO, V57, P257; Mizushima N, 2010, NAT CELL BIOL, V12, P823, DOI 10.1038/ncb0910-823; Murai M, 2005, CLIN CANCER RES, V11, P1021; Nguyen TG, 2014, ASSAY DRUG DEV TECHN, V12, P176, DOI 10.1089/adt.2013.561; Saha S, 2018, BIOMED PHARMACOTHER, V104, P485, DOI 10.1016/j.biopha.2018.05.007; Schaaf MBE, 2016, FASEB J, V30, P3961, DOI 10.1096/fj.201600698R; Shpilka T, 2011, GENOME BIOL, V12, DOI 10.1186/gb-2011-12-7-226; Wang L, 2015, CANCER BIOL THER, V16, P383, DOI 10.1080/15384047.2014.1002331; Wild P, 2014, J CELL SCI, V127, P3, DOI 10.1242/jcs.140426; Yang MP, 2015, ONCOTARGET, V6, P7084, DOI 10.18632/oncotarget.3054; Yoshioka A, 2008, INT J ONCOL, V33, P461, DOI 10.3892/ijo_00000028; Yu ZQ, 2012, AUTOPHAGY, V8, P883, DOI 10.4161/auto.19652; Zhang L, 2016, CANCER LETT, V373, P19, DOI 10.1016/j.canlet.2016.01.022	33	21	21	1	14	HUMANA PRESS INC	TOTOWA	999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA	1357-0560	1559-131X		MED ONCOL	Med. Oncol.	DEC	2018	35	12							159	10.1007/s12032-018-1220-6			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GY7YP	WOS:000448834300002	30374741	Green Published, hybrid			2022-04-25	
J	Bednarczyk, M; Muc-Wierzgon, M; Waniczek, D; Fatyga, E; Klakla, K; Mazurek, U; Wierzgon, J				Bednarczyk, M.; Muc-Wierzgon, M.; Waniczek, D.; Fatyga, E.; Klakla, K.; Mazurek, U.; Wierzgon, J.			AUTOPHAGY-RELATED GENE EXPRESSION IN COLORECTAL CANCER PATIENTS	JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS			English	Article						autophagy; autophagy-related genes; colorectal cancer; healthy tissues; clinical stages	MITOCHONDRIAL; ROLES; DEATH	There is evidence that autophagy can play a dual role in tumor cells - as a tumor suppressor, and a process involved in tumor cell survival. The aim of this work was to assess the expression of the genes engaged in the autophagy process in biopsies taken from the colon, confirmed as adenocarcinoma, and normal tissue and to relate them to the clinical stage of the tumor. A total of 20 pairs of surgically removed tumors and healthy (marginal) tissue samples from colorectal cancer patients at clinical stages (CS) I-IV were analyzed. Gene expression profile analysis was performed using HG-U133A microarrays. Differentially expressed genes were identified, using the PL-Grid Infrastructure. Only for CSI, there were two specific genes: FOXO1 and BNIP1; further in CSII - LAMP2, MET and BCL2L, in CSIII HIF1A and 2 ID mRNAs for HGF and 18 genes were specific for CSIV in comparison to controls. PINK1 is the only gene that differentiates all transcriptome groups from controls. Furthermore, examination of the expression of genes associated with the autophagy process may allow for better knowledge and understanding of the processes occurring during the development of colon cancer. The presented genes may be used as prognostic markers of clinical stages of colorectal cancer, contributing to the development of new lines of therapy focused on reducing metastasis of the primary tumor.	[Bednarczyk, M.; Mazurek, U.] Med Univ Silesia, Sch Pharm, Dept Mol Biol, Div Lab Med Sosnowiec, Sosnowiec, Poland; [Bednarczyk, M.; Muc-Wierzgon, M.; Fatyga, E.; Klakla, K.] Med Univ Silesia, Sch Publ Hlth, Dept Internal Med, Zeromskiego 7 St, PL-41902 Bytom, Poland; [Waniczek, D.] Med Univ Silesia, Chair Gen Colorectal & Polytrauma Surg, Dept Propedeut Surg, SHS Katowice, Bytom, Poland; [Wierzgon, J.] Maria Sklodowska Curie Mem Canc Ctr, Dept Oncol & Reconstruct Surg, Gliwice, Poland; [Wierzgon, J.] Inst Oncol, Gliwice Branch, Gliwice, Poland		Muc-Wierzgon, M (corresponding author), Med Univ Silesia, Sch Publ Hlth, Dept Internal Med, Zeromskiego 7 St, PL-41902 Bytom, Poland.	mwierzgon@sum.edu.plm	Waniczek, Dariusz/ABD-1692-2020	Waniczek, Dariusz/0000-0002-0410-8604; Muc-Wierzgon, Malgorzata/0000-0001-6562-7072; Wierzgon, Janusz/0000-0001-5746-5720; Fatyga, Edyta/0000-0003-0389-206X; Bednarczyk, Martyna/0000-0001-8360-9126			Arena G, 2013, CELL DEATH DIFFER, V20, P920, DOI 10.1038/cdd.2013.19; Badadani M., 2012, ISRN CELL BIOL, V2012, P1, DOI DOI 10.5402/2012/927064; Baehrecke EH, 2005, NAT REV MOL CELL BIO, V6, P505, DOI 10.1038/nrm1666; Braczkowski R, 2001, J BIOL REG HOMEOS AG, V15, P366; Chen ZH, 2013, DIGEST DIS SCI, V58, P2887, DOI 10.1007/s10620-013-2732-8; Feng YC, 2014, CELL RES, V24, P24, DOI 10.1038/cr.2013.168; Gil J, 2016, BIOMARK MED, V10, P1081, DOI 10.2217/bmm-2016-0083; Groulx JF, 2012, AUTOPHAGY, V8, P893, DOI 10.4161/auto.19738; Guo GF, 2011, WORLD J GASTROENTERO, V17, P4779, DOI 10.3748/wjg.v17.i43.4779; Ivankovic D, 2016, J NEUROCHEM, V136, P388, DOI 10.1111/jnc.13412; Koukourakis MI, 2010, BRIT J CANCER, V103, P1209, DOI 10.1038/sj.bjc.6605904; Lockshin RA, 2004, INT J BIOCHEM CELL B, V36, P2405, DOI 10.1016/j.biocel.2004.04.011; Nagelkerke A, 2015, SEMIN CANCER BIOL, V31, P89, DOI 10.1016/j.semcancer.2014.05.004; Rosenfeldt MT, 2011, CARCINOGENESIS, V32, P955, DOI 10.1093/carcin/bgr031; Ye LC, 2015, J BIOL REG HOMEOS AG, V29, P307	15	5	6	0	2	BIOLIFE SAS	SILVA MARINA (TE)	VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY	0393-974X	1724-6083		J BIOL REG HOMEOS AG	J. Biol. Regul. Homeost. Agents	OCT-DEC	2017	31	4					923	927					5	Endocrinology & Metabolism; Immunology; Medicine, Research & Experimental; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Endocrinology & Metabolism; Immunology; Research & Experimental Medicine; Physiology	FX6HP	WOS:000426184600009	29254294				2022-04-25	
J	Li, WY; Liu, C; Huang, ZL; Shi, L; Zhong, CAQ; Zhou, WW; Meng, PP; Li, ZY; Wang, SY; Luo, FH; Yan, JH; Wu, T				Li, Wanyun; Liu, Cong; Huang, Zilan; Shi, Lei; Zhong, Chuanqi; Zhou, Wenwen; Meng, Peipei; Li, Zhenyu; Wang, Shengyu; Luo, Fanghong; Yan, Jianghua; Wu, Ting			AKR1B10 negatively regulates autophagy through reducing GAPDH upon glucose starvation in colon cancer	JOURNAL OF CELL SCIENCE			English	Article						Neuropilin1; NRP1; Aldo-keto reductase family 1 B10; AKR1B10; Glucose starvation; Glyceraldehyde-3-phosphate dehydrogenase; GAPDH; Nuclear translocation; Reductase activity	KETO REDUCTASE 1B10; COLORECTAL-CANCER; CORTICAL-NEURONS; NRF2 ACTIVATION; RETENTION TIME; CELLS REVEALS; MEMBER B10; IDENTIFICATION; NEUROPILIN-1; TUMOR	Autophagy is considered to be an important switch for facilitating normal to malignant cell transformation during colorectal cancer development. Consistent with other reports, we found that the membrane receptor Neuropilin1 (NRP1) is greatly upregulated in colon cancer cells that underwent autophagy upon glucose deprivation. However, the mechanism underlying NRP1 regulation of autophagy is unknown. We found that knockdown of NRP1 inhibits autophagy and largely upregulates the expression of aldo-keto reductase family 1 B10 (AKR1B10). Moreover, we demonstrated that AKR1B10 interacts with and inhibits the nuclear importation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and then subsequently represses autophagy. Interestingly, we also found that an NADPH-dependent reduction reaction could be induced when AKR1B10 interacts with GAPDH, and the reductase activity of AKR1B10 is important for its repression of autophagy. Together, our findings unravel a novel mechanism of NRP1 in regulating autophagy through AKR1B10.	[Li, Wanyun; Liu, Cong; Huang, Zilan; Shi, Lei; Zhou, Wenwen; Meng, Peipei; Li, Zhenyu; Wang, Shengyu; Luo, Fanghong; Yan, Jianghua; Wu, Ting] Xiamen Univ, Sch Med, Canc Res Ctr, Xiamen 361000, Peoples R China; [Zhong, Chuanqi] Xiamen Univ, Sch Life Sci, Innovat Ctr Cellular Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361000, Peoples R China; [Wu, Ting] Xiamen Univ, Sch Med, Dept Basic Med, Xiamen 361000, Peoples R China; [Wu, Ting] Xiamen Univ, Xiangan Hosp, Sch Med, Res Ctr Retroperitoneal Tumor Comm Oncol Soc Chin, Xiamen 361000, Peoples R China; [Wu, Ting] Joint Lab Xiamen Univ Sch Med & Shanghai Jiangxia, Xiamen 361000, Peoples R China		Luo, FH; Yan, JH; Wu, T (corresponding author), Xiamen Univ, Sch Med, Canc Res Ctr, Xiamen 361000, Peoples R China.; Wu, T (corresponding author), Xiamen Univ, Sch Med, Dept Basic Med, Xiamen 361000, Peoples R China.; Wu, T (corresponding author), Xiamen Univ, Xiangan Hosp, Sch Med, Res Ctr Retroperitoneal Tumor Comm Oncol Soc Chin, Xiamen 361000, Peoples R China.; Wu, T (corresponding author), Joint Lab Xiamen Univ Sch Med & Shanghai Jiangxia, Xiamen 361000, Peoples R China.	luofanghong@xmu.edu.cn; jhyan@xmu.edu.cn; wuting78@189.cn		Liu, Cong/0000-0003-1927-5912; Shi, Lei/0000-0002-3378-1590	National Basic Research Program of China (973 Program)National Basic Research Program of China [2015CB553800]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31401180, 81773770]; Special Fund of Public Welfare Research Institutes in Fujian Province [2018parallel toR1036-1, 2018parallel toR1036-3, 2019R1001-2]; Shanghai Jiangxia Blood Technology Co., Ltd [0070-K81B0019]	This work was supported by the National Basic Research Program of China (973 Program 2015CB553800), the National Natural Science Foundation of China (31401180 and 81773770); the Special Fund of Public Welfare Research Institutes in Fujian Province (2018 parallel to R1036-1, 2018 parallel to R1036-3 and 2019R1001-2); and the research fund of Shanghai Jiangxia Blood Technology Co., Ltd (0070-K81B0019).	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Cell Sci.	APR	2021	134	8							jcs255273	10.1242/jcs.255273			15	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	SF9ZU	WOS:000653106900015	33758077	Bronze			2022-04-25	
J	Kumar, B; Ahmad, R; Sharma, S; Gowrikumar, S; Primeaux, M; Rana, S; Natarajan, A; Oupicky, D; Hopkins, CR; Dhawan, P; Singh, AB				Kumar, Balawant; Ahmad, Rizwan; Sharma, Swagat; Gowrikumar, Saiprasad; Primeaux, Mark; Rana, Sandeep; Natarajan, Amarnath; Oupicky, David; Hopkins, Corey R.; Dhawan, Punita; Singh, Amar B.			PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells	CANCERS			English	Article						autophagy; 5-FloroUracil; PI3KC3; chemoresistance; cancer stem cells	AUTOPHAGY INHIBITOR; TARGETING AUTOPHAGY; BETA-CATENIN; STRATEGIES; RESISTANCE; EXPANSION; POTENT; CSCS	Simple Summary Colorectal cancer (CRC) represents a heterogeneous population of tumor cells and cancer stem cells (CSCs) where CSCs are postulated to resist the chemotherapy, and support cancer malignancy. Eliminating CSC can therefore improve CRC therapy and patient survival; however, such strategies have not yielded the desired outcome. Inhibiting autophagy has shown promise in suppressing therapy resistance; however, current autophagy inhibitors have failed in the clinical trials. In the current study, we provided data supporting the efficacy of 36-077, a potent inhibitor of PIK3C3/VPS34, in inhibiting autophagy to kill the CSC to promote the efficacy of colon cancer therapy. Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3 beta/Wnt/beta-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3 beta/Wnt/beta-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.	[Kumar, Balawant; Ahmad, Rizwan; Gowrikumar, Saiprasad; Primeaux, Mark; Dhawan, Punita; Singh, Amar B.] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, 985870 Nebraska Med Ctr, Omaha, NE 68198 USA; [Sharma, Swagat; Oupicky, David; Hopkins, Corey R.] Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Omaha, NE 68198 USA; [Rana, Sandeep; Natarajan, Amarnath] Univ Nebraska Med Ctr, Eppley Inst, Canc Res Program, Omaha, NE 68198 USA; [Natarajan, Amarnath; Dhawan, Punita; Singh, Amar B.] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USA; [Dhawan, Punita; Singh, Amar B.] VA Nebraska Western Iowa Hlth Care Syst, Omaha, NE 68105 USA		Singh, AB (corresponding author), Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, 985870 Nebraska Med Ctr, Omaha, NE 68198 USA.; Singh, AB (corresponding author), Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USA.; Singh, AB (corresponding author), VA Nebraska Western Iowa Hlth Care Syst, Omaha, NE 68105 USA.	balawant.kumar@unmc.edu; rizwan.ahmad@unmc.edu; swagat.sharma@unmc.edu; sai.gowrikumar@unmc.edu; mark.primeaux@unmc.edu; sandeep.rana@nih.gov; anatarajan@unmc.edu; david.oupicky@unmc.edu; corey.hopkins@unmc.edu; punita.dhawan@unmc.edu; amar.singh@unmc.edu	kumar, Balawant/ABB-2847-2021; Kumar, Balawant/AAW-9616-2021; Oupicky, David/AAR-1655-2021	kumar, Balawant/0000-0002-8187-3078; rana, sandeep/0000-0001-5802-5970; Primeaux, Mark/0000-0001-7589-3745; Natarajan, Amarnath/0000-0001-5067-0203	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK124095, CA216746]; Veterans Health Merit award [BX002761, BX002086]	This research was supported in part by the funds from the National Institutes of Health (DK124095 to A.B.S., and D.O.) and CA216746 (P.D.), Veterans Health Merit award BX002761 (A.B.S.) and BX002086 (P.D.).	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J	Boyle, KA; Van Wickle, J; Hill, RB; Marchese, A; Kalyanaraman, B; Dwinell, MB				Boyle, Kathleen A.; Van Wickle, Jonathan; Hill, R. Blake; Marchese, Adriano; Kalyanaraman, Balaraman; Dwinell, Michael B.			Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation	JOURNAL OF BIOLOGICAL CHEMISTRY			English	Article						AMP-activated kinase (AMPK); cancer biology; cell growth; mitophagy; mitochondrial metabolism; colon cancer; KRAS proto-oncogene; cell proliferation; metformin	ACTIVATED PROTEIN-KINASE; COLORECTAL-CANCER; CARCINOMA-CELLS; IN-VIVO; S6 KINASE; AUTOPHAGY; GROWTH; PHOSPHORYLATION; ANTIOXIDANT; THERAPY	Mutations in the KRAS proto-oncogene are present in 50% of all colorectal cancers and are increasingly associated with chemotherapeutic resistance to frontline biologic drugs. Accumulating evidence indicates key roles for overactive KRAS mutations in the metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis in cancer cells. Here, we sought to exploit the more negative membrane potential of cancer cell mitochondria as an untapped avenue for interfering with energy metabolism in KRAS variant-containing and KRAS WT colorectal cancer cells. Mitochondrial function, intracellular ATP levels, cellular uptake, energy sensor signaling, and functional effects on cancer cell proliferation were assayed. 3-Carboxyl proxyl nitroxide (Mito-CP) and Mito-Metformin, two mitochondria-targeted compounds, depleted intracellular ATP levels and persistently inhibited ATP-linked oxygen consumption in both KRAS WT and KRAS variant-containing colon cancer cells and had only limited effects on nontransformed intestinal epithelial cells. These anti-proliferative effects reflected the activation of AMP-activated protein kinase (AMPK) and the phosphorylation-mediated suppression of the mTOR target ribosomal protein S6 kinase B1 (RPS6KB1 or p70S6K). Moreover, Mito-CP and Mito-Metformin released Unc-51-like autophagy-activating kinase 1 (ULK1) from mTOR-mediated inhibition, affected mitochondrial morphology, and decreased mitochondrial membrane potential, all indicators of mitophagy. Pharmacological inhibition of the AMPK signaling cascade mitigated the anti-proliferative effects of Mito-CP and Mito-Metformin. This is the first demonstration that drugs selectively targeting mitochondria induce mitophagy in cancer cells. Targeting bioenergetic metabolism with mitochondria-targeted drugs to stimulate mitophagy provides an attractive approach for therapeutic intervention in KRAS WT and overactive mutant-expressing colon cancer.	[Boyle, Kathleen A.; Van Wickle, Jonathan; Dwinell, Michael B.] Med Coll Wisconsin, Dept Microbiol & Immunol, Milwaukee, WI 53226 USA; [Hill, R. Blake; Marchese, Adriano] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA; [Kalyanaraman, Balaraman] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA; [Dwinell, Michael B.] Med Coll Wisconsin, Dept Surg, 8700 W Wisconsin Ave, Milwaukee, WI 53226 USA; [Boyle, Kathleen A.; Hill, R. Blake; Marchese, Adriano; Kalyanaraman, Balaraman; Dwinell, Michael B.] Med Coll Wisconsin, MCW Canc Ctr, Milwaukee, WI 53226 USA		Dwinell, MB (corresponding author), 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA.	mdwinell@mcw.edu			NCI, National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01 CA178960, R01 CA152810]; Medical College of Wisconsin Cancer Center; Advancing a Healthier Wisconsin Endowment; Bobbie Nick Voss Charitable Foundation; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA178960, R01CA152810] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM122889, R01GM067180] Funding Source: NIH RePORTER	This work was supported by grants from the NCI, National Institutes of Health Grants U01 CA178960 (to M. B. D. and B. K.) and R01 CA152810 (to B. K.), the Medical College of Wisconsin Cancer Center (to M. B. D. and B. K.), the Advancing a Healthier Wisconsin Endowment (to M. B. D.), and the Bobbie Nick Voss Charitable Foundation continuing philanthropic donations (to M. B. D.). M. B. D. has ownership interests in Protein Foundry, LLC. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.	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Biol. Chem.	SEP 21	2018	293	38					14891	14904		10.1074/jbc.RA117.001469			14	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	GV5PS	WOS:000446155000024	30087121	Green Published, hybrid			2022-04-25	
J	Wubetu, GY; Utsunomiya, T; Ishikawa, D; Ikemoto, T; Yamada, S; Morine, Y; Iwahashi, S; Saito, Y; Arakawa, Y; Imura, S; Arimochi, H; Shimada, M				Wubetu, Gizachew Yismaw; Utsunomiya, Tohru; Ishikawa, Daichi; Ikemoto, Tetsuya; Yamada, Shinichiro; Morine, Yuji; Iwahashi, Shuichi; Saito, Yu; Arakawa, Yusuke; Imura, Satoru; Arimochi, Hideki; Shimada, Mitsuo			Branched Chain Amino Acid Suppressed Insulin-initiated Proliferation of Human Cancer Cells Through Induction of Autophagy	ANTICANCER RESEARCH			English	Article						Autophagy; BCAA; colorectal cancer; insulin; liver cancer	COLORECTAL-CANCER; SUPPLEMENTATION; GROWTH; COLON; APOPTOSIS; TUMORIGENESIS; INHIBITION; SURVIVAL; OBESITY; TUMORS	Background: Branched chain amino acid (BCAA) dietary supplementation inhibits activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis in diabetic animal models. However, the in vitro effect of BCAA on human cancer cell lines under hyper-insulinemic conditions remains unclear. Materials and Methods: Colon (HCT-116) and hepatic (HepG2) tumor cells were treated with varying concentrations of BCAA with or without fluorouracil (5-FU). The effect of BCAA on insulin-initiated proliferation was determined. Gene and protein expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Results: BCAA supplementation had no significant effect on cell proliferation and did not show significant synergistic or antagonistic effects with 5-FU. However, BCAA significantly decreased insulin-initiated proliferation of human colon and hepatic cancer cell lines in vitro. BCAA supplementation caused a marked decrease in activated IGF-IR expression and significantly enhanced both mRNA and protein expression of LC3-II and BECN1 (BECLIN-1). Conclusion: BCAA could be a useful chemopreventive modality for cancer in hyperinsulinemic conditions.	[Wubetu, Gizachew Yismaw; Utsunomiya, Tohru; Ishikawa, Daichi; Ikemoto, Tetsuya; Yamada, Shinichiro; Morine, Yuji; Iwahashi, Shuichi; Saito, Yu; Arakawa, Yusuke; Imura, Satoru; Shimada, Mitsuo] Univ Tokushima, Dept Surg, Shinkuracho, Tokushima 7708503, Japan; [Arimochi, Hideki] Univ Tokushima, Dept Immunol & Parasitol, Shinkuracho, Tokushima 7708503, Japan		Shimada, M (corresponding author), Univ Tokushima, Dept Surg, 3-18-15 Kuramoto Cho, Shinkuracho, Tokushima 7708503, Japan.	mitsuo.shimada@tokushima-u.ac.jp		Ikemoto, Tetsuya/0000-0001-9800-1359	Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan	This study was supported by the Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.	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SEP	2014	34	9					4789	4796					8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AP1VS	WOS:000341860700021	25202059				2022-04-25	
J	Sikder, MOF; Sivaprakasam, S; Brown, MP; Thangaraju, M; Bhutia, YD; Ganapathy, V				Sikder, Mohd O. F.; Sivaprakasam, Sathish; Brown, Mothy P.; Thangaraju, Muthusamy; Bhutia, Yangzom D.; Ganapathy, Vadivel			SLC6A14, a Na+/Cl--coupled amino acid transporter, functions as a tumor promoter in colon and is a target for Wnt signaling	BIOCHEMICAL JOURNAL			English	Article							COLORECTAL-CANCER; ATB(0,+) SLC6A14; UP-REGULATION; DRUG TARGET; EXPRESSION; CELLS; ANTIPORTER; SYSTEM; GROWTH; RELEVANCE	SLC6A14 is a Na+/Cl--coupled transporter for neutral and cationic amino acids. It is expressed at basal levels in the normal colon but is up-regulated in colon cancer. However, the relevance of this up-regulation to cancer progression and the mechanisms involved in the up-regulation remain unknown. Here, we show that SLC6A14 is essential for colon cancer and that its up-regulation involves, at least partly, Wnt signaling. The up-regulation of the transporter is evident in most human colon cancer cell lines and also in a majority of patient-derived xenografts. These findings are supported by publicly available TCGA (The Cancer Genome Atlas) database. Treatment of colon cancer cells with a-methyltryptophan (alpha-MT), a blocker of SLC6A14, induces amino acid deprivation, decreases mTOR activity, increases autophagy, promotes apoptosis, and suppresses cell proliferation and invasion. In xenograft and syngeneic mouse tumor models, silencing of SLC6A14 by shRNA or blocking its function by a-MT reduces tumor growth. Similarly, the deletion of Slc6a14 in mice protects against colon cancer in two different experimental models (inflammation-associated colon cancer and genetically driven colon cancer). In colon cancer cells, expression of the transporter is reduced by Wnt antagonist or by silencing of beta-catenin whereas Wnt agonist or overexpression of beta-catenin shows the opposite effect. Finally, SLC6A14 as a target for beta-catenin is confirmed by chromatin immunoprecipitation. These studies demonstrate that SLC6A14 plays a critical role in the promotion of colon cancer and that its up-regulation in cancer involves Wnt signaling. These findings identify SLC6A14 as a promising drug target for the treatment of colon cancer.	[Sikder, Mohd O. F.; Sivaprakasam, Sathish; Brown, Mothy P.; Bhutia, Yangzom D.; Ganapathy, Vadivel] Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, Lubbock, TX 79430 USA; [Thangaraju, Muthusamy] Augusta Univ, Dept Biochem & Mol Biol, Augusta, GA 30912 USA		Ganapathy, V (corresponding author), Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, Lubbock, TX 79430 USA.	vadivel.ganapathy@ttuhsc.edu	Sivaprakasam, Sathish/E-9367-2018	Sivaprakasam, Sathish/0000-0002-9230-0144	Welch Endowed Chair in Biochemistry at Texas Tech University Health Sciences Center [BI-0028]	This work was supported by the Welch Endowed Chair in Biochemistry, Grant no. BI-0028, at Texas Tech University Health Sciences Center.	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J.	APR	2020	477	8					1409	1425		10.1042/BCJ20200099			17	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	LG7VG	WOS:000528303100005	32219372	hybrid, Green Published			2022-04-25	
J	Hwang, CH; Lin, YL; Liu, YK; Chen, CH; Wu, HY; Chang, CC; Chang, CY; Chang, YK; Chiu, YH; Liao, KW; Lai, YK				Hwang, Chia-Hsiang; Lin, Yu-Ling; Liu, Yen-Ku; Chen, Chia-Hung; Wu, Hsin-Yi; Chang, Cheng-Chang; Chang, Chao-Yuan; Chang, Yu-Kuo; Chiu, Yi-Han; Liao, Kuang-Wen; Lai, Yiu-Kay			7,7 ''-Dimethoxyagastisflavone-induced Apoptotic or Autophagic Cell Death in Different Cancer Cells	PHYTOTHERAPY RESEARCH			English	Article						7; 7 ''-dimethoxyagastisflavone; biflavonoid; Taxus media cv; Hicksii; apoptosis; autophagy	BACCATIN III; PACLITAXEL; NECROSIS; AGATHIS	7,7''-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus X media cv. Hicksii, was evaluated for its antiproliferative and antineoplastic effects in three human cancer cell lines. Interestingly, DMGF caused cell death via different pathways in different cancer cells. DMGF induced apoptosis, activated caspase-3 activity and changed the mitochondrial membrane potential in HT-29 human colon cancer cells. However, the apoptotic pathway is not the major pathway involved in DMGF-induced cell death in A549 human lung cancer cells and HepG2 human hepatoma cells. Treatment with 3-MA, an inhibitor of autophagy, significantly decreased DMGF-induced cell death in HepG2 and A549 cells, but did not affect DMGF-induced cell death in HT-29 cells. Following DMGF treatment, the HepG2 cells increased expression of LC3B-II, a marker used to monitor autophagy in cells. Thus, DMGF induced apoptotic cell death in HT-29 cells, triggered both apoptotic and autophagic death in A549 cells and induced autophagic cell death in HepG2 cells. Copyright (C) 2011 John Wiley & Sons, Ltd.	[Wu, Hsin-Yi; Liao, Kuang-Wen] Natl Chiao Tung Univ, Dept Biol Sci & Technol, Hsinchu 30050, Taiwan; [Hwang, Chia-Hsiang; Lai, Yiu-Kay] Natl Tsing Hua Univ, Dept Life Sci, Inst Biotechnol, Hsinchu 30013, Taiwan; [Hwang, Chia-Hsiang; Chang, Cheng-Chang; Chang, Chao-Yuan; Chang, Yu-Kuo] Yung Shin Pharmaceut Ind Co Ltd, Taichung, Taiwan; [Lin, Yu-Ling; Liu, Yen-Ku; Chen, Chia-Hung; Liao, Kuang-Wen] Natl Chiao Tung Univ, Inst Mol Med & Bioengn, Hsinchu 30050, Taiwan; [Chiu, Yi-Han] Tzu Chi Univ, Dept Life Sci, Hualien, Taiwan		Liao, KW (corresponding author), Natl Chiao Tung Univ, Dept Biol Sci & Technol, Hsinchu 30050, Taiwan.	liaonms@pchome.com.tw; yklai@life.nthu.edu.tw	Chiu, Yi-Han/AAL-8783-2021	Chiu, Yi-Han/0000-0001-6209-7897	Yung-Shin Pharmaceutical Industry Co., Ltd [98 C117]	The authors acknowledge the financial assistance provided by Yung-Shin Pharmaceutical Industry Co., Ltd under the cooperative grant scheme (Project No. 98 C117).	Amaravadi RK, 2007, CLIN CANCER RES, V13, P7271, DOI 10.1158/1078-0432.CCR-07-1595; Baloglu E, 1999, J NAT PROD, V62, P1068, DOI 10.1021/np990040k; Barth S, 2010, J PATHOL, V221, P117, DOI 10.1002/path.2694; Chattopadhyay SK, 2006, BIOORG MED CHEM LETT, V16, P2446, DOI 10.1016/j.bmcl.2006.01.077; Choi IK, 2010, BIOCHEM BIOPH RES CO, V393, P849, DOI 10.1016/j.bbrc.2010.02.097; Cotter TG, 2009, NAT REV CANCER, V9, P501, DOI 10.1038/nrc2663; Dai J, 2006, CHEM PHARM BULL, V54, P306, DOI 10.1248/cpb.54.306; Georgopoulou K, 2007, PLANTA MED, V73, P1081, DOI 10.1055/s-2007-981579; Goncalez E, 2001, BRAZ J MED BIOL RES, V34, P1453, DOI 10.1590/S0100-879X2001001100013; Guruvayoorappan Chandrasekharan, 2008, J Exp Ther Oncol, V7, P207; Hung JY, 2009, J AGR FOOD CHEM, V57, P9809, DOI 10.1021/jf902315e; Jiang SG, 2008, INT J ONCOL, V33, P103; KHAN NU, 1972, TETRAHEDRON, V28, P5689, DOI 10.1016/S0040-4020(01)88913-4; Ko H, 2009, BIOSCI BIOTECH BIOCH, V73, P2183, DOI 10.1271/bbb.90250; Krysko DV, 2008, METHODS, V44, P205, DOI 10.1016/j.ymeth.2007.12.001; Miller MC, 1999, CANCER CHEMOTH PHARM, V44, P444, DOI 10.1007/s002800051117; NICOLAOU KC, 1994, NATURE, V367, P630, DOI 10.1038/367630a0; OFMAN DJ, 1995, PHYTOCHEMISTRY, V38, P1223, DOI 10.1016/0031-9422(94)00783-P; Pang XF, 2009, CANCER RES, V69, P518, DOI 10.1158/0008-5472.CAN-08-2531; Reed JC, 2003, CANCER CELL, V3, P17, DOI 10.1016/S1535-6108(02)00241-6; Rello S, 2005, APOPTOSIS, V10, P201, DOI 10.1007/s10495-005-6075-6; Wang TH, 2000, CANCER, V88, P2619, DOI 10.1002/1097-0142(20000601)88:11<2619::AID-CNCR26>3.0.CO;2-J; Yu J, 2003, CANCER BIOL THER, V2, P694	23	11	11	1	10	WILEY-BLACKWELL	MALDEN	COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA	0951-418X			PHYTOTHER RES	Phytother. Res.	APR	2012	26	4					528	534		10.1002/ptr.3583			7	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	923LE	WOS:000302620000009	21915931				2022-04-25	
J	Koukourakis, MI; Giatromanolaki, A; Sivridis, E; Pitiakoudis, M; Gatter, KC; Harris, AL				Koukourakis, M. I.; Giatromanolaki, A.; Sivridis, E.; Pitiakoudis, M.; Gatter, K. C.; Harris, A. L.			Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia	BRITISH JOURNAL OF CANCER			English	Article						Beclin 1; colon cancer; autophagy; HIF1 alpha; LDH	AUTOPHAGY-RELATED PROTEIN; HEPATOCELLULAR-CARCINOMA; EXPRESSION; CELLS; GENE; TUMORIGENESIS; ANGIOGENESIS; ASSOCIATION; INHIBITION; PATHWAY	INTRODUCTION: Autophagy enables cells to recycle long-lived proteins or damaged organelles. Beclin 1, the mammalian orthologue of the yeast Apg6/Vps30 gene, functions as a scaffold for the formation of autophagosomes. MATERIALS AND METHODS: The immunohistochemical patterns of Beclin 1 expression and their prognostic relevance were studied in formalin-fixed tissues from 155 patients with colorectal adenocarcinoma treated with surgery alone. RESULTS: Using the weak homogeneous expression of Beclin 1 in normal colonic tissues as a basis for assessing tumours, the following grouping/staining patterns were recognised in colorectal carcinomas: a normal-like pattern in 62 of 155 (40%) cases, an underexpression pattern in 24 of 155 (15.5%) cases, extensive overexpression of Beclin 1 in 33 of 155 (21.3%) tumours and limited overexpression of the protein in 36 of 155 (23.2%) tumours. Extensive overexpression of Beclin 1 was significantly linked with overexpression of HIF1 alpha and LDH5, as well as with high histological grade, vascular invasion and nodal involvement. Furthermore, patients with extensive over-or underexpression of Beclin 1 had a significantly poorer overall survival compared with the other two groups (P<0.0001). Beclin 1 had an independent prognostic relevance in multivariate analysis. CONCLUSIONS: Beclin 1 has an important role in growth and metastasis of colorectal cancer. Loss of Beclin 1 expression (allelic loss or microRNA regulatory activity, as suggested in the literature) defines poor prognosis presumably by promoting anti-apoptotic pathways, while overexpression of the protein, being linked with tumour hypoxia and acidity, also defines subgroups of tumours with aggressive clinical behaviour. British Journal of Cancer (2010) 103, 1209-1214. doi:10.1038/sj.bjc.6605904 www.bjcancer.com Published online 14 September 2010 (C) 2010 Cancer Research UK	[Koukourakis, M. I.] Democritus Univ Thrace, Dept Radiotherapy Oncol, Alexandroupolis 68100, Greece; [Koukourakis, M. I.; Giatromanolaki, A.; Sivridis, E.; Pitiakoudis, M.] Univ Gen Hosp Alexandroupolis, Alexandroupolis 68100, Greece; [Giatromanolaki, A.; Sivridis, E.] Democritus Univ Thrace, Dept Pathol, Alexandroupolis 68100, Greece; [Pitiakoudis, M.] Democritus Univ Thrace, Dept Surg, Alexandroupolis 68100, Greece; [Gatter, K. C.; Harris, A. L.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Canc Res UK,Mol Oncol Labs, Oxford OX3 7LJ, England; [Gatter, K. C.; Harris, A. L.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 7LJ, England		Koukourakis, MI (corresponding author), Democritus Univ Thrace, Dept Radiotherapy Oncol, Alexandroupolis 68100, Greece.	targ@her.forthnet.gr	Harris, Adrian/ABA-3343-2020	Harris, Adrian/0000-0003-1376-8409	Cancer Research UKCancer Research UK Funding Source: Medline		Ahn CH, 2007, APMIS, V115, P1344, DOI 10.1111/j.1600-0463.2007.00858.x; Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Anai S, 2007, MOL CANCER THER, V6, P101, DOI 10.1158/1535-7163.MCT-06-0367; Apel A, 2008, CANCER RES, V68, P1485, DOI 10.1158/0008-5472.CAN-07-0562; Cao Y, 2007, CELL RES, V17, P839, DOI 10.1038/cr.2007.78; Chen YS, 2009, PATHOL ONCOL RES, V15, P487, DOI 10.1007/s12253-008-9143-8; Ding ZB, 2008, CANCER RES, V68, P9167, DOI 10.1158/0008-5472.CAN-08-1573; Holbrook, 1975, ENZYMES, V11, P191; Kihara A, 2001, EMBO REP, V2, P330, DOI 10.1093/embo-reports/kve061; Kim KW, 2008, AUTOPHAGY, V4, P659, DOI 10.4161/auto.6058; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Koukourakis MI, 2006, J CLIN ONCOL, V24, P4301, DOI 10.1200/JCO.2006.05.9501; Li BX, 2009, AUTOPHAGY, V5, P303, DOI 10.4161/auto.5.3.7491; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Liang XH, 2001, CANCER RES, V61, P3443; Maiuri MC, 2009, CELL DEATH DIFFER, V16, P87, DOI 10.1038/cdd.2008.131; Mari M, 2007, NAT CELL BIOL, V9, P1125, DOI 10.1038/ncb1007-1125; Miracco C, 2007, INT J ONCOL, V30, P429; Pirtoli L, 2009, AUTOPHAGY, V5, P930, DOI 10.4161/auto.5.7.9227; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Salceda S, 1997, J BIOL CHEM, V272, P22642, DOI 10.1074/jbc.272.36.22642; Samokhvalov V, 2008, AUTOPHAGY, V4, P1034, DOI 10.4161/auto.6994; Song JR, 2009, AUTOPHAGY, V5, P1131, DOI 10.4161/auto.5.8.9996; Zhu H, 2009, AUTOPHAGY, V5, P816, DOI 10.4161/auto.9064; Zois CE, 2009, AUTOPHAGY, V5, P442, DOI 10.4161/auto.5.4.7667	25	126	137	0	13	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	0007-0920			BRIT J CANCER	Br. J. Cancer	OCT 12	2010	103	8					1209	1214		10.1038/sj.bjc.6605904			6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	671WL	WOS:000283542900010	20842118	Green Published, hybrid			2022-04-25	
J	Cottone, L; Capobianco, A; Gualteroni, C; Perrotta, C; Bianchi, ME; Rovere-Querini, P; Manfredi, AA				Cottone, Lucia; Capobianco, Annalisa; Gualteroni, Chiara; Perrotta, Cristiana; Bianchi, Marco E.; Rovere-Querini, Patrizia; Manfredi, Angelo A.			5-Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells	INTERNATIONAL JOURNAL OF CANCER			English	Article						5-fluorouracil; autophagy; HMGB1; chemoattraction; peritoneal carcinomatosis	TUMOR-INFILTRATING LYMPHOCYTES; REGULATES AUTOPHAGY; CANCER-CELLS; MACROPHAGES; INFLAMMATION; CHEMOTHERAPY; RECRUITMENT; MIGRATION; IMMUNOTHERAPY; CHEMOTAXIS	Signals released by leukocytes contribute to tumor growth and influence the efficacy of antineoplastic treatments. The outcome of peritoneal carcinomatosis treatments is unsatisfactory, possibly because chemotherapy activates events that have in the long-term deleterious effects. In this study we offer evidence that 5-fluorouracile (5-FU), besides provoking apoptosis of MC38 colon carcinoma cells, induces a striking attraction of leukocytes both in an orthotopic model of colon carcinomatosis in vivo and in monocyte-migration assays in vitro. Leukocyte attraction depends on the presence of High Mobility Group Box 1 (HMGB1), an endogenous immune adjuvant and chemoattractant released by dying cells. Leukocyte recruitment is prevented in vivo and in vitro using blocking antibodies against HMGB1 and its competitive antagonist BoxA or by interfering with HMGB1 expression. Autophagy is required for leukocyte chemoattraction, since the latter abates upon pharmacological blockade of the autophagic flux while activation of autophagy per se, in the absence of death of colon carcinoma cells, is not sufficient to attract leukocytes. Our results identify autophagy induction and HMGB1 release in colon carcinoma cells as key events responsible for 5-FU elicited leukocyte attraction and define a novel rate-limiting target for combinatorial therapies. What's New? Anti-cancer drugs can sometimes help the tumors they are meant to destroy. One reason is because stressed or dying cancer cells release molecular factors that can attract leukocytes, and some of those leukocytes can contribute to tumor survival. In this study, the authors found that this is precisely what happens during intraperitoneal treatment of colon-cancer carcinomatosis with 5-fluorouracil (5-FU). Their results suggest that blocking autophagy and the release of HMGB1 are potential therapeutic targets for enhancing standard chemotherapy.	[Cottone, Lucia; Capobianco, Annalisa; Gualteroni, Chiara; Rovere-Querini, Patrizia; Manfredi, Angelo A.] Ist Sci San Raffaele, Div Regenerat Med, I-20132 Milan, Italy; [Cottone, Lucia; Bianchi, Marco E.; Rovere-Querini, Patrizia; Manfredi, Angelo A.] Univ Vita Salute San Raffaele, Sch Med, Milan, Italy; [Perrotta, Cristiana] Univ Milan, Dept Biomed & Clin Sci L Sacco, Milan, Italy; [Bianchi, Marco E.] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy		Manfredi, AA (corresponding author), Ist Sci San Raffaele, DIBIT 3A1, Via Olgettina 58, I-20132 Milan, Italy.	manfredi.angelo@hsr.it	Perrotta, Cristiana/I-2835-2016; Manfredi, Angelo A./C-7018-2014; Annalisa, Capobianco/AAN-3844-2020; Cottone, Lucia/W-4847-2019; Rovere-Querini, Patrizia/J-2340-2012; Bianchi, Marco Emilio/K-3417-2018	Perrotta, Cristiana/0000-0001-6680-4536; Manfredi, Angelo A./0000-0001-8370-6970; Bianchi, Marco Emilio/0000-0002-5329-6445; Cottone, Lucia/0000-0002-9397-4925	AIRC (Associazione Italiana Ricerca Cancro), MIUR, by the Ministero della SanitaFondazione AIRC per la ricerca sul cancro [IG11761]	Grant sponsor: AIRC (Associazione Italiana Ricerca Cancro), MIUR, by the Ministero della Sanita; Grant number: IG11761.	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J. Cancer	MAR 15	2015	136	6					1381	1389		10.1002/ijc.29125			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AY6XD	WOS:000347705200044	25098891	Bronze			2022-04-25	
J	Wozniak, M; Makuch, S; Winograd, K; Wisniewski, J; Ziolkowski, P; Agrawal, S				Wozniak, Marta; Makuch, Sebastian; Winograd, Kinga; Wisniewski, Jerzy; Ziolkowski, Piotr; Agrawal, Siddarth			6-Shogaol enhances the anticancer effect of 5-fluorouracil, oxaliplatin, and irinotecan via increase of apoptosis and autophagy in colon cancer cells in hypoxic/aglycemic conditions	BMC COMPLEMENTARY MEDICINE AND THERAPIES			English	Article						5-fluorouracil; 6-shogaol; Autophagy; Chemosensitivity; Colon cancer; Hypoxia	DRUG-RESISTANCE; ACTIVATION; DEATH; MECHANISMS; THERAPY; PATHWAY	Background: The development and growth of colorectal cancer based on constitutive activation of numerous signaling pathways that stimulate proliferation and metastasis. Plant-derived agents excel by targeting multiple aspects of tumor progression. Previous investigations have shown that ginger derivatives-shogaols possess anti-cancer and anti-inflammatory effects. In the present study, we have examined the anti-cancer effects of 6-shogaol alongside with the most widely used chemotherapeutic agents/regimens in the tumor-like microenvironment conditions. Methods: Cytotoxicity on two colon cancer cell lines (SW480 and SW620) was measured by MTT test. Apoptosisassay, immunocytochemical and Western blotting analysis for autophagy and apoptosis detection were performed. Results: Here, we report that 6-shogaol by itself or in combination with chemotherapeutic agents/regimens exerted a cytotoxic effect on CRC cells. Cell death might be linked with the activation of autophagy and apoptosis-related pathways. In the tumor-like microenvironment, which is characterized by hypoxia and glucose starvation, 6-shogaol with chemotherapeutics is significantly more potent than conventional chemotherapy alone. Conclusions: Collectively, our data suggest that the addition of 6-shogaol to established chemotherapeutic regimens could potentially be a remarkable therapeutic strategy for colorectal cancer.	[Wozniak, Marta; Makuch, Sebastian; Ziolkowski, Piotr; Agrawal, Siddarth] Wroclaw Med Univ, Dept Pathol, Ul K Marcinkowskiego, PL-150368 Wroclaw, Poland; [Winograd, Kinga] Wroclaw Univ Sci & Technol, Dept Chem, Wroclaw, Poland; [Wisniewski, Jerzy] Wroclaw Med Univ, Dept Biochem, Wroclaw, Poland; [Agrawal, Siddarth] Wroclaw Med Univ, Dept & Clin Internal Med Occupat Dis Hypertens &, Wroclaw, Poland		Wozniak, M (corresponding author), Wroclaw Med Univ, Dept Pathol, Ul K Marcinkowskiego, PL-150368 Wroclaw, Poland.	marta1wozniak@wp.pl	Wiśniewski, Jerzy/AAV-7279-2020; Makuch, Sebastian/ABD-4283-2021; Ziolkowski, Piotr/AAU-2452-2021; Wozniak, Marta/ABD-2161-2021; Makuch, Sebastian/ABH-4515-2020	Wozniak, Marta/0000-0001-7978-6330; Makuch, Sebastian/0000-0002-9904-1181; Agrawal, Siddarth/0000-0003-1118-5090; Ziolkowski, Piotr/0000-0003-3036-2611	National Science CenterNational Science Centre, Poland [DEC-2015/19/N/NZ5/0001]; Wroclaw Medical University [STM.A011.17.005]	Funding by the National Science Center grant no. DEC-2015/19/N/NZ5/0001 and Wroclaw Medical University STM.A011.17.005. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.	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Med. Ther.	MAY 11	2020	20	1							141	10.1186/s12906-020-02913-8			10	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	MM7TI	WOS:000550355300001	32393373	Green Published, gold			2022-04-25	
J	Garcia-Barros, M; Coant, N; Kawamori, T; Wada, M; Snider, AJ; Truman, JP; Wu, BX; Furuya, H; Clarke, CJ; Bialkowska, AB; Ghaleb, A; Yang, VW; Obeid, LM; Hannun, YA				Garcia-Barros, Monica; Coant, Nicolas; Kawamori, Toshihiko; Wada, Masayuki; Snider, Ashley J.; Truman, Jean-Philip; Wu, Bill X.; Furuya, Hideki; Clarke, Christopher J.; Bialkowska, Agnieszka B.; Ghaleb, Amr; Yang, Vincent W.; Obeid, Lina M.; Hannun, Yusuf A.			Role of neutral ceramidase in colon cancer	FASEB JOURNAL			English	Article						sphingolipids ceramide; aberrant crypt foci; azoxymethane; apoptosis	RENAL MESANGIAL CELLS; NECROSIS-FACTOR-ALPHA; SPHINGOSINE KINASE 1; BETA-CATENIN; COLORECTAL-CANCER; IN-VIVO; INTESTINAL TUMORIGENESIS; TUMOR-GROWTH; CRYPT FOCI; CF1 MICE	Alterations in sphingolipid metabolism, especially ceramide and sphingosine 1-phosphate, have been linked to colon cancer, suggesting that enzymes of sphingolipid metabolism may emerge as novel regulators and targets in colon cancer. Neutral ceramidase (nCDase), a key enzyme in sphingolipid metabolism that hydrolyzes ceramide into sphingosine, is highly expressed in the intestine; however, its role in colon cancer has not been defined. Here we show that molecular and pharmacological inhibition of nCDase in colon cancer cells increases ceramide, and this is accompanied by decreased cell survival and increased apoptosis and autophagy, with minimal effects on noncancerous cells. Inhibition of nCDase resulted in loss of beta-catenin and inhibition of ERK, components of pathways relevant for colon cancer development. Furthermore, inhibition of nCDase in a xenograft model delayed tumor growth and increased ceramide while decreasing proliferation. It is noteworthy that mice lacking nCDase treated with azoxymethane were protected from tumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and these data suggest that this enzyme is a suitable and novel target for colon cancer therapy.	[Garcia-Barros, Monica; Coant, Nicolas; Wada, Masayuki; Snider, Ashley J.; Truman, Jean-Philip; Clarke, Christopher J.; Bialkowska, Agnieszka B.; Ghaleb, Amr; Yang, Vincent W.; Obeid, Lina M.; Hannun, Yusuf A.] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA; [Hannun, Yusuf A.] SUNY Stony Brook, Dept Biochem, Stony Brook, NY 11794 USA; [Hannun, Yusuf A.] SUNY Stony Brook, Dept Pharmacol, Stony Brook, NY 11794 USA; [Hannun, Yusuf A.] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA; [Garcia-Barros, Monica; Coant, Nicolas; Wada, Masayuki; Snider, Ashley J.; Truman, Jean-Philip; Clarke, Christopher J.; Obeid, Lina M.; Hannun, Yusuf A.] SUNY Stony Brook, Stony Brook Canc Ctr, Stony Brook, NY 11794 USA; [Kawamori, Toshihiko; Furuya, Hideki] Univ Hawaii, Ctr Canc, Canc Biol Program, Honolulu, HI 96822 USA; [Kawamori, Toshihiko] Tokyo Leon Clin, Res Inst Canc Prevent & Pathol Diag, Nagoya, Aichi, Japan; [Snider, Ashley J.; Obeid, Lina M.] Northport Vet Affairs Med Ctr, Northport, NY USA; [Wu, Bill X.] Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC USA		Hannun, YA (corresponding author), Dept Biochem, 101 Nicolls Rd,T15,023, Stony Brook, NY 11794 USA.; Hannun, YA (corresponding author), Dept Pharmacol, 101 Nicolls Rd,T15,023, Stony Brook, NY 11794 USA.; Hannun, YA (corresponding author), Dept Pathol, 101 Nicolls Rd,T15,023, Stony Brook, NY 11794 USA.; Hannun, YA (corresponding author), Dept Med, 101 Nicolls Rd,T15,023, Stony Brook, NY 11794 USA.	yusuf.hannun@stonybrookmedicine.edu	Furuya, Hideki/AAH-5719-2021	Furuya, Hideki/0000-0002-9536-8662; COANT, Nicolas/0000-0001-9237-2132	U.S. National Institutes of Health, National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01-CA172517, P01-CA97132, R01-CA172113]; ONO Co.; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P01CA097132, R01CA172517, R01CA172113] Funding Source: NIH RePORTER	This work was supported by U.S. National Institutes of Health, National Cancer Institute Grants R01-CA172517 (to Y.A.H.), P01-CA97132 (to L.M.O.), and R01-CA172113 (to V.W.Y.). The authors thank the Lipidomics Core facility at the State University of New York at Stony Brook for lipid analysis, the Lipidomic Facility at the Medical University of South Carolina for providing the nCDase inhibitor, the Flow Cytometry Core facility for assistance with cell cycle analysis, the Research Core Histology Laboratory at Stony Brook University for technical assistance, and Dr. Takuji Tanaka (certified pathologist and toxicologist; Gifu Municipal Hospital, Gifu, Japan) for assistance with AOM-induced tumors diagnosis. The laboratory of Dr. Y.A.H. has research support from ONO Co., for a distinct project.	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DEC	2016	30	12					4159	4171		10.1096/fj.201600611R			13	Biochemistry & Molecular Biology; Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology	EC5UG	WOS:000388201500022	27609772	Green Published			2022-04-25	
J	Trnski, D; Sabol, M; Gojevic, A; Martinic, M; Ozretic, P; Musani, V; Ramic, S; Levanat, S				Trnski, Diana; Sabol, Maja; Gojevic, Ante; Martinic, Marina; Ozretic, Petar; Musani, Vesna; Ramic, Snjezana; Levanat, Sonja			GSK3 beta and Gli3 play a role in activation of Hedgehog-Gli pathway in human colon cancer - Targeting GSK3 beta downregulates the signaling pathway and reduces cell proliferation	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE			English	Article						Hedgehog signaling; Gli3; GSK3 beta; Autophagy; Apoptosis; Colon cancer	COLORECTAL-CANCER; SONIC HEDGEHOG; EXPRESSION; SUPPRESSOR; AUTOPHAGY; LITHIUM; APOPTOSIS; SUFU; GLYCOGEN-SYNTHASE-KINASE-3-BETA; INVOLVEMENT	The role of Hedgehog-Gli (Hh-Gli) signaling in colon cancer tumorigenesis has not yet been completely elucidated. Here we provide strong evidence of Hh-Gli signaling involvement in survival of colon cancer cells, with the main trigger of activation being deregulated GSK3 beta. Our clinical data reveals high expression levels of GSK3 beta and Gli3 in human colon cancer tissue samples, with positive correlation between GSK3 beta expression and DUKES' stage. Further experiments on colon cancer cell lines have shown that a deregulated GSK3 beta upregulates Hh-Gli signaling and positively affects colon cancer cell survival. We show that inhibition of GSK3 beta with lithium chloride enhances Gli3 processing into its repressor form, consequently downregulating Hh-Gli signaling, reducing cell proliferation and inducing cell death. Analysis of the molecular mechanisms revealed that lithium chloride enhances Gli3-SuFu-GSK3 beta complex formation leading to more efficient Gli3 cleavage and Hh-Gli signaling downregulation. This work proposes that activation of the Hh-Gli signaling pathway in colon cancer cells occurs non-canonically via deregulated GSK3 beta. Gli3 seems to be the main pathway effector, highlighting the activator potential of this transcription factor, which is highly dependent on GSK3 beta function and fine tuning of the Gli3-SuFu-GSK3 beta platform. (C) 2015 Elsevier B.V. All rights reserved.	[Trnski, Diana; Sabol, Maja; Martinic, Marina; Ozretic, Petar; Musani, Vesna; Levanat, Sonja] Rudjer Boskovic Inst, Div Mol Med, Zagreb 10000, Croatia; [Gojevic, Ante] Univ Hosp Ctr Zagreb, Dept Surg, Zagreb, Croatia; [Ramic, Snjezana] Univ Hosp Tumors, Sestre Milosrdnice Univ Hosp Ctr, Dept Pathol, Zagreb, Croatia		Levanat, S (corresponding author), Rudjer Boskovic Inst, Div Mol Med, Bijenicka 54, Zagreb 10000, Croatia.	diana.trnski@irb.hr; maja.sabol@irb.hr; ante.gojevic@xnet.hr; marina.martinic.87@gmail.com; pozretic@irb.hr; vmusani@irb.hr; snjezana.ramic@zg.t-com.hr; levanat@irb.hr	Ozretić, Petar/G-5189-2014; Musani, Vesna/K-7972-2019; Sabol, Maja/G-4177-2011; Ramic, Snjezana/K-8650-2019; Trnski, Diana/N-6816-2015	Ozretić, Petar/0000-0001-9757-6636; Sabol, Maja/0000-0001-6968-2327; Musani, Vesna/0000-0001-9927-3727; Ramic, Snjezana/0000-0002-5916-8815; Trnski, Diana/0000-0003-2441-8439	Croatian Ministry of Science, Education and SportsMinistry of Science, Education and Sports, Republic of Croatia [098-0982464-2461]	The authors wish to thank Dr. Sanja Kapitanovic and Dr. Marijeta Kralj for the colon cancer cell lines, Dr. Marijeta Kralj and Dr. Ana-Matea Mikecin for help with autophagy analysis, Dr. Andreja Ambriovic-Ristov for the alpha-PARP and alpha-caspase-3 antibodies, Lucija Horvat for help with confocal microscopy. We also wish to thank all the patients who participated in this study, Dr. Fabijan Knezevic from the Sestre Milosrdnice University Hospital Center for the use of the autostainer and professor Romana Halapir Frankovic from the 5th High School (for math and science) in Zagreb for use of the microscope and camera. This study was funded by the Croatian Ministry of Science, Education and Sports (grant. no. 098-0982464-2461). The funding source had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.	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Biophys. Acta-Mol. Basis Dis.	DEC	2015	1852	12					2574	2584		10.1016/j.bbadis.2015.09.005			11	Biochemistry & Molecular Biology; Biophysics; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics; Cell Biology	CU8XL	WOS:000363827300002	26385428	Bronze			2022-04-25	
J	Qian, HR; Shi, ZQ; Zhu, HP; Gu, LH; Wang, XF; Yang, Y				Qian, Hao-Ran; Shi, Zhao-Qi; Zhu, He-Pan; Gu, Li-Hu; Wang, Xian-Fa; Yang, Yi			Interplay between apoptosis and autophagy in colorectal cancer	ONCOTARGET			English	Review						colorectal cancer; autophagy; apoptosis; cross-talk	ADVANCED SOLID TUMORS; COLON-CANCER; CELL-DEATH; THERAPEUTIC TARGET; TRIGGERS APOPTOSIS; CROSS-TALK; BCL-X; INHIBITION; EXPRESSION; PATHWAY	Autophagy and apoptosis are two pivotal mechanisms in mediating cell survival and death. Cross-talk of autophagy and apoptosis has been documented in the tumorigenesis and progression of cancer, while the interplay between the two pathways in colorectal cancer (CRC) has not yet been comprehensively summarized. In this study, we outlined the basis of apoptosis and autophagy machinery firstly, and then reviewed the recent evidence in cellular settings or animal studies regarding the interplay between them in CRC. In addition, several key factors that modulate the cross-talk between autophagy and apoptosis as well as its significance in clinical practice were discussed. Understanding of the interplay between the cell death mechanisms may benefit the translation of CRC treatment from basic research to clinical use.	[Qian, Hao-Ran; Shi, Zhao-Qi; Zhu, He-Pan; Gu, Li-Hu; Wang, Xian-Fa] Zhejiang Univ, Sir Run Run Shaw Hosp, Surg Zhejiang Univ, Dept Gen Surg,Inst Minimally Invas,Sch Med, Hangzhou 310016, Zhejiang, Peoples R China; [Yang, Yi] Hangzhou Normal Univ, Sch Med, Hangzhou Key Lab Med Neurobiol, Dept Pharmacol, Hangzhou 310036, Zhejiang, Peoples R China		Qian, HR (corresponding author), Zhejiang Univ, Sir Run Run Shaw Hosp, Surg Zhejiang Univ, Dept Gen Surg,Inst Minimally Invas,Sch Med, Hangzhou 310016, Zhejiang, Peoples R China.; Yang, Y (corresponding author), Hangzhou Normal Univ, Sch Med, Hangzhou Key Lab Med Neurobiol, Dept Pharmacol, Hangzhou 310036, Zhejiang, Peoples R China.	websterqian@126.com; yyang@hznu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81401043]; Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LY17H310005, LY17H160027]	This study is supported by National Natural Science Foundation of China (81401043) and Zhejiang Provincial Natural Science Foundation of China (LY17H310005, LY17H160027).	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Zhang X, 2016, J CANCER RES CLIN, V142, P453, DOI 10.1007/s00432-015-1997-z; Zhao S, 2017, ONCOTARGET, V8, P7502, DOI 10.18632/oncotarget.10649; Zhou CX, 2017, ONCOTARGET, V8, P14736, DOI 10.18632/oncotarget.14718	91	29	30	1	14	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	SEP 5	2017	8	37					62759	62768		10.18632/oncotarget.18663			10	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	FF8GI	WOS:000409254200166	28977986	Green Published, gold			2022-04-25	
J	Guo, XZ; Ye, XL; Xiao, WZ; Wei, XN; You, QH; Che, XH; Cai, YJ; Chen, F; Yuan, H; Liu, XJ; Yu, MH				Guo, Xian-Zhi; Ye, Xiao-Lei; Xiao, Wei-Zhong; Wei, Xue-Ni; You, Qing-Hua; Che, Xiao-Hang; Cai, Yan-Jun; Chen, Fang; Yuan, Hao; Liu, Xiao-Jian; Yu, Ming-Hua			Downregulation of VMP1 confers aggressive properties to colorectal cancer	ONCOLOGY REPORTS			English	Article						vacuole membrane protein 1 colorectal cancer; lentivirus; invasion; proliferation; chemotherapy	HEPATOCELLULAR-CARCINOMA; CELL POLARITY; COLON-CANCER; BECLIN 1; AUTOPHAGY; EXPRESSION; METASTASIS; APOPTOSIS; PATTERNS; SURVIVAL	Vacuole membrane protein 1 (VMP1) was recently found to be involved in the process of tumor metastasis and is also considered to play a vital role in balancing apoptosis and autophagy. In the present study, the expression of VMP1 in colorectal cancer and matched adjacent non-cancerous tissues was evaluated by immunohistochemistry (IHC) for studying the role of VMP1 in the process of colorectal cancer. Kaplan-Meier analysis and the log-rank test were used to calculate the correlation of classic clinicopathological characteristics related to survival and the expression of VMP1. In vitro, a VMP1 stable gene silencing cell model was constructed using a lentiviral vector. The invasive ability and proliferation of colorectal cancer cells were evaluated by Transwell and MTT assays, respectively, and the underlying signaling pathway was explored by western blotting. Additionally, drug susceptibility to cisplatin, oxaliplatin and 5-FU was tested before and after VMP1 knockout. Finally, an animal model was constructed to explore the role of VMP1 in the physiopathologic process of colorectal cancer. Our results indicated that VMP1 showed increased expression in the adjacent non-cancer tissues compared with that in the colorectal cancer tissues. For different stages of colorectal cancer, expression of VMP1 had a negative correlation with the malignancy of the cancer. In clinical research, we also found that the median survival of patients with low VMP1 expression was much shorter than the survival of patients with high expression. In vitro, after infection with the lentivirus,,cells with VMP1 knockout gained significant aggressive properties in regards to invasion and proliferation, and the mechanisms may be related to the activation of the PI3K/Akt/ZO-1/E-cadherin pathway. We also found that shVMP1 cells were more sensitive to 5-FU, but not cisplatin and oxaliplatin. Finally, we found a higher number of formed nodules in nude mice after intraperitoneal injection with shVMP1 cells in the in vivo study.	[Guo, Xian-Zhi; Liu, Xiao-Jian; Yu, Ming-Hua] Fudan Univ, Pudong Med Ctr, Shanghai Pudong Hosp, Dept Med Oncol, Shanghai 201399, Peoples R China; [Ye, Xiao-Lei; Che, Xiao-Hang] Ningbo Inst Med Sci, Drugs & Pharmacol Lab, Ningbo 315020, Zhejiang, Peoples R China; [Xiao, Wei-Zhong; Cai, Yan-Jun] Fudan Univ, Pudong Med Ctr, Dept Internal Neurol, Shanghai Pudong Hosp, Shanghai 201399, Peoples R China; [You, Qing-Hua] Fudan Univ, Pudong Med Ctr, Dept Pathol, Shanghai Pudong Hosp, Shanghai 201399, Peoples R China; [Yuan, Hao] Fudan Univ, Pudong Med Ctr, Dept Gen Surg, Shanghai Pudong Hosp, Shanghai 201399, Peoples R China; [Wei, Xue-Ni] China Pharmaceut Univ, Dept Pharmacol, Nanjing 211198, Jiangsu, Peoples R China; [Chen, Fang] Southern Med Univ, Nanfang Hosp, Dept Hematol, Guangzhou 510515, Guangdong, Peoples R China		Liu, XJ (corresponding author), Fudan Univ, Pudong Med Ctr, Shanghai Pudong Hosp, Dept Med Oncol, 2800 Gongwei Rd, Shanghai 201399, Peoples R China.	lxj068@hotmail.com; ymh3011@hotmail.com	Liu, Xiaojian/E-3263-2015	Liu, Xiaojian/0000-0003-0694-2181; Che, Xiaohang/0000-0002-8910-0205	Young Medical Talents Training Program of Pudong Health Bureau of Shanghai [PWRq2012-31]; Academic Leaders Training Program of Pudong Health Bureau of Shanghai [PWRd2012-15]; Natural Science Foundation of Ningbo [2011A610048]	The present study was supported by the Young Medical Talents Training Program of Pudong Health Bureau of Shanghai (no. PWRq2012-31), the Academic Leaders Training Program of Pudong Health Bureau of Shanghai (no. PWRd2012-15), and the Natural Science Foundation of Ningbo (no. 2011A610048).	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Rep.	NOV	2015	34	5					2557	2566		10.3892/or.2015.4240			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CT5NO	WOS:000362857300042	26328607	Bronze			2022-04-25	
J	Liu, ZY; Yang, L; Zhong, CB; Zhou, L				Liu, Zhongyuan; Yang, Le; Zhong, Chongbai; Zhou, Ling			EZH2 regulates H2B phosphorylation and elevates colon cancer cell autophagy	JOURNAL OF CELLULAR PHYSIOLOGY			English	Article						ATG genes; cell autophagy; colon cancer; EZH2; histone phosphorylation	HISTONE; PATHOGENESIS; EXPRESSION; INSIGHTS; GENES	Epigenetic alterations, especially histone modification, play vital roles in the pathogenesis of colon cancer. Upregulation of the enhancer of zeste homolog 2 (EZH2) has been reported to contribute to the initiation and progression of colon cancer. This study analyzed the association between EZH2 and phosphorylation of H2B at tyrosine 37 (H2B(Y37ph)) in colon cancer tissues and cells, along with the influences of the EZH2-H2B(Y37ph) axis on colon cancer cell autophagy. Immunohistochemistry was utilized to assess EZH2 and H2B(Y37ph) expressions in clinical samples of colon cancer. Cell transfection was carried out to alter EZH2 and H2B(Y37ph) expressions in colon cancer cells. Co-immunoprecipitation analysis and glutathione-S-transferase (GST) pull down assay were conducted to analyze the association between EZH2 and H2B(Y37ph). Western blotting was utilized to measure proteins expressions related to cell autophagy. We found that there was a positive association between EZH2 and H2B(Y37ph) in colon cancer tissues and cells. EZH2 directly interacted with H2B and promoted H2B(Y37ph) in colon cancer cells using ATP as a phosphate donor. Moreover, EZH2 levated colon cancer cell autophagy in starvation condition. H2B(Y37ph) was required for EZH2-elevated colon cancer cell autophagy under starvation condition. The EZH2-H2B(Y37ph) axis elevated colon cancer cell autophagy possibly via activating transcriptional regulation of ATG genes. In conclusion, EZH2-elevated colon cancer initiation and progression at least in part via inducing colon cancer cell autophagy. EZH2 could phosphorylate H2B(Y37) and then induce transcription activation of ATG genes in colon cancer cells under starvation condition.	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Cell. Physiol.	FEB	2020	235	2					1494	1503		10.1002/jcp.29069		JUL 2019	10	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	JQ2GV	WOS:000477553700001	31283006				2022-04-25	
J	Fu, W; Li, X; Lu, XP; Zhang, LY; Li, R; Zhang, N; Liu, S; Yang, X; Wang, Y; Zhao, Y; Meng, XB; Zhu, WG				Fu, Wan; Li, Xue; Lu, Xiaopeng; Zhang, Luyao; Li, Ran; Zhang, Nan; Liu, Shan; Yang, Xin; Wang, Yue; Zhao, Ying; Meng, Xiangbao; Zhu, Wei-Guo			A novel acridine derivative, LS-1-10 inhibits autophagic degradation and triggers apoptosis in colon cancer cells	CELL DEATH & DISEASE			English	Article							PHASE-II TRIAL; LYSOSOMAL MEMBRANE PERMEABILIZATION; MALIGNANT GLIOMA-CELLS; DNA-DAMAGE RESPONSE; TUMOR MICROENVIRONMENT; SEQUESTOSOME 1/P62; TOPOISOMERASE-II; AMSACRINE; DEATH; INDUCTION	Autophagy promotes cancer cell survival and drug resistance by degrading harmful cellular components and maintaining cellular energy levels. Disruption of autophagy may be a promising approach to sensitize cancer cells to anticancer drugs. The combination of autophagic inhibitors, such as chloroquine (CQ) and lucanthone with conventional cancer therapeutics has been investigated in clinical trials, but adverse drug-drug interactions are a high possibility. Here we designed and synthesized a novel, small-molecule library based on an acridine skeleton and the CQ structure with various modifications and substitutions and screened the compounds for effective autophagy inhibition. We found that 9-chloro-2-(3-(dimethylamino) propyl) pyrrolo[2,3,4-kl] acridin-1(2H)-one (LS-1-10) was the most effective from our library at inhibiting autophagic-mediated degradation and could decrease the viability of multiple colon cancer cells. In addition, LS-1-10 induced DNA damage and caspase 8-mediated apoptosis. Overall, this small molecule was more efficient at reducing the viability of cancer cells than other conventional chemotherapeutic agents, such as CQ and amsacrine. The anticancer and autophagy-inhibiting activities of LS-1-10 were confirmed in vivo in a xenograft mouse model. Collectively, this study has identified a new and efficient single compound with both autophagy-inhibiting and anticancer activity, which may provide a novel approach for cancer therapy.	[Fu, Wan; Li, Xue; Lu, Xiaopeng; Zhang, Luyao; Li, Ran; Zhang, Nan; Liu, Shan; Yang, Xin; Wang, Yue; Zhao, Ying; Meng, Xiangbao; Zhu, Wei-Guo] Peking Univ, Key Lab Carcinogenesis & Translat Res,Sch Basic M, State Key Lab Nat & Biomimet Drugs,Minist Educ,De, Beijing Key Lab Prot Posttranslat Modificat & Cel, Beijing 100191, Peoples R China; [Lu, Xiaopeng; Zhu, Wei-Guo] Shenzhen Univ, Sch Med, Dept Biochem & Mol Biol, Shenzhen 518060, Peoples R China; [Zhu, Wei-Guo] Peking Univ, Peking Tsinghua Univ Ctr Life Sci, Beijing 100871, Peoples R China		Zhao, Y; Meng, XB; Zhu, WG (corresponding author), Peking Univ, Dept Biochem & Mol Biol, Key Lab Carcinogenesis & Translat Res, State Key Lab Nat & Biomimet Drugs,Minist Educ, Xueyuan Rd 38, Beijing 100191, Peoples R China.	zhaoying0812@bjmu.edu.cn; xbmeng@bjmu.edu.cn; zhuweiguo@bjmu.edu.cn		Zhu, Wei-Guo/0000-0001-8385-6581	National Key Research and Development Program of China (Protein Machinery and Life Science Grant ) [2013CB911000]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31570812, 81530074, 81222028, 81621063, 81573272, 81472581]; Discipline Construction Funding of Shenzhen; Shenzhen Municipal Commission of Science and Technology Innovation [JCYJ20160427104855100]; Beijing Natural Science FoundationBeijing Natural Science Foundation [7162109]	This study was supported by the National Key Research and Development Program of China (Protein Machinery and Life Science Grant 2013CB911000) and the National Natural Science Foundation of China (grant numbers 31570812, 81530074, 81621063, 81222028, 81621063, 81573272 and 81472581); Discipline Construction Funding of Shenzhen (2016); the Shenzhen Municipal Commission of Science and Technology Innovation (grant number JCYJ20160427104855100) and the Beijing Natural Science Foundation (7162109). We thank Dr. Jessica Tamanini of ETediting for language editing.. XM and SL are inventors on a patent (CN201410065618.6), and patent applications (WO 2015/127878 A1, US-2017-0015664-A1, EP3098222 (A1), 2016-554241 (JP), 2015222590 (Au)) held by Peking University that covers the preparation and use of acridine derivatives.	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OCT	2017	8								e3086	10.1038/cddis.2017.498			13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	FL2CV	WOS:000414022900073	28981103	Green Published, gold			2022-04-25	
J	Din, FVN; Valanciute, A; Houde, VP; Zibrova, D; Green, KA; Sakamoto, K; Alessi, DR; Dunlop, MG				Din, Farhat V. N.; Valanciute, Asta; Houde, Vanessa P.; Zibrova, Daria; Green, Kevin A.; Sakamoto, Kei; Alessi, Dario R.; Dunlop, Malcolm G.			Aspirin Inhibits mTOR Signaling, Activates AMP-Activated Protein Kinase, and Induces Autophagy in Colorectal Cancer Cells	GASTROENTEROLOGY			English	Article						Chemoprevention; Colon Cancer; Oncogene; Tumor Suppressor	GROWTH; PROLIFERATION; METFORMIN; PATHWAY; LKB1; PHOSPHORYLATION; EXPRESSION; MORTALITY; APOPTOSIS; TARGET	BACKGROUND & AIMS: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPK alpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha 1/alpha 2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPK alpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC.	[Din, Farhat V. N.] Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Colon Canc Genet Grp,MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland; [Din, Farhat V. N.; Valanciute, Asta; Dunlop, Malcolm G.] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland; [Din, Farhat V. N.; Valanciute, Asta; Dunlop, Malcolm G.] Western Gen Hosp Edinburgh, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland; [Houde, Vanessa P.; Zibrova, Daria; Sakamoto, Kei; Alessi, Dario R.] Univ Dundee, Med Res Council Prot Phosphorylat Unit, Dundee, Scotland; [Green, Kevin A.] Univ Dundee, Coll Life Sci, Dundee, Scotland		Din, FVN (corresponding author), Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Colon Canc Genet Grp,MRC Human Genet Unit, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland.	Farhat.Din@igmm.ed.ac.uk	Dunlop, Malcolm G/F-1973-2011; sakamoto, kei/C-8806-2019; Din, Farhat/A-1944-2015	Dunlop, Malcolm G/0000-0002-3033-5851; sakamoto, kei/0000-0001-8839-5980; 	Cancer Research UKCancer Research UK [C26031/A11378]; CORE Charity; Cancer Research UKCancer Research UK [11378, 12076] Funding Source: researchfish; Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [MC_U127015387, MC_U127088492, MC_U127527198, MC_PC_U127527198] Funding Source: researchfish; MRCUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [MC_PC_U127527198, MC_U127527198, MC_U127015387, MC_U127088492] Funding Source: UKRI	This work was funded by a clinician scientist fellowship to FVND from Cancer Research UK (C26031/A11378) and additional funding from a Centre grant to MGD from CORE Charity.	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J	Tian, ML; Wan, YL; Tang, JQ; Li, H; Yu, G; Zhu, J; Ji, SQ; Guo, H; Zhang, N; Li, WR; Gai, JW; Wang, L; Dai, LF; Liu, D; Lei, LD; Zhu, SG				Tian, Maolin; Wan, Yuanlian; Tang, Jianqiang; Li, Hui; Yu, Ge; Zhu, Jing; Ji, Shiqi; Guo, Hui; Zhang, Nan; Li, Weiren; Gai, Junwei; Wang, Lei; Dai, Lifang; Liu, Die; Lei, Liandi; Zhu, Shigong			Depletion of tissue factor suppresses hepatic metastasis and tumor growth in colorectal cancer via the downregulation of MMPs and the induction of autophagy and apoptosis	CANCER BIOLOGY & THERAPY			English	Article						MMPs; colon cancer; tissue factor; hepatic metastasis; autophagy; unfolded protein response (UPR); PERK	PROTEIN-SYNTHESIS	Tissue factor (TF) is a significant risk factor for hepatic metastasis in patients with colorectal cancer (CRC). However, the mechanism by which TF promotes hepatic metastasis in CRC remains elusive. In this study, we first confirmed that TF expression was significantly correlated with lymph node metastasis, hepatic metastasis and TNM staging in clinical CRC samples, and found that TF expression in colon cancer cell lines was correlated with the invasion ability. Next, by employing TF-overexpressing LOVO cell line as a model we demonstrated that lentivirus mediated knockdown of TF suppressed the migration and invasion of LOVO cells in vitro, and hepatic metastasis of colorectal cancer in nude mice orthotopic model. Mechanistically, we found that TF knockdown decreases colony formation ability and induced autophagy and apoptosis of LOVO cells, and this was at least partly mediated by the activation of unfolded protein response/PERK signaling. In conclusion, our data provide new insight into hepatic metastasis of CRC. Agents targeting TF should be developed as adjuvant therapeutics for CRC metastasis.	[Tian, Maolin; Wan, Yuanlian; Tang, Jianqiang; Li, Hui; Yu, Ge; Zhu, Jing] Peking Univ First Hosp, Dept Gen Surg, Beijing, Peoples R China; [Ji, Shiqi; Guo, Hui; Zhang, Nan; Li, Weiren; Gai, Junwei; Wang, Lei] Peking Univ First Hosp, Dept Urol, Beijing, Peoples R China; [Dai, Lifang; Liu, Die] Peking Univ First Hosp, Dept Pediat, Beijing, Peoples R China; [Lei, Liandi] Peking Univ, Hlth Sci Anal Ctr, Beijing 100871, Peoples R China; [Zhu, Shigong] Peking Univ Hlth Sci Ctr, Dept Physiol & Pathophysiol, Beijing, Peoples R China; [Tian, Maolin] Capital Med Univ, Beijing Chaoyang Hosp, Dept Hernia & Abdominal Wall Surg, Beijing, Peoples R China		Wan, YL (corresponding author), Peking Univ First Hosp, Dept Gen Surg, Beijing, Peoples R China.	wan@bjmu.edu.cn; tjq@hotmail.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30872469]; National Natural Science Youth Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30801092]	This work was supported by the grants from the National Natural Science Foundation of China (No. 30872469) and National Natural Science Youth Foundation of China (No. 30801092).	Cheng K. C., 2008, Hong Kong Medical Journal, V14, P432; Deng L, 2010, CELL DEATH DIS, V1, DOI 10.1038/cddis.2010.9; Kang MR, 2009, J PATHOL, V217, P702, DOI 10.1002/path.2509; Kenific CM, 2010, CURR OPIN CELL BIOL, V22, P241, DOI 10.1016/j.ceb.2009.10.008; Klionsky DJ, 2003, DEV CELL, V5, P539, DOI 10.1016/S1534-5807(03)00296-X; Lee CJ, 2010, THROMB RES, V125, pS7, DOI 10.1016/j.thromres.2010.01.022; Lin WS, 2009, NAT NEUROSCI, V12, P379, DOI 10.1038/nn.2273; Mukherjee S, 2010, J TRANSL MED, V8, DOI 10.1186/1479-5876-8-91; Noda NN, 2008, GENES CELLS, V13, P1211, DOI 10.1111/j.1365-2443.2008.01238.x; Ogata M, 2006, MOL CELL BIOL, V26, P9220, DOI 10.1128/MCB.01453-06; Pavitt GD, 2009, BIOCHEM SOC T, V37, P1298, DOI 10.1042/BST0371298; Rak J, 2006, SEMIN THROMB HEMOST, V32, P54, DOI 10.1055/s-2006-933341; Rouschop KMA, 2010, J CLIN INVEST, V120, P127, DOI 10.1172/JCI40027; Satoo K, 2009, EMBO J, V28, P1341, DOI 10.1038/emboj.2009.80; Scheper GC, 2007, NAT REV GENET, V8, P711, DOI 10.1038/nrg2142; So MK, 2006, NAT BIOTECHNOL, V24, P339, DOI 10.1038/nbt1188; Sorbye Halfdan, 2008, Tidsskr Nor Laegeforen, V128, P194; Wang L, 2007, APOPTOSIS, V12, P1489, DOI 10.1007/s10495-007-0073-9; Zerbib P, 2009, J SURG RES, V153, P239, DOI 10.1016/j.jss.2008.05.014; Zhang XX, 2011, J BIOL CHEM, V286, P1429, DOI 10.1074/jbc.M110.146530; Zucker S, 2004, CANCER METAST REV, V23, P101, DOI 10.1023/A:1025867130437	21	20	21	2	9	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	1538-4047	1555-8576		CANCER BIOL THER	Cancer Biol. Ther.	NOV 15	2011	12	10					896	907		10.4161/cbt.12.10.17679			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	849ZW	WOS:000297165200006	22052255	Green Published, Bronze			2022-04-25	
J	Qian, K; Sun, LY; Zhou, GQ; Ge, HX; Meng, Y; Li, JF; Li, X; Fang, XQ				Qian, Kun; Sun, Laiyu; Zhou, Guoqing; Ge, Haixia; Meng, Yue; Li, Jingfen; Li, Xiao; Fang, Xinqiang			Trifluoperazine as an alternative strategy for the inhibition of tumor growth of colorectal cancer	JOURNAL OF CELLULAR BIOCHEMISTRY			English	Article						apoptosis; autophagy; colorectal cancer; epithelial-mesenchymal transition; trifluoperazine	COLON-CANCER; CALMODULIN; THERAPY; SCHIZOPHRENIA; EXPRESSION; AUTOPHAGY; CELLS	The development of cancer in patients with schizophrenia is affected by genetic and environmental factors and antipsychotic medication. Several studies found that schizophrenia was associated with decreased risk of some cancers, and the neuroleptic medication might help to reduce the risk of colorectal cancer (CRC). Phenothiazine drugs including trifluoperazine (TFP) are widely used antipsychotic drugs and showed some antitumor effects, we here investigated the potential application of TFP in the treatment of colon cancer. A series doses of TFP were treated to the colon cancer cell line HCT116 and the inhibitory concentration (IC50) of TFP for HCT116 was determined by cell counting kit-8. The results indicated that the treatment of TFP impaired the cell vitality of HCT116 in a dose- and time-dependent manner. Meanwhile, the Edu assay demonstrated that the proliferation was also inhibited by TFP, which was accompanied with the induction of apoptosis and autophagy. The expression of CCNE1, CDK4, and antiapoptosis factor BCL-2 was downregulated but the proapoptosis factor BAX was upregulated. The autophagy inhibitor chloroquine could significantly reverse the TFP-induced apoptosis. Moreover, the ability of migration and invasion of HCT116 was found to be suppressed by TFP, which was associated with the inhibition of epithelial-mesenchymal transition (EMT). The function of TFP in vivo was further confirmed. The results showed that the administration of TFP remarkably abrogated the tumor growth with decreased tumor volume and proliferation index Ki-67 level in tumor tissues. The EMT phenotype was also confirmed to be inhibited by TFP in vivo, suggesting the promising antitumor effects of TFP in CRC.	[Qian, Kun; Sun, Laiyu; Zhou, Guoqing; Ge, Haixia; Meng, Yue; Li, Jingfen; Li, Xiao; Fang, Xinqiang] Huzhou Univ, Coll Life Sci, 759 E 2nd Rd, Huzhou 313000, Zhejiang, Peoples R China		Qian, K (corresponding author), Huzhou Univ, Coll Life Sci, 759 E 2nd Rd, Huzhou 313000, Zhejiang, Peoples R China.	qiankun@zjhu.edu.cn			Public Projects of Zhejiang Province [LGC19B070002]; Huzhou science and technology planning project [2016GY04]	Public Projects of Zhejiang Province, Grant/Award Number: LGC19B070002; Huzhou science and technology planning project, Grant/Award Number: 2016GY04	Berchtold MW, 2014, BBA-MOL CELL RES, V1843, P398, DOI 10.1016/j.bbamcr.2013.10.021; Booth LA, 2014, CELL SIGNAL, V26, P549, DOI 10.1016/j.cellsig.2013.11.028; Brenner H, 2014, LANCET, V383, P1490, DOI 10.1016/S0140-6736(13)61649-9; Brosius SN, 2014, J NEUROPATH EXP NEUR, V73, P1078, DOI 10.1097/NEN.0000000000000126; Chen MH, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0027186; Dalton SO, 2006, BRIT J CANCER, V95, P934, DOI 10.1038/sj.bjc.6603259; Dienstmann R, 2015, J CLIN ONCOL, V33, P1787, DOI 10.1200/JCO.2014.60.0213; Ding L, 2015, BBA-MOL BASIS DIS, V1852, P2494, DOI 10.1016/j.bbadis.2015.08.011; Freeman HJ, 2013, WORLD J GASTROENTERO, V19, P8468, DOI 10.3748/wjg.v19.i46.8468; Gangopadhyay S, 2007, MUTAT RES-GEN TOX EN, V633, P117, DOI 10.1016/j.mrgentox.2007.05.011; Huang KY, 2013, BMC BIOINFORMATICS, V14, DOI 10.1186/1471-2105-14-S16-S10; Ji JG, 2013, SCHIZOPHRENIA BULL, V39, P527, DOI 10.1093/schbul/sbs065; Kim JH, 2015, WORLD J GASTROENTERO, V21, P5158, DOI 10.3748/wjg.v21.i17.5158; Kim SE, 2015, WORLD J GASTROENTERO, V21, P5167, DOI 10.3748/wjg.v21.i17.5167; Kurniali PC, 2014, WORLD J GASTROENTERO, V20, P1910, DOI 10.3748/wjg.v20.i8.1910; Lee MS, 2007, CANCER RES, V67, P11359, DOI 10.1158/0008-5472.CAN-07-2235; Polischouk AG, 2007, MOL CANCER THER, V6, P2303, DOI 10.1158/1535-7163.MCT-06-0402; Preti A, 2011, PSYCHIAT INVEST, V8, P77, DOI 10.4306/pi.2011.8.2.77; Pulkoski-Gross A, 2015, MOL PHARMACOL, V87, P501, DOI 10.1124/mol.114.096941; Qi L, 2013, SCI CHINA LIFE SCI, V56, P1020, DOI 10.1007/s11427-013-4561-6; Shin SY, 2006, EUR J PHARM SCI, V28, P300, DOI 10.1016/j.ejps.2006.03.002; Shin SY, 2001, J BIOL CHEM, V276, P7797, DOI 10.1074/jbc.M009465200; Tamas K, 2015, CANCER TREAT REV, V41, P671, DOI 10.1016/j.ctrv.2015.06.007; Wiklund ED, 2010, INT J CANCER, V126, P28, DOI 10.1002/ijc.24813; Yeh CT, 2012, AM J RESP CRIT CARE, V186, P1180, DOI 10.1164/rccm.201207-1180OC; Yuan KY, 2015, ONCOTARGET, V6, P25308, DOI 10.18632/oncotarget.4490	26	12	12	2	8	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0730-2312	1097-4644		J CELL BIOCHEM	J. Cell. Biochem.	SEP	2019	120	9					15756	15765		10.1002/jcb.28845			10	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	IK7WN	WOS:000476804200147	31081173				2022-04-25	
J	Leng, ZG; Lin, SJ; Wu, ZR; Guo, YH; Cai, L; Shang, HB; Tang, H; Xue, YJ; Lou, MQ; Zhao, WX; Le, WD; Zhao, WG; Zhang, X; Wu, ZB				Leng, Zhi Gen; Lin, Shao Jian; Wu, Ze Rui; Guo, Yu Hang; Cai, Lin; Shang, Han Bing; Tang, Hao; Xue, Ya Jun; Lou, Mei Qing; Zhao, Wenxiu; Le, Wei-Dong; Zhao, Wei Guo; Zhang, Xun; Wu, Zhe Bao			Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death	AUTOPHAGY			English	Article						autophagic cell death; cabergoline; dopamine agonist; dopamine receptor D5; MTOR; prolactinoma; reactive oxygen species	UP-REGULATION; NEUROBLASTOMA-CELLS; PITUITARY-ADENOMAS; CANCER-THERAPY; PROLACTINOMAS; BROMOCRIPTINE; DEGRADATION; ANTAGONIST; PATHWAY; STIMULATION	Dopamine agonists such as bromocriptine and cabergoline have been successfully used in the treatment of pituitary prolactinomas and other neuroendocrine tumors. However, their therapeutic mechanisms are not fully understood. In this study we demonstrated that DRD5 (dopamine receptor D5) agonists were potent inhibitors of pituitary tumor growth. We further found that DRD5 activation increased production of reactive oxygen species (ROS), inhibited the MTOR pathway, induced macroautophagy/autophagy, and led to autophagic cell death (ACD) in vitro and in vivo. In addition, DRD5 protein was highly expressed in the majority of human pituitary adenomas, and treatment of different human pituitary tumor cell cultures with the DRD5 agonist SKF83959 resulted in growth suppression, and the efficacy was correlated with the expression levels of DRD5 in the tumors. Furthermore, we found that DRD5 was expressed in other human cancer cells such as glioblastomas, colon cancer, and gastric cancer. DRD5 activation in these cell lines suppressed their growth, inhibited MTOR activity, and induced autophagy. Finally, in vivo SKF83959 also inhibited human gastric cancer cell growth in nude mice. Our studies revealed novel mechanisms for the tumor suppressive effects of DRD5 agonists, and suggested a potential use of DRD5 agonists as a novel therapeutic approach in the treatment of different human tumors and cancers.	[Leng, Zhi Gen; Wu, Ze Rui; Guo, Yu Hang; Cai, Lin; Wu, Zhe Bao] Wenzhou Med Univ, Affiliated Hosp 1, Dept Neurosurg, Wenzhou, Peoples R China; [Lin, Shao Jian; Shang, Han Bing; Tang, Hao; Zhao, Wei Guo; Wu, Zhe Bao] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Neurosurg, Shanghai, Peoples R China; [Xue, Ya Jun; Lou, Mei Qing] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Neurosurg, Shanghai, Peoples R China; [Le, Wei-Dong] Dalian Med Univ, Affiliated Hosp 1, Ctr Clin Res Neurol Dis, Dalian, Peoples R China; [Zhao, Wenxiu; Zhang, Xun] Massachusetts Gen Hosp, Neuroendocrine Res Lab, Boston, MA 02114 USA; [Zhao, Wenxiu; Zhang, Xun] Harvard Med Sch, Boston, MA 02114 USA; [Leng, Zhi Gen] Peoples Hosp Yichun City, Dept Neurosurg, Yichun 336000, Jiangxi, Peoples R China		Zhang, X (corresponding author), Massachusetts Gen Hosp, Neuroendocrine Res Lab, Boston, MA 02114 USA.; Zhang, X (corresponding author), Harvard Med Sch, Boston, MA 02114 USA.; Wu, ZB (corresponding author), Ruijin Hosp, Dept Neurosurg, 197 Ruijin Er Rd, Shanghai 200025, Peoples R China.	xzhang5@mgh.harvard.edu; zhebaowu@aliyun.com	Wu, Zhe Bao/AAH-8078-2020; Cai, Lin/AAD-3411-2022	Wu, Zhe Bao/0000-0002-1611-8228; Cai, Lin/0000-0002-7087-4948	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81471392, 81271523]; Zhejiang Open Foundation of the Top Key Discipline [LKYJ015]; Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support [20161407]	This work was supported by the National Natural Science Foundation of China under Grant number 81471392 and 81271523; the Zhejiang Open Foundation of the Top Key Discipline under Grant number LKYJ015; and Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support under Grant number 20161407.	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J	Zhai, HY; Fesler, A; Ba, YF; Wu, S; Ju, JF				Zhai, Haiyan; Fesler, Andrew; Ba, Yufeng; Wu, Song; Ju, Jingfang			Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy	ONCOTARGET			English	Article						hsa-miR-140-5p; smad2; autophagy; metastasis; colon cancer stem cell	TGF-BETA; TUMOR-GROWTH; COLON-CANCER; DOWN-REGULATION; MICRORNA; METASTASIS; PROLIFERATION; RECEPTOR; MIR-140; ACTIVATION	Colorectal cancer (CRC) is the third highest mortality cancer in the United States and frequently metastasizes to liver and lung. Smad2 is a key element downstream of the TGF-beta signaling pathway to regulate cancer metastasis by promoting epithelial to mesenchymal transition and maintaining the cancer stem cell (CSC) phenotype. In this study, we show that hsa-miR-140-5p directly targets Smad2 and overexpression of hsa-miR-140-5p in CRC cell lines decreases Smad2 expression levels, leading decreased cell invasion and proliferation, and increasing cell cycle arrest. Ectopic expression of hsa-miR-140-5p in colorectal CSCs inhibited CSC growth and sphere formation in vitro by disrupting autophagy. We have systematically identified targets of hsa-miR-140-5p involved in autophagy. Furthermore, overexpression of hsa-miR-140-5p in CSCs abolished tumor formation and metastasis in vivo. In addition, there is a progressive loss of hsa-miR-140-5p expression from normal colorectal mucosa to primary tumor tissues, with further reduction in liver metastatic tissues. Higher hsa-miR-140 expression is significantly correlated with better survival in stage III and IV colorectal cancer patients. The functional and clinical significance of hsa-miR-140-5p suggests that it is a key regulator in CRC progression and metastasis, and may have potential as a novel therapeutic molecule to treat CRC.	[Zhai, Haiyan; Fesler, Andrew; Ju, Jingfang] SUNY Stony Brook, Dept Pathol, Translat Res Lab, Stony Brook, NY 11794 USA; [Ba, Yufeng] Canc Hosp Henan, Dept Thorac Surg, Zhengzhou 450008, Henan, Peoples R China; [Wu, Song] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA		Ju, JF (corresponding author), SUNY Stony Brook, Dept Pathol, Translat Res Lab, Stony Brook, NY 11794 USA.	jingfang.ju@stonybrookmedicine.edu			National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA155019, R33CA147966]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA155019, R33CA147966] Funding Source: NIH RePORTER	We thank Stony Brook Medicine Research Histology Core Lab, especially Stephanie Burke and Mallory Korman, for technical support in clinical CRC tissue processing. This study was supported by National Cancer Institute R01CA155019 (J. Ju) and R33CA147966 (J. Ju).	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J	Wu, YC; Wu, WKK; Li, YM; Yu, L; Li, ZJ; Wong, CCM; Li, HT; Sung, JJY; Cho, CH				Wu, Ya Chun; Wu, William Ka Kei; Li, Youming; Yu, Le; Li, Zhi Jie; Wong, Clover Ching Man; Li, Hai Tao; Sung, Joseph Jao Yiu; Cho, Chi Hin			Inhibition of macroautophagy by bafilomycin A(1) lowers proliferation and induces apoptosis in colon cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Bafilomycin A(1); Macroautophagy; Proliferation; Colon cancer	PROTEASOME INHIBITOR; PROTEIN-DEGRADATION; H+-ATPASE; AUTOPHAGY; DISEASE; DEATH; PATHWAYS; SURVIVAL; MG-132; ROLES	Macroautophagy is a process by which cytoplasmic content and organelles are sequestered by double-membrane bound vesicles and subsequently delivered to lysosomes for degradation. Macroautophagy serves as a major intracellular pathway for protein degradation and as a pro-survival mechanism in time of stress by generating nutrients. In the present study, bafilomycin A(1) a vacuolar type H+-ATPase inhibitor, Suppresses macroautophagy by preventing acidification of lysosomes in colon cancer cells. Diminished macroautophagy was evidenced by the accumulation of undegraded LC3 protein. Suppression of macroautophagy by bafilomycin A(1) induced G(0)/G(1) cell cycle arrest and apoptosis which were accompanied by the down-regulation of cyclin D, and cyclin E, the up-regulation of p21(Cip1) as well as cleavages of caspases-3, -7, -8, and -9 and PARP. Further investigation revealed that bafilomycin A(1) increased the phosphorylation of ERK, JNK, and p38. In this regard, p38 inhibitor partially reversed the anti-proliferative effect of bafilomycin A(1). To conclude, inhibition of macroautophagy by bafilornycin A(1) lowers G(1)-S transition and induces apoptosis in colon cancer cells. Our results not only indicate that inhibitors of macroautophagy may be used therapeutically to inhibit cancer growth, but also delineate the relationship between macroautophagy and apoptosis. (C) 2009 Elsevier Inc. All rights reserved.	[Wu, Ya Chun; Wu, William Ka Kei; Yu, Le; Li, Zhi Jie; Wong, Clover Ching Man; Li, Hai Tao; Cho, Chi Hin] Chinese Univ Hong Kong, Dept Pharmacol, Shatin, Hong Kong, Peoples R China; [Wu, Ya Chun; Li, Youming] Zhejiang Univ, Coll Med, Affiliated Hosp 1, Dept Gastroenterol, Hangzhou 310003, Zhejiang, Peoples R China; [Wu, William Ka Kei; Sung, Joseph Jao Yiu; Cho, Chi Hin] Chinese Univ Hong Kong, Inst Digest Dis, Shatin, Hong Kong, Peoples R China; [Wu, William Ka Kei; Sung, Joseph Jao Yiu] Chinese Univ Hong Kong, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China		Cho, CH (corresponding author), Chinese Univ Hong Kong, Dept Pharmacol, Basic Med Sci Bldg, Shatin, Hong Kong, Peoples R China.	wukakei@cuhk.edu.hk; chcho@cuhk.edu.hk	Cho, Chi Hin/C-6543-2014; Wu, William K.K./A-3277-2009; Sung, Joseph J. Y./R-3203-2018	Cho, Chi Hin/0000-0002-7658-3260; Wu, William K.K./0000-0002-5662-5240; Sung, Joseph J. 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Biophys. Res. Commun.	MAY 1	2009	382	2					451	456		10.1016/j.bbrc.2009.03.051			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	434MR	WOS:000265279300043	19289106				2022-04-25	
J	Qiu, F; Wang, Y; Chu, XQ; Wang, J				Qiu, Fei; Wang, Yun; Chu, Xianqun; Wang, Jing			ASF1A regulates H4(Y72) phosphorylation and promotes autophagy in colon cancer cells via a kinase activity (Publication with Expression of Concern. See vol. 48, pg. 707, 2020)	ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY			English	Article; Publication with Expression of Concern						Colon cancer; histone modification; ASF1A; H4Y72ph; autophagy	HISTONE CHAPERONE ASF1A; COLORECTAL-CANCER; SURVIVAL	Colon cancer is one of the most malignant cancers. Histone modification is closely related to tumour development. Our study explored the functions of anti-silencing function 1A (ASF1A) on H4(Y72ph) in colon cancer cells. Colon cancer cell lines and clinical specimens were obtained and/or transfected with full length ASF1A or interference mRNA to mimic or silence of ASF1A expression. Immunoprecipitation and GST pull down was used to target targeting ASF1A or H4(Y72ph). Cells were transfected with H4(WT) or H4(Y72ph)-expressing. An in vitro kinase activity assay was set to determine whether ASH A could phosphorylate H4. The severity of autophagy was measured by detecting number of autophagosomes, number of EGFP-LC3, LC3-II/I, percentage of degradation and expression of autophagy associated gene (ATG). ASF1A positively regulated H4(Y72ph); Immunoprecipitation assay and GST pull down results showed that ASF1A interacted directly with H4. In addition, ASF1A silence inhibited autophagosomes number, EGFP-LC3 number, LC3-II/I, percentage of degradation and ATG expression. Moreover, H4 Y72F impaired the promoting autophagy effects of ASF1A. The ASF1A-H4(Y72ph) axis promoted colon cancer autophagy via transcriptional regulation of ATG genes. ASF1A regulated H4(Y72ph) and promotes autophagy in colon cancer cells via a kinase activity through regulation of ATG.	[Qiu, Fei; Wang, Yun; Chu, Xianqun; Wang, Jing] Jining 1 Peoples Hosp, Dept Gastrointestinal Surg, 6 Jiankang Rd, Jining 272000, Peoples R China; [Qiu, Fei] Jining Med Univ, Affiliated Jining Peoples Hosp Jining Med Univ 1, Jining, Peoples R China		Wang, J (corresponding author), Jining 1 Peoples Hosp, Dept Gastrointestinal Surg, 6 Jiankang Rd, Jining 272000, Peoples R China.	wangjing0016hbs@sina.com					Ahluwalia A, 2014, CURR PHARM DESIGN, V20, P1041, DOI 10.2174/1381612819999131218175905; Asare EA, 2016, CANCER-AM CANCER SOC, V122, P213, DOI 10.1002/cncr.29744; Audia JE, 2016, CSH PERSPECT BIOL, V8, DOI 10.1101/cshperspect.a019521; Balakrishnan L, 2017, VIRUSES-BASEL, V9, DOI 10.3390/v9110346; Chou RH, 2014, DEV CELL, V30, P224, DOI 10.1016/j.devcel.2014.06.008; Deb M, 2016, GENE, V581, P75, DOI 10.1016/j.gene.2016.01.029; Dhar S, 2017, PHILOS T R SOC B, V372, DOI 10.1098/rstb.2016.0284; Drake KR, 2010, PLOS ONE, V5, DOI 10.1371/journal.pone.0009806; Dryhurst D, 2014, CANCER METAST REV, V33, P429, DOI 10.1007/s10555-013-9486-9; Fullgrabe J, 2014, AUTOPHAGY, V10, P556, DOI 10.4161/auto.27280; Gao Y, 2018, P NATL ACAD SCI USA, V115, pE6162, DOI 10.1073/pnas.1801909115; Gonzalez-Munoz E, 2014, SCIENCE, V345, P822, DOI 10.1126/science.1254745; Hanada T, 2007, J BIOL CHEM, V282, P37298, DOI 10.1074/jbc.C700195200; Hattori N, 2014, BIOCHEM BIOPH RES CO, V455, P3, DOI 10.1016/j.bbrc.2014.08.140; Henrique R, 2017, EBIOMEDICINE, V21, P45, DOI 10.1016/j.ebiom.2017.06.009; Jaskelioff M, 2000, MOL CELL BIOL, V20, P3058, DOI 10.1128/MCB.20.9.3058-3068.2000; Landreau P, 2015, J GASTROEN HEPATOL, V30, P82, DOI 10.1111/jgh.12685; Lennartsson A, 2009, BBA-GEN SUBJECTS, V1790, P863, DOI 10.1016/j.bbagen.2008.12.006; Levy JMM, 2017, NAT REV CANCER, V17, P528, DOI 10.1038/nrc.2017.53; Liang XM, 2017, EBIOMEDICINE, V21, P104, DOI 10.1016/j.ebiom.2017.06.007; Lin WM, 2015, GENET MOL RES, V14, P16905, DOI 10.4238/2015.December.14.18; Muilenburg D, 2014, ANTICANCER RES, V34, P631; Okugawa Y, 2015, GASTROENTEROLOGY, V149, P1204, DOI 10.1053/j.gastro.2015.07.011; Portela A, 2010, NAT BIOTECHNOL, V28, P1057, DOI 10.1038/nbt.1685; Tamas K, 2015, CANCER TREAT REV, V41, P671, DOI 10.1016/j.ctrv.2015.06.007; Tessarz P, 2014, NAT REV MOL CELL BIO, V15, P703, DOI 10.1038/nrm3890; Varghese F, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0096801; Wang C, 2015, ONCOTARGET, V6, P29599, DOI 10.18632/oncotarget.5011; Wen J, 2016, INT J MOL MED, V37, P126, DOI 10.3892/ijmm.2015.2409; Wu L, 2017, IRAN J BASIC MED SCI, V20, P990, DOI 10.22038/IJBMS.2017.9263; Yang JH, 2016, EXP MOL MED, V48, DOI 10.1038/emm.2016.68; Yang SC, 2018, INT J ADV MANUF TECH, V96, P2431, DOI 10.1007/s00170-018-1807-2; Yang WY, 2014, J CANCER RES THER, V10, pC240, DOI 10.4103/0973-1482.151450; Yoon J, 2018, J MOL BIOL, V430, P822, DOI 10.1016/j.jmb.2018.01.015; Yoshii SR, 2017, INT J MOL SCI, V18, DOI 10.3390/ijms18091865; Zeng MX, 2017, CELL MOL BIOL LETT, V22, DOI 10.1186/s11658-017-0041-5	36	3	3	1	4	TAYLOR & FRANCIS LTD	ABINGDON	2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND	2169-1401	2169-141X		ARTIF CELL NANOMED B	Artif. Cell. Nanomed. Biotechnol.		2019	47	1					2754	2763		10.1080/21691401.2019.1617725			10	Biotechnology & Applied Microbiology; Engineering, Biomedical; Materials Science, Biomaterials	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Engineering; Materials Science	IH5XV	WOS:000474567700001	31286799	gold			2022-04-25	
J	Khan, S				Khan, Shahanavaj			Potential role of Escherichia coli DNA mismatch repair proteins in colon cancer	CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY			English	Review						E. coli; DNA repair genes; In-silico; Protein targeting; Aetiology; CRC	CYTOLETHAL DISTENDING TOXIN; NONPOLYPOSIS COLORECTAL-CANCER; CROHNS-DISEASE; CELL-CYCLE; E. COLI; SUBCELLULAR-LOCALIZATION; INTESTINAL MICROFLORA; GENE-EXPRESSION; HOST-CELLS; MUTL-ALPHA	The epithelium of gastrointestinal tract organizes many innate defense systems against microbial intruders such as integrity of epithelial, rapid eviction of infected cells, quick turnover of epithelial cell, intrinsic immune responses and autophagy. However, Enteropathogenic Escherichia coli (EPEC) are equipped with well developed infectious tricks that evade the host defense systems and utilize the gastrointestinal epithelium as a multiplicative foothold. During multiplication on and within the epithelium, EPEC secrete various toxins that can weaken, usurp, and use many host cellular systems. However, the possible mechanisms of pathogenesis are still poorly elusive. Recent study reveals the existence of EPEC in colorectal cancer patients and their potential role in depletion of DNA mismatch repair (MMR) proteins of host cell in colonic cell lines. The EPEC colonised intracellularly in colon mucosa of colorectal carcinoma whereas extracellular strain was detected in mucosa of normal colon cells. Interestingly, alteration in MutS, MutL complexes and MUTYH of mammalian cells may be involved in development of CRC. These data propose that MMR of E. coli may be potential therapeutic targets and early detection biomarkers for CRC. This article reviews the potential role of E. coli MutS, MutL and MutY protein in CRC aetiology. (C) 2015 Elsevier Ireland Ltd. All rights reserved.	[Khan, Shahanavaj] King Saud Univ, Coll Pharm, Dept Pharmaceut, Nanomed & Biotechnol Res Unit, Riyadh 11451, Saudi Arabia		Khan, S (corresponding author), King Saud Univ, Coll Pharm, Dept Pharmaceut, Nanomed & Biotechnol Res Unit, POB 2457, Riyadh 11451, Saudi Arabia.	khan.shahanavaj@gmail.com	Khan, Shahanavaj/F-1032-2019				Acharya S, 2003, MOL CELL, V12, P233, DOI 10.1016/S1097-2765(03)00219-3; [Anonymous], 2009, NAT CELL BIOL, V11, P509, DOI 10.1038/ncb0509-509b; Antonic V, 2013, J CANCER, V4, P227, DOI 10.7150/jca.5835; Arthur JC, 2012, SCIENCE, V338, P120, DOI 10.1126/science.1224820; Barnich N, 2007, J CLIN INVEST, V117, P1566, DOI 10.1172/JCI30504; Baylin SB, 2001, HUM MOL GENET, V10, P687, DOI 10.1093/hmg/10.7.687; Bonnet M, 2014, CLIN CANCER RES, V20, P859, DOI 10.1158/1078-0432.CCR-13-1343; BORRESEN AL, 1995, HUM MOL GENET, V4, P2065, DOI 10.1093/hmg/4.11.2065; Buc E, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0056964; Charpentier X, 2004, J BACTERIOL, V186, P5486, DOI 10.1128/JB.186.16.5486-5495.2004; 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Rev. Oncol./Hematol.	DEC	2015	96	3					475	482		10.1016/j.critrevonc.2015.05.002			8	Oncology; Hematology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Hematology	CY6RP	WOS:000366536800008	26014615				2022-04-25	
J	Wang, S; Wang, KX; Zhang, CD; Zhang, WF; Xu, Q; Wang, YT; Zhang, YL; Li, Y; Zhang, Y; Zhu, HF; Song, FZ; Lei, YL; Bu, YQ				Wang, Sen; Wang, Kexin; Zhang, Chundong; Zhang, Wanfeng; Xu, Qian; Wang, Yitao; Zhang, Yulin; Li, Yi; Zhang, Ying; Zhu, Huifang; Song, Fangzhou; Lei, Yunlong; Bu, Youquan			Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells	CELL DEATH & DISEASE			English	Article							TUMOR-SUPPRESSOR P53; MUTANT P53; COLON-CANCER; CYTOTOXIC AUTOPHAGY; STRESS-RESPONSE; GASTRIC-CANCER; IN-VITRO; AKT-MTOR; THERAPY; PATHWAY	Betulinic acid (BA) exhibits cytotoxic activity against some cancer cells. However, the molecular mechanism of BA against CRC cells was little reported. Here, we proved that BA elicited CRC cells' growth inhibition and apoptosis in a dose-dependent manner. In addition, BA treatment induced autophagy via inhibiting the AKT-MTOR signaling pathway. Inhibition of autophagy by either administration of autophagic inhibitor chloroquine or siRNA-mediated knockdown of ATG5 could augment BA-induced apoptotic cell death as well as inhibition of cell proliferation. Moreover, we found that p53 was firstly activated by short exposure to BA and then was rapidly degraded via the ubiquitin-mediated degradation pathway in both wtp53 and mutp53 CRC cells. Notably, more preferential cytotoxicity of BA was obtained in mutp53 cells (IC50 values: HT29, 125 mu M; SW480, 58 mu M) rather than wtp53 cells (IC50 values: HCT116, 178 mu M). Further experiments demonstrated that siRNA-mediated p53 knockdown attenuated BA-induced autophagy, and forced overexpression of p53 augmented BA-induced autophagy, indicating that p53-enhanced BA-induced autophagy. Moreover, BA enhanced the sensitivity of mutp53 cells to chemotherapy drugs such as 5-FU and ADR by degradation of mutp53. Overall, our study proved that BA could induce CRC cell death by inducing apoptosis and reduce the overaccumulation of BA-induced protective autophagy by degrading wtp53 and mutp53 dependent on the ubiquitin-mediated degradation pathway to achieve killer effect, suggesting that BA might serve as a novel desirable drug for mutp53 cancer therapy.	[Wang, Sen; Zhang, Chundong; Wang, Yitao; Li, Yi; Zhang, Ying; Zhu, Huifang; Song, Fangzhou; Lei, Yunlong; Bu, Youquan] Chongqing Med Univ, Dept Biochem & Mol Biol, Chongqing 400016, Peoples R China; [Wang, Sen; Zhang, Chundong; Wang, Yitao; Li, Yi; Zhang, Ying; Zhu, Huifang; Song, Fangzhou; Lei, Yunlong; Bu, Youquan] Chongqing Med Univ, Mol Med & Canc Res Ctr, Chongqing 400016, Peoples R China; [Wang, Kexin] Southwest Med Univ, Affiliated Hosp, Dept Radiol, Luzhou 646000, Sichuan, Peoples R China; [Zhang, Wanfeng] Chongqing Med Univ, Dept Bioinformat, Chongqing 400016, Peoples R China; [Xu, Qian] North Sichuan Med Coll, Dept Anesthesiol, Nanchong 637000, Sichuan, Peoples R China; [Zhang, Yulin] Chongqing Med Univ, Dept Basic Med, Chongqing 400016, Peoples R China		Lei, YL; Bu, YQ (corresponding author), Chongqing Med Univ, Dept Biochem & Mol Biol, Mol Med & Canc Res Ctr, Yixueyuan Rd, Chongqing 400016, Peoples R China.	leiyunlong@126.com; buyqcn@aliyun.com		Zhang, Wanfeng/0000-0002-8717-1552; Wang, Sen/0000-0001-6358-1672; Lei, Yunlong/0000-0002-7918-0221; Bu, Youquan/0000-0002-0833-0640	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81401951, 81401889, 81501979]; Chongqing Natural Science FoundationNatural Science Foundation of Chongqing [cstc2016jcyjA0227]; Chongqing Municipal Education Commission [KJ1400207]	This work was supported by the National Natural Science Foundation of China (81401951 to YL, 81401889 to HZ, and 81501979 to CZ), Chongqing Natural Science Foundation (cstc2016jcyjA0227 to YL), and Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJ1400207 to YL).	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OCT	2017	8								e3087	10.1038/cddis.2017.485			12	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	FL2CV	WOS:000414022900072	28981110	Green Published, gold			2022-04-25	
J	De Albuquerque-Xavier, AC; Bastos, LGR; De Freitas, JCM; Leve, F; De Souza, WF; De Araujo, WM; Wanderley, JLM; Tanaka, MN; De Souza, W; Morgado-Diaz, JA				De Albuquerque-Xavier, Ana Cristina; Bastos, Lilian Goncalves R.; Madureira De Freitas, Julio Cesar, Jr.; Leve, Fernanda; De Souza, Waldemir Fernandez; De Araujo, Wallace Martins; Mendes Wanderley, Joao Luiz; Tanaka, Marcelo Neves; De Souza, Wanderley; Morgado-Diaz, Jose Andres			Blockade of irradiation-induced autophagosome formation impairs proliferation but does not enhance cell death in HCT-116 human colorectal carcinoma cells	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						autophagy; colorectal cancer; radiotherapy; cell signaling; proliferation	CANCER-CELLS; IN-VITRO; RADIATION; BECLIN-1; PATHWAY; INHIBITION; MATURATION; VACUOLES; PHOSPHORYLATION; CONTRIBUTES	This work was undertaken to gain further information on the molecular mechanisms underlying autophagosome formation and its relation with tumor cell survival in response to radiation in colon cancer. A human colon cancer cell line, HCT-116, was examined with respect to cell survival after blockade of irradiation-induced autophagosome formation by pharmacological interference. Autophagosome formation was confirmed using a kinetic study with incorporated bovine serum albumin gold-conjugate (BSA-Au) analyzed by electron microscopy and an autophagosome-associated LC3B antibody measured by immunofluorescence and Western blotting. Annexin V/PI double staining was used to monitor cell death by apoptosis, and cell cycle profiles by flow cytometry. Ionizing radiation (IR) promoted autophagosome formation in the HCT-116 IR-surviving cells. Pharmacological interference showed that PI3K/Akt and Src were involved in early stages of autophagosome formation. IR alone decreased cell proliferation by arresting cells in the G(2)/M phase, and pharmacological interference of autophagosome formation decreased proliferation, but did not affect cell survival. Also, our data suggest that decreased proliferation caused by PI3K and Src inhibitors could be through S phase cell cycle delay. Our results clearly indicate that blockade of IR-induced autophagosome formation impairs proliferation but does not enhance cell death in colon cancer cells.	[De Albuquerque-Xavier, Ana Cristina; Bastos, Lilian Goncalves R.; Madureira De Freitas, Julio Cesar, Jr.; Leve, Fernanda; De Souza, Waldemir Fernandez; De Araujo, Wallace Martins; Tanaka, Marcelo Neves; Morgado-Diaz, Jose Andres] Jose Alencar Natl Canc Inst, Div Cellular Biol, BR-20231050 Rio De Janeiro, RJ, Brazil; [Mendes Wanderley, Joao Luiz] Jose Alencar Natl Canc Inst, Div Expt Med, BR-20231050 Rio De Janeiro, RJ, Brazil; [Mendes Wanderley, Joao Luiz] Univ Fed Rio de Janeiro, Polo Univ, Rio De Janeiro, RJ, Brazil; [De Souza, Wanderley] Univ Fed Rio de Janeiro, Dept Cellular Biol & Parasitol, Carlos Chagas Biophys Inst, Rio De Janeiro, RJ, Brazil		Morgado-Diaz, JA (corresponding author), Jose Alencar Natl Canc Inst, Div Cellular Biol, Rua Andre Cavalcanti,37-5 Andar, BR-20231050 Rio De Janeiro, RJ, Brazil.	jmorgado@inca.gov.br	de Souza, Waldemir/B-3612-2015; Araujo, Wallace/O-7736-2015; Wanderley, Joao Luiz/J-6711-2014; Morgado-Diaz, Jose A./A-9649-2010; de Freitas, Julio Cesar/M-5754-2013	de Souza, Waldemir/0000-0003-3258-6758; de Freitas, Julio Cesar/0000-0002-2070-1432; DE ARAUJO, WALLACE/0000-0003-2979-4070; Leve, Fernanda/0000-0001-5466-0950	Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ); Ministerio da Satide, Brasil; Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado de Rio de Janeiro (FAPERJ)Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio De Janeiro (FAPERJ)	This study was sponsored by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Ministerio da Satide, Brasil, and Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado de Rio de Janeiro (FAPERJ). We are grateful to Barbara DuRocher for her valuable help in the interpretation of the cell cycle experiments, Livia Goto-Silva for suggestions made at the beginning of the present study, the Programa de Cooperacao INCA/FIOCRUZ for the use of their facility and the employers of Departamento de Hemoterapia-INCA for the use of gamma irradiator.	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J. Oncol.	APR	2012	40	4					1267	1276		10.3892/ijo.2012.1329			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	910LI	WOS:000301637800044	22246348	Bronze, Green Published			2022-04-25	
J	Zhou, XH; Kang, J; Zhong, ZD; Cheng, Y				Zhou, Xing-Hua; Kang, Jian; Zhong, Zhen-Dong; Cheng, Yue			Osthole induces apoptosis of the HT-29 cells via endoplasmic reticulum stress and autophagy	ONCOLOGY LETTERS			English	Article						osthole; apoptosis; endoplasmic reticulum stress; autophagy; colon cancer	COLON-CANCER; INFLAMMATION; DYSFUNCTION; CROSSTALK	Endoplasmic reticulum stress (ERS) and autophagy are important pathways, which induce apoptosis of tumor cells. Osthole has been demonstrated to exert anticancer effects via the induction of apoptosis in several human colon cancer lines, but the mechanism underlying its involvement in the induction of ERS and autophagy in the human HT-29 colorectal cancer cell line remains unknown. The present study aimed to identify the possible signaling pathways involved in osthole-induced apoptosis of HT29 cells. Methodologically, colony formation and Cell Counting Kit-8 assays were used to assess cell proliferation and viability, respectively, while flow cytometry was performed to investigate apoptosis. Signaling pathways, including apoptosis, autophagy and ERS, were also investigated in the HT-29 cell line using western blot analysis. The results demonstrated that osthole inhibited cellular proliferation and viability in a dose-dependent manner. In addition, osthole induced the expression level of proteins associated with mitochondria-mediated cell apoptosis, autophagy and ERS. The association between autophagy and ERS in osthole-induced apoptosis in the HT-29 cell line was further clarified. Inhibiting cell autophagy with the inhibitor, 3-methyladenine, suppressed osthole-induced cell apoptosis and enhanced osthole-induced ERS. By contrast, alleviating ERS with the inhibitor, 4-phenylbutyric acid attenuated osthole-induced cell apoptosis and autophagy. In conclusion, osthole could significantly suppress the proliferation and viability of the HT-29 colorectal cancer cell line and induce cell apoptosis via autophagy and ERS. Furthermore, ERS may play a more important role in osthole-induced cell apoptosis.	[Zhou, Xing-Hua; Kang, Jian; Cheng, Yue] Chengdu Univ Tradit Chinese Med, Affiliated Hosp, Dept Anorectal Dis, 39 Shier Qiao Rd, Chengdu 610075, Sichuan, Peoples R China; [Zhong, Zhen-Dong] Sichuan Prov Peoples Hosp, Anim Expt Res Inst, Chengdu 610000, Sichuan, Peoples R China		Cheng, Y (corresponding author), Chengdu Univ Tradit Chinese Med, Affiliated Hosp, Dept Anorectal Dis, 39 Shier Qiao Rd, Chengdu 610075, Sichuan, Peoples R China.	msmscycy@hotmail.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81873073]; Science and Technology Development Fund of Affiliated Hospital of Chengdu University of Traditional Chinese Medicine [18MZ27]	The present study was supported by the National Natural Science Foundation of China (grant no. 81873073) and Science and Technology Development Fund of Affiliated Hospital of Chengdu University of Traditional Chinese Medicine (grant no. 18MZ27).	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Lett.	OCT	2021	22	4							726	10.3892/ol.2021.12987			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	UB8HI	WOS:000686080000001	34429766	Green Published, gold			2022-04-25	
J	Jeong, S; Kim, DY; Kang, SH; Yun, HK; Kim, JL; Kim, BR; Park, SH; Na, YJ; Jo, MJ; Jeong, YA; Kim, BG; Lee, DH; Oh, SC				Jeong, Soyeon; Kim, Dae Yeong; Kang, Sang Hee; Yun, Hye Kyeong; Kim, Jung Lim; Kim, Bo Ram; Park, Seong Hye; Na, Yoo Jin; Jo, Min Jee; Jeong, Yoon A.; Kim, Bu Gyeom; Lee, Dae-Hee; Oh, Sang Cheul			Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer	CANCERS			English	Article						Oxaliplatin; docosahexaenoic acid; Sestrin 2; autophagic cell death; colon cancer	APOPTOSIS; BEVACIZUMAB; INDUCTION; SESTRIN-2; ARREST; MTOR	Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.	[Jeong, Soyeon; Kim, Jung Lim; Kim, Bo Ram; Lee, Dae-Hee; Oh, Sang Cheul] Korea Univ, Guro Hosp, Coll Med, Dept Oncol, Seoul 08308, South Korea; [Kim, Dae Yeong; Yun, Hye Kyeong; Park, Seong Hye; Na, Yoo Jin; Jo, Min Jee; Jeong, Yoon A.; Kim, Bu Gyeom; Lee, Dae-Hee; Oh, Sang Cheul] Korea Univ, Coll Med, Grad Sch Med, Seoul 08308, South Korea; [Kang, Sang Hee] Korea Univ, Guro Hosp, Coll Med, Dept Surg, Seoul 08308, South Korea		Lee, DH; Oh, SC (corresponding author), Korea Univ, Guro Hosp, Coll Med, Dept Oncol, Seoul 08308, South Korea.; Lee, DH; Oh, SC (corresponding author), Korea Univ, Coll Med, Grad Sch Med, Seoul 08308, South Korea.	neogene@korea.ac.kr; sachoh@korea.ac.kr	Kang, Sanghee/W-1117-2019	Kang, Sanghee/0000-0002-6097-8831; Jeong, Soyeon/0000-0002-4568-4579	National Research Foundation (NRF) of Korea - Korean government (MSIP) [NRF-2017R1A2B2011684, NRF-2017R1D1A1B03030703]	This work was supported by a National Research Foundation (NRF) of Korea grant funded by the Korean government (MSIP) (NRF-2017R1A2B2011684) and (NRF-2017R1D1A1B03030703). Moreover, we thank professor Kyu Lim for providing the GFP-LC3 vector, AA, alpha-LA, EPA.	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J	Bermudez, M; Aguilar-Medina, M; Lizarraga-Verdugo, E; Avendano-Felix, M; Silva-Benitez, E; Lopez-Camarillo, C; Ramos-Payan, R				Bermudez, Mercedes; Aguilar-Medina, Maribel; Lizarraga-Verdugo, Erik; Avendano-Felix, Mariana; Silva-Benitez, Erika; Lopez-Camarillo, Cesar; Ramos-Payan, Rosalio			LncRNAs as Regulators of Autophagy and Drug Resistance in Colorectal Cancer	FRONTIERS IN ONCOLOGY			English	Review						lncRNA; colorectal cancer; autophagy; chemoresistance; drug resistance; macroautophagy	LONG NONCODING RNA; EPITHELIAL-MESENCHYMAL TRANSITION; MEDIATES METHOTREXATE RESISTANCE; ADENOCARCINOMA TRANSCRIPT 1; PROMOTES TUMOR-GROWTH; H19 ONCOFETAL RNA; CELL LUNG-CANCER; POOR-PROGNOSIS; PROSTATE-CANCER; COLON-CANCER	Colorectal cancer (CRC) is a common malignancy with 1. 8 million cases in 2018. Autophagy helps to maintain an adequate cancer microenvironment in order to provide nutritional supplement under adverse conditions such as starvation and hypoxia. Additionally, most of the cases of CRC are unresponsive to chemotherapy, representing a significant challenge for cancer therapy. Recently, autophagy induced by therapy has been shown as a unique mechanism of resistance to anticancer drugs. In this regard, long non-coding RNAs (lncRNAs) analysis are important for cancer detection, progression, diagnosis, therapy response, and prognostic values. With increasing development of quantitative detection techniques, lncRNAs derived from patients' non-invasive samples (i.e., blood, stools, and urine) has become into a novel approach in precision oncology. Tumorspecific GAS5, HOTAIR, H19, and MALAT are novels CRC related lncRNAs detected in patients. Nonetheless, the effect and mechanism of lncRNAs in cancer autophagy and chemoresistance have not been extensively characterized. Chemoresistance and autophagy are relevant for cancer treatment and lncRNAs play a pivotal role in resistance acquisition for several drugs. LncRNAs such as HAGLROS, KCNQ1OT1, and H19 are examples of lncRNAs related to chemoresistance leaded by autophagy. Finally, clinical implications of lncRNAs in CRC are relevant, since they have been associated with tumor differentiation, tumor size, histological grade, histological types, Dukes staging, degree of differentiation, lymph node metastasis, distant metastasis, recurrent free survival, and overall survival (OS).	[Bermudez, Mercedes; Aguilar-Medina, Maribel; Lizarraga-Verdugo, Erik; Avendano-Felix, Mariana; Ramos-Payan, Rosalio] Univ Autonoma Sinaloa, Fac Ciencias Quim Biol, Culiacan, Sinaloa, Mexico; [Silva-Benitez, Erika] Univ Autonoma Sinaloa, Fac Odontol, Culiacan, Sinaloa, Mexico; [Lopez-Camarillo, Cesar] Univ Autonoma Ciudad Mexico, Posgrad Ciencias Genom, Mexico City, DF, Mexico		Ramos-Payan, R (corresponding author), Univ Autonoma Sinaloa, Fac Ciencias Quim Biol, Culiacan, Sinaloa, Mexico.	rosaliorp@uas.edu.mx	; Lopez-Camarillo, Cesar/I-1946-2019	Ramos-Payan, Rosalio/0000-0001-7500-7571; Lopez-Camarillo, Cesar/0000-0002-9417-2609	Consejo Nacional de Ciencia y Tecnologia CONACyT, MexicoConsejo Nacional de Ciencia y Tecnologia (CONACyT) [290311]	Consejo Nacional de Ciencia y Tecnologia CONACyT, Mexico (Grant 290311).	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Oncol.	OCT 2	2019	9								1008	10.3389/fonc.2019.01008			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JO4MO	WOS:000497553900001	31632922	gold, Green Published			2022-04-25	
J	Alnuqaydan, AM; Rah, B; Almutary, AG; Chauhan, SS				Alnuqaydan, Abdullah M.; Rah, Bilal; Almutary, Abdulmajeed G.; Chauhan, Shailender Singh			Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells	AMERICAN JOURNAL OF CANCER RESEARCH			English	Article						Synergistic effect; endoplasmic reticulum; autophagy; apoptosis; colorectal cancer	ER STRESS; COLON-CANCER; C-MYC; BETA-CATENIN; G2/M ARREST; MECHANISMS; INHIBITION; PATHWAY; TARGET; GROWTH	The development of chemo-resistance against 5-fluorouracil (5-FU) in tumor cells is one of the main debacles in colorectal cancer (CRC) patients. A recent combination of 5-FU with oxaliplatin or cetuximab drastically improves the survival rate in CRC patients; however, the toxicity issue cannot be evaded completely. Thus, searching for novel drug combinations with high specificity and low toxicity is seemingly important. Owing to the less undesirable effects of natural products on normal cells, here we investigated the synergistic antitumor effect of withaferin-A (WA) in combination with 5-FU. Our results demonstrate that the combination of WA and 5-FU induces a significant antiproliferative effect and modulates endoplasmic reticulum (ER) stress in favor of cell death in colorectal cancer (CRC) cells. Mechanistically, the combination upregulates the expression of ER stress sensors (BiP, PERK, CHOP, ATF-4, and eIF2 alpha) and executes PERK axis mediated apoptosis in CRC cells. Additionally, the combined treatment of WA and 5-FU mediated ER stress induces autophagy and apoptosis, which were confirmed by immunoblotting, acridine orange (AO) staining and annexin-V FITC by flow cytometry. In contrast, inhibition of ER stress with salubrinal significantly decreases both autophagic and apoptotic cell populations. Moreover, pharmacological inhibition of either autophagy or apoptosis by their respective inhibitors 3-methyladenine (3-MA) or carbobenzoxy-valyl-alanylaspartyl-[O-methyl]-fluoro-methyl ketone (Z-VAD-FMK) decreases their respective population of cells but could not affect either of the population significantly. Finally, the combination attenuates the expression of beta-catenin pathway associated proteins and arrests cell cycle at the G(2)M phase in CRC cells. In summary, the combination of WA and 5-FU decreases cell viability by inducing ER stress-mediated induction of autophagy and apoptosis, inhibiting the beta-catenin pathway and arresting the cell cycle at a G(2)M phase in CRC cells.	[Alnuqaydan, Abdullah M.; Rah, Bilal; Almutary, Abdulmajeed G.] Qassim Univ, Coll Appl Med Sci, Dept Med Biotechnol, GPO POB 6666, Buraydah 51452, Saudi Arabia; [Chauhan, Shailender Singh] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ USA		Alnuqaydan, AM; Rah, B (corresponding author), Qassim Univ, Coll Appl Med Sci, Dept Med Biotechnol, GPO POB 6666, Buraydah 51452, Saudi Arabia.	ami.alnuqaydan@qu.edu.sa; b.rah@qu.edu.sa	Chauhan, Shailender Singh/AAM-5269-2020	Chauhan, Shailender Singh/0000-0002-1975-2734	Deanship of Scientific Research, Qassim University; Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia	Researchers would like to thank the Deanship of Scientific Research, Qassim University for funding the publication of this project. The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for partial funding this research work through the post-doc project.	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J. Cancer Res.		2020	10	3					799	815					17	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	KY7DY	WOS:000522735400007	32266092				2022-04-25	
J	Mohapatra, P; Preet, R; Das, D; Satapathy, SR; Choudhuri, T; Wyatt, MD; Kundu, CN				Mohapatra, Purusottam; Preet, Ranjan; Das, Dipon; Satapathy, Shakti Ranjan; Choudhuri, Tathagata; Wyatt, Michael D.; Kundu, Chanakya Nath			Quinacrine-Mediated Autophagy and Apoptosis in Colon Cancer Cells Is Through a p53- and p21-Dependent Mechanism	ONCOLOGY RESEARCH			English	Article						Quinacrine (QC); Colon cancer; p21; p53; Autophagy; Apoptosis	BREAST-TUMOR CELLS; NF-KAPPA-B; CHLOROQUINE; DEATH; INHIBITION; ACTIVATION; INDUCTION; ROLES; CARCINOMA; THERAPY	We previously showed that quinacrine (QC), a small molecule antimalarial agent, also presented anticancer activity in breast cancer cells through activation of p53, p21, and inhibition of topoisomerase activity. Here we have systematically studied the detailed cell death mechanism of this drug using three colon cancer cell lines (HCT-116 parental, isogenic HCT-116 p53(-/-), and HCT-116 p21(-/-) sublines). QC caused a dose-dependent reduction in cell viability in all three cell lines. However, the parental cells were more susceptible to QC-mediated cell death, suggesting that p53- and p21-dependent processes were involved. QC-mediated cell death was measured with the following endpoints: the Bax/BcI-xL ratio, cleaved PARP, apoptotic nuclei visualized by DAPI staining, and COMET formation. In addition, markers of autophagy were measured. Acridine orange staining revealed increased accumulation of autophagic vacuoles (AVs) after QC treatment in a dose-dependent manner in parental cells, and decreased staining in isogenic HCT-116 p53-/- and HCT-116 P21(-/-) cells. Immunofluorescence of LC3B was significantly lowered in QC-treated cells lacking p53 or p2I, compared to the parental cells. Interestingly, the expression of the autophagy marker LC3B-II after exposure to QC was decreased in either p53 or p21 null cells compared to parental cells. After deletion of p21 in HCT-116 p53(-/-) cells, no change in LC3B-II expression was noted following QC treatment. Collectively, the results suggest that QC-mediated autophagy and apoptosis dependent on p53 and p21.	[Wyatt, Michael D.] Univ S Carolina, S Carolina Coll Pharm, Dept Pharmaceut & Biomed Sci, Columbia, SC 29208 USA		Kundu, CN (corresponding author), KIIT Univ, KIIT Sch Biotechnol, Campus-11, Bhubaneswar 751024, Orissa, India.	cnkundu@gmail.com	Satapathy, Shakti Ranjan/AAB-5787-2021; Das, Dipon/J-6991-2019; Das, Dipon/K-4554-2019; Choudhuri, Tathagata/F-8139-2011; Satapathy, Shakti Ranjan/L-3124-2018	Satapathy, Shakti Ranjan/0000-0002-3212-8960; Satapathy, Shakti Ranjan/0000-0002-3212-8960; Preet, Ranjan/0000-0001-6117-2701; Kundu, Chanakya/0000-0003-0297-1030; Mohapatra, Purusottam/0000-0001-8059-4141; Wyatt, Michael/0000-0003-1815-9565	Indian Council of Medical ResearchIndian Council of Medical Research (ICMR); Department of Biotechnology, Govt. of IndiaDepartment of Biotechnology (DBT) India	We acknowledge Prof Bert Vogelstein of Johns Hopkins. Baltimore for providing HCT-116 p53<SUP>-/-</SUP> and HCT-116 p21<SUP>-/-</SUP> cell lines. We are grateful to Mr. Bhabani Sankar Sahoo of Institute of Life Sciences, Bhubaneswar for excellent technical assistance with confocal laser microscopy. This work was supported by grants from Indian Council of Medical Research and Department of Biotechnology, Govt. of India. The authors state no conflict of interest.	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Res.		2012	20	2-3					81	91		10.3727/096504012X13473664562628			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	036UX	WOS:000311058800004	23193914				2022-04-25	
J	You, HX; Zhou, YH; Tan, SY; She, TH				You, Hong-Xia; Zhou, Yan-Hong; Tan, Shi-Yun; She, Tong-Hui			Effects of silencing RIP1 with siRNA on the biological behavior of the LoVo human colon cancer cell line	ONCOLOGY LETTERS			English	Article						RNA interference; RIP1 gene; colorectal carcinoma	NF-KAPPA-B; DEATH DOMAIN; KINASE; INTERACTS; NECROSIS; COMPLEX; IMMUNOTHERAPY; NECROPTOSIS; METASTASIS; AUTOPHAGY	The present study aimed to investigate the effects of silencing RIP1 by small interfering RNA (siRNA) on the biological behavior of the LoVo human colorectal carcinoma cell line and to provide evidence for the feasibility of colorectal cancer gene therapy. LoVo cells were divided into the RIP1 siRNA group, the blank control group and the negative control group. Chemically synthesized siRNA targeting RIP1 (RIP1 siRNA) was transfected into LoVo cells. Following transfection of the RIP1-targeted siRNA into the LoVo cells, the expression of the RIP1 gene was effectively inhibited. The results demonstrated that RIP1 effectively regulated the malignant biological behavior of the LoVo colon cancer cell line. Furthermore, the proliferation, motility and invasiveness of LoVo cells were inhibited by siRNA knockdown of RIP1. The results revealed that the RIP1 gene has an important role in the regulation of proliferation and apoptosis in colorectal carcinoma cells.	[You, Hong-Xia; Zhou, Yan-Hong; She, Tong-Hui] Hubei Univ Sci & Technol, Dept Gastroenterol, Xianning 437100, Hubei, Peoples R China; [You, Hong-Xia; Tan, Shi-Yun] Wuhan Univ, Renmin Hosp, Dept Gastroenterol, Wuhan 430060, Hubei, Peoples R China		Zhou, YH (corresponding author), Hubei Univ Sci & Technol, Dept Gastroenterol, 88 Xianning Ave, Xianning 437100, Hubei, Peoples R China.	yanhongzhou326@gmail.com; tanshiyun@medmail.com.cn			Natural Science Foundation of Hubei ProvinceNatural Science Foundation of Hubei Province [2009CDZ001, 2010CDB06908]; Research Project of Hubei Educational Department [Q20092801]; Foundation for Young Scientists of the Health Department of Hubei Province [QJX2010-30]; Science and Technology Commission of Wuhan Municipality [201060938363-05]	The present study was supported by grants from the Natural Science Foundation of Hubei Province (no. 2009CDZ001), the Research Project of Hubei Educational Department (no. Q20092801), the Foundation for Young Scientists of the Health Department of Hubei Province (no. QJX2010-30), the Science and Technology Commission of Wuhan Municipality (no. 201060938363-05) and the Natural Science Foundation of Hubei Province (no. 2010CDB06908).	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Lett.	JUN	2014	7	6					2065	2072		10.3892/ol.2014.2040			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AI0QY	WOS:000336555200064	24932290	Green Published, Green Submitted, gold			2022-04-25	
J	Yang, JH; Nishihara, R; Zhang, XH; Ogino, SJ; Qian, ZR				Yang, Juhong; Nishihara, Reiko; Zhang, Xuehong; Ogino, Shuji; Qian, Zhi Rong			Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer?	JOURNAL OF DIABETES AND ITS COMPLICATIONS			English	Article						PRKA; Biomarker; Carcinoma; Colon; Energy balance; Molecular pathologic epidemiology	BODY-MASS INDEX; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; ACTIVATED PROTEIN-KINASE; DISEASE-FREE SURVIVAL; DNA-DAMAGE; CELL-SURVIVAL; COLON-CANCER; RESVERATROL SUPPLEMENTATION; PRECISION MEDICINE; TUMOR-SUPPRESSOR	The recently rapid increase of obesity and type 2 diabetes mellitus has caused great burden to our society. A positive association between type 2 diabetes and risk of colorectal cancer has been reported by increasing epidemiological studies. The molecular mechanism of this connection remains elusive. However, type 2 diabetes may result in abnormal carbohydrate and lipid metabolism, high levels of circulating insulin, insulin growth factor-1, and adipocytolcines, as well as chronic inflammation. All these factors could lead to the alteration of energy sensing pathways such as the AMP activated kinase (PRKA), mechanistic (mammalian) target of rapamycin (mTOR), SIRT1, and autophagy signaling pathways. The resulted impaired SIRT1 and autophagy signaling pathway could increase the risk of gene mutation and cancer genesis by decreasing genetic stability and DNA mismatch repair. The dysregulated mTOR and PRKA pathway could remodel cell metabolism during the growth and metastasis of cancer in order for the cancer cell to survive the unfavorable microenvironment such as hypoxia and low blood supply. Moreover, these pathways may be coupling metabolic and epigenetic alterations that are central to oncogenic transformation. Further researches including molecular pathologic epidemiologic studies are warranted to better address the precise links between these two important diseases. (C) 2017 Elsevier Inc. All rights reserved.	[Yang, Juhong; Nishihara, Reiko; Ogino, Shuji; Qian, Zhi Rong] Dana Farber Canc Inst, Dept Oncol Pathol, 450 Brookline Ave, Boston, MA 02215 USA; [Yang, Juhong; Nishihara, Reiko; Ogino, Shuji; Qian, Zhi Rong] Harvard Med Sch, 450 Brookline Ave, Boston, MA 02215 USA; [Nishihara, Reiko; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA; [Nishihara, Reiko; Zhang, Xuehong; Ogino, Shuji] Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA; [Nishihara, Reiko; Ogino, Shuji] Harvard Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA; [Zhang, Xuehong] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA; [Yang, Juhong] Tianjin Med Univ, Collaborat Innovat Ctr Tianjin Med Epigenet 211, Key Lab Hormone & Dev, Minist Hlth,Metab Dis Hosp, Tianjin 300070, Peoples R China; [Yang, Juhong] Tianjin Med Univ, Tianjin Inst Endocrinol, Tianjin 300070, Peoples R China		Yang, JH (corresponding author), Tianjin Med Univ, Dept Diabet Nephropathy, Tianjin Metab Dis Hosp, 66 Tongan Rd, Tianjin 300070, Peoples R China.; Qian, ZR (corresponding author), Harvard Med Sch, Dana Farber Canc Inst, Dept Oncol Pathol, 450 Brookline Ave,Room M420, Boston, MA 02215 USA.	megii0315@126.com; Zhirong_Qian@dfci.harvard.edu		Ogino, Shuji/0000-0002-3909-2323	U.S.A. National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K07 CA190673, R01 CA151993, R35CA197735]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81473472, 81200612]; Tianjin Municipal Natural Science Foundation of China [13JCZDJC30500]; Tianjin City High School Science &Technology Fund Planning Project [20102217]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA151993, K07CA190673, R35CA197735] Funding Source: NIH RePORTER	This work was supported by grants from the U.S.A. National Institutes of Health (NIH) [K07 CA190673 (to RN.), R01 CA151993 and R35CA197735 (to S.O.)]; National Natural Science Foundation of China (81473472, 81200612); Tianjin Municipal Natural Science Foundation of China (13JCZDJC30500); Tianjin City High School Science &Technology Fund Planning Project (20102217).	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Diabetes Complications	JUL	2017	31	7					1228	1236		10.1016/j.jdiacomp.2017.04.012			9	Endocrinology & Metabolism	Science Citation Index Expanded (SCI-EXPANDED)	Endocrinology & Metabolism	EY6JK	WOS:000404088700027	28465145	Green Accepted			2022-04-25	
J	Sasaki, K; Tsuno, NH; Sunami, E; Kawai, K; Hongo, K; Hiyoshi, M; Kaneko, M; Murono, K; Tada, N; Nirei, T; Takahashi, K; Kitayama, J				Sasaki, Kazuhito; Tsuno, Nelson H.; Sunami, Eiji; Kawai, Kazushige; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Murono, Koji; Tada, Noriko; Nirei, Takako; Takahashi, Koki; Kitayama, Joji			Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study	ANTI-CANCER DRUGS			English	Article						autophagy; chloroquine; colorectal cancer; 5-fluorouracil	CELL-DEATH; AUTOPHAGY; APOPTOSIS; INHIBITION; GROWTH; VITRO; ACTIVATION; INDUCTION; NECROSIS; DISEASE	Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer. Anti-Cancer Drugs 23:675-682 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.	[Sasaki, Kazuhito; Tsuno, Nelson H.; Sunami, Eiji; Kawai, Kazushige; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Murono, Koji; Tada, Noriko; Nirei, Takako; Kitayama, Joji] Univ Tokyo, Fac Med Sci, Dept Surg Oncol, Tokyo, Japan; [Tsuno, Nelson H.; Takahashi, Koki] Univ Tokyo, Fac Med Sci, Dept Transfus Med, Tokyo, Japan		Sasaki, K (corresponding author), 7-3-1 Hongo,Bunkyo ku, Tokyo 1138655, Japan.	sasakik-sur@h.u-tokyo.ac.jp	Murono, Koji/AAC-3958-2020; Kawai, Kazushige/AAF-4334-2020	Kawai, Kazushige/0000-0002-5881-0036			Amaravadi RK, 2007, CLIN CANCER RES, V13, P7271, DOI 10.1158/1078-0432.CCR-07-1595; AUGUSTIJNS P, 1992, EUR J CLIN PHARMACOL, V42, P429; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Breckenridge AM, 1997, ANN TROP MED PARASIT, V91, P727, DOI 10.1080/00034989760464; Cecconi F, 2008, DEV CELL, V15, P344, DOI 10.1016/j.devcel.2008.08.012; Chen TH, 2005, PHARMACOL RES, V51, P329, DOI 10.1016/j.phrs.2004.10.004; Cuervo AM, 2004, TRENDS CELL BIOL, V14, P70, DOI 10.1016/j.tcb.2003.12.002; DiMasi JA, 2003, J HEALTH ECON, V22, P151, DOI 10.1016/S0167-6296(02)00126-1; Ding ZB, 2011, CLIN CANCER RES, V17, P6229, DOI 10.1158/1078-0432.CCR-11-0816; Fan CD, 2006, BIOORGAN MED CHEM, V14, P3218, DOI 10.1016/j.bmc.2005.12.035; Harris SM, 2005, BRIT J CANCER, V92, P722, DOI 10.1038/sj.bjc.6602403; Jiang PD, 2008, CELL PHYSIOL BIOCHEM, V22, P431, DOI 10.1159/000185488; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kiffin R, 2004, MOL BIOL CELL, V15, P4829, DOI 10.1091/mbc.E04-06-0477; Levine B, 2008, AUTOPHAGY, V4, P600, DOI 10.4161/auto.6260; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Li J, 2010, EUR J CANCER, V46, P1900, DOI 10.1016/j.ejca.2010.02.021; Lim YJ, 2007, WORLD J GASTROENTERO, V13, P1947, DOI 10.3748/wjg.v13.i13.1947; Longley DB, 2003, NAT REV CANCER, V3, P330, DOI 10.1038/nrc1074; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038/nrm2239; Meinao IM, 1996, LUPUS, V5, P237, DOI 10.1177/096120339600500313; Mizushima N, 2004, INT J BIOCHEM CELL B, V36, P2491, DOI 10.1016/j.biocel.2004.02.005; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Nishikawa T, 2010, ANN SURG ONCOL, V17, P592, DOI 10.1245/s10434-009-0696-x; Pandey AV, 2001, BIOCHEM J, V355, P333, DOI 10.1042/0264-6021:3550333; Rahim R, 2009, ANTI-CANCER DRUG, V20, P736, DOI 10.1097/CAD.0b013e32832f4e50; Rao R, 2012, MOL CANC THER, P24; Sasaki K, 2010, BMC CANCER, V10, DOI 10.1186/1471-2407-10-370; Solomon VR, 2009, EUR J PHARMACOL, V625, P220, DOI 10.1016/j.ejphar.2009.06.063; Tasdemir Ezgi, 2008, V445, P29, DOI 10.1007/978-1-59745-157-4_3; Xu R, 2006, HISTOL HISTOPATHOL, V21, P867, DOI 10.14670/HH-21.867; Yorimitsu T, 2005, CELL DEATH DIFFER, V12, P1542, DOI 10.1038/sj.cdd.4401765; Zhao H, 2005, RADIAT RES, V164, P250, DOI 10.1667/RR3436.1; Zheng YZ, 2009, CANCER INVEST, V27, P286, DOI 10.1080/07357900802427927	34	49	49	0	17	LIPPINCOTT WILLIAMS & WILKINS	PHILADELPHIA	530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA	0959-4973			ANTI-CANCER DRUG	Anti-Cancer Drugs	AUG	2012	23	7					675	682		10.1097/CAD.0b013e328353f8c7			8	Oncology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	967GM	WOS:000305894700001	22561420				2022-04-25	
J	Bu, HQ; Liu, DL; Zhang, GL; Chen, L; Song, ZF				Bu, Heqi; Liu, Dianlei; Zhang, Guolin; Chen, Li; Song, Zhangfa			AMPK/mTOR/ULK1 Axis-Mediated Pathway Participates in Apoptosis and Autophagy Induction by Oridonin in Colon Cancer DLD-1 Cells	ONCOTARGETS AND THERAPY			English	Article						oridonin; AMPK/mTOR/ULK1 pathway; autophagy; apoptosis; colon cancer	PROTECTIVE AUTOPHAGY; DEATH; INHIBITION; STRESS	Background: Oridonin has been demonstrated to exert strong antitumor activities in various types of human cancers. Our previous study established that oridonin induced the apoptosis of and exerted an inhibitory effect on colon cancer cells in vitro and in vivo. However, the mechanisms behind the antitumor effects of oridonin on colorectal cancer are not clearly known. This study explored whether autophagy was involved in antitumorigenesis effects caused by the usage of oridonin in colon cancer and examined whether the AMPK/mTOR/ULK1 signaling pathway was involved in this process. Methods: Cell viability was determined using CCK-8 assay. The distribution of cell apoptosis was evaluated using flow cytometry. RT-PCR and Western blotting analysis were conducted to identify the key target genes and proteins involved in the AMPK/mTOR cascade. AMPK siRNA was used to disturb AMPK expression. A DLD-1 cell orthotopic transplantation tumor model was established to explore the anti-cancer effects in vivo. Results: Oridonin exhibited a suppressive effect on DLD-1 cells in a concentration- and time-dependent manner. Additionally, in a dose-dependent manner, oridonin induced cell apoptosis via inducing the protein expression levels of cleaved caspase-3, cleaved PARP and stimulated autophagy by increasing protein expression levels of Becin1, LC3-II, decreasing protein expression levels of LC3-I, p62, which were respectively attenuated and elevated by autophagy inhibitor 3-MA. Furthermore, oridonin upregulated the expression level of p-AMPK and downregulated the expression levels of p-mTOR, p-ULK1 in the DLD-1 cells in a dose-dependent manner. Moreover, knockdown of AMPK by a specific siRNA reversed the expression levels of proteins involved in the AMPK/mTOR pathway, autophagy and apoptosis. In addition, outcomes from the in vivo experiments also showed that oridonin treatment significantly repressed tumorigenic growth of DLD-1 cells without any side effects, which was accompanied by the upregulation of p-AMPK, LC3-II, active caspase-3 protein expression levels and the downregulation of p-mTOR and p-ULK1 protein expression levels. Conclusion: This study demonstrated that oridonin induced apoptosis and autophagy of colon cancer DLD-1 cells via regulating the AMPK/mTOR/ULK1 pathway, which indicated that oridonin may be used as a novel therapeutic intervention for patients with colorectal cancer.	[Bu, Heqi; Zhang, Guolin; Chen, Li; Song, Zhangfa] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Colorectal Surg, Sch Med, 3 East Qingchun Rd, Hangzhou 310016, Peoples R China; [Bu, Heqi] Tongde Hosp Zhejiang Prov, Dept Coloproctol Surg, Hangzhou 310012, Peoples R China; [Liu, Dianlei] Zhejiang Univ, Womens Hosp, Dept Surg, Sch Med, Hangzhou 310006, Peoples R China		Song, ZF (corresponding author), Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Colorectal Surg, Sch Med, 3 East Qingchun Rd, Hangzhou 310016, Peoples R China.	songzhangfa@zju.edu.cn		Zhang, Guolin/0000-0002-5836-4478	Science and Technology Planning Project of Zhejiang Province, China [2018KY325]; basic public welfare research project of Zhejiang [LGD19H160006]	This study was supported by Science and Technology Planning Project of Zhejiang Province, China (Grant no. 2018KY325) and the basic public welfare research project of Zhejiang (grant no. LGD19H160006).	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J	Iftikhar, R; Penrose, HM; King, AN; Samudre, JS; Collins, ME; Hartono, AB; Lee, SB; Lau, F; Baddoo, M; Flemington, EF; Crawford, SE; Savkovic, SD				Iftikhar, Rida; Penrose, Harrison M.; King, Angelle N.; Samudre, Joshua S.; Collins, Morgan E.; Hartono, Alifiani B.; Lee, Sean B.; Lau, Frank; Baddoo, Melody; Flemington, Erik F.; Crawford, Susan E.; Savkovic, Suzana D.			Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity	ONCOGENESIS			English	Article							TRIGLYCERIDE LIPASE ATGL; LIPID-METABOLISM; DENSITY-LIPOPROTEIN; EXPRESSION; INFLAMMATION; AUTOPHAGY; GROWTH; FOXO3; PROLIFERATION; DEFICIENCY	Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LD) utilization, in obesity-driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis, and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses (ATG2B, PCK2, PGAM1, SPTLC2, IGFBP1, and ABCC3) and others with established roles (MYC and MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establish the therapeutic significance of ATGL in obesity-reinforced colon cancer progression.	[Iftikhar, Rida; Penrose, Harrison M.; King, Angelle N.; Samudre, Joshua S.; Collins, Morgan E.; Hartono, Alifiani B.; Lee, Sean B.; Baddoo, Melody; Flemington, Erik F.; Savkovic, Suzana D.] Tulane Univ, Sch Med, Dept Pathol & Lab Med, 1430 Tulane Ave, New Orleans, LA 70112 USA; [Lau, Frank] Louisiana State Univ, Hlth Sci Ctr, Dept Surg, New Orleans, LA USA; [Crawford, Susan E.] Univ Chicago, Pritzker Sch Med, NorthShore Univ Res Inst, Evanston, IL USA		Savkovic, SD (corresponding author), Tulane Univ, Sch Med, Dept Pathol & Lab Med, 1430 Tulane Ave, New Orleans, LA 70112 USA.	ssavkovi@tulane.edu		Lee, Sean/0000-0001-6211-3498	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 CA252055]; Crohn's & Colitis Foundation [663445]	We thank Dr. Jenisha Ghimire for her valuable technical support in this project. This work is supported by NIH award R01 CA252055 and by Crohn's & Colitis Foundation award 663445.	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J	Li, HB; Yi, X; Gao, JM; Ying, XX; Guan, HQ; Li, JC				Li, Hai-bo; Yi, Xin; Gao, Jian-mei; Ying, Xi-xiang; Guan, Hong-quan; Li, Jian-chun			Magnolol-induced H460 cells death via autophagy but not apoptosis	ARCHIVES OF PHARMACAL RESEARCH			English	Article						magnolol; H460; autophagy; apoptosis	LIVER-CANCER CELLS; TUMOR-SUPPRESSOR; HT-29 CELLS; HUMAN COLON; KINASE-B; MACROAUTOPHAGY; INHIBITION; PROTEIN; 3-METHYLADENINE; MECHANISMS	We have reported that the protective effect of Magnolol on TBHP-induced injury in human non-small lung cancer H460 cells is partially via a p53 dependent mechanism. In this study, we found that Magnolol displayed a stimulatory effect at low concentrations (<= 20 mu M) whilst inhibitory effect at high concentrations (>= 40 mu M) in H460 cells. To investigate the mechanism of inducing the biphasic effect in H460 cells with Magnolol, we showed that Magnolol stimulated DNA synthesis at low concentrations and displayed an inhibition effect at high concentrations in H460 cells. More importantly, the inhibition of DNA synthesis was accompanied by the S phase cell cycle arrest and the appearance of intense intracytoplasmic vacuoles. These vacuoles can be labeled by autophagic marker monodansylcadaverin (MDC), 3-methyladenine (3MA), an inhibitor of autophagy, was able to inhibit the occurrence of autophagy. The results of the LDH activity assay and TUNEL assay also showed that Magnolol at high concentrations inhibiting H460 cell growth was not via apoptotic pathway. Furthermore, accompanied by the occurrence of autophagy, the expression of phospho-Akt was down-regulated but PTEN significantly was up-regulated. In conclusion, Magnolol induces H460 cells death by autophagy but not apoptotic pathway. Blockade of PI3K/PTEN/Akt pathway is maybe related to Magnolol-induced autophagy. Autophagic cells death induction by Magnolol underlines the potential utility of its induction as a new cancer treatment modality.	[Gao, Jian-mei; Li, Jian-chun] Shenyang Pharmaceut Univ, Dept Pharm, Shenyang 110016, Peoples R China; [Li, Hai-bo; Guan, Hong-quan] Liaoning Univ TCM, Sch Basic Med Sci, Shenyang 110032, Peoples R China; [Yi, Xin] Inst Basic Med Sci, Dept Pathobiol, Beijing 100850, Peoples R China; [Ying, Xi-xiang] Liaoning Univ TCM, Sch Pharm, Shenyang 110032, Peoples R China		Li, JC (corresponding author), Shenyang Pharmaceut Univ, Dept Pharm, Wenhua Rd 103, Shenyang 110016, Peoples R China.	longqiaoqian@gmail.com					Abraham MC, 2004, TRENDS CELL BIOL, V14, P184, DOI 10.1016/j.tcb.2004.03.002; Arico S, 2001, J BIOL CHEM, V276, P35243, DOI 10.1074/jbc.C100319200; BIEDERBICK A, 1995, EUR J CELL BIOL, V66, P3; Bowen ID, 1996, MICROSC RES TECHNIQ, V34, P202, DOI 10.1002/(SICI)1097-0029(19960615)34:3<202::AID-JEMT3>3.0.CO;2-R; Brognard J, 2001, CANCER RES, V61, P3986; BURSCH W, 1994, BIOCHEM CELL BIOL, V72, P669, DOI 10.1139/o94-088; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; Chang BS, 1998, PLANTA MED, V64, P367, DOI 10.1055/s-2006-957453; CLARK AM, 1981, J PHARM SCI, V70, P951, DOI 10.1002/jps.2600700833; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; DUNN WA, 1990, J CELL BIOL, V110, P1923, DOI 10.1083/jcb.110.6.1923; Gerber HP, 1998, J BIOL CHEM, V273, P13313, DOI 10.1074/jbc.273.21.13313; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Ikeda K, 2002, BIOL PHARM BULL, V25, P1546, DOI 10.1248/bpb.25.1546; Iwamaru A, 2007, ONCOGENE, V26, P1840, DOI 10.1038/sj.onc.1209992; Jia L, 1997, BRIT J HAEMATOL, V98, P673, DOI 10.1046/j.1365-2141.1997.2623081.x; Kishimoto H, 2007, BLOOD, V109, P3316, DOI 10.1182/blood-2006-07-038059; KONOSHIMA T, 1991, J NAT PROD, V54, P816, DOI 10.1021/np50075a010; Larsen KE, 2002, HISTOL HISTOPATHOL, V17, P897, DOI 10.14670/HH-17.897; Lee JO, 1999, CELL, V99, P323, DOI 10.1016/S0092-8674(00)81663-3; Lee YM, 2001, EUR J PHARMACOL, V422, P159, DOI 10.1016/S0014-2999(01)01069-X; LI H, IN PRESS, P53; Lin SY, 2002, J CELL BIOCHEM, V84, P532, DOI 10.1002/jcb.10059; Lin SY, 2001, MOL CARCINOGEN, V32, P73, DOI 10.1002/mc.1066; Mizushima N, 2005, CELL DEATH DIFFER, V12, P1535, DOI 10.1038/sj.cdd.4401728; Pattingre S, 2004, METHOD ENZYMOL, V390, P17; Pattingre S, 2003, J BIOL CHEM, V278, P16667, DOI 10.1074/jbc.M210998200; Pedro M, 2006, TOXICOL LETT, V164, P24, DOI 10.1016/j.toxlet.2005.11.007; Petiot A, 2000, J BIOL CHEM, V275, P992, DOI 10.1074/jbc.275.2.992; Rani MRS, 2002, J BIOL CHEM, V277, P38456, DOI 10.1074/jbc.M203204200; SEGLEN PO, 1982, P NATL ACAD SCI-BIOL, V79, P1889, DOI 10.1073/pnas.79.6.1889; Shih HC, 2004, SHOCK, V22, P358, DOI 10.1097/01.shk.0000142251.92887.94; Stambolic V, 2001, MOL CELL, V8, P317, DOI 10.1016/S1097-2765(01)00323-9; Stroikin Y, 2004, EUR J CELL BIOL, V83, P583, DOI 10.1078/0171-9335-00433; ZAKERI ZF, 1994, BIOCHEM CELL BIOL, V72, P603, DOI 10.1139/o94-080	35	41	49	0	15	PHARMACEUTICAL SOC KOREA	SEOUL	1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA	0253-6269	1976-3786		ARCH PHARM RES	Arch. Pharm. Res.	DEC	2007	30	12					1566	1574		10.1007/BF02977326			9	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	246QC	WOS:000252021000011	18254244				2022-04-25	
J	Chen, Q; Zhong, L; Zhou, C; Feng, Y; Liu, QX; Zhou, D; Lu, X; Du, GS; Jian, D; Luo, H; Wang, D; Zheng, H; Qiu, Y				Chen, Qian; Zhong, Li; Zhou, Chao; Feng, Yan; Liu, Quan-xing; Zhou, Dong; Lu, Xiao; Du, Guang-Sheng; Jian, Dan; Luo, Hao; Wang, Dong; Zheng, Hong; Qiu, Yuan			Knockdown of Parkinson's disease-related gene ATP13A2 reduces tumorigenesis via blocking autophagic flux in colon cancer	CELL AND BIOSCIENCE			English	Article						Colon cancer; Autophagy; Tumorigenesis	EXPRESSION; CELLS; RISK; MAINTENANCE; SURVIVAL; IMPACT	Background Accumulating evidence shows that Parkinson's disease is negatively associated with colon cancer risk, indicating that Parkinson's disease family proteins may be involved in the initiation of colon cancer. Here, we aimed to identify a Parkinson's disease-related gene involved in colon cancer, elucidate the underlying mechanisms, and test whether it can be used as a target for cancer therapy. Methods We first screened colon cancer and normal tissues for differential expression of Parkinson's disease-associated genes and identified ATP13A2, which encodes cation-transporting ATPase 13A2, as a putative marker for colon cancer. We next correlated ATP13A2 expression with colon cancer prognosis. We performed a series of ATP13A2 knockdown and overexpression studies in vitro to identify the contribution of ATP13A2 in the stemness and invasive capacity of colon cancer cells. Additionally, autophagy flux assay were determined to explore the mechanism of ATP13A2 induced stemness. Finally, we knocked down ATP13A2 in mice using siRNA to determine whether it can be used as target for colon cancer treatment. Results Colon cancer patients with high ATP13A2 expression exhibit shorter overall survival than those with low ATP13A2. Functionally, ATP13A2 acts as a novel stimulator of stem-like traits. Furthermore, knockdown of ATP13A2 in HCT116 resulted in decreased levels of cellular autophagy. Additionally, bafilomycin A1, an autophagy inhibitor, reversed the ATP13A2-induced stemness of colon cancer cells. Lastly treatment with ATP13A2 siRNA reduced the volume of colon cancer xenografts in mice. Conclusions The PD-associated gene ATP13A2 is involved in colon cancer stemness through regulation of autophagy. Furthermore, ATP13A2 is a novel prognostic biomarker for colon cancer and is a potential target for colon cancer therapy.	[Chen, Qian; Zhong, Li; Feng, Yan; Jian, Dan; Luo, Hao; Wang, Dong] Army Med Univ, Mil Med Univ 3, Daping Hosp, Canc Ctr, Chongqing 400037, Peoples R China; [Zhou, Chao; Du, Guang-Sheng; Qiu, Yuan] Army Med Univ, Mil Med Univ 3, Dept Gen Surg, Xinqiao Hosp, Chongqing 400037, Peoples R China; [Liu, Quan-xing; Zhou, Dong; Lu, Xiao; Zheng, Hong] Army Med Univ, Mil Med Univ 3, Dept Thorac Surg, Xinqiao Hosp, Chongqing 400037, Peoples R China; [Chen, Qian; Qiu, Yuan] Army Med Univ, Mil Med Univ 3, State Key Lab Trauma Burn & Combined Injury, Chongqing 400037, Peoples R China		Qiu, Y (corresponding author), Army Med Univ, Mil Med Univ 3, Dept Gen Surg, Xinqiao Hosp, Chongqing 400037, Peoples R China.; Zheng, H (corresponding author), Army Med Univ, Mil Med Univ 3, Dept Thorac Surg, Xinqiao Hosp, Chongqing 400037, Peoples R China.	ziecoe@tmmu.edu.cn; xiaoq2037@qq.com	Zheng, Hong/O-9604-2018	Zheng, Hong/0000-0003-3725-4541; Luo, Hao/0000-0002-2321-9924; Liu, Quan-Xing/0000-0002-6725-385X	Surface Project of Chongqing Natural Science Foundation [csts2020jcyj-msx'mX0230]; Miaopu Talent Grant from Army medical University [2019R045]; Open Project Program of the State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University [SKLKF201904]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [82002656]	This study was supported by grants from the Surface Project of Chongqing Natural Science Foundation (csts2020jcyj-msx'mX0230) and Miaopu Talent Grant from Army medical University (to Yuan Qiu 2019R045), the Open Project Program of the State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (to Yuan Qiu SKLKF201904), and National Natural Science Foundation of China (82002656).	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J	John, S; Briatka, T; Rudolf, E				John, Stanislav; Briatka, Tomas; Rudolf, Emil			Diverse sensitivity of cells representing various stages of colon carcinogenesis to increased extracellular zinc: Implications for zinc chemoprevention	ONCOLOGY REPORTS			English	Article						apoptosis; autophagy; zinc; colon cancer; in vitro	ERK-DEPENDENT ACTIVATION; COLORECTAL-CANCER CELLS; APOPTOSIS; PATHWAY; DEATH; PROLIFERATION; NECROSIS; RECEPTOR; GROWTH	The relationship between zinc intake and risk of colon cancer is widely recognized: Despite reported mechanisms of zinc-mediated effects in colonic cells no information is available on whether zinc is capable of inducing cell death of malignant colonocytes. The present study shows that increased external zinc concentrations inhibit cell growth of three different colon cancer cell lines representing different stages of colon cancer: HCT-116, HT-29 and SW620 cells and induce their death. Of the tested cell lines, SW620 cells proved to be the most sensitive to externally added zinc and this sensitivity was at least partly due to increased levels of intracellular free zinc and the inability to overexpress metallothionein. Further studies into the mechanisms of zinc-induced cell injury and cell death revealed oxidative stress as the most important underlying mechanism activating stress kinase-dependent signaling, perturbation of mitochondria and plasma membrane damage. In addition, observed cell death in individual cell populations was cell line-dependent and variable including cells displaying features of apoptosis, necrosis, autophagy and other mixed-types. In conclusion, presented results for the first time show variability of responses to zinc in colon cancer at different stages as modeled in vitro and suggest that zinc-induced cell death despite common underlying mechanism(s) might have a variable nature.	[John, Stanislav; Briatka, Tomas; Rudolf, Emil] Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Hradec Kralove 50038 1, Czech Republic		Rudolf, E (corresponding author), Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Simkova 870, Hradec Kralove 50038 1, Czech Republic.	rudolf@lfhk.cuni.cz	Rudolf, Emil/B-5956-2017	Rudolf, Emil/0000-0002-9526-3174	GAUK [132808]; Ministry of Education [MSM 0021620820]	This study was supported by GAUK No. 132808 and Ministry of Education Research Project No. MSM 0021620820.	Azriel-Tamir H, 2004, J BIOL CHEM, V279, P51804, DOI 10.1074/jbc.M406581200; Carter JW, 1997, NUTR CANCER, V27, P217, DOI 10.1080/01635589709514529; De Flora S, 2005, MUTAT RES-FUND MOL M, V591, P8, DOI 10.1016/j.mrfmmm.2005.02.029; Eom SJ, 2001, MOL PHARMACOL, V59, P981, DOI 10.1124/mol.59.5.981; Fraker PJ, 1997, P SOC EXP BIOL MED, V215, P229, DOI 10.3181/00379727-215-44132; Franklin RB, 2007, ARCH BIOCHEM BIOPHYS, V463, P211, DOI 10.1016/j.abb.2007.02.033; Hamatake M, 2000, J BIOCHEM-TOKYO, V128, P933, DOI 10.1093/oxfordjournals.jbchem.a022844; Jaiswal AS, 2004, J CELL BIOCHEM, V93, P345, DOI 10.1002/jcb.20156; Kim YH, 1999, NEUROSCIENCE, V89, P175, DOI 10.1016/S0306-4522(98)00313-3; Kondoh M, 2002, EUR J BIOCHEM, V269, P6204, DOI 10.1046/j.1432-1033.2002.03339.x; Lansdown ABG, 2007, WOUND REPAIR REGEN, V15, P2, DOI 10.1111/j.1524-475X.2006.00179.x; LEE HH, 1989, AM J PHYSIOL, V256, pG87, DOI 10.1152/ajpgi.1989.256.1.G87; Liuzzi JP, 2004, ANNU REV NUTR, V24, P151, DOI 10.1146/annurev.nutr.24.012003.132402; MacDonald RS, 2000, J NUTR, V130, p1500S, DOI 10.1093/jn/130.5.1500S; Malhotra A, 2009, J ENVIRON PATHOL TOX, V28, P351, DOI 10.1615/JEnvironPatholToxicolOncol.v28.i4.90; MATEO MCM, 1988, CLIN PHYSIOL BIOCH, V6, P321; NELSON RL, 1987, ANTICANCER RES, V7, P259; Park KS, 2004, EXP MOL MED, V36, P557, DOI 10.1038/emm.2004.71; Park KS, 2003, AM J PHYSIOL-GASTR L, V285, pG1181, DOI 10.1152/ajpgi.00047.2003; Park KS, 2002, BRIT J PHARMACOL, V137, P597, DOI 10.1038/sj.bjp.0704909; Prasad AS, 1998, MOL CELL BIOCHEM, V188, P63, DOI 10.1023/A:1006868305749; Provinciali M, 2002, FREE RADICAL BIO MED, V32, P431, DOI 10.1016/S0891-5849(01)00830-9; SONG MK, 1993, J NATL CANCER I, V85, P667, DOI 10.1093/jnci/85.8.667; Wu WD, 2005, AM J PHYSIOL-LUNG C, V289, pL883, DOI 10.1152/ajplung.00197.2005	24	24	24	0	4	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	MAR	2011	25	3					769	780		10.3892/or.2010.1124			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	727JF	WOS:000287794000020	21206977	Bronze			2022-04-25	
J	Wang, YY; Luo, Q; He, XL; Wei, H; Wang, T; Shao, JC; Jiang, XN				Wang, Yuanyuan; Luo, Qin; He, Xianlu; Wei, He; Wang, Ting; Shao, Jichun; Jiang, Xinni			Emodin Induces Apoptosis of Colon Cancer Cells via Induction of Autophagy in a ROS-Dependent Manner	ONCOLOGY RESEARCH			English	Article						Emodin; Colon cancer; Apoptosis; Autophagy; Reactive oxygen species (ROS)	OXIDATIVE STRESS; MITOCHONDRIA	Recent studies revealed that emodin extracted from Chinese herbs exhibits an anticancer effect on different cancer types, including colon cancer. However, the mechanism is not well understood. In our study, we confirmed that emodin treatment inhibited cell viability and induced apoptosis in colon cancer cells. Further experiments found that emodin was also able to induce autophagy, which is indispensible for apoptosis induced by emodin. More interestingly. emodin treatment also results in mitochondrial dysfunction and ROS accumulation in colon cancer cells. Finally, we stressed that ROS accumulation is essential for autophagy and apoptosis induced by emodin. In conclusion, emodin induces apoptosis in colon cancer cells through induction of autophagy, during which ROS generation is of the essence. Our findings improve understanding of emodin's effect on colon cancer suppression and provide a new theoretical basis for colon cancer therapy.	[Wang, Yuanyuan; Luo, Qin; Wei, He; Wang, Ting; Jiang, Xinni] Chengdu Med Coll, Dept Biomed Sci, Chengdu 610051, Sichuan, Peoples R China; [He, Xianlu] China Natl Nucl Corp, Hosp 416, Chengdu Med Coll, Dept Gen Surg,Affiliated Hosp 2, Chengdu, Sichuan, Peoples R China; [Shao, Jichun] China Natl Nucl Corp, Hosp 416, Chengdu Med Coll, Dept Urol,Affiliated Hosp 2, Chengdu, Sichuan, Peoples R China		Jiang, XN (corresponding author), Chengdu Med Coll, Dept Biomed Sci, Chengdu 610051, Sichuan, Peoples R China.; Shao, JC (corresponding author), China Natl Nucl Corp, Hosp 416, Chengdu Med Coll, Dept Urol,Affiliated Hosp 2, Chengdu, Sichuan, Peoples R China.	shaoji93@163.com; 404810676@qq.com			Key Fund Project of Sichuan Provincial Department of Education [16ZA0291]; Discipline Building Project of Biology of Chengdu Medical College [CYXK2012011]; Project of Research and Innovation Teams of Chengdu Medical College [CYTD15-02]	This work was supported by the Key Fund Project of Sichuan Provincial Department of Education (No. 16ZA0291), the Discipline Building Project of Biology of Chengdu Medical College (CYXK2012011), and the Project of Research and Innovation Teams of Chengdu Medical College (CYTD15-02).	Cunningham D, 2010, LANCET, V375, P1030, DOI 10.1016/S0140-6736(10)60353-4; Fandy TE, 2014, CLIN CANCER RES, V20, P1249, DOI 10.1158/1078-0432.CCR-13-1453; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Galloway CA, 2012, J GEN PHYSIOL, V139, P455, DOI 10.1085/jgp.201210771; Komatsu M, 2007, CELL, V131, P1149, DOI 10.1016/j.cell.2007.10.035; Lee J, 2012, BIOCHEM J, V441, P523, DOI 10.1042/BJ20111451; Lee KH, 2017, MOL MED REP, V15, P2163, DOI 10.3892/mmr.2017.6254; Monisha BA, 2016, ADV EXP MED BIOL, V928, P47, DOI 10.1007/978-3-319-41334-1_3; Navarro-Yepes J, 2014, ANTIOXID REDOX SIGN, V21, P66, DOI 10.1089/ars.2014.5837; Ohsumi Y, 2014, CELL RES, V24, P9, DOI 10.1038/cr.2013.169; Pattingre S, 2005, CELL, V122, P927, DOI 10.1016/j.cell.2005.07.002; Qiu MN, 2017, ONCOL LETT, V13, P1137, DOI 10.3892/ol.2016.5535; Rahal A, 2014, BIOMED RES INT, V2014, DOI 10.1155/2014/761264; Scherz-Shouval R, 2007, TRENDS CELL BIOL, V17, P422, DOI 10.1016/j.tcb.2007.07.009; Su J, 2017, ONCOL REP, V37, P1565, DOI 10.3892/or.2017.5428; Su ZY, 2015, ONCOTARGET, V6, P8474, DOI 10.18632/oncotarget.3523; Wei YJ, 2008, MOL CELL, V30, P678, DOI 10.1016/j.molcel.2008.06.001; Zhang F, 2017, ONCOTARGET, V8, P35460, DOI 10.18632/oncotarget.16727; Zhang L, 2017, BIOMED PHARMACOTHER, V90, P222, DOI 10.1016/j.biopha.2017.03.046; Zhang P, 2017, AUTOPHAGY, V17, P1, DOI DOI 10.2174/1566524018666171219101142; Zhang SX, 2015, SCI REP-UK, V5, DOI 10.1038/srep13626	21	32	33	7	26	COGNIZANT COMMUNICATION CORP	PUTNAM VALLEY	18 PEEKSKILL HOLLOW RD, PO BOX 37, PUTNAM VALLEY, NY 10579 USA	0965-0407	1555-3906		ONCOL RES	Oncol. Res.		2018	26	6					889	899		10.3727/096504017X15009419625178			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GM2LO	WOS:000437917600007	28762328	Green Published			2022-04-25	
J	Sheng, YH; Giri, R; Davies, J; Schreiber, V; Alabbas, S; Movva, R; He, YW; Wu, A; Hooper, J; McWhinney, B; Oancea, I; Kijanka, G; Hasnain, S; Lucke, AJ; Fairlie, DP; McGuckin, MA; Florin, TH; Begun, J				Sheng, Yong Hua; Giri, Rabina; Davies, Julie; Schreiber, Veronika; Alabbas, Saleh; Movva, Ramya; He, Yaowu; Wu, Andy; Hooper, John; McWhinney, Brett; Oancea, Iulia; Kijanka, Gregor; Hasnain, Sumaira; Lucke, Andrew J.; Fairlie, David P.; McGuckin, Michael A.; Florin, Timothy H.; Begun, Jakob			A Nucleotide Analog Prevents Colitis-Associated Cancer via Beta-Catenin Independently of Inflammation and Autophagy	CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY			English	Article						Colon Cancer; beta-Catenin; Thioguanine; Autophagy	BOWEL-DISEASE; COLORECTAL NEOPLASIA; RAC1 ACTIVATION; EXPRESSION; PATHWAY; RISK; AZATHIOPRINE; THIOPURINES; MODEL; 5-AMINOSALICYLATE	Colitis increases the risk of bowel cancer. We show in mouse models that a thioguanine nucleotide can inhibit Wnl/bcalenin signaling via Rac1 in colonic epithelial cells to prevent carcinogenesis. The novel mechanism is independent of inflammation and autophagy. BACKGROUND & AIMS: Chronic bowel inflammation increases the risk of colon cancer; colitis-associated cancer (CAC). Thiopurine treatments are associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/beta-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/beta-catenin signalling. Autophagy is implicated in colonic tumors, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms. METHODS: Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harboring intestinal epithelial cell-specific deletion of autophagy related 7 gene (Atg7(Delta IEC)). TG or vehicle was administered intrarectally, and the effect on tumor burden and beta-catenin activity was assessed. The mechanisms of action of TG were investigated in vitro and in vivo. RESULTS: TG ameliorated DSS colitis in wild-type but not Atg7(Delta IEC) mice, demonstrating that anti-inflammatory effects of locally delivered TG are autophagy-dependent. However, TG inhibited CAC in both wild-type and Atg7(Delta IEC) mice. This was associated with decreased beta-catenin activation/nuclear translocation demonstrating that TG's inhibition of tumorigenesis occurred independently of anti-inflammatory and pro-autophagic actions. These results were confirmed in cell lines, and the dependency on Rac1 GTPase was demonstrated by siRNA knockdown and overexpression of constitutively active Rac1. CONCLUSIONS: Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemo-prophylactic approaches.	[Sheng, Yong Hua; Giri, Rabina; Davies, Julie; Schreiber, Veronika; Alabbas, Saleh; Movva, Ramya; Florin, Timothy H.; Begun, Jakob] Univ Queensland, Translat Res Inst, Mater Res Inst, Inflammatory Bowel Dis Grp, Woolloongabba, Qld, Australia; [Sheng, Yong Hua; Hasnain, Sumaira; Begun, Jakob] Univ Queensland, Translat Res Inst, Mater Res Inst, Inflammatory Dis Biol & Therapeut Grp, Woolloongabba, Qld, Australia; [He, Yaowu; Hooper, John] Univ Queensland, Mater Res Inst, Canc Biol Grp, Woolloongabba, Qld, Australia; [Wu, Andy] Univ Queensland, Translat Res Inst, Mater Res Inst, Bones & Immunol Grp, Woolloongabba, Qld, Australia; [McWhinney, Brett] Queensland Pathol Serv, Herston, Qld, Australia; [Oancea, Iulia; Begun, Jakob] Univ Queensland, Fac Med, Sch Clin Med, Brisbane, Qld, Australia; [Kijanka, Gregor] Univ Queensland, Translat Res Inst, Mater Res Inst, Immune Profiling & Canc Grp, Woolloongabba, Qld, Australia; [McGuckin, Michael A.] Univ Melbourne, Fac Med Dent & Hlth Sci, Parkville, Vic, Australia; [Lucke, Andrew J.; Fairlie, David P.] Univ Queensland, ARC Ctr Excellence Adv Mol Imaging, Inst Mol Biosci, Brisbane, Qld, Australia		Florin, TH; Begun, J (corresponding author), Univ Queensland, Translat Res Inst, Mater Res Inst, 37 Kent St, Brisbane, Qld 4102, Australia.	t.florin@uq.edu.au; jakob.begun@mater.uq.edu.au	Davies, Julie/AAU-7129-2021; sheng, yong H/C-5052-2013; Begun, Jakob/J-6793-2014; Hooper, John/C-1481-2016; Kijanka, Gregor/O-4300-2014; Hasnain, Sumaira/N-3412-2014	sheng, yong H/0000-0002-4623-9098; Begun, Jakob/0000-0001-5256-7672; Wu, Andy C/0000-0002-0864-4447; Schreiber, Veronika/0000-0001-6088-7828; Giri, Rabina/0000-0002-6712-6076; Hooper, John/0000-0003-1054-8486; Florin, Tim/0000-0003-1866-9848; HE, Yaowu/0000-0002-7828-263X; Davies, Julie/0000-0003-4035-6047; Kijanka, Gregor/0000-0003-2557-234X; Hasnain, Sumaira/0000-0001-8577-8628	Australian GovernmentAustralian GovernmentCGIAR; Mater Foundation; UQ Reginald Ferguson Fellowship; ARC grantAustralian Research Council; NHMRCNational Health and Medical Research Council (NHMRC) of Australia	The Translational Research Institute (TRI) is supported by a grant from the Australian Government. Mater Research Institute is supported by Mater Foundation. JB has a UQ Reginald Ferguson Fellowship. AJL is supported by an ARC grant and DPF by the NHMRC.	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Mol. Gastroenterol. Hepatol.		2021	11	1					33	53		10.1016/j.jcmgh.2020.05.012			21	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	PH8BZ	WOS:000600632200003	32497793	Green Published, gold			2022-04-25	
J	Cabang, AB; De Mukhopadhyay, K; Meyers, S; Morris, J; Zimba, PV; Wargovich, MJ				Cabang, April B.; De Mukhopadhyay, Keya; Meyers, Sarah; Morris, Jay; Zimba, Paul V.; Wargovich, Michael J.			Therapeutic effects of the euglenoid ichthyotoxin, euglenophycin, in colon cancer	ONCOTARGET			English	Article						euglenophycin; colon cancer; ichthyotoxin; autophagy; therapy	MULTITARGET THERAPEUTICS; NATURAL-PRODUCTS; AUTOPHAGY; APOPTOSIS; CELLS; TRICHORMAMIDES; IDENTIFICATION; CHEMOTHERAPY; INHIBITION; SOLENOPSIN	Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and the 3rd leading cause of cancer-related mortality. The emergence of drug resistance poses a major challenge in CRC care or treatment. This can be addressed by determining cancer mechanisms, discovery of druggable targets, and development of new drugs. In search for novel agents, aquatic microorganisms offer a vastly untapped pharmacological source that can be developed for cancer therapeutics. In this study, we characterized the anti-colorectal cancer potential of euglenophycin, a microalgal toxin from Euglena sanguinea. The toxin (49.1-114.6 mu M) demonstrated cytotoxic, anti-proliferative, anti-clonogenic, and anti-migration effects against HCT116, HT29, and SW620 CRC cells. We identified G1 cell cycle arrest and cell type - dependent modulation of autophagy as mechanisms of growth inhibition. We validated euglenophycin's anti-tumorigenic activity in vivo using CRL:Nu(NCr) Foxn1(nu) athymic nude mouse CRC xenograft models. Intraperitoneal toxin administration (100 mg/kg; 5 days) decreased HCT116 and HT29 xenograft tumor volumes (n=10 each). Tumor inhibition was associated with reduced expression of autophagy negative regulator mechanistic target of rapamycin (mTOR) and decreased trend of serum pro-inflammatory cytokines. Together, these results provide compelling evidence that euglenophycin can be a promising anti-colorectal cancer agent targeting multiple cancer-promoting processes. Furthermore, this study supports expanding natural products drug discovery to freshwater niches as prospective sources of anti-cancer compounds.	[Cabang, April B.; De Mukhopadhyay, Keya; Morris, Jay; Wargovich, Michael J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA; [Meyers, Sarah] Coll Charleston, Charleston, SC 29424 USA; [Zimba, Paul V.] Texas A&M Corpus Christi, Ctr Coastal Studies, Corpus Christi, TX 78412 USA; [Zimba, Paul V.] Texas A&M Corpus Christi, Dept Life Sci, Corpus Christi, TX 78412 USA		Wargovich, MJ (corresponding author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA.	wargovich@uthscsa.edu	Zimba, Paul V/O-2778-2013	Zimba, Paul V/0000-0001-6541-2055	Morris L. Lichtenstein, Jr. Medical Research Foundation	This study is supported by the Morris L. Lichtenstein, Jr. Medical Research Foundation.	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J	Rubio, MF; Lira, MC; Rosa, FD; Sambresqui, AD; Gumes, MCS; Costas, MA				Fernanda Rubio, Maria; Cecilia Lira, Maria; Damian Rosa, Francisco; Dario Sambresqui, Adrian; Salazar Gumes, Maria Cecilia; Alejandra Costas, Monica			RAC3 influences the chemoresistance of colon cancer cells through autophagy and apoptosis inhibition	CANCER CELL INTERNATIONAL			English	Article						Colorectal cancer; RAC3; Chemoresistance; Apoptosis; Autophagy	COLORECTAL-CANCER; COACTIVATOR; PROLIFERATION; BREAST; AIB1; OVEREXPRESSION; CHEMOTHERAPY; GROWTH; INFLAMMATION; PROGRESSION	Background: RAC3 coactivator overexpression has been implicated in tumorigenesis, contributing to inhibition of apoptosis and autophagy. Both mechanisms are involved in resistance to treatment with chemotherapeutic agents. The aim of this study was to investigate its role in chemoresistance of colorectal cancer. Methods: The sensitivity to 5-fluorouracil and oxaliplatin in colon cancer cells HT-29, HCT 116 and Lovo cell lines, expressing high or low natural levels of RAC3, was investigated using viability assays. Results: In HCT 116 cells, we found that although 5-fluorouracil was a poor inducer of apoptosis, autophagy was strongly induced, while oxaliplatin has shown a similar ability to induce both of them. However, in HCT 116 cells expressing a short hairpin RNA for RAC3, we found an increased sensitivity to both drugs if it is compared with control cells. 5-Fluorouracil and oxaliplatin treatment lead to an enhanced caspase 3-dependent apoptosis and produce an increase of autophagy. In addition, both process have shown to be trigged faster than in control cells, starting earlier after stimulation. Conclusions: Our results suggest that RAC3 expression levels influence the sensitivity to chemotherapeutic drugs. Therefore, the knowledge of RAC3 expression levels in tumoral samples could be an important contribution to design new improved therapeutic strategies in the future.	[Fernanda Rubio, Maria; Cecilia Lira, Maria; Damian Rosa, Francisco; Dario Sambresqui, Adrian; Salazar Gumes, Maria Cecilia; Alejandra Costas, Monica] Univ Buenos Aires, Fac Med, Inst Invest Med A Lanari, Buenos Aires, DF, Argentina; [Fernanda Rubio, Maria; Cecilia Lira, Maria; Damian Rosa, Francisco; Alejandra Costas, Monica] Univ Buenos Aires, Inst Invest Med IDIM, Lab Mol Biol & Apoptosis, CONICET, Buenos Aires, DF, Argentina; [Dario Sambresqui, Adrian] UBA, Inst Invest Med Dr A Lanari, Dept Gastroenterol, Buenos Aires, DF, Argentina; [Salazar Gumes, Maria Cecilia] UBA, Dept Oncol, Inst Invest Med Dr A Lanari, Buenos Aires, DF, Argentina		Costas, MA (corresponding author), Univ Buenos Aires, Fac Med, Inst Invest Med A Lanari, Buenos Aires, DF, Argentina.; Costas, MA (corresponding author), Univ Buenos Aires, Inst Invest Med IDIM, Lab Mol Biol & Apoptosis, CONICET, Buenos Aires, DF, Argentina.	mcostasra@hotmail.com		Costas, Monica/0000-0002-4773-3389	National Research Council of Argentina (CONICET)Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Agencia Nacional de Promocion Cientifica y Tecnologica, ArgentinaANPCyT [ANPCyT Prestamo BID 2014-1424]	This work has been supported by grants from the National Research Council of Argentina (CONICET 2015-2017), and Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina (ANPCyT Prestamo BID 2014-1424, 2016-2019).	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NOV 28	2017	17								111	10.1186/s12935-017-0483-x			17	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FO4FW	WOS:000416798100002	29209153	Green Published, gold			2022-04-25	
J	Kim, SW; Moon, JH; Park, SY				Kim, Sung-Wook; Moon, Ji-Hong; Park, Sang-Youel			Activation of autophagic flux by epigallocatechin gallate mitigates TRAIL-induced tumor cell apoptosis via down-regulation of death receptors	ONCOTARGET			English	Article						EGCG; autophagy; TRAIL; death receptor	MEDIATED AUTOPHAGY; EPITHELIAL-CELLS; PROSTATE-CANCER; COLON-CANCER; SURVIVAL; PROTEIN; LIGAND; APO2L/TRAIL; COMBINATION; DEPRIVATION	Epigallocatechin gallate (EGCG) is a major polyphenol in green tea. Recent studies have reported that EGCG can inhibit TRAIL-induced apoptosis and activate autophagic flux in cancer cells. However, the mechanism behind these processes is unclear. The present study found that EGCG prevents tumor cell death by antagonizing the TRAIL pathway and activating autophagy flux. Our results indicate that EGCG dose-dependently inhibits TRAIL-induced apoptosis and decreases the binding of death receptor 4 and 5 (DR4 and 5) to TRAIL. In addition, EGCG activates autophagy flux, which is involved in the inhibition of TRAIL cell death. We confirmed that the protective effect of EGCG can be reversed using genetic and pharmacological tools through re-sensitization to TRAIL. The inhibition of autophagy flux affects not only the re-sensitization of tumor cells to TRAIL, but also the restoration of death receptor proteins. This study demonstrates that EGCG inhibits TRAIL-induced apoptosis through the manipulation of autophagic flux and subsequent decrease in number of death receptors. On the basis of these results, we suggest further consideration of the use of autophagy activators such as EGCG in combination anti-tumor therapy with TRAIL.	[Kim, Sung-Wook; Moon, Ji-Hong; Park, Sang-Youel] Chonbuk Natl Univ, Coll Vet Med, Dept Vet Med, Biosafety Res Inst, Iksan 54596, Jeonbuk, South Korea		Park, SY (corresponding author), Chonbuk Natl Univ, Coll Vet Med, Dept Vet Med, Biosafety Res Inst, Iksan 54596, Jeonbuk, South Korea.	sypark@chonbuk.ac.kr	Park, Sang-Youel/D-5966-2012	Park, Sang-Youel/0000-0003-0575-6045	National Research Foundation of Korea (NRF) - Korean government (MISP) [2016R1A2B2009293]	This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (MISP) (2016R1A2B2009293).	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J	Pellerito, O; Notaro, A; Sabella, S; De Blasio, A; Vento, R; Calvaruso, G; Giuliano, M				Pellerito, Ornella; Notaro, Antonietta; Sabella, Selenia; De Blasio, Anna; Vento, Renza; Calvaruso, Giuseppe; Giuliano, Michela			WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPAR gamma down-regulation	APOPTOSIS			English	Article						Cannabinoids; PPAR gamma; ER stress; Autophagy/apoptosis interplay; Colon carcinoma cells	ENDOPLASMIC-RETICULUM STRESS; ER STRESS; CANNABINOID RECEPTORS; STIMULATION; NUCLEAR; ADIPOGENESIS; ACTIVATION; INHIBITOR; PROSTATE; THERAPY	Cannabinoids have been reported to possess anti-tumorigenic activity in cancer models although their mechanism of action is not well understood. Here, we show that the synthetic cannabinoid WIN55,212-2 (WIN)-induced apoptosis in colon cancer cell lines is accompanied by endoplasmic reticulum stress induction. The formation of acidic vacuoles and the increase in LC3-II protein indicated the involvement of autophagic process which seemed to play a pro-survival role against the cytotoxic effects of the drug. However, the enhanced lysosomal membrane permeabilization (LMP) blocked the autophagic flux after the formation of autophagosomes as demonstrated by the accumulation of p62 and LC3, two markers of autophagic degradation. Data also provided evidence for a role for nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) in cannabinoid signalling. PPAR gamma expression, at both protein and mRNA levels, was significantly down-regulated after WIN treatment and its inhibition, either by specific antagonists or by down-regulation via gene silencing, induced effects on cell viability as well as on ER stress and autophagic markers similar to those obtained in the presence of WIN. Moreover, the observation that the increase in p62 level and the induction of LMP were also modified by PPAR gamma antagonists seemed to indicate that PPAR gamma down-regulation was crucial to determinate the block of autophagic flux, thus confirming the critical role of PPAR gamma in WIN action. In conclusion, at our knowledge, our results are the first to show that the reduction of PPAR gamma levels contributes to WIN-induced colon carcinoma cell death by blocking the pro-survival autophagic response of cells.	[Pellerito, Ornella] Univ Laval, Fac Med, Lab Cellular & Dev Genet, Dept Mol Biol Med Biochem & Pathol,PROTEO, Quebec City, PQ G1K 7P4, Canada; [Pellerito, Ornella] Univ Laval, IBIS, Quebec City, PQ, Canada; [Notaro, Antonietta; Sabella, Selenia; De Blasio, Anna; Vento, Renza; Calvaruso, Giuseppe; Giuliano, Michela] Univ Palermo, Policlin Univ, Dipartimento STEBICEF Sci & Tecnol Biol Chim & Fa, Lab Biochim, I-90127 Palermo, Italy		Giuliano, M (corresponding author), Univ Palermo, Policlin Univ, Dipartimento STEBICEF Sci & Tecnol Biol Chim & Fa, Lab Biochim, Via Vespro 129, I-90127 Palermo, Italy.	michela.giuliano@unipa.it		Notaro, Antonietta/0000-0002-9822-0823	University of Palermo [ORPA07EZ5Z, ORPA06F3TB]	This work was supported by University of Palermo [Grant ORPA07EZ5Z and ORPA06F3TB].	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J	Katona, BW; Hojnacki, T; Glynn, RA; Paulosky, KE; Szigety, KM; Cao, Y; Zhang, XY; Feng, ZJ; He, X; Ma, J; Hua, XX				Katona, Bryson W.; Hojnacki, Taylor; Glynn, Rebecca A.; Paulosky, Kayla E.; Szigety, Katherine M.; Cao, Yan; Zhang, Xuyao; Feng, Zijie; He, Xin; Ma, Jian; Hua, Xianxin			Menin-mediated Repression of Glycolysis in Combination with Autophagy Protects Colon Cancer Against Small-molecule EGFR Inhibitors	MOLECULAR CANCER THERAPEUTICS			English	Article							TYROSINE KINASE INHIBITOR; MLL INTERACTION; RAS MUTATIONS; PHASE-II; GEFITINIB; RECEPTOR; GROWTH; TARGETS; TRIAL; CHEMOTHERAPY	Menin serves both tumor suppressor and promoter roles in a highly tumor-specific manner. In colorectal cancer, menin is over-expressed and plays a critical role in regulating transcription of SKP2, and combined treatment with a menin inhibitor and smallmolecule EGFR inhibitor (EGFRi) leads to synergistic killing of colorectal cancer cells. However, the full spectrum of menin function in colorectal cancer remains uncertain. Herein, we demonstrate that menin inhibition increases glycolysis in colorectal cancer cells. This menin inhibitor-induced increase in glycolysis occurs in an mTOR-independent manner and enhances the sensitivity of colorectal cancer cells to EGFRis. In addition, we show that EGFRis induce autophagy in colorectal cancer cells, which is important for cell survival in the setting of combined treatment with an EGFRi and menin inhibitor. Inhibition of autophagy with chloroquine further sensitizes colorectal cancers to treatment with the combination of an EGFRi and menin inhibitor. Together, these findings uncover a novel role for menin in colorectal cancer as a repressor of glycolysis and demonstrate that menin inhibitor-induced increases in glycolysis sensitize colorectal cancer cells to EGFRis. In addition, these findings illustrate the importance of autophagy as a protective mechanism against EGFRis, especially in the presence of menin inhibition. Ultimately, these data open the possibility of using menin-mediated regulation of glycolysis to potentially improve treatment modalities for colorectal cancer.	[Katona, Bryson W.] Univ Penn, Perelman Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA; [Katona, Bryson W.; Hojnacki, Taylor; Glynn, Rebecca A.; Paulosky, Kayla E.; Szigety, Katherine M.; Cao, Yan; Zhang, Xuyao; Feng, Zijie; He, Xin; Ma, Jian; Hua, Xianxin] Univ Penn, Abramson Family Canc Res Inst, Dept Canc Biol, Perelman Sch Med, 421 Curie Blvd,412 BRB 2-3, Philadelphia, PA 19104 USA		Katona, BW; Hua, XX (corresponding author), Univ Penn, Abramson Family Canc Res Inst, Dept Canc Biol, Perelman Sch Med, 421 Curie Blvd,412 BRB 2-3, Philadelphia, PA 19104 USA.; Katona, BW (corresponding author), Univ Penn, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.; Katona, BW; Hua, XX (corresponding author), Univ Penn, Dept Canc Biol, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA.	Bryson.Katona@pennmedicine.upenn.edu; huax@pennmedicine.upenn.edu		Paulosky, Kayla/0000-0001-9741-2228; Katona, Bryson/0000-0001-8186-9119; Feng, Zijie/0000-0002-5633-3686; He, Xin/0000-0002-2131-2092; Zhang, Xuyao/0000-0003-1654-5550	NIH/NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [K08DK106489, R03DK120946]; NIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01NCI563378]; Institute for Translational Medicine and Therapeutics [ITMAT014001]; NIH/NIDDKCenter for Molecular Studies in Digestive and Liver Diseases at the University of Pennsylvania [P30DK050306]	We would like to thank Dr. Anthony Mancuso at the University of Pennsylvania Laboratory for Quantitative Metabolomics for his assistance with the metabolism experiments. We would like to acknowledge the following support: NIH/NIDDK K08DK106489 (to B.W. Katona) and R03DK120946 (to B.W. Katona), NIH/NCI R01NCI563378 (to X. Hua), the Institute for Translational Medicine and Therapeutics (ITMAT014001, to X. Hua), and the NIH/NIDDKCenter for Molecular Studies in Digestive and Liver Diseases at the University of Pennsylvania (P30DK050306) including its pilot grant funding (to B.W. Katona) and its core facilities (molecular pathology and imaging, and cell culture).	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Cancer Ther.	NOV 1	2020	19	11					2319	2329		10.1158/1535-7163.MCT-20-0101			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	OP2KR	WOS:000587913900009	32879052	Green Accepted			2022-04-25	
J	Zheng, C; Zhang, Y; Mao, W; Li, Q				Zheng, Chao; Zhang, Yu; Mao, Wei; Li, Qing			Increasing colorectal cancer cell sensitivity to oxaliplatin through hyperthermia and chloroquine treatment	INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY			English	Article						Colorectal cancer; hyperthermia; oxaliplatin; chloroquine; apoptosis; autophagy	COLON-CANCER; IN-VIVO; APOPTOSIS; DEATH; INHIBITOR; GLIOBLASTOMA; COMBINATION; AUTOPHAGY; REVEALS; MODEL	Colorectal cancer is the third most lethal form of cancer worldwide, with most patients dying of liver metastases. Patients with metastatic livers can be treated with hyperthermia therapy, which often uses IHP (Isolated Hepatic Perfusion). Hyperthermia has become as a highly anticipated method. Using traditional hyperthermia alone is unable to inhibit tumor cell proliferation. Tumor can be inhibited effectively by combining oxaliplatin with a 42 degrees C hot water bath. However, this combination has been shown to induce autophagy in colorectal cancer cell lines, which inhibits tumor cell death to some extent. In order to combat this problem, we used oxaliplatin in combination with autophagy inhibitor chloroquine (CQ) at 42 degrees C. We found that oxaliplatin combined with CQ at 42 degrees C induces caspase-dependent apoptosis in colorectal cancer cells. This treatment not only impacts BCL-2 family proteins, but also downregulates the HSP and IAP family proteins. Activated caspase and PRAP (poly ADP-ribose polymerase) proteins are all upregulated. The results are suggesting that oxaliplatin combined with CQ at 42 degrees C is a novel anti-tumor approach against colorectal cancer.	[Zheng, Chao; Zhang, Yu; Mao, Wei; Li, Qing] Zhejiang Chinese Med Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, 54 Youdian Rd, Hangzhou 310006, Zhejiang, Peoples R China		Li, Q (corresponding author), Zhejiang Chinese Med Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, 54 Youdian Rd, Hangzhou 310006, Zhejiang, Peoples R China.	zyn515@126.com					Chen F, 2008, CELL BIOL INT, V32, P715, DOI 10.1016/j.cellbi.2008.02.010; Chen HC, 2015, NAT CELL BIOL, V17, P1270, DOI 10.1038/ncb3236; Fulda S, 2012, NAT REV DRUG DISCOV, V11, P109, DOI 10.1038/nrd3627; Garcia S, 2015, MEDIAT INFLAMM, V2015, DOI 10.1155/2015/837250; Gorman AM, 2005, BIOCHEM BIOPH RES CO, V327, P801, DOI 10.1016/j.bbrc.2004.12.066; Hui KKW, 2011, CELL DEATH DIFFER, V18, P1780, DOI 10.1038/cdd.2011.50; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kabeya Y, 2004, J CELL SCI, V117, P2805, DOI 10.1242/jcs.01131; Karpel-Massler G, 2015, ONCOTARGET, V6, P36456, DOI 10.18632/oncotarget.5505; Liang XL, 2014, MOL MED REP, V10, P719, DOI 10.3892/mmr.2014.2234; Liu MY, 2015, INT J MOL MED, V36, P975, DOI 10.3892/ijmm.2015.2328; Milan E, 2015, AUTOPHAGY, V11, P1161, DOI 10.1080/15548627.2015.1052928; Pankiv S, 2007, J BIOL CHEM, V282, P24131, DOI 10.1074/jbc.M702824200; Pham PA, 2015, PLANT MOL BIOL, V89, P319, DOI 10.1007/s11103-015-0363-5; Raemy E, 2014, CHEM PHYS LIPIDS, V179, P70, DOI 10.1016/j.chemphyslip.2013.12.002; Rahmani M, 2015, HAEMATOLOGICA, V100, P1553, DOI 10.3324/haematol.2015.130351; Selvakumaran M, 2013, CLIN CANCER RES, V19, P2995, DOI 10.1158/1078-0432.CCR-12-1542; Song XX, 2012, MOL CANCER RES, V10, P1567, DOI 10.1158/1541-7786.MCR-12-0209-T; Stankiewicz AR, 2005, J BIOL CHEM, V280, P38729, DOI 10.1074/jbc.M509497200; Yang DH, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0097352; Yang WS, 2014, CELL CYCLE, V13, P992, DOI 10.4161/cc.27880; Zhang Shou-De, 2015, Chin J Nat Med, V13, P660, DOI 10.1016/S1875-5364(15)30063-7; Zmuda F, 2015, J MED CHEM, V58, P8683, DOI 10.1021/acs.jmedchem.5b01324	23	0	0	1	6	E-CENTURY PUBLISHING CORP	MADISON	40 WHITE OAKS LN, MADISON, WI 53711 USA	1936-2625			INT J CLIN EXP PATHO	Int. J. Clin. Exp. Pathol.		2016	9	2					496	508					13	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	DG1EU	WOS:000371809200007					2022-04-25	
J	Hou, N; Han, J; Li, J; Liu, YX; Qin, YN; Ni, L; Song, TS; Huang, C				Hou, Ni; Han, Jia; Li, Jie; Liu, Yingxun; Qin, Yannan; Ni, Lei; Song, Tusheng; Huang, Chen			MicroRNA Profiling in Human Colon Cancer Cells during 5-Fluorouracil-Induced Autophagy	PLOS ONE			English	Article							PREDICTION; MECHANISMS; PROTEINS; TARGET	Autophagy modulation is now recognized as a potential therapeutic approach for cancer (including colorectal cancer), yet the molecular mechanisms regulating autophagy in response to cellular stress are still not well understood. MicroRNAs (miRNAs) have been found to play important roles in controlling many cellular functions, including growth, metabolism and stress response. The physiological importance of the miRNA-autophagy interconnection is only beginning to be elucidated. MiRNA microarray technology facilitates analysis of global miRNA expression in certain situations. In this study, we explored the expression profile of miRNAs during the response of human colon cancer cells (HT29s) to 5-FU treatment and nutrient starvation using miRNA microarray analysis. The alteration of miRNA expression showed the same pattern under both conditions was further testified by qRT-PCR in three human colon cancer cell lines. In addition, bioinformatic prediction of target genes, pathway analysis and gene network analysis were performed to better understand the roles of these miRNAs in the regulation of autophagy. We identified and selected four downregulated miRNAs including hsa-miR-302a-3p and 27 upregulated miRNAs under these two conditions as having the potential to target genes involved in the regulation of autophagy in human colon cancer cells. They have the potential to modulate autophagy in 5-FU-based chemotherapy in colorectal cancer.	[Hou, Ni; Han, Jia; Liu, Yingxun; Qin, Yannan; Ni, Lei; Song, Tusheng; Huang, Chen] Xi An Jiao Tong Univ, Dept Genet & Mol Biol, Sch Med, Xian 710049, Peoples R China; [Li, Jie] Xi An Jiao Tong Univ, Affiliated Hosp 2, Sch Med, Dept Gen Surg, Xian 710049, Peoples R China; [Huang, Chen] Xi An Jiao Tong Univ, Key Lab Environm & Genes Related Dis, Sch Med, Xian 710049, Peoples R China; [Huang, Chen] Xi An Jiao Tong Univ, Cardiovasc Res Ctr, Sch Med, Xian 710049, Peoples R China		Huang, C (corresponding author), Xi An Jiao Tong Univ, Dept Genet & Mol Biol, Sch Med, Xian 710049, Peoples R China.	hchen@mail.xjtu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31100969, 81172358]; Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education MinistryScientific Research Foundation for the Returned Overseas Chinese Scholars [2013-09]	This work was supported by grants from the National Natural Science Foundation of China (grant No. 31100969) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (2013-09) to Dr. Hou. It was also supported by a grant from the National Natural Science Foundation of China (grant No. 81172358) to Dr. Li. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Saleem, S; Tariq, S; Aleem, I; Shaheed, SU; Tahseen, M; Atiq, A; Hassan, S; Abu Bakar, M; Khattak, S; Syed, AA; Ahmad, AH; Hussain, M; Yusuf, MA; Sutton, C				Saleem, Saira; Tariq, Sahrish; Aleem, Iffat; Shaheed, Sadr-ul; Tahseen, Muhammad; Atiq, Aribah; Hassan, Sadia; Abu Bakar, Muhammad; Khattak, Shahid; Syed, Aamir Ali; Ahmad, Asad Hayat; Hussain, Mudassar; Yusuf, Muhammed Aasim; Sutton, Chris			Proteomics analysis of colon cancer progression	CLINICAL PROTEOMICS			English	Article						Colon cancer; iTRAQ proteomics; Orbitrap fusion; Biomarkers	COLORECTAL-CANCER; SERUM MATRIX-METALLOPROTEINASE-9; CELL-MIGRATION; CAVEOLIN-1; EXPRESSION; CARCINOMA; MECHANISMS; NEOPLASIA; CACHEXIA; PREDICTS	Background The aim of this pilot study was to identify proteins associated with advancement of colon cancer (CC). Methods A quantitative proteomics approach was used to determine the global changes in the proteome of primary colon cancer from patients with non-cancer normal colon (NC), non-adenomatous colon polyp (NAP), non-metastatic tumor (CC NM) and metastatic tumor (CC M) tissues, to identify up- and down-regulated proteins. Total protein was extracted from each biopsy, trypsin-digested, iTRAQ-labeled and the resulting peptides separated using strong cation exchange (SCX) and reverse-phase (RP) chromatography on-line to electrospray ionization mass spectrometry (ESI-MS). Results Database searching of the MS/MS data resulted in the identification of 2777 proteins which were clustered into groups associated with disease progression. Proteins which were changed in all disease stages including benign, and hence indicative of the earliest molecular perturbations, were strongly associated with spliceosomal activity, cell cycle division, and stromal and cytoskeleton disruption reflecting increased proliferation and expansion into the surrounding healthy tissue. Those proteins changed in cancer stages but not in benign, were linked to inflammation/immune response, loss of cell adhesion, mitochondrial function and autophagy, demonstrating early evidence of cells within the nutrient-poor solid mass either undergoing cell death or adjusting for survival. Caveolin-1, which decreased and Matrix metalloproteinase-9, which increased through the three disease stages compared to normal tissue, was selected to validate the proteomics results, but significant patient-to-patient variation obfuscated interpretation so corroborated the contradictory observations made by others. Conclusion Nevertheless, the study has provided significant insights into CC stage progression for further investigation.	[Saleem, Saira; Tariq, Sahrish; Aleem, Iffat] Shaukat Khanum Mem Canc Hosp & Res Ctr, Bas Sci Res, 7-A Block R-3, Lahore 54000, Pakistan; [Shaheed, Sadr-ul; Sutton, Chris] Univ Bradford, Inst Canc Therapeut, Tumbling Hill St, Bradford BD7 1BD, W Yorkshire, England; [Tahseen, Muhammad; Atiq, Aribah; Ahmad, Asad Hayat; Hussain, Mudassar] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Pathol, 7-A Block R-3, Lahore 54000, Pakistan; [Hassan, Sadia] Shaukat Khanum Mem Canc Hosp & Res Ctr, Clin Res Off, 7-A Block R-3, Lahore 54000, Pakistan; [Abu Bakar, Muhammad] Shaukat Khanum Mem Canc Hosp & Res Ctr, Canc Registry & Clin Data Management, 7-A Block R-3, Lahore 54000, Pakistan; [Khattak, Shahid; Syed, Aamir Ali] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Surg Oncol, 7-A Block R-3, Lahore 54000, Pakistan; [Yusuf, Muhammed Aasim] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Internal Med, 7-A Block R-3, Lahore 54000, Pakistan		Saleem, S (corresponding author), Shaukat Khanum Mem Canc Hosp & Res Ctr, Bas Sci Res, 7-A Block R-3, Lahore 54000, Pakistan.	sairas@skm.org.pk		Aleem, Iffat/0000-0003-4824-2757	Shaukat Khanum Memorial Cancer hospital and Research Center, Pakistan; Yorkshire Cancer Research, UK	This work was supported by Shaukat Khanum Memorial Cancer hospital and Research Center, Pakistan Chris Sutton and Sadr ul Shaheed work is supported by Yorkshire Cancer Research, UK. They had no involvement in the study design and writing of article.	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Proteom.	DEC 28	2019	16	1							44	10.1186/s12014-019-9264-y			17	Biochemical Research Methods	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	KK2OE	WOS:000512586900001	31889941	gold, Green Published			2022-04-25	
J	Kaleagasioglu, F; Ali, DM; Berger, MR				Kaleagasioglu, Ferda; Ali, Doaa M.; Berger, Martin R.			Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators	FRONTIERS IN PHARMACOLOGY			English	Review						types of autophagy; autophagy as drug target; alkylphosphocholines; Akt; mTOR pathway; miltefosine; perifosine; erufosine	CHAPERONE-MEDIATED AUTOPHAGY; ADVANCED SOLID TUMORS; PHASE-I TRIAL; MYELOGENOUS LEUKEMIA-CELLS; SIGNALING PATHWAYS; COLORECTAL-CANCER; ANTITUMOR-ACTIVITY; PANCREATIC-CANCER; DUAL INHIBITION; ERUFOSINE	Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described,i.e.chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt (i.e.protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second- and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagyin vitroandin vivo. mTOR is a down-stream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.	[Kaleagasioglu, Ferda] Near East Univ, Fac Med, Dept Pharmacol, Mersin, Turkey; [Ali, Doaa M.; Berger, Martin R.] German Canc Res Ctr, Toxicol & Chemotherapy Unit, Heidelberg, Germany; [Ali, Doaa M.] Alexandria Univ, Med Res Inst, Dept Pharmacol & Expt Therapeut, Alexandria, Egypt		Berger, MR (corresponding author), German Canc Res Ctr, Toxicol & Chemotherapy Unit, Heidelberg, Germany.	m.berger@dkfz-heidelberg.de	Kaleagasioglu, Ferda/E-9447-2011	Kaleagasioglu, Ferda/0000-0003-1511-0432			Abdik EA, 2019, ANTI-CANCER DRUG, V30, P383, DOI 10.1097/CAD.0000000000000736; Agarraberes FA, 2001, J CELL SCI, V114, P2491; Ali DM, 2019, CELL DEATH DISCOV, V5, DOI 10.1038/s41420-019-0206-2; Alistar A, 2017, LANCET ONCOL, V18, P770, DOI 10.1016/S1470-2045(17)30314-5; Ansari SS, 2018, CELL DEATH DIS, V9, DOI 10.1038/s41419-018-0342-2; Ansari Shariq S, 2018, Oncotarget, V9, P5797, DOI 10.18632/oncotarget.23537; Ansari SS, 2017, CELL ONCOL, V40, P89, DOI 10.1007/s13402-016-0302-8; Arnaout A, 2019, BREAST CANCER RES TR, V178, P327, DOI 10.1007/s10549-019-05381-y; 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Pharmacol.	APR 29	2020	11								547	10.3389/fphar.2020.00547			23	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	MV9AV	WOS:000556642300001	32410999	Green Published, gold			2022-04-25	
J	Peng, Y; Qiu, L; Xu, D; Zhang, L; Yu, HX; Ding, YD; Deng, LL; Lin, JG				Peng, Ying; Qiu, Ling; Xu, Dong; Zhang, Li; Yu, Huixin; Ding, Yuedi; Deng, Lili; Lin, Jianguo			M4IDP, a zoledronic acid derivative, induces G1 arrest, apoptosis and autophagy in HCT116 colon carcinoma cells via blocking PI3K/Akt/mTOR pathway	LIFE SCIENCES			English	Article						Bisphosphonate; Zoledronic acid derivative; Colorectal cancer; PI3K/Akt/mTOR; Apoptosis; Autophagy	MEDIATED ER STRESS; CANCER CELLS; OXIDATIVE STRESS; INHIBITS GROWTH; BH3 PROTEINS; IN-VITRO; BISPHOSPHONATES; AKT; DEATH; MECHANISMS	Aims: The aim of this work was to examine the antitumor effects and mechanisms of M4IDP, a zoledronic acid derivative, on human colorectal cancer (CRC) HCT116 cells. Main methods: The effects of M4IDP on proliferation, cell cycle and ROS production were determined by CCK-8 and flow cytometry assays. Annexin-V-FITC/PI, Hoechst 33258, MDC staining assays and Ad-mCherry-GFP-LC3B fluorescence assay were performed to investigate apoptosis and autophagy. The effects of M4IDP on the induction of ER stress as well as the expression of cell cycle, apoptosis and autophagy-related proteins were analyzed by western blot assay. Key findings: M4IDP exhibited strong and sustained inhibitory effect on the growth of HCT116 cells. G1 arrest caused by M4IDP might be attributed to the enhancement of p27 and reduction of cyclin D1 expression. Proper time treatment of M4IDP activated autophagy and promoted autophagic flux, while long-time treatment might inhibit the autophagic degradation and undermine the autophagy. M4IDP-induced apoptosis and autophagy were related to the ROS production and subsequent ER stress. M4IDP treatment increased the expression of PTEN, inhibited the phosphorylation of PDK1, Akt, mTOR, p7056K, and increased the phosphorylation of GSK-3 beta and Bad, suggesting that the inhibition of PI3K/Akt/mTOR pathway might be involved in the antitumor activities of M4IDP. Significance: Our study indicates the antitumor properties of M4IDP and its potential clinical use in CRC therapy by blocking PI3K/Akt/mTOR pathway. This study also provides a better understanding of the antitumor effects and the underlying mechanisms of bisphosphonates in the field of CRC therapy.	[Peng, Ying; Qiu, Ling; Xu, Dong; Zhang, Li; Yu, Huixin; Ding, Yuedi; Deng, Lili; Lin, Jianguo] Jiangsu Inst Nucl Med, Jiangsu Key Lab Mol Nucl Med, Minist Hlth, Key Lab Nucl Med, Wuxi 214063, Jiangsu, Peoples R China		Lin, JG (corresponding author), Jiangsu Inst Nucl Med, Jiangsu Key Lab Mol Nucl Med, Minist Hlth, Key Lab Nucl Med, Wuxi 214063, Jiangsu, Peoples R China.	linjianguo@jsinm.org			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21371082, 21501074, 81402214]; Natural Science Foundation of Jiangsu ProvinceNatural Science Foundation of Jiangsu Province [BK20141102, BK20151118]; 333 Project of Jiangsu ProvinceNatural Science Foundation of Jiangsu Province [BRA2016518]; Key Youth Medical Talent Project of Jiangsu Province [QNRC20162016626, QNRC20162016629]	This work was supported by the National Natural Science Foundation of China [21371082, 21501074 and 81402214]; the Natural Science Foundation of Jiangsu Province [BK20141102 and BK20151118]; the 333 Project of Jiangsu Province [BRA2016518], and the Key Youth Medical Talent Project of Jiangsu Province [QNRC20162016626 and QNRC20162016629].	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SEP 15	2017	185						63	72		10.1016/j.lfs.2017.07.024			10	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	FF2BB	WOS:000408701800009	28751160				2022-04-25	
J	Zhong, XL; Chen, O; Zhou, TJ; Lu, MH; Wan, JY				Zhong, Xiaolin; Chen, Ou; Zhou, TieJun; Lu, Muhan; Wan, Juyi			Cytotoxin-Associated Gene A-Positive Helicobacter pylori Promotes Autophagy in Colon Cancer Cells by Inhibiting miR-125b-5p	CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY			English	Article							INFECTION; STATISTICS; EXPRESSION; DISEASE	Objectives. To investigate the effects of cytotoxin-associated gene A- (CagA-) positive Helicobacter pylori on proliferation, invasion, autophagy, and expression of miR-125b-5p in colon cancer cells. Methods. Colon cancer cells were cocultured with H. pylori (CagA+) to analyze the effects of H. pylori on miR-125b-5p and autophagy. Colon cancer cells infected with H. pylori (CagA+) were mimicked by transfection of CagA plasmid. The effects of CagA on the proliferation, invasion, and autophagy of colon cancer cells were analyzed. Cell counting kit-8 (CCK-8), clone formation, and Transwell assays were used to detect cell viability, proliferation, and invasion ability, respectively. Proteins and miRNAs were detected by western blotting and qPCR, respectively. Results. H. pylori (CagA+) inhibited expression of miR-125b-5p and promoted autophagy in colon cancer cells. MiR-125 b-5p was underexpressed in colon cancer cells after CagA overexpression. CagA promoted colon cancer cell proliferation, invasion, and autophagy. Overexpression of miR-125b-5p inhibited the proliferation, invasion, and autophagy of colon cancer cells and reversed the effects of CagA. Conclusion. H. pylori (CagA+) infection may promote the development and invasion of colon cancer by inhibiting miR-125b-5p.	[Zhong, Xiaolin; Lu, Muhan] Southwest Med Univ, Dept Gastroenterol, Affiliated Hosp, Luzhou 646000, Peoples R China; [Zhong, Xiaolin; Lu, Muhan] Nucl Med & Mol Imaging Key Lab Sichuan Prov, Luzhou 646000, Peoples R China; [Chen, Ou] Yaan Peoples Hosp, Dept Gastroenterol, Yaan 625000, Peoples R China; [Zhou, TieJun] Southwest Med Univ, Dept Pathol, Affiliated Hosp, Luzhou 646000, Peoples R China; [Wan, Juyi] Southwest Med Univ, Dept Cardiovasc Surg, Affiliated Hosp, Luzhou 646000, Peoples R China; [Wan, Juyi] Cardiovasc & Metab Dis Key Lab Luzhou, Luzhou 646000, Peoples R China; [Wan, Juyi] Southwest Med Univ, Collaborat Innovat Ctr Prevent Cardiovasc Dis, Key Lab Med Electrophysiol, Inst Cardiovasc Res,Minist Educ, Luzhou 646000, Peoples R China; [Wan, Juyi] Southwest Med Univ, Collaborat Innovat Ctr Prevent Cardiovasc Dis, Med Electrophysiol Key Lab Sichuan Prov, Inst Cardiovasc Res, Luzhou 646000, Peoples R China		Wan, JY (corresponding author), Southwest Med Univ, Dept Cardiovasc Surg, Affiliated Hosp, Luzhou 646000, Peoples R China.; Wan, JY (corresponding author), Cardiovasc & Metab Dis Key Lab Luzhou, Luzhou 646000, Peoples R China.; Wan, JY (corresponding author), Southwest Med Univ, Collaborat Innovat Ctr Prevent Cardiovasc Dis, Key Lab Med Electrophysiol, Inst Cardiovasc Res,Minist Educ, Luzhou 646000, Peoples R China.; Wan, JY (corresponding author), Southwest Med Univ, Collaborat Innovat Ctr Prevent Cardiovasc Dis, Med Electrophysiol Key Lab Sichuan Prov, Inst Cardiovasc Res, Luzhou 646000, Peoples R China.	wanjuyi@yeah.net			Sichuan Province Science and Technology Projects [2020YJ0190, 2021YFH0148]; Science and Technology Strategic Cooperation Programs of Luzhou Municipal People's Government; Southwest Medical University [2019LZXNYDJ27, 2019LZXNYDJ30]; Sichuan Science and Technology Grant for Overseas Students [19059]; Medical Research Project of Sichuan Province [Q16081]	This study was supported in part by the following funding sources: Sichuan Province Science and Technology Projects (2020YJ0190 and 2021YFH0148), Science and Technology Strategic Cooperation Programs of Luzhou Municipal People's Government and Southwest Medical University (2019LZXNYDJ27 and 2019LZXNYDJ30), Sichuan Science and Technology Grant for Overseas Students (19059), and Medical Research Project of Sichuan Province (Q16081).	Amieva M, 2016, GASTROENTEROLOGY, V150, P64, DOI 10.1053/j.gastro.2015.09.004; Cao WT, 2018, BIOMED PHARMACOTHER, V99, P791, DOI 10.1016/j.biopha.2018.01.119; Carroll RG, 2013, CANCER CELL, V23, P425, DOI 10.1016/j.ccr.2013.04.001; Chen SY, 2014, INT J ONCOL, V45, P764, DOI 10.3892/ijo.2014.2444; Chen WQ, 2012, CHINESE J CANCER RES, V24, P1, DOI 10.1007/s11670-012-0001-6; Chen WQ, 2015, CHINESE J CANCER RES, V27, P1, DOI 10.3978/j.issn.1000-9604.2015.02.07; Espinoza JL, 2018, CANCER LETT, V414, P147, DOI 10.1016/j.canlet.2017.11.009; Horridge DN, 2017, PATHOG DIS, V75, DOI 10.1093/femspd/ftx113; Hu Y, 2017, FRONT CELL INFECT MI, V7, DOI 10.3389/fcimb.2017.00168; Huang MH, 2020, HEPATOLOGY, V71, P76, DOI 10.1002/hep.30820; Ibrahim M, 2014, EUR J CONTRACEP REPR, V19, P78, DOI 10.3109/13625187.2013.873399; Krzysiek-Maczka G, 2018, HELICOBACTER, V23, DOI 10.1111/hel.12538; Kuo SH, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-14102-8; Li M, 2019, ONCOL LETT, V18, P145, DOI 10.3892/ol.2019.10304; Li NS, 2018, J EXP CLIN CANC RES, V37, DOI 10.1186/s13046-018-0962-5; Li R, 2019, HORM CANCER-US, V10, P150, DOI 10.1007/s12672-019-00366-1; Li YZ, 2018, BIOCHEM BIOPH RES CO, V504, P277, DOI 10.1016/j.bbrc.2018.08.172; Mei LL, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0185636; Mellis D, 2018, BIOCHEM SOC T, V46, P11, DOI 10.1042/BST20170037; NOMURA A, 1991, NEW ENGL J MED, V325, P1132, DOI 10.1056/NEJM199110173251604; Pan ZJ, 1997, J CLIN MICROBIOL, V35, P1344, DOI 10.1128/JCM.35.6.1344-1347.1997; Park JY, 2018, TOXINS, V10, DOI 10.3390/toxins10040163; Qu M, 2017, EUR REV MED PHARMACO, V21, P3384; Ritchie W, 2017, METHODS MOL BIOL, V1513, P193, DOI 10.1007/978-1-4939-6539-7_13; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Teimoorian Fatemeh, 2018, Iran J Pathol, V13, P325; Weinberg BA, 2017, ONCOLOGY-NY, V31, P381; Xiao CC, 2018, CIRC RES, V123, P564, DOI 10.1161/CIRCRESAHA.118.312758; Xie GC, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0168822; Xu J, 2019, EXP THER MED, V18, P1458, DOI 10.3892/etm.2019.7689; Xu LM, 2016, TUMOR BIOL, V37, P8721, DOI 10.1007/s13277-015-4737-8; Yang D, 2017, SCI REP-UK, V7, DOI 10.1038/srep43109; You YN, 2015, SURG ONCOL, V24, P61, DOI 10.1016/j.suronc.2015.02.001; Zhong XL, 2020, CELL MOL GASTROENTER, V10, P341, DOI 10.1016/j.jcmgh.2020.04.005; Zumkeller N, 2006, HELICOBACTER, V11, P75, DOI 10.1111/j.1523-5378.2006.00381.x	35	2	2	1	1	HINDAWI LTD	LONDON	ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND	1712-9532	1918-1493		CAN J INFECT DIS MED	Can. J. Infect. Dis. Med. Microbiol.	MAR 2	2021	2021								6622092	10.1155/2021/6622092			9	Infectious Diseases; Microbiology	Science Citation Index Expanded (SCI-EXPANDED)	Infectious Diseases; Microbiology	RH5MU	WOS:000636263400001	33791049	Green Published, gold			2022-04-25	
J	Zhou, WG; Zhang, SJ; Li, HB; Cai, ZY; Tang, ST; Chen, LX; Lang, JY; Chen, Z; Chen, XL				Zhou, Weige; Zhang, Shijing; Li, Hui-biao; Cai, Zheyou; Tang, Shuting; Chen, Li-xia; Lang, Jian-ying; Chen, Zheng; Chen, Xin-lin			Development of Prognostic Indicator Based on Autophagy-Related lncRNA Analysis in Colon Adenocarcinoma	BIOMED RESEARCH INTERNATIONAL			English	Article							COLORECTAL-CANCER; INACTIVATION; INSIGHTS	There were no systematic researches about autophagy-related long noncoding RNA (lncRNA) signatures to predict the survival of patients with colon adenocarcinoma. It was necessary to set up corresponding autophagy-related lncRNA signatures. The expression profiles of lncRNAs which contained 480 colon adenocarcinoma samples were obtained from The Cancer Genome Atlas (TCGA) database. The coexpression network of lncRNAs and autophagy-related genes was utilized to select autophagy-related lncRNAs. The lncRNAs were further screened using univariate Cox regression. In addition, Lasso regression and multivariate Cox regression were used to develop an autophagy-related lncRNA signature. A risk score based on the signature was established, and Cox regression was used to test whether it was an independent prognostic factor. The functional enrichment of autophagy-related lncRNAs was visualized using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Ten prognostic autophagy-related lncRNAs (AC027307.2, AC068580.3, AL138756.1, CD27-AS1, EIF3J-DT, LINC01011, LINC01063, LINC02381, AC073896.3, and SNHG16) were identified to be significantly different, which made up an autophagy-related lncRNA signature. The signature divided patients with colon adenocarcinoma into the low-risk group and the high-risk group. A risk score based on the signature was a significantly independent factor for the patients with colon adenocarcinoma (HR=1.088,95%CI=1.057-1.120;P<0.001). Additionally, the ten lncRNAs were significantly enriched in autophagy process, metabolism, and tumor classical pathways. In conclusion, the ten autophagy-related lncRNAs and their signature might be molecular biomarkers and therapeutic targets for the patients with colon adenocarcinoma.	[Zhou, Weige; Zhang, Shijing; Cai, Zheyou; Chen, Li-xia; Lang, Jian-ying; Chen, Xin-lin] Guangzhou Univ Chinese Med, Sch Basic Med Sci, Guangzhou, Peoples R China; [Li, Hui-biao] Guangzhou Univ Chinese Med, Affiliated Hosp 1, Guangzhou, Peoples R China; [Tang, Shuting] Guangzhou Univ Chinese Med, Clin Coll 1, Guangzhou, Peoples R China; [Chen, Zheng] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Stomatol, Guangzhou, Peoples R China		Chen, XL (corresponding author), Guangzhou Univ Chinese Med, Sch Basic Med Sci, Guangzhou, Peoples R China.; Chen, Z (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 3, Dept Stomatol, Guangzhou, Peoples R China.	1364569514@qq.com; 386558374@qq.com; gzzyydx2011@163.com; 838782814@qq.com; 1772338334@qq.com; gzclx@gzucm.edu.cn; langjy@gzucm.edu.cn; chenzh68@mail.sysu.edu.cn; chenxlsums@126.com	Chen, Xin-lin/AAZ-7287-2021	Chen, Xin-lin/0000-0002-2650-8051; chen, zheng/0000-0002-3505-0396	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81774451]; Natural Science Foundation of Guangdong ProvinceNational Natural Science Foundation of Guangdong Province [2017A030313827]; Science Program for Overseas Scholar (Xinhuo plan) of Guangzhou University of Chinese Medicine [XH20190102]	This study was funded by the National Natural Science Foundation of China (81774451), the Natural Science Foundation of Guangdong Province (2017A030313827), and Science Program for Overseas Scholar (Xinhuo plan) of Guangzhou University of Chinese Medicine (XH20190102).	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Int.	SEP 3	2020	2020								9807918	10.1155/2020/9807918			14	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	NS2CM	WOS:000572072700002	32964050	Green Published, gold			2022-04-25	
J	Petroni, G; Bagni, G; Iorio, J; Duranti, C; Lottini, T; Stefanini, M; Kragol, G; Becchetti, A; Arcangeli, A				Petroni, Giulia; Bagni, Giacomo; Iorio, Jessica; Duranti, Claudia; Lottini, Tiziano; Stefanini, Matteo; Kragol, Goran; Becchetti, Andrea; Arcangeli, Annarosa			Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K	CELL DEATH & DISEASE			English	Article							COLON-CANCER; CELL-DEATH; MACROLIDE ANTIBIOTICS; INDUCE APOPTOSIS; BECLIN 1; 5-FLUOROURACIL; RESISTANCE; EXPRESSION; CHLOROQUINE; BORTEZOMIB	We have studied how the macrolide antibiotic Clarithromycin (Cla) regulates autophagy, which sustains cell survival and resistance to chemotherapy in cancer. We found Cla to inhibit the growth of human colorectal cancer (CRC) cells, by modulating the autophagic flux and triggering apoptosis. The accumulation of cytosolic autophagosomes accompanied by the modulation of autophagic markers LC3-II and p62/SQSTM1, points to autophagy exhaustion. Because Cla is known to bind human Ether-a-go-go Related Gene 1 (hERG1) K+ channels, we studied if its effects depended on hERG1 and its conformational states. By availing of hERG1 mutants with different gating properties, we found that fluorescently labelled Cla preferentially bound to the closed channels. Furthermore, by sequestering the channel in the closed conformation, Cla inhibited the formation of a macromolecular complex between hERG1 and the p85 subunit of PI3K. This strongly reduced Akt phosphorylation, and stimulated the p53-dependent cell apoptosis, as witnessed by late caspase activation. Finally, Cla enhanced the cytotoxic effect of 5-fluorouracil (5-FU), the main chemotherapeutic agent in CRC, in vitro and in a xenograft CRC model. We conclude that Cla affects the autophagic flux by impairing the signaling pathway linking hERG1 and PI3K. Combining Cla with 5-FU might be a novel therapeutic option in CRC.	[Petroni, Giulia; Bagni, Giacomo; Iorio, Jessica; Duranti, Claudia; Lottini, Tiziano; Stefanini, Matteo; Arcangeli, Annarosa] Univ Firenze, Dept Expt & Clin Med, Viale GB Morgagni 50, I-50134 Florence, Italy; [Kragol, Goran] Fidelta Ltd, Prilaz Baruna Filipovica 29, Zagreb 10000, Croatia; [Becchetti, Andrea] Univ Milano Bicocca, Dept Biosci & Biotechnol, Piazza Sci 2, I-20126 Milan, Italy		Arcangeli, A (corresponding author), Univ Firenze, Dept Expt & Clin Med, Viale GB Morgagni 50, I-50134 Florence, Italy.	annarosa.arcangeli@unifi.it	Kragol, Goran/AGJ-3512-2022; Petroni, Giulia/AAR-7219-2020	Petroni, Giulia/0000-0002-0558-5322	Associazione Italiana per la Ricerca sul CancroFondazione AIRC per la ricerca sul cancro [15627, 21510]; PAR FAS-Linea di Azione 1.1-Azione 1.1.2-Bando FAS Salute 2014 Project OMITERC [DD 4042/2014]; FAR 2018	We thank M. Lulli (University of Florence, Italy) for acquiring images of immunofluorescence-labeled cells. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (#15627 and #21510 to A.A.); PAR FAS-Linea di Azione 1.1-Azione 1.1.2-Bando FAS Salute 2014 (DD 4042/2014) Project OMITERC to A.A.; FAR 2018 to A.B.	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MAR 2	2020	11	3							161	10.1038/s41419-020-2349-8			18	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	KW1NS	WOS:000520938800007	32123164	Green Published, gold			2022-04-25	
J	Wei, JS; Ge, XX; Tang, Y; Qian, YC; Lu, W; Jiang, K; Fang, YM; Hwang, M; Fu, DL; Xiao, Q; Ding, KF				Wei, Jingsun; Ge, Xiaoxu; Tang, Yang; Qian, Yucheng; Lu, Wei; Jiang, Kai; Fang, Yimin; Hwang, Maxwell; Fu, Dongliang; Xiao, Qian; Ding, Kefeng			An Autophagy-Related Long Noncoding RNA Signature Contributes to Poor Prognosis in Colorectal Cancer	JOURNAL OF ONCOLOGY			English	Article							CELL APOPTOSIS; STATISTICS; INHIBITION; EXPRESSION; PATHWAY; DEATH	Purpose. Colorectal cancer is one of the most common malignant primary tumors, prone to metastasis, and associated with a poor prognosis. As autophagy is closely related to the development and treatment of colorectal cancer, we investigated the potential prognostic value of long noncoding RNA (lncRNA) associated with autophagy in colorectal cancer. Methods. In this study, we acquired information on the expression of lncRNAs in colorectal cancer from the Cancer Genome Atlas (TCGA) database and found that 860 lncRNAs were associated with autophagy-related genes. Subsequently, univariate Cox regression analysis was used to investigate 32 autophagy-related lncRNAs linked to colon cancer prognosis. Subsequently, eight of the 32 autophagy-related lncRNAs (i.e., long intergenic nonprotein coding RNA 1503 [LINC01503], ZEB1 antisense RNA 1 [ZEB1-AS1], AC087481.3, AC008760.1, AC073896.3, AL138756.1, AL022323.1, and TNFRSF10A-AS1) were selected through multivariate Cox regression analysis. Based on these autophagy-related lncRNAs, a risk signature was constructed, and the patients were divided into highand low-risk groups. Results. The high-risk group's overall survival time was significantly shorter than that of the low-risk group (p < 0.0001). Receiver operating characteristic curve analysis was performed to further confirm the validity of the model (area under the curve: 0.689). Moreover, multivariate regression suggested that the risk score was a significant prognostic risk factor in colorectal cancer. Gene set enrichment analysis showed that these gene sets are significantly enriched in cancer-related pathways, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling. Conclusion. (e risk signature of eight autophagy-related lncRNAs has prognostic potential for colorectal cancer. These autophagy-related lncRNAs may play a vital role in the biology of colorectal cancer.	[Wei, Jingsun; Ge, Xiaoxu; Tang, Yang; Qian, Yucheng; Lu, Wei; Jiang, Kai; Fang, Yimin; Hwang, Maxwell; Fu, Dongliang; Xiao, Qian; Ding, Kefeng] Zhejiang Univ Sch Med, Affiliated Hosp 2, Dept Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent,Minist Educ, Hangzhou, Zhejiang, Peoples R China		Ding, KF (corresponding author), Zhejiang Univ Sch Med, Affiliated Hosp 2, Dept Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent,Minist Educ, Hangzhou, Zhejiang, Peoples R China.	dingkefeng@zju.edu.cn		Wei, jingsun/0000-0002-4425-0533	National Key R&D Program of China [2017YFC0908200]; Key Technology Research and Development Program of Zhejiang Province [2017C03017]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81772545]	This study was funded by the National Key R&D Program of China (2017YFC0908200) the Key Technology Research and Development Program of Zhejiang Province (no. 2017C03017) and the National Natural Science Foundation of China (grant no. 81772545).	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Oncol.	OCT 23	2020	2020								4728947	10.1155/2020/4728947			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	OT6JR	WOS:000590950900001	33149738	Green Published, gold			2022-04-25	
J	Biggers, JW; Nguyen, T; Di, X; Gupton, JT; Henderson, SC; Emery, SM; Alotaibi, M; White, KL; Brown, R; Almenara, J; Gewirtz, DA				Biggers, Jonathan W.; Tuyen Nguyen; Di, Xu; Gupton, John T.; Henderson, Scott C.; Emery, Sean M.; Alotaibi, Moureq; White, Kimber L., Jr.; Brown, Ronetta; Almenara, Jorge; Gewirtz, David A.			Autophagy, cell death and sustained senescence arrest in B16/F10 melanoma cells and HCT-116 colon carcinoma cells in response to the novel microtubule poison, JG-03-14	CANCER CHEMOTHERAPY AND PHARMACOLOGY			English	Article						Melanoma; Colon cancer; Microtubule poison; Autophagy; Senescence	BREAST-TUMOR CELLS; CANCER-CELLS; ACCELERATED SENESCENCE; APOPTOSIS; INHIBITION; RADIATION; THERAPY; AGENT; CHEMOTHERAPY; DEGRADATION	Previous studies have shown that the novel microtubule poison, JG-03-14, which binds to the colchicine binding site of tubulin, has the capacity to kill breast tumor cells primarily through the promotion of autophagy. The current work was designed to determine whether autophagy was, in fact, the primary mode of action as well as susceptibility to JG-03-14 in two additional tumor cell models, the B16/F10 murine melanoma cell line and the HCT-116 human colon cancer cell line. Drug cytotoxicity was monitored based on viable cell number and clonogenic survival. Apoptosis was assessed by DAPI staining, the TUNEL assay and/or FACS analysis. Autophagy was monitored based on staining with acridine orange, redistribution and punctuation of RFP-LC3 and electron microscopy as well as p62 degradation. Senescence was evaluated based on beta-galactosidase staining and alterations in cell morphology. Drug effects were also evaluated in a murine model of B16/F10 cells that localizes to the lungs while peripheral neuropathy was assessed by three complementary behavioral assays. Both HCT-116 colon cancer cells and B16/F10 melanoma cells were sensitive to JG-03-14 in that the drug demonstrated tumor cell killing. However, there was minimal induction of apoptosis. In contrast, there was clear evidence for autophagy and autophagic flux while the residual surviving cells appeared to be in a state of irreversible senescence. Inhibition of drug-induced autophagy in either the melanoma cells or the colon carcinoma cells was only slightly protective as the cells instead died by apoptosis. JG-03-14 reduced the size of tumor nodules in mice lungs; furthermore, the drug did not promote peripheral neuropathy. Taken together with evidence for its actions as a vascular disrupting agent, these observations support the potential utility of JG-03-14 to effectively treat malignancies that might be resistant to conventional chemotherapy through evasion of apoptosis.	[Biggers, Jonathan W.; Tuyen Nguyen; Di, Xu; Emery, Sean M.; Alotaibi, Moureq; White, Kimber L., Jr.; Brown, Ronetta; Gewirtz, David A.] Virginia Commonwealth Univ, Dept Pharmacol & Pharmacol, Massey Canc Ctr, Richmond, VA 23298 USA; [Gupton, John T.] Univ Richmond, Dept Chem, Richmond, VA 23173 USA; [Henderson, Scott C.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA 23173 USA; [Almenara, Jorge] Virginia Commonwealth Univ, Dept Anat Pathol, Richmond, VA 23173 USA		Gewirtz, DA (corresponding author), Virginia Commonwealth Univ, Dept Pharmacol & Pharmacol, Massey Canc Ctr, POB 980035, Richmond, VA 23298 USA.	gewirtz@vcu.edu	Henderson, Scott/AAP-2785-2021	Henderson, Scott/0000-0002-1076-3867	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [2R15 CA067236-04, RO1 CA135043-01A1, P30CA16059]; NIH-NINDS Center core grant [P30NS047463]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA135043, R15CA067236, P30CA016059] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [P30NS047463] Funding Source: NIH RePORTER	This work was supported, in part, by NIH Grant # 2R15 CA067236-04 to Dr. John Gupton and NIH Grant # RO1 CA135043-01A1 to Dr. David Gewirtz. Electron microscopy was performed at the VCU-Department of Neurobiology and Anatomy Microscopy Facility, supported, in part, with funding from NIH-NINDS Center core grant P30NS047463. We acknowledge the support of the Flow cytometry shared resource facility supported in part by NIH Grant P30CA16059. We are grateful to the Anatomic Pathology Research Services for the histology work. The RFP-LC3 vector was generously provided by Dr. Keith Miskimins at the University of South Dakota and was originally developed by the laboratory of Dr. A. M. Tolkovsky. We are grateful to Dr. Fiorenza Ianzini at the University of Iowa for guidance with the assessment of mitotic catastrophe.	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Pharmacol.	FEB	2013	71	2					441	455		10.1007/s00280-012-2024-6			15	Oncology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	077RC	WOS:000314044200019	23178952				2022-04-25	
J	Wang, HF; Cheng, X; Zhang, L; Xu, SC; Zhang, QX; Lu, RR				Wang, Huifang; Cheng, Xian; Zhang, Li; Xu, Shichen; Zhang, Qiuxiang; Lu, Rongrong			A surface-layer protein from Lactobacillus acidophilus NCFM induces autophagic death in HCT116 cells requiring ROS-mediated modulation of mTOR and JNK signaling pathways	FOOD & FUNCTION			English	Article							CANCER-CELLS; COLON-CANCER; PROBIOTICS; INDUCTION; PROLIFERATION; PI3K/AKT/MTOR; INHIBITION; BACTERIA; ADHESION; STRAINS	A surface-layer protein (Slp) derived from Lactobacillus acidophilus NCFM has been reported to possess multiple biological properties, including anti-inflammatory, inhibition of apoptosis in pathogen-invaded HT-29 cells and oxidative stress relief. However, its anti-tumor ability and underlying molecular mechanism are unknown. Here, we report that Slp suppresses cell proliferation and induces autophagic cell death in HCT116 cells. Accumulation of Beclin-1 and microtubule-associated protein 1 light chain 3 from II (LC3-II), and the degradation of p62 were observed when cells were treated with various concentrations of Slp (25, 50, 100 mu g mL(-1)) for 24 h. We also found that the mammalian targets of rapamycin (mTOR) and c-Jun N-terminal kinase (JNK) signaling pathways were crucial mediators regulating Slp-induced autophagic cell death. Additionally, treatment with Slp resulted in the obvious formation of reactive oxygen species (ROS). SP600125, a JNK inhibitor, and N-acetylcysteine (NAC), a ROS inhibitor, attenuated Slp-induced autophagic cell death in HCT116 cells. Furthermore, NAC was found to prevent Slp-induced p70 and JNK phosphorylation. Taken together, our results suggest a novel mechanism of action of Slp induced autophagy, acting simultaneously through the ROS-mediated mTOR and JNK signaling pathways in HCT116 colon cancer cells.	[Wang, Huifang; Zhang, Qiuxiang; Lu, Rongrong] Jiangnan Univ, Sch Food Sci & Technol, 1800 Lihu Ave, Wuxi 214122, Jiangsu, Peoples R China; [Cheng, Xian; Zhang, Li; Xu, Shichen] Minist Hlth, Key Lab Nucl Med, Jiangsu Inst Nucl Med, 20 Qian Rong, Wuxi 214063, Jiangsu, Peoples R China		Lu, RR (corresponding author), Jiangnan Univ, Sch Food Sci & Technol, 1800 Lihu Ave, Wuxi 214122, Jiangsu, Peoples R China.	lurr@jiangnan.edu.cn		Lu, Rongrong/0000-0001-8671-9144	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31471696]	This research was supported by the National Natural Science Foundation of China (No. 31471696). We would like to appreciate Mr Qingzhu Liu (Jiangsu Institute of Nuclear Medicine) for providing the HCT116 cells, and Miss Jie Pan and Miss Jiangxia Zheng for their enthusiastic support in this work.	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JUL 1	2019	10	7					4102	4112		10.1039/c9fo00109c			11	Biochemistry & Molecular Biology; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Food Science & Technology	IK6GK	WOS:000476683600024	31233063				2022-04-25	
J	Lucas, C; Salesse, L; Hoang, MHT; Bonnet, M; Sauvanet, P; Larabi, A; Godfraind, C; Gagniere, J; Pezet, D; Rosenstiel, P; Barnich, N; Bonnet, R; Dalmasso, G; Nguyen, HTT				Lucas, Cecily; Salesse, Laurene; My Hanh Thi Hoang; Bonnet, Mathilde; Sauvanet, Pierre; Larabi, Anais; Godfraind, Catherine; Gagniere, Johan; Pezet, Denis; Rosenstiel, Philip; Barnich, Nicolas; Bonnet, Richard; Dalmasso, Guillaume; Hang Thi Thu Nguyen			Autophagy of Intestinal Epithelial Cells Inhibits Colorectal Carcinogenesis Induced by Colibactin-Producing Escherichia coil in Apc(Min/+) Mice	GASTROENTEROLOGY			English	Article						Microbiome; Pathogenic Bacteria; Toxin; Colon Cancer	TUMOR-GROWTH; HUMAN GUT; E. COLI; CANCER; TUMORIGENESIS; COLONIZATION; ELIMINATION; INSTABILITY; EXPRESSION; MICROBIOTA	BACKGROUND & AIMS: Colibactin-producing Escherichia coli (CoPEC) colonize the colonic mucosa of a higher proportion of patients with vs without colorectal cancer (CRC) and promote colorectal carcinogenesis in susceptible mouse models of CRC. Autophagy degrades cytoplasmic contents, including intracellular pathogens, via lysosomes and regulates intestinal homeostasis. We investigated whether inhibiting autophagy affects colorectal carcinogenesis in susceptible mice infected with CoPEC. METHODS: Human intestinal epithelial cells (IECs) (HCT-116) were infected with a strain of CoPEC (11G5 strain) isolated from a patient or a mutant strain that does not produce colibactin (11G5 Delta clbQ). Levels of ATG5, ATG16L1, and SQSTM1 (also called p62) were knocked down in HCT-116 cells using small interfering RNAs. Apc(Min/+) mice and Apc(Min/+) mice with IEC-specific disruption of Atg1611 (Apc(Min/+)/Atg16l1(Delta IEG)) were infected with 11G5 or 11G5AclbQ. Colonic tissues were collected from mice and analyzed for tumor size and number and by immunohistochemical staining, immunoblot, and quantitative reverse transcription polymerase chain reaction for markers of autophagy, DNA damage, cell proliferation, and inflammation. We analyzed levels of messenger RNAs (mRNAs) encoding proteins involved in autophagy in colonic mucosal tissues from patients with sporadic CRC colonized with vs without CoPEC by quantitative reversetranscription polymerase chain reaction. RESULTS: Patient colonic mucosa with CoPEC colonization had higher levels of mRNAs encoding proteins involved in autophagy than colonic mucosa without these bacteria. Infection of cultured IECs with 11G5 induced autophagy and DNA damage repair, whereas infection with 11G5 Delta clbQ did not. Knockdown of ATG5 in HCT-116 cells increased numbers of intracellular 11G5, secretion of interleukin (IL) 6 and IL8, and markers of DNA double-strand breaks but reduced markers of DNA repair, indicating that autophagy is required for bacteria-induced DNA damage repair. Knockdown of ATG5 in HCT-116 cells increased 11G5-induced senescence, promoting proliferation of uninfected cells. Under uninfected condition, Apc(Min/+)/Atg16l1(Delta IEG) mice developed fewer and smaller colon tumors than Apc(Min/+) mice. However, after infection with 11G5, Apc(Min/+)/Atg16l1(Delta IEG) mice developed more and larger tumors, with a significant increase in mean histologic score, than infected Apc(Min/+) mice. Increased levels of 116, Tnf, and Cxcl/mRNAs, decreased level of 1110 mRNA, and increased markers of DNA double-strand breaks and proliferation were observed in the colonic mucosa of 11G5-infected Apc(Min/+)/Atg16l1(Delta IEG) A1Ec mice vs 11G5-infected Apc(Min/+) mice. CONCLUSION: Infection of IECs and susceptible mice with CoPEC promotes autophagy, which is required to prevent colorectal tumorigenesis. Loss of ATG16L1 from IECs increases markers of inflammation, DNA damage, and cell proliferation and increases colorectal tumorigenesis in 11G5-infected Apc(Min/+) mice. These findings indicate the importance of autophagy in response to CoPEC infection, and strategies to induce autophagy might be developed for patients with CRC and CoPEC colonization.	[Lucas, Cecily; Salesse, Laurene; My Hanh Thi Hoang; Bonnet, Mathilde; Sauvanet, Pierre; Larabi, Anais; Godfraind, Catherine; Gagniere, Johan; Pezet, Denis; Barnich, Nicolas; Bonnet, Richard; Dalmasso, Guillaume; Hang Thi Thu Nguyen] Univ Clermont Auvergne, INSERM, UMR 1071, M2iSH, 28 Pl Henri Dunant, F-63001 Clermont Ferrand, France; [My Hanh Thi Hoang] Vietnam Natl Univ, Univ Sci, Fac Biol, Dept Cell Biol, Hanoi, Vietnam; [Sauvanet, Pierre; Gagniere, Johan; Pezet, Denis] CHU Clermont Ferrand, Dept Digest & Hepatobiliary Surg, Clermont Ferrand, France; [Godfraind, Catherine] CHU Gabriel Montpied, Dept Pathol, Clermont Ferrand, France; [Rosenstiel, Philip] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany; [Rosenstiel, Philip] Univ Hosp Schleswig Holstein, Kiel, Germany; [Bonnet, Richard] CHU Gabriel Montpied, Dept Bacteriol, Clermont Ferrand, France		Nguyen, HTT (corresponding author), Univ Clermont Auvergne, INSERM, UMR 1071, M2iSH, 28 Pl Henri Dunant, F-63001 Clermont Ferrand, France.	hang.nguyen@uca.fr	Nguyen, Hang/N-2441-2018; Dalmasso, Guillaume/N-2443-2018; Rosenstiel, Philip/A-5137-2009; Bonnet, Mathilde/T-2835-2017	Nguyen, Hang/0000-0001-7431-5126; Dalmasso, Guillaume/0000-0002-3433-870X; Rosenstiel, Philip/0000-0002-9692-8828; Lucas, Cecily/0000-0002-4276-723X; Bonnet, Mathilde/0000-0003-3629-7267	Ministere de la Recherche et de la Technologie; Inserm (Institut national de la sante et de la recherche medicale)Institut National de la Sante et de la Recherche Medicale (Inserm) [UMR1071]; INRAE (Institut national de recherche en agriculture, alimentation et environnement; USC 2018); Agence Nationale de la Recherche of the French government through the program "Investissements d'Avenir"French National Research Agency (ANR) [16-IDEX-0001 CAP 20-25]; European Union FP7 People Marie Curie International Incoming Fellowship; DFG (Deutsche Forschungsgemeinschaft)German Research Foundation (DFG) [CRC1182]	This work was supported by the Ministere de la Recherche et de la Technologie, Inserm (Institut national de la sante et de la recherche medicale; UMR1071), INRAE (Institut national de recherche en agriculture, alimentation et environnement; USC 2018), the Agence Nationale de la Recherche of the French government through the program "Investissements d'Avenir" (16-IDEX-0001 CAP 20-25) (to Hang Thi Thu Nguyen), the European Union FP7 People Marie Curie International Incoming Fellowship (to Hang Thi Thu Nguyen) and the DFG (Deutsche Forschungsgemeinschaft) ExC Precision Medicine in Chronic Inflammation and the CRC1182 project C2 (to Philip Rosenstiel).	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J	Harmse, L; Dahan-Farkas, N; Panayides, JL; van Otterlo, W; Penny, C				Harmse, Leonie; Dahan-Farkas, Nurit; Panayides, Jenny-Lee; van Otterlo, Willem; Penny, Clement			Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues	PLOS ONE			English	Article							CYTOCHROME-C RELEASE; COLON-CANCER; DRUG-RESISTANCE; WILD-TYPE; MITOCHONDRIA; DEATH; P53; BAX; MECHANISMS; BCL-2	Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 mu M, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.	[Harmse, Leonie; Dahan-Farkas, Nurit] Univ Witwatersrand, Div Pharmacol, Dept Pharm & Pharmacol, Fac Hlth Sci, ZA-2193 Parktown, South Africa; [Panayides, Jenny-Lee; van Otterlo, Willem] Univ Witwatersrand, Inst Mol Sci, Sch Chem, Fac Sci, ZA-2050 Johannesburg, South Africa; [van Otterlo, Willem] Univ Stellenbosch, Dept Chem & Polymer Sci, ZA-7602 Matieland, South Africa; [Penny, Clement] Univ Witwatersrand, Dept Internal Med, Fac Hlth Sci, ZA-2193 Parktown, South Africa		Harmse, L (corresponding author), Univ Witwatersrand, Div Pharmacol, Dept Pharm & Pharmacol, Fac Hlth Sci, 7 York Rd, ZA-2193 Parktown, South Africa.	Leonie.Harmse@wits.ac.za			Research Niche Areas Program of the National Research Foundation (NRF) of South Africa; University of the Witwatersrand Faculty of Health Sciences Research Committee; NRF Scarce Skill Program	This work was supported by the Research Niche Areas Program of the National Research Foundation (NRF) of South Africa and the University of the Witwatersrand Faculty of Health Sciences Research Committee. JLP was supported by the NRF Scarce Skill Program for studies towards a Ph.D. The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript.	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J	Conacci-Sorrell, M; Ngouenet, C; Anderson, S; Brabletz, T; Eisenman, RN				Conacci-Sorrell, Maralice; Ngouenet, Celine; Anderson, Sarah; Brabletz, Thomas; Eisenman, Robert N.			Stress-induced cleavage of Myc promotes cancer cell survival	GENES & DEVELOPMENT			English	Article						Myc; Myc-nick; hypoxia; autophagy; motility; fascin	C-MYC; COLORECTAL-CANCER; BETA-CATENIN; INVASION FRONT; CYCLE ARREST; AUTOPHAGY; APOPTOSIS; HYPOXIA; FASCIN; ACETYLATION	Evasion of apoptosis is critical in Myc-induced tumor progression. Here we report that cancer cells evade death under stress by activating calpain-mediated proteolysis of Myc. This generates Myc-nick, a cytoplasmic, transcriptionally inactive cleavage product of Myc. We found conversion of Myc into Myc-nick in cell lines and tissues derived from multiple cancers. In colon cancer, the production of Myc-nick is enhanced under stress conditions such as hypoxia and nutrient deprivation. Under these conditions, ectopic expression of Myc-nick promotes anchorage-independent growth and cell survival at least in part by promoting autophagy. Myc-nick also delays colon cancer cell death after treatment with chemotherapeutic drugs such as etoposide, cisplatin, and imatinib. Furthermore, colon cancer cells expressing a cleavage-resistant form of Myc undergo extensive apoptosis but are rescued by overexpression of Myc-nick. We also found that ectopic expression of Myc-nick results in the induction of the actin-bundling protein fascin, formation of filopodia, and increased cell motility-all mediators of tumor metastasis. Myc-nick-induced survival, autophagy, and motility require Myc box II ( MBII), a region of Myc-nick that recruits acetyltransferases that in turn modify cytoplasmic proteins, including a-tubulin and ATG3. Our results suggest that Myc-nick-induced survival and motility contribute to colon cancer progression and metastasis.	[Conacci-Sorrell, Maralice; Ngouenet, Celine; Anderson, Sarah; Eisenman, Robert N.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA; [Brabletz, Thomas] Univ Freiburg, Ctr Comprehens Canc, Dept Visceral Surg, D-79095 Freiburg, Germany		Eisenman, RN (corresponding author), Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA.	eisenman@fhcrc.org	Sorrell, Maralice/ABD-6764-2021		National Institutes of Health/National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA20525]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R37CA020525, R01CA020525] Funding Source: NIH RePORTER	We are grateful to Nao Ikegaki, William Tansey, John Sedivy, Jonathan Grim, Bruce Clurman, Markus Welker, Lukas Low, Brian Freie, and Denise Galloway for advice, protocols, reagents, and equipment essential for this work. We also thank James Olson for mouse medulloblastoma samples, and Peter Nelson for prostate cancer xenografts. This work was supported by National Institutes of Health/National Cancer Institute grant CA20525 (to R.N.E.).	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APR 1	2014	28	7					689	707		10.1101/gad.231894.113			19	Cell Biology; Developmental Biology; Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Developmental Biology; Genetics & Heredity	AE9UA	WOS:000334354700004	24696454	Green Published, gold, Green Submitted			2022-04-25	
J	Panda, PK; Naik, PP; Praharaj, PP; Meher, BR; Gupta, PK; Verma, RS; Maiti, TK; Shanmugam, MK; Chinnathambi, A; Alharbi, SA; Sethi, G; Agarwal, R; Bhutia, SK				Panda, Prashanta K.; Naik, Prajna P.; Praharaj, Prakash P.; Meher, Biswa R.; Gupta, Piyush K.; Verma, Rama S.; Maiti, Tapas K.; Shanmugam, Muthu K.; Chinnathambi, Arunachalam; Alharbi, Sulaiman A.; Sethi, Gautam; Agarwal, Rajesh; Bhutia, Sujit K.			Abrus agglutinin stimulates BMP-2-dependent differentiation through autophagic degradation of -catenin in colon cancer stem cells	MOLECULAR CARCINOGENESIS			English	Article						beta-catenin; Abrus agglutinin; BMP-2; cancer stem cells; differentiation; hVps34	PROMOTES DIFFERENTIATION; RETINOIC ACID; SELF-RENEWAL; IN-VITRO; APOPTOSIS; KINETICS; SURVIVAL; AGENT; ROS	Eradicating cancer stem cells (CSCs) in colorectal cancer (CRC) through differentiation therapy is a promising approach for cancer treatment. Our retrospective tumor-specimen analysis elucidated alteration in the expression of bone morphogenetic protein 2 (BMP-2) and -catenin during the colon cancer progression, indicating that their possible intervention through forced differentiation in colon cancer remission. We reveal that Abrus agglutinin (AGG) induces the colon CSCs differentiation, and enhances sensitivity to the anticancer therapeutics. The low dose AGG (max. dose=100ng/mL) decreased the expression of stemness-associated molecules such as CD44 and -catenin in the HT-29 cell derived colonospheres. Further, AGG augmented colonosphere differentiation, as demonstrated by the enhanced CK20/CK7 expression ratio and induced alkaline phosphatase activity. Interestingly, the AGG-induced expression of BMP-2 and the AGG-induced differentiation were demonstrated to be critically dependent on BMP-2 in the colonospheres. Similarly, autophagy-induction by AGG was associated with colonosphere differentiation and the gene silencing of BMP-2 led to the reduced accumulation of LC3-II, suggesting that AGG-induced autophagy is dependent on BMP-2. Furthermore, hVps34 binds strongly to BMP-2, indicating a possible association of BMP-2 with the process of autophagy. Moreover, the reduction in the self-renewal capacity of the colonospheres was associated with AGG-augmented autophagic degradation of -catenin through an interaction with the autophagy adaptor protein p62. In the subcutaneous HT-29 xenograft model, AGG profoundly inhibited the growth of tumors through an increase in BMP-2 expression and LC3-II puncta, and a decrease in -catenin expression, confirming the antitumor potential of AGG through induction of differentiation in colorectal cancer.	[Panda, Prashanta K.; Naik, Prajna P.; Praharaj, Prakash P.; Bhutia, Sujit K.] Natl Inst Technol, Dept Life Sci, Rourkela, India; [Meher, Biswa R.] Berhampur Univ, Dept Bot, Berhampur, Orissa, India; [Gupta, Piyush K.; Verma, Rama S.] Indian Inst Technol Madras, Dept Biotechnol, Bhupat & Jyoti Mehta Sch Biosci, Madras, Tamil Nadu, India; [Maiti, Tapas K.] Indian Inst Technol, Dept Biotechnol, Kharagpur, W Bengal, India; [Shanmugam, Muthu K.; Sethi, Gautam] Natl Univ Singapore, Dept Pharmacol, Yong Loo Lin Sch Med, Singapore, Singapore; [Chinnathambi, Arunachalam; Alharbi, Sulaiman A.] King Saud Univ, Dept Bot & Microbiol, Coll Sci, Riyadh, Saudi Arabia; [Sethi, Gautam] Curtin Univ, Sch Biomed Sci, Curtin Hlth Innovat Res Inst, Perth, WA, Australia; [Agarwal, Rajesh] Univ Colorado Denver, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA		Bhutia, SK (corresponding author), Natl Inst Technol, Dept Life Sci, Rourkela, India.; Bhutia, SK (corresponding author), Natl Inst Technol Rourkela, Dept Life Sci, Rourkela 769008, Odisha, India.	sujitb@nitrkl.ac.in	Praharaj, Prakash P./J-5515-2018; Sethi, Gautam/F-2372-2011; Naik, Prajna Paramita/AAV-8237-2020; GUPTA, Dr PIYUSH KUMAR/H-1588-2015	Praharaj, Prakash P./0000-0003-0425-5118; Sethi, Gautam/0000-0002-8677-8475; Naik, Prajna Paramita/0000-0002-6086-3022; GUPTA, Dr PIYUSH KUMAR/0000-0002-3346-910X; Meher, Biswa Ranajn/0000-0003-0519-9074; Chinnathambi, Arunachalam/0000-0001-5075-5901; Bhutia, Sujit Kumar/0000-0003-0962-3354	Department of Biotechnology, Ministry of Science and Technology [BT/PR7791/BRB/10/1187/2013]; Board of Research in Nuclear SciencesDepartment of Atomic Energy (DAE)Board of Research in Nuclear Sciences (BRNS) [37(1)/14/38/2016-BRNS/37276]; International Scientific Partnership Program ISPP at King Saud University [ISPP# 0091]; Science and Engineering Research Board [EMR/2016/001246]; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA195708]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA195708] Funding Source: NIH RePORTER	Department of Biotechnology, Ministry of Science and Technology, Grant number: BT/PR7791/BRB/10/1187/2013; Board of Research in Nuclear Sciences, Grant number: 37(1)/14/38/2016-BRNS/37276; International Scientific Partnership Program ISPP at King Saud University, Grant number: ISPP# 0091; Science and Engineering Research Board, Grant number: EMR/2016/001246; National Cancer Institute, Grant number: CA195708	Alborzinia H, 2013, J CELL SCI, V126, P117, DOI 10.1242/jcs.109777; Bagaria A, 2006, J BIOL CHEM, V281, P34465, DOI 10.1074/jbc.M601777200; Bai ZG, 2010, CELL BIOL INT, V34, P1141, DOI 10.1042/CBI20090481; Bhutia SK, 2016, INT J CANCER, V139, P457, DOI 10.1002/ijc.30055; Dasgupta N, 2015, EXP CELL RES, V334, P323, DOI 10.1016/j.yexcr.2015.03.020; DEGOS L, 1995, BLOOD, V85, P2643, DOI 10.1182/blood.V85.10.2643.bloodjournal85102643; Dow LE, 2015, CELL, V161, P1539, DOI 10.1016/j.cell.2015.05.033; Futter CE, 2001, J CELL BIOL, V155, P1251, DOI 10.1083/jcb.200108152; Groulx JF, 2012, AUTOPHAGY, V8, P893, DOI 10.4161/auto.19738; Guo L, 2017, STEM CELLS INT, V2017, DOI 10.1155/2017/1651325; He XC, 2004, NAT GENET, V36, P1117, DOI 10.1038/ng1430; 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Wang CR, 2016, J CELL BIOL, V212, P545, DOI 10.1083/jcb.201507023; Wang CR, 2013, NAT NEUROSCI, V16, P532, DOI 10.1038/nn.3365; Wang JR, 2008, AUTOPHAGY, V4, P947, DOI 10.4161/auto.6787; Wielenga MCB, 2015, CELL REP, V13, P489, DOI 10.1016/j.celrep.2015.09.016; Zhang WV, 2004, CELL COMMUN ADHES, V11, P89, DOI 10.1080/15419060490951790; Zhang YY, 2014, ONCOL REP, V32, P1013, DOI 10.3892/or.2014.3308; Zhuang WZ, 2012, CANCER SCI, V103, P684, DOI 10.1111/j.1349-7006.2011.02198.x	48	18	18	0	9	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0899-1987	1098-2744		MOL CARCINOGEN	Mol. Carcinog.	MAY	2018	57	5					664	677		10.1002/mc.22791			14	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	GB2MZ	WOS:000428888600009	29457276				2022-04-25	
J	Wang, Z; Zhang, QQ; Zhou, L; Liu, G; Wu, QF; Chen, CW				Wang, Zhang; Zhang, Qinqin; Zhou, Ling; Liu, Gao; Wu, Quanfeng; Chen, Changwang			Norwogonin flavone suppresses the growth of human colon cancer cells via mitochondrial mediated apoptosis, autophagy induction and triggering G2/M phase cell cycle arrest	JOURNAL OF BUON			English	Article						Colorectal cancer; apoptosis; autophagy; cell cycle arrest; flow cytometry	CARCINOMA; PATHWAYS; CHEMOTHERAPY; TOXICITY	Purpose: Colorectal cancer is one of the deadly malignancies and is one of the top three most common cancers and the third leading cause of cancer-related deaths. The main objective of the study was to investigate the anticancer effects of norwogonin - a naturally occurring plant flavone. We also examined its effects on programmed cell death, autophagy and cell cycle phase distribution. Methods: Cell viability of colon cancer cells was evaluated by MTT assay while apoptotic studies were carried out by fluorescence microscopy using acridine orange (AO)/ethidium bromide (EB) and Comet assays. Transmission electron microscopy (TEM) was used to study formation of autophagosomes reminiscent of autophagy. Furthermore, western blot assay was used to study the effects of norwogonin on apoptosis-related protein expressions including Bax, Bcl-2 and autophagy-related proteins. Effects on cell cycle were evaluated by flow cytometry. Results: The results showed that norwogonin causes substantial reduction in the viability of the human colorectal carcinoma cells in a dose-dependent manner, exhibiting an IC50 of 15.5 mu M in cancer cells and IC50 of 90 mu M in normal cell lines. The AO/EB staining assay showed that norwogonin suppresses the viability of cancer cells via induction of apoptotic cell death which was associated with increase in Bax and decrease in Bcl-2 levels. Comet assay results also confirmed that norwogonin induces apoptosis. Norwogonin also led to induction of autophagy along with triggering G2/M phase cell cycle arrest. Conclusions: In conclusion, the current study shows that norwogonin has a potential to inhibit in vitro colorectal cancer cells growth by triggering apoptosis, autophagy and cell cycle arrest and as such could be developed as a possible anticancer agent.	[Wang, Zhang; Liu, Gao; Wu, Quanfeng; Chen, Changwang] Cent Hosp Enshi Tujia & Miao Autonomous Prefectur, Dept Gastrointestinal Surg, Enshi 445000, Hubei, Peoples R China; [Zhang, Qinqin] Hualong Hosp Enshi Tujia & Miao Autonomous Prefec, Dept Digest Med, Enshi 445000, Hubei, Peoples R China; [Zhou, Ling] Cent Hosp Enshi Tujia & Miao Autonomous Prefectur, Dept Dermatol, 158 WuYang St, Enshi 445000, Hubei, Peoples R China		Chen, CW (corresponding author), Cent Hosp Enshi Tujia & Miao Autonomous Prefectur, Dept Dermatol, 158 WuYang St, Enshi 445000, Hubei, Peoples R China.	LauriSchmittwzc@yahoo.com					Abd El-Hafeez AA, 2019, PHARMACOL REP, V71, P289, DOI 10.1016/j.pharep.2019.01.001; Chow LM, 2008, J CELL BIOCHEM, V103, P1394, DOI 10.1002/jcb.21528; Compton CC, 2003, MODERN PATHOL, V16, P376, DOI 10.1097/01.MP.0000062859.46942.93; Dancey J, 1996, BRIT J CANCER, V74, P327, DOI 10.1038/bjc.1996.362; El-Shami K, 2015, CA-CANCER J CLIN, V65, P427, DOI 10.3322/caac.21286; Ghobrial IM, 2005, CA-CANCER J CLIN, V55, P178, DOI 10.3322/canjclin.55.3.178; Haggar Fatima A, 2009, Clin Colon Rectal Surg, V22, P191, DOI 10.1055/s-0029-1242458; Lakshmi S, 2008, MED CHEM RES, V17, P335, DOI 10.1007/s00044-007-9069-9; Lavrik IN, 2005, J CLIN INVEST, V115, P2665, DOI 10.1172/JCI26252; Lee KW, 2011, NAT REV CANCER, V11, P211, DOI 10.1038/nrc3017; MOSMANN T, 1983, J IMMUNOL METHODS, V65, P55, DOI 10.1016/0022-1759(83)90303-4; Ouyang L, 2012, CELL PROLIFERAT, V45, P487, DOI 10.1111/j.1365-2184.2012.00845.x; Ping Kwan Yuet, 2013, Asian Pacific Journal of Tropical Biomedicine, V3, P692, DOI 10.1016/S2221-1691(13)60140-9; Schuell B, 2005, BRIT J CANCER, V93, P744, DOI 10.1038/sj.bjc.6602783; Sillars-Hardebol AH, 2010, TUMOR BIOL, V31, P89, DOI 10.1007/s13277-009-0012-1; Valachis A, 2012, J CLIN ONCOL, V30, P1316, DOI 10.1200/JCO.2011.38.6078; Wiela-Hojenska A, 2015, ADV CLIN EXP MED, V24, P103, DOI 10.17219/acem/38154	17	1	1	1	3	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	MAY-JUN	2020	25	3					1449	1454					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	NE1UI	WOS:000562382600024	32862589				2022-04-25	
J	Chang, CH; Lee, CY; Lu, CC; Tsai, FJ; Hsu, YM; Tsao, JW; Juan, YN; Chiu, HY; Yang, JS; Wang, CC				Chang, Chao-Hsiang; Lee, Chao-Ying; Lu, Chi-Cheng; Tsai, Fuu-Jen; Hsu, Yuan-Man; Tsao, Je-Wei; Juan, Yu-Ning; Chiu, Hong-Yi; Yang, Jai-Sing; Wang, Ching-Chiung			Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						resveratrol; autophagic death; apoptosis; AMP-activated protein kinase; cisplatin-resistant oral cancer cell	HUMAN COLON-CANCER; ENDOPLASMIC-RETICULUM STRESS; MITOCHONDRIAL DYSFUNCTION; MEDIATED APOPTOSIS; TUMOR XENOGRAFTS; IN-VITRO; DEATH; PATHWAYS; KINASE; PROTEINS	Resveratrol is known to be an effective chemopreventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy- and pro-apoptosis-related signals in resveratrol-treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells. Overall, our findings indicate that resveratrol is likely to induce autophagic and apoptotic death in drug-resistant oral cancer cells and might become a new approach for oral cancer treatment in the near future.	[Chang, Chao-Hsiang; Wang, Ching-Chiung] Taipei Med Univ, Sch Pharm, Coll Pharm, Taipei 110, Taiwan; [Lee, Chao-Ying] China Med Univ, Sch Pharm, Taichung 404, Taiwan; [Lu, Chi-Cheng; Tsao, Je-Wei; Juan, Yu-Ning; Yang, Jai-Sing] China Med Univ, Dept Med Res, China Med Univ Hosp, Taichung 404, Taiwan; [Tsai, Fuu-Jen] China Med Univ Hosp, Human Genet Ctr, Taichung 404, Taiwan; [Tsai, Fuu-Jen] China Med Univ, Sch Postbaccalaureate Chinese Med, Taichung 404, Taiwan; [Hsu, Yuan-Man] China Med Univ, Dept Biol Sci & Technol, Taichung 404, Taiwan; [Chiu, Hong-Yi] Buddhist Tzu Chi Gen Hosp, Dept Pharm, Hualien 970, Taiwan		Wang, CC (corresponding author), Taipei Med Univ, Sch Pharm, Coll Pharm, 250 Wu Hsing St, Taipei 11042, Taiwan.; Yang, JS (corresponding author), China Med Univ, Dept Med Res, China Med Univ Hosp, 2 Yuh Der Rd, Taichung 40447, Taiwan.	jaisingyang@gmail.com; crystal@tmu.edu.tw	Hsu, Yuan-Man/K-7074-2015; Lu, Chi-Cheng/N-7770-2013; Yang, Jai Sing/M-1162-2015	Hsu, Yuan-Man/0000-0002-4575-7475; Lu, Chi-Cheng/0000-0003-3149-0914; Yang, Jai Sing/0000-0001-7302-8248	China Medical University Hospital, Taichung, Taiwan [DMR-105-096]	This study was supported by the grant from China Medical University Hospital, Taichung, Taiwan (DMR-105-096).	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J. Oncol.	MAR	2017	50	3					873	882		10.3892/ijo.2017.3866			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EN7MH	WOS:000396186400014	28197628	Bronze			2022-04-25	
J	Yang, C; Deng, SP				Yang, Chun; Deng, Shaoping			High level of Helicobacter pylori infection contributes to the survival of colon cancer via up-regulating autophagy in vitro	INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE			English	Article						Helicobacter pylori; survival; colon cancer; beclin1	INDUCED APOPTOSIS; COLORECTAL-CANCER; EXPRESSION; PROLIFERATION; PATHOGENESIS; INHIBITION; PATHWAY; DISEASE; BECLIN1; RISK	Colon cancer (CRC) is one of the most prevalent gastrointestinal malignancies and the fourth leading cause of cancer death in the world. Helicobacter pylori (H. pylori) infection is prevalent in the population and is associated with kinds of digestive system diseases. In this study, we aimed to investigate the effect of H. pylori infection on the survival of colon cancer in vitro. Firstly, the expression of autophagy related protein-beclin1 was found aberrantly overexpressed in the tissue sample from colon cancer patients compared with the healthy control. Further research showed that cell apoptosis rate in SW480 cells was suppressed by H. pylori infection in a dose dependent manner. Western blot analysis showed that the expression of beclin1 was increased by H. pylori infection in dose dependent manner and the microtubule-associated protein 1 light chain 3 (LC3)-II/I ratio was obviously increased and the level of autophagy specific degradation protein p62 was decreased by H. pylori infection at 100 MOI. Moreover, high level of H. pylori infection promoted cell viability and suppressed cell apoptosis in SW480 cells. The expression of proliferation marker (Ki67) and apoptosis suppressing protein Bcl-2 was both up-regulated and the rate of cleaved-caspase-3/caspase-3 and the level of apoptosis promoting protein Bax was both suppressed in H. pylori infected SW480 cells compared with the control group. Moreover, autophagy inhibitor 3-MA counteracted the effect of H. pylori infection on cell viability. Taken together, we revealed that high level of H. pylori infection contributes to the survival of colon cancer in vitro. In consideration of the aberrant expression of beclin1, we speculated that beclin1 mediated the tumor-promoting activity of H. pylori infection.	[Yang, Chun; Deng, Shaoping] Univ Elect Sci & Technol China, Sch Med, Chengdu, Sichuan, Peoples R China; [Yang, Chun; Deng, Shaoping] Sichuan Acad Med Sci, Dept Gastrointestinal Surg, Chengdu, Sichuan, Peoples R China; [Yang, Chun; Deng, Shaoping] Sichuan Prov Peoples Hosp, Chengdu, Sichuan, Peoples R China		Deng, SP (corresponding author), Univ Elect Sci & Technol China, Sch Med, Chengdu, Sichuan, Peoples R China.; Deng, SP (corresponding author), Sichuan Acad Med Sci, Dept Gastrointestinal Surg, Chengdu, Sichuan, Peoples R China.; Deng, SP (corresponding author), Sichuan Prov Peoples Hosp, Chengdu, Sichuan, Peoples R China.	dengshaopingestu@163.com					[Anonymous], 1994, IARC Monogr Eval Carcinog Risks Hum, V61, P177; Cai MB, 2014, INT J MOL SCI, V15, P5292, DOI 10.3390/ijms15045292; Cao Y, 2007, CELL RES, V17, P839, DOI 10.1038/cr.2007.78; Chiozzi V, 2009, J PHYSIOL PHARMACOL, V60, P23; Cid TP, 2013, HELICOBACTER, V18, P12, DOI 10.1111/hel.12076; Coker-Gurkan A, 2014, EXP CELL RES, V328, P87, DOI 10.1016/j.yexcr.2014.07.022; Covacci A, 1999, SCIENCE, V284, P1328, DOI 10.1126/science.284.5418.1328; DOLL R, 1981, JNCI-J NATL CANCER I, V66, P1191, DOI 10.1093/jnci/66.6.1192; Fashner J, 2015, AM FAM PHYSICIAN, V91, P236; GORBACH SL, 1982, INFECTION, V10, P379, DOI 10.1007/BF01642307; Greenfield LK, 2013, TRENDS MICROBIOL, V21, P602, DOI 10.1016/j.tim.2013.09.004; Inoue I, 2014, WORLD J GASTROENTERO, V20, P1485, DOI 10.3748/wjg.v20.i6.1485; Jiang LL, 2014, ONCOL REP, V32, P1931, DOI 10.3892/or.2014.3432; Kihara A, 2001, EMBO REP, V2, P330, DOI 10.1093/embo-reports/kve061; Meng WB, 2015, DISCOV MED, V20, P285; Mimuro H, 2007, CELL HOST MICROBE, V2, P250, DOI 10.1016/j.chom.2007.09.005; Mizushima N, 2011, CELL, V147, P728, DOI 10.1016/j.cell.2011.10.026; Murata-Kamiya N, 2007, ONCOGENE, V26, P4617, DOI 10.1038/sj.onc.1210251; Neu B, 2002, AM J PHYSIOL-GASTR L, V283, pG309, DOI 10.1152/ajpgi.00546.2001; Pugh SA, 2016, ANN SURG, V263, P1143, DOI 10.1097/SLA.0000000000001351; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Shimizu T, 2015, GASTROENTEROL CLIN N, V44, P625, DOI 10.1016/j.gtc.2015.05.011; Suzuki M, 2009, CELL HOST MICROBE, V5, P23, DOI 10.1016/j.chom.2008.11.010; Tenesa A, 2009, NAT REV GENET, V10, P353, DOI 10.1038/nrg2574; Terebiznik MR, 2009, AUTOPHAGY, V5, P370, DOI 10.4161/auto.5.3.7663; Viala J, 2004, NAT IMMUNOL, V5, P1166, DOI 10.1038/ni1131; Wan XK, 2016, HELICOBACTER, V21, P554, DOI 10.1111/hel.12311; Wang F, 2014, CANCER LETT, V345, P196, DOI 10.1016/j.canlet.2013.08.016; Wang Y, 2013, HEPATOLOGY, V58, P995, DOI 10.1002/hep.26394; Wang Y, 2014, ONCOL LETT, V8, P1947, DOI 10.3892/ol.2014.2487; WARREN JR, 1983, LANCET, V1, P1273; Watanabe T, 2010, J CLIN INVEST, V120, P1645, DOI 10.1172/JCI39481; Wu SH, 2015, INT J CLIN EXP PATHO, V8, P3882; Xie JH, 2016, INT IMMUNOPHARMACOL, V35, P43, DOI 10.1016/j.intimp.2016.02.022; Yang SH, 2011, GENE DEV, V25, P717, DOI 10.1101/gad.2016111; Yang ZL, 2015, CLIN RES HEPATOL GAS, V39, P98, DOI 10.1016/j.clinre.2014.06.014; Ying L, 2013, MOL BIOSYST, V9, P407, DOI 10.1039/c2mb25386k; Zhai H, 2013, ONCOGENE, V32, P1570, DOI 10.1038/onc.2012.167; Zhang Y, 2017, DEV COMP IMMUNOL, V73, P46, DOI 10.1016/j.dci.2017.03.010; Zhao YS, 2008, INT J COLORECTAL DIS, V23, P875, DOI 10.1007/s00384-008-0479-z; Zheng S, 2017, J MOL NEUROSCI; Zhou FF, 2011, FEBS J, V278, P403, DOI 10.1111/j.1742-4658.2010.07965.x	42	1	1	1	7	E-CENTURY PUBLISHING CORP	MADISON	40 WHITE OAKS LN, MADISON, WI 53711 USA	1940-5901			INT J CLIN EXP MED	Int. J. Clin. Exp. Med.		2018	11	11					11901	11910					10	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	HC5SO	WOS:000451862900052					2022-04-25	
J	Koom, WS; Sai, S; Suzuki, M; Fujimori, A; Yamada, S; Tsujii, H				Koom, Woong Sub; Sai, Sei; Suzuki, Masao; Fujimori, Akira; Yamada, Shigeru; Tsujii, Hirohiko			Superior Effect of the Combination of Carbon-Ion Beam Irradiation and 5-Fluorouracil on Colorectal Cancer Stem Cells in vitro and in vivo	ONCOTARGETS AND THERAPY			English	Article						colorectal cancer stem cell; heavy ion radiation; 5-FU	COLON-CANCER; ADJUVANT CHEMOTHERAPY; RADIATION-THERAPY; SURVIVAL; 5-FU; RADIOSENSITIVITY; MODULATION; PROGNOSIS; CARCINOMA; APOPTOSIS	Background: The aim of this study was to investigate whether carbon-ion beam irradiation in combination with 5-fluorouracil (5-FU) is superior to carbon-ion beam irradiation alone in targeting colorectal cancer stem-like cells (CSCs). Materials and Methods: Human colorectal cancer (CRC) cells, HCT116 and HT29, were treated with carbon-ion beam irradiation alone or in combination with 5-FU. Cell viability assay, colony and spheroid formation assay, apoptotic assay, and quantitative real-time PCR analysis of apoptosis- and autophagy-related gene expression were performed. Results: Carbon-ion beam irradiation dose-dependently decreased CRC cell viability and showed significantly enhanced cell killing effect when combined with 5-FU. Carbon-ion beam irradiation in combination with 5-FU significantly increased the percentage of apoptotic cells. The expression of some apoptotic and autophagy-related genes such as Bax, Bcl2, Beclin1 and ATG7 was significantly induced by carbon-ion beam irradiation alone and was further enhanced when the beam was combined with 5-FU. The spheroid forming capacity of CD133+ cell subpopulations was significantly inhibited by carbon-ion beam in combination with 5-FU. Histopathologically, the combination of carbon-ion beam irradiation and 5-FU destroyed more xenograft tumor cells, and resulted in increased necrosis, cavitation, and fibrosis, compared to carbon-ion beam irradiation alone. Conclusion: In conclusion, carbon-ion beam treatment combined with 5-FU has the potential to kill CRC cells including CSCs by inducing increased apoptosis and autophagy.	[Koom, Woong Sub] Yonsei Univ, Dept Radiat Oncol, Coll Med, Yonsei Canc Ctr, Seoul, South Korea; [Koom, Woong Sub; Yamada, Shigeru; Tsujii, Hirohiko] QST Hosp, Natl Inst Quantum & Radiol Sci & Technol QST, Chiba, Japan; [Sai, Sei; Suzuki, Masao; Fujimori, Akira] Natl Inst Quantum & Radiol Sci & Technol QST, Natl Inst Radiol Sci NIRS, Dept Basic Med Sci Radiat Damages, Chiba, Japan		Sai, S (corresponding author), Natl Inst Quantum & Radiol Sci & Technol QST, Natl Inst Radiol Sci NIRS, Dept Basic Med Sci Radiat Damages, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan.	sai.sei@qst.go.jp		Koom, Woong Sub/0000-0002-9435-7750			Abugomaa A, 2020, EXPERT REV PRECIS ME, V5, P1, DOI 10.1080/23808993.2020.1715794; Abugomaa A, 2020, CELLS-BASEL, V9, DOI 10.3390/cells9010235; Balart J, 2002, PANCREATOLOGY, V2, P40, DOI 10.1159/000049447; Bao SD, 2006, NATURE, V444, P756, DOI 10.1038/nature05236; Baumann M, 2008, NAT REV CANCER, V8, P545, DOI 10.1038/nrc2419; Cui X, 2011, CANCER RES, V71, P3676, DOI 10.1158/0008-5472.CAN-10-2926; Diehn M, 2006, J NATL CANCER I, V98, P1755, DOI 10.1093/jnci/djj505; Dingli D, 2006, STEM CELLS, V24, P2603, DOI 10.1634/stemcells.2006-0136; Elbadawy M, 2019, INT J MOL SCI, V20, DOI 10.3390/ijms20092340; Farhat W, 2019, WORLD J SURG ONCOL, V17, DOI 10.1186/s12957-019-1718-1; Fu KK, 1997, SEMIN RADIAT ONCOL, V7, P274, DOI 10.1016/S1053-4296(97)80026-4; Grothey A, 2018, NEW ENGL J MED, V378, P1177, DOI 10.1056/NEJMoa1713709; Gustavsson B, 2015, CLIN COLORECTAL CANC, V14, P1, DOI 10.1016/j.clcc.2014.11.002; Guyot F, 2005, ANN ONCOL, V16, P756, DOI 10.1093/annonc/mdi151; Hambardzumyan D, 2006, CANCER CELL, V10, P454, DOI 10.1016/j.ccr.2006.11.008; Harris CA, 2016, ANN SURG, V264, P323, DOI 10.1097/SLA.0000000000001524; Hashiguchi Y, 2020, INT J CLIN ONCOL, V25, P1, DOI 10.1007/s10147-019-01485-z; Kim EH, 2020, CANCERS, V12, DOI 10.3390/cancers12030698; Kornmann M, 2008, EJSO-EUR J SURG ONC, V34, P1316, DOI 10.1016/j.ejso.2008.01.019; Lips DJ, 2011, BMC SURG, V11, DOI 10.1186/1471-2482-11-11; Loree JM, 2016, FUTURE ONCOL, V12, P2021, DOI 10.2217/fon-2016-0109; Neugut AI, 2006, J CLIN ONCOL, V24, P2368, DOI 10.1200/JCO.2005.04.5005; Nita ME, 1998, BRIT J CANCER, V78, P986, DOI 10.1038/bjc.1998.617; O'Brien CA, 2007, NATURE, V445, P106, DOI 10.1038/nature05372; Oonishi K, 2012, RADIOTHER ONCOL, V105, P258, DOI 10.1016/j.radonc.2012.08.009; Osaki M, 1997, APOPTOSIS, V2, P221, DOI 10.1023/A:1026476801463; Renehan AG, 2016, CLIN ONCOL-UK, V28, P103, DOI 10.1016/j.clon.2015.11.006; Ricci-Vitiani L, 2007, NATURE, V445, P111, DOI 10.1038/nature05384; Rich JN, 2007, CANCER RES, V67, P8980, DOI 10.1158/0008-5472.CAN-07-0895; Ryuk JP, 2014, ANN SURG TREAT RES, V86, P143, DOI 10.4174/astr.2014.86.3.143; Sai S, 2020, AM J CANCER RES, V10, P2371; Sai Sei, 2018, Oncotarget, V9, P14849, DOI 10.18632/oncotarget.23756; Sai S, 2015, MOL CANCER, V14, DOI 10.1186/s12943-015-0429-7; Sai S, 2015, ONCOTARGET, V6, P5517, DOI 10.18632/oncotarget.3584; Shiba S, 2019, FRONT ONCOL, V9, DOI 10.3389/fonc.2019.00702; Shinoto M, 2019, RADIOTHER ONCOL, V132, P236, DOI 10.1016/j.radonc.2018.10.007; Short SS, 2012, J SURG ONCOL, V106, P119, DOI 10.1002/jso.23057; SMALLEY SR, 1991, INT J RADIAT ONCOL, V20, P207, DOI 10.1016/0360-3016(91)90091-H; Tang JC, 2016, CHINESE MED J-PEKING, V129, P456, DOI 10.4103/0366-6999.176069; Urick ME, 2011, CLIN CANCER RES, V17, P5038, DOI 10.1158/1078-0432.CCR-11-0358; Westberg K, 2018, EJSO-EUR J SURG ONC, V44, P100, DOI 10.1016/j.ejso.2017.11.013; WONG CS, 1991, INT J RADIAT ONCOL, V21, P1291, DOI 10.1016/0360-3016(91)90288-F; Xiong HY, 2010, CANCER LETT, V288, P68, DOI 10.1016/j.canlet.2009.06.039; Yamada S, 2016, INT J RADIAT ONCOL, V96, P93, DOI 10.1016/j.ijrobp.2016.04.022; Yang JW, 2018, J CANCER RES THER, V14, pS1141, DOI 10.4103/0973-1482.204898	45	1	1	1	2	DOVE MEDICAL PRESS LTD	ALBANY	PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND	1178-6930			ONCOTARGETS THER	OncoTargets Ther.		2020	13						12625	12635		10.2147/OTT.S276035			11	Biotechnology & Applied Microbiology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Oncology	PE8QZ	WOS:000598627300005	33335403	gold, Green Published			2022-04-25	
J	Li, X; Guo, J; Ding, AP; Qi, WW; Zhang, PH; Lv, J; Qiu, WS; Sun, ZQ				Li, Xian; Guo, Jing; Ding, Ai-Ping; Qi, Wei-Wei; Zhang, Pei-Hua; Lv, Jing; Qiu, Wen-Sheng; Sun, Zhen-Qing			Association of Mixed Lineage Kinase Domain-Like Protein Expression With Prognosis in Patients With Colon Cancer	TECHNOLOGY IN CANCER RESEARCH & TREATMENT			English	Article						MLKL; necroptosis; prognostic value; colon cancer	COLORECTAL-CANCER; CELL-DEATH; NECROPTOSIS; CARCINOMA; TUMOR; APOPTOSIS; AUTOPHAGY; MECHANISM; MLKL	Background: The mixed lineage kinase domain-like protein has recently been identified as a key downstream component of tumor necrosis factor-induced necroptosis, which is an important pathway of cancer cell death. The goal of the current study is to explore the expression of mixed lineage kinase domain-like protein in colon cancer tissues and evaluate the prognostic value in patients with colon cancer. Methods: We collected normal and cancer colon tissues from 135 patients diagnosed with colon cancer after radical operation during July 2007 to April 2009 at The Affiliated Hospital of Qingdao University. Immunohistochemistry analysis was scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival and overall survival for all patients and 2 subsets of patients. The relationship between mixed lineage kinase domain-like protein expression and prognosis parameter (recurrence-free survival, overall survival) was analyzed by univariate and multivariate Cox regression analyses. Results: The median age of all patients was 67 years and 56.3% were male. Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (78.6 vs 81.2 months; P = .011) in all patients. In the subset of 79 patients who received adjuvant chemotherapy, low expression of mixed lineage kinase domain-like protein was associated with decreased recurrence-free survival 60.4 vs 72.8 months; P = .032) and decreased overall survival ( 66.3 vs 72.9 months; P = .005). Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (4.9 vs 79.8 months; P = .006) and recurrence-free survival (69.6 vs 78.8 months; P = .005) among patients with Tumor Node Metastasis (TNM) stage II colon cancer. Conclusions: Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival in all patient-group with resected colon cancer. It is associated with decreased recurrencefree survival and overall survival in the subset of patients who receive adjuvant chemotherapy and patients who were TNM stage II. Mixed lineage kinase domain-like protein may provide important prognostic information in patients with colon cancer.	[Li, Xian; Sun, Zhen-Qing] Qingdao Univ, Affiliated Hosp, Dept Surg, 59 Haier Rd, Qingdao 266000, Shandong, Peoples R China; [Guo, Jing; Ding, Ai-Ping; Qi, Wei-Wei; Zhang, Pei-Hua; Lv, Jing; Qiu, Wen-Sheng] Qingdao Univ, Affiliated Hosp, Dept Oncol, Qingdao, Shandong, Peoples R China		Sun, ZQ (corresponding author), Qingdao Univ, Affiliated Hosp, Dept Surg, 59 Haier Rd, Qingdao 266000, Shandong, Peoples R China.	sunzhanqing0532@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472338]; Project of Shandong Province Higher Educational Science and Technology Program [J15LL58]	The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the National Natural Science Foundation of China under award numbers 81472338 to Qiu and a Project of Shandong Province Higher Educational Science and Technology Program award J15LL58 to Lv.	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Cancer Res. Treat.	AUG	2017	16	4					428	434		10.1177/1533034616655909			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EZ8TN	WOS:000405001000005	27432118	Green Published, Bronze			2022-04-25	
J	Pecoraro, A; Carotenuto, P; Franco, B; De Cegli, R; Russo, G; Russo, A				Pecoraro, Annalisa; Carotenuto, Pietro; Franco, Brunella; De Cegli, Rossella; Russo, Giulia; Russo, Annapina			Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						cancer; chemotherapy; nucleolar stress; nucleolus; p53; ribosomal proteins; uL3; autophagy	RIBOSOMAL-PROTEINS; GENE-EXPRESSION; HNRNP H1; RPL3; RESISTANCE; RNA	The nucleolus is the site of ribosome biogenesis and has been recently described as important sensor for a variety of cellular stressors. In the last two decades, it has been largely demonstrated that many chemotherapeutics act by inhibiting early or late rRNA processing steps with consequent alteration of ribosome biogenesis and activation of nucleolar stress response. The overall result is cell cycle arrest and/or apoptotic cell death of cancer cells. Our previously data demonstrated that ribosomal protein uL3 is a key sensor of nucleolar stress activated by common chemotherapeutic agents in cancer cells lacking p53. We have also demonstrated that uL3 status is associated to chemoresistance; down-regulation of uL3 makes some chemotherapeutic drugs ineffective. Here, we demonstrate that in colon cancer cells, the uL3 status affects rRNA synthesis and processing with consequent activation of uL3-mediated nucleolar stress pathway. Transcriptome analysis of HCT 116(p53-/-) cells expressing uL3 and of a cell sub line stably depleted of uL3 treated with Actinomycin D suggests a new extra-ribosomal role of uL3 in the regulation of autophagic process. By using confocal microscopy and Western blotting experiments, we demonstrated that uL3 acts as inhibitory factor of autophagic process; the absence of uL3 is associated to increase of autophagic flux and to chemoresistance. Furthermore, experiments conducted in presence of chloroquine, a known inhibitor of autophagy, indicate a role of uL3 in chloroquine-mediated inhibition of autophagy. On the basis of these results and our previous findings, we hypothesize that the absence of uL3 in cancer cells might inhibit cancer cell response to drug treatment through the activation of cytoprotective autophagy. The restoration of uL3 could enhance the activity of many drugs thanks to its pro-apoptotic and anti-autophagic activity.	[Pecoraro, Annalisa; Russo, Giulia; Russo, Annapina] Univ Naples Federico II, Dept Pharm, Via Domenico Montesano 49, Naples 80131, Italy; [Carotenuto, Pietro; Franco, Brunella; De Cegli, Rossella] Telethon Inst Genet & Med TIGEM, Via Campi Flegrei 34, Naples 80078, Italy; [Carotenuto, Pietro] Inst Canc Res, Canc Therapeut Unit, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England; [Franco, Brunella] Univ Naples Federico II, Dept Translat Med Sci, Med Genet, Via Sergio Pansini 5, Naples 80131, Italy		Russo, A (corresponding author), Univ Naples Federico II, Dept Pharm, Via Domenico Montesano 49, Naples 80131, Italy.	annalisa.pecoraro@unina.it; p.carotenuto@tigem.it; franco@tigem.it; decegli@tigem.it; giulia.russo@unina.it; annapina.russo@unina.it	De Cegli, Rossella/ABA-4372-2020; Pecoraro, Annalisa/AFQ-5507-2022; Russo, Annapina/O-7545-2015	Carotenuto, Pietro/0000-0002-6622-183X; Russo, Annapina/0000-0002-7509-3702	Regione Campania-POR FERS 2014/2020 "Combattere la resistenza tumorale: piattaforma integrata multidiscilinare per un approccio tecnologico innovativo alle oncoterapie-Campania Oncoterapie" [B61G18000470007]; Fondo di ricerca di base FFABR-2017 Ministero della Universita e della ricerca (MIUR)Ministry of Education, Universities and Research (MIUR); POR CAMPANIA FESR 2014/2020 "Genomica e Terapia" grant; Italian Association for Cancer Research (AIRC)Fondazione AIRC per la ricerca sul cancro [IG 17711/2015]; Marie Sklodowska-Curie Career Re-Integration Grant from AIRC; European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grantSKA South Africa [800924]	Annapina Russo gratefully acknowledge Regione Campania-POR FERS 2014/2020 "Combattere la resistenza tumorale: piattaforma integrata multidiscilinare per un approccio tecnologico innovativo alle oncoterapie-Campania Oncoterapie"-PROJECT N: B61G18000470007; Fondo di ricerca di base FFABR-2017 Ministero della Universita e della ricerca (MIUR) for financial support. Carotenuto P. is supported by POR CAMPANIA FESR 2014/2020 "Genomica e Terapia" grant, by the Italian Association for Cancer Research (AIRC) (grant n. IG 17711/2015 to B.F.); Carotenuto P. is recipient of a Marie Sklodowska-Curie Career Re-Integration Grant funding from AIRC and the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 800924.	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J. Mol. Sci.	MAR	2020	21	6							2143	10.3390/ijms21062143			21	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	LJ0UU	WOS:000529890200239	32244996	Green Published, gold			2022-04-25	
J	Ziolkowska, B; Wozniak, M; Ziolkowski, P				Ziolkowska, Barbara; Wozniak, Marta; Ziolkowski, Piotr			Co-expression of autophagic markers following photodynamic therapy in SW620 human colon adenocarcinoma cells	MOLECULAR MEDICINE REPORTS			English	Article						photodynamic therapy; autophagy; cell death; cancer; colon cancer cells	REGULATES AUTOPHAGY; MACHINERY; APOPTOSIS	Photodynamic therapy (PDT) is a minimally invasive cancer treatment. It involves the combination of a photosensitizer and light of a specific wavelength to generate singlet oxygen and other reactive oxygen species that lead to tumor cell death. Autophagy is one of the pathways that tumor cells undergo during photodamage and it is common in photodynamic therapy. The aim of this study was to examine the effect of in vitro PDT on the expression of autophagy-related proteins, autophagy related 7 (Atg7), light chain 3 (LC3) and Beclin-1. Human SW620 colon carcinoma cells were treated with 5-aminolevulinic acid (ALA)-based PDT at a dose of 3 mM. The irradiation was performed using 4.5 J/cm(2) total light and a fluence rate of 60 mW/cm(2). Autophagy was evaluated by immunocytochemistry using specific antibodies to Atg7, Beclin-1 and LC3. The evaluation was repeated at several time points (0, 4, 8 and 24 h) following irradiation. The induction of autophagy was observed directly following the 5-ALA-mediated PDT procedure with the strongest expression of autophagy-related proteins at 4 and 8 h after irradiation as demonstrated using immunocytochemistry. It was characterized by significantly increased expression of Beclin-1, Atg7 and LC3. To the best of our knowledge this is the first study to analyze Beclin-1, Atg7 and LC3 expression in a PDT-related experiment. This study enhances the understanding of the role of autophagy in PDT, which may contribute to better and more effective tumor responses to this therapy.	[Ziolkowska, Barbara; Wozniak, Marta; Ziolkowski, Piotr] Wrocaw Med Univ, Dept Pathol, Ul Marcinkowskiego 1, PL-50368 Wroclaw, Poland		Ziolkowski, P (corresponding author), Wrocaw Med Univ, Dept Pathol, Ul Marcinkowskiego 1, PL-50368 Wroclaw, Poland.	ziolkows@interia.pl	Wozniak, Marta/ABD-2161-2021; Ziolkowski, Piotr/AAU-2452-2021	Wozniak, Marta/0000-0001-7978-6330; Ziolkowska, Barbara/0000-0002-3087-8303; Ziolkowski, Piotr/0000-0003-3036-2611			Azad MB, 2009, ANTIOXID REDOX SIGN, V11, P777, DOI 10.1089/ARS.2008.2270; Brech A, 2009, MOL ONCOL, V3, P366, DOI 10.1016/j.molonc.2009.05.007; Castano AP, 2005, PHOTODIAGN PHOTODYN, V2, P1, DOI 10.1016/S1572-1000(05)00030-X; Chen Y, 2009, CELL DEATH DIFFER, V16, P1040, DOI 10.1038/cdd.2009.49; Dewaele M, 2011, J CELL MOL MED, V15, P1402, DOI 10.1111/j.1582-4934.2010.01118.x; Dougherty TJ, 1998, JNCI-J NATL CANCER I, V90, P889, DOI 10.1093/jnci/90.12.889; Fimia GM, 2007, NATURE, V447, P1121, DOI 10.1038/nature05925; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Hara T, 2006, NATURE, V441, P885, DOI 10.1038/nature04724; Ichimura Y, 2000, NATURE, V408, P488, DOI 10.1038/35044114; Itakura E, 2008, MOL BIOL CELL, V19, P5360, DOI 10.1091/mbc.E08-01-0080; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Kessel D, 2004, J PORPHYR PHTHALOCYA, V8, P1009, DOI 10.1142/S1088424604000374; Kessel D, 2007, PHOTOCH PHOTOBIO SCI, V6, P1290, DOI 10.1039/b707953b; Kessel D, 2007, PHOTOCHEM PHOTOBIOL, V83, P1024, DOI 10.1111/j.1751-1097.2007.00088.x; Kessel D, 2006, AUTOPHAGY, V2, P289, DOI 10.4161/auto.2792; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Komatsu M, 2005, J CELL BIOL, V169, P425, DOI 10.1083/jcb.200412022; Kroemer G, 2010, MOL CELL, V40, P280, DOI 10.1016/j.molcel.2010.09.023; Mandelbaum J., 2015, AUTOPHAGY, DOI [10.1080/15548627.2015.1056966., DOI 10.1080/15548627.2015.1056966]; Mizushima N, 1998, NATURE, V395, P395, DOI 10.1038/26506; Mizushima N, 2011, ANNU REV CELL DEV BI, V27, P107, DOI 10.1146/annurev-cellbio-092910-154005; Ohsumi Y, 2001, NAT REV MOL CELL BIO, V2, P211, DOI 10.1038/35056522; Reiners JJ, 2010, AUTOPHAGY, V6, P7, DOI 10.4161/auto.6.1.10220; Scherz-Shouval R, 2019, EMBO J, V38, DOI 10.15252/embj.2019101812; Song J, 2015, EXP NEUROBIOL, V24, P117, DOI 10.5607/en.2015.24.2.117; Taherbhoy AM, 2011, MOL CELL, V44, P451, DOI 10.1016/j.molcel.2011.08.034; Tanida I, 2001, J BIOL CHEM, V276, P1701, DOI 10.1074/jbc.C000752200; Tanida Isei, 2008, V445, P77, DOI 10.1007/978-1-59745-157-4_4; TSUKADA M, 1993, FEBS LETT, V333, P169, DOI 10.1016/0014-5793(93)80398-E; White E, 2009, CLIN CANCER RES, V15, P5308, DOI 10.1158/1078-0432.CCR-07-5023; Xie ZP, 2007, NAT CELL BIOL, V9, P1102, DOI 10.1038/ncb1007-1102; Xue LY, 2001, ONCOGENE, V20, P3420, DOI 10.1038/sj.onc.1204441; Yorimitsu T, 2005, CELL DEATH DIFFER, V12, P1542, DOI 10.1038/sj.cdd.4401765; Zhong Y, 2009, AUTOPHAGY, V5, P890, DOI 10.4161/auto.9162	36	5	6	0	10	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1791-2997	1791-3004		MOL MED REP	Mol. Med. Rep.	SEP	2016	14	3					2548	2554		10.3892/mmr.2016.5541			7	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	DU8EF	WOS:000382445400088	27485939	Green Published, hybrid			2022-04-25	
J	Huang, W; Zeng, C; Hu, SB; Wang, L; Liu, J				Huang, Wei; Zeng, Chong; Hu, Shanbiao; Wang, Lei; Liu, Jie			ATG3, a Target of miR-431-5p, Promotes Proliferation and Invasion of Colon Cancer via Promoting Autophagy	CANCER MANAGEMENT AND RESEARCH			English	Article						colon cancer; proliferation; invasion; ATG3; miR-431-5p; autophagy	GENE-EXPRESSION; UP-REGULATION; BECLIN 1; DEGRADATION; CELLS; APOPTOSIS; INTERACTS; BECN1	Background: Studies have indicated that ATG3 could mediate the effects of other tumor-related regulators in carcinogenesis. However, the expression, role, and mechanism of ATG3 itself in cancers are rarely revealed. Thus, we explored the expression, function, and mechanism of ATG3 in colon cancer. Materials and methods: The expression of ATG3 was detected in colon cancer tissues and cell lines, as well as in adjacent tumor tissues and normal colon epithelial cells. The effects of ATG3 alteration on proliferation and invasion were further analyzed. The expression and role of miR-431-5p, a potential negative regulator of ATG3, were also studied. Eventually, the role of autophagy in ATG3 related effects in colon cancer was checked. Results: ATG3 is upregulated in colon cancer tissues and cells demonstrated by qPCR and IHC. ATG3 knockdown significantly suppressed proliferation and invasion of colon cancer cells indicated by plate clone formation and Transwell invasion assays. The expression of miR-431-5p is downregulated and negatively correlates with ATG3 in colon cancer. Furthermore, luciferase report system, plate clone formation and Transwell invasion assays demonstrated that miR-431-5p could prohibit cell proliferation and invasion via directly targeting ATG3 in colon cancer. Eventually, Western blot, plate clone formation and Transwell invasion assays proved that autophagy block could antagonize the promotive functions of ATG3 on proliferation and invasion in cancer suggesting autophagy activation accounts for the promotive role of ATG3 on proliferation and invasion in colon cancer. Conclusion: Collectively, ATG3 upregulation, caused by downregulated miR-435-5p, promotes proliferation and invasion via an autophagy-dependent manner in colon cancer suggesting that miR-431-5p/ATG3/autophagy may be a potential therapeutic target in colon cancer.	[Huang, Wei; Liu, Jie] Changsha Cent Hosp, Dept Pathol, 161 Shaoshan South Rd, Changsha 410004, Hunan, Peoples R China; [Huang, Wei] Cent S Univ, Xiangya Hosp, Res Ctr Carcinogenesis & Targeted Therapy, Changsha, Hunan, Peoples R China; [Zeng, Chong] Hunan Rongjun Hosp, Dept Resp & Neurol, Changsha, Hunan, Peoples R China; [Hu, Shanbiao] Cent S Univ, Xiangya Hosp 2, Dept Urol Organ Transplantat, Changsha, Hunan, Peoples R China; [Wang, Lei] Cent S Univ, Sch Basic Med Sci, Collaborat Innovat Ctr Canc Med, Canc Res Inst, Changsha, Hunan, Peoples R China		Liu, J (corresponding author), Changsha Cent Hosp, Dept Pathol, 161 Shaoshan South Rd, Changsha 410004, Hunan, Peoples R China.	lj511907352@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81702924]; Natural Science Foundation of Hunan Province of ChinaNatural Science Foundation of Hunan Province [2018JJ3811]	The present study was supported by the National Natural Science Foundation of China (nos. 81702924) and the Natural Science Foundation of Hunan Province of China (nos. 2018JJ3811).	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Res.		2019	11						10275	10285		10.2147/CMAR.S226828			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JV3IE	WOS:000502259100001	31849517	Green Published, gold			2022-04-25	
J	Nakayama, S; Karasawa, H; Suzuki, T; Yabuuchi, S; Takagi, K; Aizawa, T; Onodera, Y; Nakamura, Y; Watanabe, M; Fujishima, F; Yoshida, H; Morikawa, T; Sase, T; Naitoh, T; Unno, M; Sasano, H				Nakayama, Shun; Karasawa, Hideaki; Suzuki, Takashi; Yabuuchi, Shinichi; Takagi, Kiyoshi; Aizawa, Takashi; Onodera, Yoshiaki; Nakamura, Yasuhiro; Watanabe, Mika; Fujishima, Fumiyoshi; Yoshida, Hiroshi; Morikawa, Takanori; Sase, Tomohiko; Naitoh, Takeshi; Unno, Michiaki; Sasano, Hironobu			p62/sequestosome 1 in human colorectal carcinoma as a potent prognostic predictor associated with cell proliferation	CANCER MEDICINE			English	Article						Cell proliferation; colorectal carcinoma; immunohistochemistry; p62; prognosis	AUTOPHAGY-DEFICIENT MICE; C COLON-CANCER; HEPATOCELLULAR-CARCINOMA; DIGESTIVE-SYSTEM; P62; PROTEIN; P62/SQSTM1; APOPTOSIS; OVEREXPRESSION; EXPRESSION	p62/sequestosome 1 (p62) is a multi-domain protein that functions as a receptor for ubiquitinated targets in the selective autophagy and serves as a scaffold in various signaling cascades. p62 have been reported to be up-regulated in several human malignancies, but the biological roles and significance of p62 are still poorly understood in colorectal carcinoma. We immunohistochemically evaluated p62 in 118 colorectal adenocarcinoma and 28 colorectal adenoma cases. We used four colon carcinoma cells (HCT8, HT29, COLO320, and SW480) in the in vitro studies. p62 immunoreactivity was detected in 11% of colorectal adenoma cases and 31% of adenocarcinoma cases, while it was negligible in the normal epithelium. The immunohistochemical p62 status was significantly associated with synchronous liver metastasis, and it turned out to be an independent adverse prognostic factor in colorectal cancer patients. Following in vitro studies revealed that HCT8 and HT29 cells transfected with p62-specific siRNA showed significantly decreased cell proliferation activity, whereas COLO320 and SW480 cells transfected with p62 expression plasmid showed significantly increased cell proliferation activity. The p62-mediated cell proliferation was not associated with the autophagy activity. These findings suggest that p62 promotes the cell proliferation mainly as a scaffold protein, and that the p62 status is a potent prognostic factor in colorectal carcinoma patients.	[Nakayama, Shun; Karasawa, Hideaki; Yabuuchi, Shinichi; Aizawa, Takashi; Yoshida, Hiroshi; Morikawa, Takanori; Sase, Tomohiko; Naitoh, Takeshi; Unno, Michiaki] Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan; [Nakayama, Shun; Watanabe, Mika; Fujishima, Fumiyoshi; Sasano, Hironobu] Tohoku Univ Hosp, Dept Pathol, Sendai, Miyagi, Japan; [Suzuki, Takashi; Takagi, Kiyoshi] Tohoku Univ, Grad Sch Med, Dept Pathol & Histotechnol, Sendai, Miyagi, Japan; [Onodera, Yoshiaki; Nakamura, Yasuhiro; Sasano, Hironobu] Tohoku Univ, Grad Sch Med, Dept Anat Pathol, Sendai, Miyagi, Japan		Suzuki, T (corresponding author), Tohoku Univ, Grad Sch Med, Dept Pathol & Histotechnol, Aoba Ku, 2-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan.	t-suzuki@patholo2.med.tohoku.ac.jp	Morikawa, Takanori/AAK-6989-2021; Karasawa, Hideaki/AAQ-2771-2021; Unno, Michiaki/A-8633-2010; Nakamura, Yasuhiro/AAR-7367-2020; Unno, Michiaki/AAX-5246-2020; Naitoh, Takeshi/K-1693-2014	Unno, Michiaki/0000-0002-2145-6416; Unno, Michiaki/0000-0002-2145-6416; Karasawa, Hideaki/0000-0003-0358-3398; Naitoh, Takeshi/0000-0003-4169-6334; Suzuki, Takashi/0000-0003-0195-815X			Allegra CJ, 2003, J CLIN ONCOL, V21, P241, DOI 10.1200/JCO.2003.05.044; American Cancer Society, 2016, CANC FACTS FIG 2016; Bjorkoy G, 2005, J CELL BIOL, V171, P603, DOI 10.1083/jcb.200507002; Brown DC, 2002, HISTOPATHOLOGY, V40, P2, DOI 10.1046/j.1365-2559.2002.01343.x; Cunningham D, 2004, NEW ENGL J MED, V351, P337, DOI 10.1056/NEJMoa033025; Duchrow M, 2003, HISTOPATHOLOGY, V42, P566, DOI 10.1046/j.1365-2559.2003.01613.x; Duran A, 2011, MOL CELL, V44, P134, DOI 10.1016/j.molcel.2011.06.038; Fan WL, 2010, AUTOPHAGY, V6, P614, DOI 10.4161/auto.6.5.12189; FURTADO JS, 1970, STAIN TECHNOL, V45, P19, DOI 10.3109/10520297009063377; Galavotti S, 2013, ONCOGENE, V32, P699, DOI 10.1038/onc.2012.111; Garrity MM, 2004, J CLIN ONCOL, V22, P1572, DOI 10.1200/JCO.2004.10.042; GERDES J, 1983, INT J CANCER, V31, P13, DOI 10.1002/ijc.2910310104; Hilska M, 2005, DIS COLON RECTUM, V48, P2197, DOI 10.1007/s10350-005-0202-x; Huang SB, 2010, AUTOPHAGY, V6, P256, DOI 10.4161/auto.6.2.11124; Ichimura Y, 2008, J BIOL CHEM, V283, P22847, DOI 10.1074/jbc.M802182200; Inami Y, 2011, J CELL BIOL, V193, P275, DOI 10.1083/jcb.201102031; Inoue D, 2012, CANCER SCI, V103, P760, DOI 10.1111/j.1349-7006.2012.02216.x; Kawakami M, 2010, SURG TODAY, V40, P245, DOI 10.1007/s00595-009-4028-3; Kimura S, 2007, AUTOPHAGY, V3, P452, DOI 10.4161/auto.4451; Kitamura H, 2006, HISTOPATHOLOGY, V48, P157, DOI 10.1111/j.1365-2559.2005.02313.x; Komatsu M, 2007, CELL, V131, P1149, DOI 10.1016/j.cell.2007.10.035; Ling JH, 2012, CANCER CELL, V21, P105, DOI 10.1016/j.ccr.2011.12.006; Luo Rong-Zhen, 2013, Onco Targets Ther, V6, P883, DOI 10.2147/OTT.S46222; Mizushima N, 2007, AUTOPHAGY, V3, P542, DOI 10.4161/auto.4600; Pankiv S, 2007, J BIOL CHEM, V282, P24131, DOI 10.1074/jbc.M702824200; Park JM, 2013, CANCER BIOL THER, V14, P100, DOI 10.4161/cbt.22954; Porter K, 2013, AUTOPHAGY, V9, P581, DOI 10.4161/auto.23568; Qian HL, 2005, WORLD J GASTROENTERO, V11, P1788; Rolland P, 2007, ENDOCR-RELAT CANCER, V14, P73, DOI 10.1677/erc.1.01312; Stumptner C, 1999, AM J PATHOL, V154, P1701, DOI 10.1016/S0002-9440(10)65426-0; Su YX, 2005, CLIN IMMUNOL, V116, P118, DOI 10.1016/j.clim.2005.04.004; Takamura A, 2011, GENE DEV, V25, P795, DOI 10.1101/gad.2016211; Thompson HGR, 2003, ONCOGENE, V22, P2322, DOI 10.1038/sj.onc.1206325; Valera V, 2005, BRIT J SURG, V92, P1002, DOI 10.1002/bjs.4858; Wu YC, 2009, BIOCHEM BIOPH RES CO, V382, P451, DOI 10.1016/j.bbrc.2009.03.051; Yang SH, 2011, GENE DEV, V25, P717, DOI 10.1101/gad.2016111; Yu H, 2011, EUR J CANCER, V47, P1585, DOI 10.1016/j.ejca.2011.01.019	37	16	16	0	5	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	2045-7634			CANCER MED-US	Cancer Med.	JUN	2017	6	6					1264	1274		10.1002/cam4.1093			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EX1ZA	WOS:000403024100012	28544335	gold, Green Published			2022-04-25	
J	Shen, H; Yin, L; Deng, GL; Guo, C; Han, Y; Li, YY; Cai, CJ; Fu, YJ; Liu, SS; Zeng, S				Shen, Hong; Yin, Ling; Deng, Ganlu; Guo, Cao; Han, Ying; Li, Yiyi; Cai, Changjing; Fu, Yaojie; Liu, Shanshan; Zeng, Shan			Knockdown of Beclin-1 impairs epithelial-mesenchymal transition of colon cancer cells	JOURNAL OF CELLULAR BIOCHEMISTRY			English	Article						autophagy; Beclin-1; colon cancer; epithelial-mesenchymal transition	HEPATOCELLULAR-CARCINOMA; FAVORABLE PROGNOSIS; PROTEIN EXPRESSION; AUTOPHAGY; INVASION; STATISTICS; ACTIVATION; LC3; P62	Activation of autophagy significantly affects cancer cell behaviors, such as proliferation, differentiation, and invasiveness. Epithelial-to-mesenchymal transition (EMT) as an initial step of malignant transformation of cancer cells was linked to the activation of autophagy, but the detailed molecular mechanisms are still unknown. The present study investigates the effects of Beclin-1, a key molecule involved in activation of autophagy, on EMT of colon cancer cells. The normal colon epithelia cell line of CCD-18Co and six colon cancer cell lines with different expression levels of Beclin-1 were used in this study. The activation of autophagy and EMT markers of cancer cells were monitored by Western blotting and quantitative real-time PCR assay in the presence or absence of rapamycin (autophagy activator) and 3-MA (autophagy inhibitor). The expression of Beclin-1 in selected cell lines was modulated using small interfering RNA, and consequentially EMT markers, and cancer cell behaviors including migration and invasion, were also explored. Activation or inhibition of autophagy in colon cancer cells had positive or negative impacts on the expression of EMT markers and malignant behaviors such as cell migration and invasion. Knockdown of beclin-1 by siRNA apparently inhibited the activation of autophagy induced by rapamycin, consequentially resulted in suppression of EMT and attenuation of invasiveness of colon cancer cells. The results in this study demonstrated an association between activation of autophagy and EMT in colon cancer cells. The results showed suppression of Beclin-1 expression significantly reduced EMT and invasive behaviors in colon cancer cells.	[Shen, Hong; Yin, Ling; Deng, Ganlu; Guo, Cao; Li, Yiyi; Fu, Yaojie; Liu, Shanshan; Zeng, Shan] Cent South Univ, Xiangya Hosp, Dept Oncol, Changsha 410008, Hunan, Peoples R China; [Shen, Hong; Yin, Ling; Deng, Ganlu; Han, Ying; Li, Yiyi; Cai, Changjing; Fu, Yaojie; Liu, Shanshan; Zeng, Shan] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha, Hunan, Peoples R China; [Shen, Hong; Guo, Cao; Han, Ying; Cai, Changjing; Zeng, Shan] Cent South Univ, Xiangya Hosp, Key Lab Mol Radiat Oncol Hunan Prov, Changsha, Hunan, Peoples R China		Zeng, S (corresponding author), Cent South Univ, Xiangya Hosp, Dept Oncol, Changsha 410008, Hunan, Peoples R China.	zengshan2000@csu.edu.cn	Shen, Hong/N-9734-2019; Yin, Ling/AAD-8990-2022; Cai, Changjing/ABA-4542-2021	Shen, Hong/0000-0002-6456-8231; Yin, Ling/0000-0003-1606-2620; 	National Nature Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81070362, 81172470, 81372629, 81772627]; Nature Science Foundation of Hunan ProvinceNatural Science Foundation of Hunan Province [2015JC3021, 2016JC2037]	National Nature Science Foundation of China, Grant numbers: 81070362, 81172470, 81372629, 81772627; Nature Science Foundation of Hunan Province, Grant numbers: 2015JC3021, 2016JC2037	Al-Shenawy HA, 2016, APMIS, V124, P229, DOI 10.1111/apm.12498; Catalano M, 2015, MOL ONCOL, V9, P1612, DOI 10.1016/j.molonc.2015.04.016; Chen YS, 2009, PATHOL ONCOL RES, V15, P487, DOI 10.1007/s12253-008-9143-8; Cicchini M, 2014, AUTOPHAGY, V10, P2036, DOI 10.4161/auto.34398; Deng GL, 2017, SCI REP-UK, V7, DOI 10.1038/srep41616; Gammoh N, 2016, AUTOPHAGY, V12, P1431, DOI 10.1080/15548627.2016.1190053; Gonzalez DM, 2014, SCI SIGNAL, V7, DOI 10.1126/scisignal.2005189; Ju LL, 2016, EUR REV MED PHARMACO, V20, P1993; Kalluri R, 2009, J CLIN INVEST, V119, P1420, DOI 10.1172/JCI39104; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Kim SY, 2014, BIOCHEM PHARMACOL, V88, P178, DOI 10.1016/j.bcp.2014.01.027; Ko YH, 2013, PANCREAS, V42, P829, DOI 10.1097/MPA.0b013e318279d0dc; Koukourakis MI, 2010, BRIT J CANCER, V103, P1209, DOI 10.1038/sj.bjc.6605904; Li BX, 2009, AUTOPHAGY, V5, P303, DOI 10.4161/auto.5.3.7491; Li J, 2013, CARCINOGENESIS, V34, P1343, DOI 10.1093/carcin/bgt063; Lin L, 2015, MOL CELL ONCOL, V2, DOI 10.4161/23723556.2014.985913; Ma J, 2017, BMP4 ENHANCES HEPATO; Masuda G, 2016, ANTICANCER RES, V36, P129; Mei Y, 2016, PROTEIN SCI, V25, P1767, DOI 10.1002/pro.2984; Miller KD, 2016, CA-CANCER J CLIN, V66, P271, DOI 10.3322/caac.21349; Nitta T, 2014, INT J CLIN EXP PATHO, V7, P4913; Park JM, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0100819; Park JM, 2013, CANCER BIOL THER, V14, P100, DOI 10.4161/cbt.22954; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Siegel RL, 2015, CA-CANCER J CLIN, V65, P5, DOI [10.3322/caac.21254, 10.3322/caac.21208, 10.1001/jamaoto.2014.2530, 10.1136/bmj.g1502]; Song JR, 2009, AUTOPHAGY, V5, P1131, DOI 10.4161/auto.5.8.9996; Tan SF, 2016, INT J MOL MED, V37, P1030, DOI 10.3892/ijmm.2016.2492; Toton E, 2014, J PHYSIOL PHARMACOL, V65, P459; Winardi D, 2014, BIOMED RES INT, V2014, DOI 10.1155/2014/723176; Won SJ, 2017, AUTOPHAGY MEDIATES C; Yang SW, 2016, ONCOTARGET, V7, P39279, DOI 10.18632/oncotarget.9827; Yang ZL, 2015, CLIN RES HEPATOL GAS, V39, P98, DOI 10.1016/j.clinre.2014.06.014; Yue ZY, 2010, J MOL CELL BIOL, V2, P305, DOI 10.1093/jmcb/mjq028; Zhang Y, 2015, INT J COLORECTAL DIS, V30, P1173, DOI 10.1007/s00384-015-2273-z; Zhong Y, 2009, NAT CELL BIOL, V11, P468, DOI 10.1038/ncb1854; Zhu HT, 2014, ONCOL REP, V32, P935, DOI 10.3892/or.2014.3298	36	25	27	3	13	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0730-2312	1097-4644		J CELL BIOCHEM	J. Cell. Biochem.	AUG	2018	119	8					7022	7031		10.1002/jcb.26912			10	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	GK9EG	WOS:000436542900068	29738069				2022-04-25	
J	Castro, ED; Mathias, PPM; Batista, WL; Sato, AYS; Toledo, MS; Almeida, VT; Curcio, MF; Costa, PE; Stern, A; Monteiro, HP				Castro, Eloisa D.; Mathias, Pedro Paulo M.; Batista, Wagner L.; Sato, Alex Yuri S.; Toledo, Mayte S.; Almeida, Victor T.; Curcio, Marli F.; Costa, Paulo E.; Stern, Arnold; Monteiro, Hugo P.			Knockdown of the inducible nitric oxide synthase (NOS2) splicing variant S3 promotes autophagic cell death from nitrosative stress in SW480 human colon cancer cells	CELL BIOLOGY INTERNATIONAL			English	Article						alternative splicing; autophagy; colon cancer cells; inducible nitric oxide synthase-NOS2; nitric oxide; nitrosative stress	INHIBITION; PROTEIN; EXPRESSION; INSIGHTS; BREAST; NITROSYLATION; MUTAGENESIS; INDUCTION; PROGRAM; TARGET	Low levels of nitric oxide (NO) produced by constitutively expressed inducible NO synthase (NOS2) in tumor cells may be an important factor in their development. NOS2 expression is associated with high mortality rates for various cancers. Alternative splicing of NOS2 down-regulates its enzymatic activity, resulting in decreased intracellular NO concentrations. Specific probes to detect alternative splicing of NOS2 were used in two isogenic human colon cancer cell lines derived either from the primary tumor (SW480) or from a lymph node metastasis (SW620). Splicing variant of NOS2 S3, lacking exons 9, 10, and 11, was overexpressed in SW480 cells. NOS2 S3 was silenced in SW480 cells. Flow-cytometry analysis was used to estimate the intracellular NO levels and to analyze the cell cycle of the studied cell lines. Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine apoptosis and autophagy markers. SW480 and SW620 cells expressed NOS2 S3. Overexpression of the NOS2 S3 in SW480 cells downregulated intracellular NO levels. SW480 cells with knocked down NOS2 S3 (referred to as S3C9 cells) had higher intracellular levels of NO compared to the wild-type SW480 cells under serum restriction. Higher NO levels resulted in the loss of viability of S3C9 cells, which was associated with autophagy. Induction of autophagy by elevated intracellular NO levels in S3C9 cells under serum restriction, suggests that autophagy operates as a cytotoxic response to nitrosative stress. The expression of NOS2 S3 plays an important role in regulating intracellular NO production and maintaining viability in SW480 cells under serum restriction. These findings may prove significant in the design of NOS2/NO-based therapies for colon cancer.	[Castro, Eloisa D.; Mathias, Pedro Paulo M.; Toledo, Mayte S.; Almeida, Victor T.; Curcio, Marli F.; Costa, Paulo E.; Monteiro, Hugo P.] Univ Fed Sao Paulo, Ctr Cellular & Mol Therapy CTCMol, Dept Biochem, Rua Mirassol 207, Sao Paulo, SP, Brazil; [Batista, Wagner L.] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Sao Paulo, Brazil; [Stern, Arnold] NYU, Grossman Sch Med, New York, NY USA; [Sato, Alex Yuri S.] Univ Fed Sao Paulo, Dept Morphol & Genet, Sao Paulo, Brazil		Monteiro, HP (corresponding author), Univ Fed Sao Paulo, Ctr Cellular & Mol Therapy CTCMol, Dept Biochem, Rua Mirassol 207, Sao Paulo, SP, Brazil.	hugo.monteiro@unifesp.br	Batista, Wagner L./C-8204-2012; Sato, Alex Yuri Simões/R-6850-2017	Sato, Alex Yuri Simões/0000-0002-4085-2000	Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES/Brazil)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, (CNPq)/BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ) [481154/2013-2]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)/BrazilFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/10470-1, 2018/15038-7]	Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES/Brazil); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, (CNPq)/Brazil, Grant/Award Number: 481154/2013-2; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)/Brazil, Grant/Award Numbers: 2012/10470-1, 2018/15038-7	Ahn CH, 2007, APMIS, V115, P1344, DOI 10.1111/j.1600-0463.2007.00858.x; Benson G, 1999, NUCLEIC ACIDS RES, V27, P573, DOI 10.1093/nar/27.2.573; Chakraborty S, 2019, CELL SIGNAL, V64, DOI 10.1016/j.cellsig.2019.109411; Chen M, 2009, NAT REV MOL CELL BIO, V10, P741, DOI 10.1038/nrm2777; Cheng RYS, 2014, NITRIC OXIDE-BIOL CH, V43, P17, DOI 10.1016/j.niox.2014.08.003; de Oliveira GA, 2017, ANTIOXID REDOX SIGN, V26, P1059, DOI 10.1089/ars.2016.6850; Eissa NT, 1998, P NATL ACAD SCI USA, V95, P7625, DOI 10.1073/pnas.95.13.7625; Eissa NT, 1996, J BIOL CHEM, V271, P27184, DOI 10.1074/jbc.271.43.27184; Eissa NT, 2001, AM J RESP CELL MOL, V24, P616, DOI 10.1165/ajrcmb.24.5.4324; Fujiwara K, 2008, J BIOL CHEM, V283, P388, DOI 10.1074/jbc.M611043200; Fukumura D, 2006, NAT REV CANCER, V6, P521, DOI 10.1038/nrc1910; Heinecke JL, 2014, P NATL ACAD SCI USA, V111, P6323, DOI 10.1073/pnas.1401799111; HIGUCHI R, 1988, NUCLEIC ACIDS RES, V16, P7351, DOI 10.1093/nar/16.15.7351; HO SN, 1989, GENE, V77, P51, DOI 10.1016/0378-1119(89)90358-2; Izuishi K, 2000, CANCER RES, V60, P6201; Jarry A, 2004, CANCER RES, V64, P4227, DOI 10.1158/0008-5472.CAN-04-0254; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Klionsky DJ, 2008, AUTOPHAGY, V4, P849, DOI 10.4161/auto.6845; LAVAL F, 1994, CARCINOGENESIS, V15, P443, DOI 10.1093/carcin/15.3.443; LEE CM, 1995, J BIOL CHEM, V270, P27403, DOI 10.1074/jbc.270.46.27403; Levine B, 2007, NATURE, V446, P745, DOI 10.1038/446745a; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Liao WB, 2019, BIOMED RES INT, V2019, DOI 10.1155/2019/6304851; Lim DY, 2005, J CELL PHYSIOL, V205, P107, DOI 10.1002/jcp.20380; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Ma Z, 2017, ENVIRON TOXICOL, V32, P2428, DOI 10.1002/tox.22457; Mauvezin C, 2015, AUTOPHAGY, V11, P1437, DOI 10.1080/15548627.2015.1066957; Mizushima N, 2011, ANNU REV CELL DEV BI, V27, P107, DOI 10.1146/annurev-cellbio-092910-154005; Monteiro HP, 2019, NITRIC OXIDE-BIOL CH, V89, P1, DOI 10.1016/j.niox.2019.04.009; Monteiro HP, 2015, BIOMED J, V38, P380, DOI 10.4103/2319-4170.158624; Oliveira CJR, 2008, NITRIC OXIDE-BIOL CH, V18, P241, DOI 10.1016/j.niox.2008.02.001; Pautz A, 2010, NITRIC OXIDE-BIOL CH, V23, P75, DOI 10.1016/j.niox.2010.04.007; Puschel F, 2020, P NATL ACAD SCI USA, V117, P9932, DOI 10.1073/pnas.1913707117; Reynolds A, 2004, NAT BIOTECHNOL, V22, P326, DOI 10.1038/nbt936; STUEHR DJ, 1989, J EXP MED, V169, P1543, DOI 10.1084/jem.169.5.1543; Swart C, 2016, EUR J CELL BIOL, V95, P598, DOI 10.1016/j.ejcb.2016.10.005; Tiscornia AC, 2004, LEUKEMIA, V18, P48, DOI 10.1038/sj.leu.2403169; Vannini F, 2015, REDOX BIOL, V6, P334, DOI 10.1016/j.redox.2015.08.009; Vasudevan D, 2014, VITAM HORM, V96, P265, DOI 10.1016/B978-0-12-800254-4.00011-8; WINK DA, 1991, SCIENCE, V254, P1001, DOI 10.1126/science.1948068; Yu L, 2004, SCIENCE, V304, P1500, DOI 10.1126/science.1096645	41	0	0	0	0	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	1065-6995	1095-8355		CELL BIOL INT	Cell Biol. Int.	JAN	2022	46	1					158	169		10.1002/cbin.11717		NOV 2021	12	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	XV4LP	WOS:000715878800001	34719858				2022-04-25	
J	Chen, GY; Meng, CL; Lin, KC; Tuan, HY; Yang, HJ; Chen, CL; Li, KC; Chiang, CS; Hu, YC				Chen, Guan-Yu; Meng, Chia-Le; Lin, Kuan-Chen; Tuan, Hsing-Yu; Yang, Hong-Jie; Chen, Chiu-Ling; Li, Kuei-Chang; Chiang, Chi-Shiun; Hu, Yu-Chen			Graphene oxide as a chemosensitizer: Diverted autophagic flux, enhanced nuclear import, elevated necrosis and improved antitumor effects	BIOMATERIALS			English	Article						Autophagy; Cisplatin; Chemoresistance; Graphene oxide; Nuclear import; Necrosis	CANCER-CELLS; CISPLATIN RESISTANCE; OVARIAN-CANCER; THERAPY; DEATH; CYTOTOXICITY; CARCINOMA; RESPONSES; DNA; INFLAMMATION	Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we demonstrated that both GO and the chemotherapy drug cisplatin (CDDP) induced autophagy but elicited low degrees of CT26 cell death. Strikingly, GO combined with CDDP (GO/COOP) potentiated the CT26 cell killing via necrosis. GO/CDDP not only elicited autophagy, but induced the nuclear import of CDDP and the autophagy marker LC3. The nuclear LC3 did not co-localize with p62 or Lamp-2, neither did blocking autolysosome formation significantly hinder the nuclear import of LC3/CDDP and necrosis, indicating that autophagosome and autolysosome formation was dispensable. Conversely, suppressing phagophore formation and importin-alpha/beta significantly alleviated the nuclear import of LO/CDDP and necrosis. These data suggested that GO/CDDP diverted the LC3 flux in the early phase of autophagy, resulting in LC3 trafficking towards the nucleus in an importin-alpha/beta-dependent manner, which concurred with the CDDP nuclear import and necrosis. Intratumoral injection of GO/CDDP into mice bearing CT26 colon tumors potentiated immune cell infiltration and promoted cell death, autophagy and HMGB1 release, thereby synergistically augmenting the antitumor effects. Altogether, we unveiled a mechanism concerning how nanomaterials chemosensitize cancer cells and demonstrated the potentials of GO as a chemosensitizer. (C) 2014 Elsevier Ltd. All rights reserved.	[Chen, Guan-Yu; Meng, Chia-Le; Lin, Kuan-Chen; Tuan, Hsing-Yu; Yang, Hong-Jie; Chen, Chiu-Ling; Li, Kuei-Chang; Hu, Yu-Chen] Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu 300, Taiwan; [Lin, Kuan-Chen; Chiang, Chi-Shiun] Natl Tsing Hua Univ, Dept Biomed Engn & Environm Sci, Hsinchu 300, Taiwan		Hu, YC (corresponding author), Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu 300, Taiwan.	ychu@mx.nthu.edu.tw	Chiang, Chi-Shiun/A-9562-2008	Chiang, Chi-Shiun/0000-0002-2581-4129; Tuan, Hsing-Yu/0000-0003-2819-2270	National Tsing Hua University (Toward World-Class University Project) [102N2051E1, 103N2051E1]; National Tsing Hua University (NTHU-CGMH Joint Research Program) [103N2758E1]; Ministry of Science and Technology, TaiwanMinistry of Science and Technology, Taiwan [NSC 102-2622-E-007-022-CC1, NSC 102-2221-E-007-023-MY3, MOST 103-2221-E-007-093-MY3]	The authors acknowledge the support from the National Tsing Hua University (Toward World-Class University Project 102N2051E1, 103N2051E1 and NTHU-CGMH Joint Research Program 103N2758E1) and Ministry of Science and Technology (NSC 102-2622-E-007-022-CC1, NSC 102-2221-E-007-023-MY3 and MOST 103-2221-E-007-093-MY3), Taiwan.	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J	Swayden, M; Bekdash, A; Fakhoury, I; El-Atat, O; Borjac-Natour, J; El-Sibai, M; Abi-Habib, RJ				Swayden, Mirna; Bekdash, Amira; Fakhoury, Isabelle; El-Atat, Oula; Borjac-Natour, Jamila; El-Sibai, Mirvat; Abi-Habib, Ralph J.			Activation of autophagy following [HuArgI (Co)-PEG5000]-induced arginine deprivation mediates cell death in colon cancer cells	HUMAN CELL			English	Article						[HuArgI (co)-PEG5000]; Colorectal cancer; Arginine auxotrophy; Autophagy	RECOMBINANT HUMAN ARGINASE; ARGININOSUCCINATE SYNTHETASE EXPRESSION; HUMAN HEPATOCELLULAR-CARCINOMA; ANTHRAX LETHAL TOXIN; I (CO)-PEG5000; L-ASPARAGINASE; CYTOTOXICITY; LEUKEMIA; PROLIFERATION; DEPLETION	Deregulating cellular energetics by reprogramming metabolic pathways, including arginine metabolism, is critical for cancer cell onset and survival. Drugs that target the specific metabolic requirements of cancer cells have emerged as promising targeted cancer therapeutics. In this study, we investigate the therapeutic potential of targeting colon cancer cells using arginine deprivation induced by a pegylated cobalt-substituted recombinant human Arginase I [HuArgI (Co)-PEG5000]. Four colon cancer cell lines were tested for their sensitivity to [HuArgI (Co)-PEG5000] as well as for their mechanism of cell death following arginine deprivation. All four cell lines were sensitive to arginine deprivation induced by [HuArgI (Co)-PEG5000]. All cells expressed ASS1 and were rescued from arginine deprivation-induced cytotoxicity by the addition of excessl-citrulline, indicating they are partially auxotrophic for arginine. Mechanistically, cells treated with [HuArgI (Co)-PEG5000] were negative for AnnexinV and lacked caspase activation. Further investigation revealed that arginine deprivation leads to a marked and prolonged activation of autophagy in both Caco-2 and T84 cell lines. Finally, we show that [HuArgI (Co)-PEG5000] causes cell death by sustained activation of autophagy as evidenced by the decrease in cell cytotoxicity upon treatment with chloroquine, an autophagy inhibitor. Altogether, these data demonstrate that colon cancer cells are partially auxotrophic for arginine and sensitive to [HuArgI (Co)-PEG5000]-induced arginine deprivation. They also show that the activation of autophagy does not play protective roles but rather, induces cytotoxicity and leads to cell death.	[Bekdash, Amira; Fakhoury, Isabelle; El-Atat, Oula; El-Sibai, Mirvat; Abi-Habib, Ralph J.] Lebanese Amer Univ, Dept Nat Sci, Sch Arts & Sci, Beirut 11022801, Lebanon; [Swayden, Mirna; Borjac-Natour, Jamila] Beirut Arab Univ, Dept Biol & Environm Sci, Sch Arts & Sci, Beirut, Lebanon		Abi-Habib, RJ (corresponding author), Lebanese Amer Univ, Dept Nat Sci, Sch Arts & Sci, Beirut 11022801, Lebanon.	ralph.abihabib@lau.edu.lb	Abi-Habib, Ralph/AAP-2397-2020; atat, oula el/AAH-7689-2019; Abi-Habib, Ralph/S-5194-2019	atat, oula el/0000-0003-1341-0204; Abi-Habib, Ralph/0000-0002-9587-7758; Bekdash, Amira/0000-0002-5065-5131	Lebanese American University	The authors thank the Lebanese American University for funding and support	Agrawal V, 2013, PROTEIN PEPTIDE LETT, V20, P392, DOI 10.2174/092986613805290426; Agrawal V, 2012, ANTI-CANCER DRUG, V23, P51, DOI 10.1097/CAD.0b013e32834ae42b; Al-Dimasi S, 2016, INT J ONCOL, V48, P1913, DOI 10.3892/ijo.2016.3431; Al-Koussa H, 2019, INT J MOL SCI, V20, DOI 10.3390/ijms20236018; Araghi M, 2019, INT J CANCER, V144, P2992, DOI 10.1002/ijc.32055; Bean GR, 2016, CELL DEATH DIS, V7, DOI 10.1038/cddis.2016.232; Bekdash A, 2015, TRANSL ONCOL, V8, P347, DOI 10.1016/j.tranon.2015.07.001; Changou CA, 2014, P NATL ACAD SCI USA, V111, P14147, DOI 10.1073/pnas.1404171111; Cheng PNM, 2007, CANCER RES, V67, P309, DOI 10.1158/0008-5472.CAN-06-1945; Cloonan SM, 2011, INT J CANCER, V128, P1712, DOI 10.1002/ijc.25477; Cramer SL, 2017, NAT MED, V23, P120, DOI 10.1038/nm.4232; Daaboul HE, 2017, CHEM-BIOL INTERACT, V275, P162, DOI 10.1016/j.cbi.2017.08.003; Davis FF, 1978, ENZYME ENG, P169; Delage B, 2012, CELL DEATH DIS, V3, DOI 10.1038/cddis.2012.83; Delage B, 2010, INT J CANCER, V126, P2762, DOI 10.1002/ijc.25202; El-Boubbou K, 2017, J BIOMED NANOTECHNOL, V13, P500, DOI 10.1166/jbn.2017.2365; Glazer ES, 2011, TRANSL ONCOL, V4, P138, DOI 10.1593/tlo.10265; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Harris JM, 2003, NAT REV DRUG DISCOV, V2, P214, DOI 10.1038/nrd1033; Hernandez CP, 2010, BLOOD, V115, P5214, DOI 10.1182/blood-2009-12-258822; Kassab E, 2013, TRANSL ONCOL, V6, P25, DOI 10.1593/tlo.12313; Khoury O, 2015, J NEURO-ONCOL, V122, P75, DOI 10.1007/s11060-014-1698-5; Kim RH, 2009, CANCER RES, V69, P700, DOI 10.1158/0008-5472.CAN-08-3157; Kuo MT, 2010, ONCOTARGET, V1, P246, DOI 10.18632/oncotarget.135; Lam TL, 2009, CANCER LETT, V277, P91, DOI 10.1016/j.canlet.2008.11.031; Lin C, 2015, APPL MICROBIOL BIOT, V99, P8487, DOI 10.1007/s00253-015-6565-6; Macintosh RL, 2012, CELL CYCLE, V11, P2022, DOI 10.4161/cc.20424; Mauldin JP, 2012, TRANSL ONCOL, V5, P26, DOI 10.1593/tlo.11262; Mizushima N, 2007, GENE DEV, V21, P2861, DOI 10.1101/gad.1599207; Morris SM, 2004, J NUTR, V134, p2743S, DOI 10.1093/jn/134.10.2743S; Muller HJ, 1998, CRIT REV ONCOL HEMAT, V28, P97, DOI 10.1016/S1040-8428(98)00015-8; Mussai F, 2013, BLOOD, V122, P749, DOI 10.1182/blood-2013-01-480129; Nasrallah A, 2014, ONCOL REP, V31, P505, DOI 10.3892/or.2013.2861; Nasreddine G, 2020, INVEST NEW DRUG, V38, P10, DOI 10.1007/s10637-019-00756-w; Periyasamy-Thandavan S, 2009, AM J PHYSIOL-RENAL, V297, pF244, DOI 10.1152/ajprenal.00033.2009; Shebaby WN, 2015, J MED FOOD, V18, P745, DOI 10.1089/jmf.2014.3225; Stone EM, 2010, ACS CHEM BIOL, V5, P333, DOI 10.1021/cb900267j; Syed N, 2013, CELL DEATH DIS, V4, DOI 10.1038/cddis.2012.197; Tanios R, 2013, LEUKEMIA RES, V37, P1565, DOI 10.1016/j.leukres.2013.08.007; Wang J, 2014, J BIOL CHEM, V289, P17163, DOI 10.1074/jbc.M114.558288; Wetzler M, 2007, BLOOD, V109, P4164, DOI 10.1182/blood-2006-09-045351; Yoon CY, 2007, INT J CANCER, V120, P897, DOI 10.1002/ijc.22322; Zhang N, 2010, AUTOPHAGY, V6, P1157, DOI 10.4161/auto.6.8.13614	43	3	4	0	1	SPRINGER JAPAN KK	TOKYO	SHIROYAMA TRUST TOWER 5F, 4-3-1 TORANOMON, MINATO-KU, TOKYO, 105-6005, JAPAN	0914-7470	1749-0774		HUM CELL	Hum. Cell	JAN	2021	34	1					152	164		10.1007/s13577-020-00437-4		SEP 2020	13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	PP2RN	WOS:000572858600001	32979152				2022-04-25	
J	Jiang, F; Zhou, JY; Zhang, D; Liu, MH; Chen, YG				Jiang, Feng; Zhou, Jin-Yong; Zhang, Dan; Liu, Ming-Hao; Chen, Yu-Gen			Artesunate induces apoptosis and autophagy in HCT116 colon cancer cells, and autophagy inhibition enhances the artesunate-induced apoptosis	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE			English	Article						apoptosis; artesunate; autophagy; colon cancer	MEDIATED INTRINSIC PATHWAY; COLORECTAL-CANCER; SKM-1 CELLS; EXPRESSION; GROWTH; SUPPRESSES; RESISTANCE; STRESS; ATG12	The present study assessed the antitumor effect of artesunate (ART) in vitro and in vivo, as well as its underlying mechanism of action in HCT116 colon cancer cells. An MTT assay, DAPI staining, flow cytometry, western blotting, immunohistochemistry, transmission electron microscopy and TUNEL assay were performed to study the molecular mechanism underlying the antitumor effects of ART in HCT116 colon cancer cells. ART was observed to inhibit proliferation by inducing the apoptosis of HCT116 cells both in vitro and in vivo. Flow cytometry analysis demonstrated that treatment with 2 and 4 mu g/ml ART for 48 h induced early apoptosis in 22.7 and 33.8% of cells, respectively. In the xenograft tumors of BALB/c nude mice, TUNEL-positive cells increased in the ART group compared with that in the normal saline group. Furthermore,the associated mitochondrial cleaved-caspase 3, poly-ADP ribose polymerase (PARP), caspase 9 and Bcl-2-associated X protein levels increased while B-cell lymphoma-2 (Bcl-2) decreased both in the cell and animal ART-treated group. ART-treated cells also exhibited autophagy induction, as evidenced by increased protein expression levels of light chain 3 (LC3) and beclin-1, and the presence of autophagosomes. Notably, pharmacological blockade of autophagy activation using hydroxychloroquine markedly enhanced ART-induced apoptosis and increased the protein levels of cleaved caspase 3 and PARP, while decreasing the levels of LC3 and beclin-1. These findings suggested that the ART-induced autophagy may have a cytoprotective effect by suppressing apoptosis. In conclusion, ART may be a potentially clinically useful anticancer drug for human colon cancer. In addition, co-treatment with ART and an autophagy inhibitor may be an effective anticancer therapy.	[Jiang, Feng; Zhang, Dan; Chen, Yu-Gen] Nanjing Univ TCM, Affiliated Hosp, Dept Colorectal Surg, 155 Hanzhong Rd, Nanjing 210029, Jiangsu, Peoples R China; [Jiang, Feng; Zhang, Dan; Liu, Ming-Hao] Nanjing Univ Chinese Med, Clin Med Coll 1, Nanjing 210023, Jiangsu, Peoples R China; [Zhou, Jin-Yong] Nanjing Univ TCM, Affiliated Hosp, Dept Cent Lab, Nanjing 210029, Jiangsu, Peoples R China		Chen, YG (corresponding author), Nanjing Univ TCM, Affiliated Hosp, Dept Colorectal Surg, 155 Hanzhong Rd, Nanjing 210029, Jiangsu, Peoples R China.	chenyg666@126.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81373645, 81573978]; Priority Academic Program Development of Jiangsu Higher Education Institutions; Jiangsu Province Special Program of Medical Science [BL2014100]; Peak Academic Talents plan of the Jiangsu Province Hospital of TCM (Jiangsu, China) [BRA2017536]	This study was supported by the National Natural Science Foundation of China (grant no. 81373645, 81573978). This study was also supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Jiangsu Province Special Program of Medical Science (grant no. BL2014100) and by the Peak Academic Talents plan (grant no. BRA2017536) of the Jiangsu Province Hospital of TCM (Jiangsu, China).	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J. Mol. Med.	SEP	2018	42	3					1295	1304		10.3892/ijmm.2018.3712			10	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	GW4IE	WOS:000446875200010	29901098	Green Published, hybrid, Green Submitted			2022-04-25	
J	Chen, MC; Lee, NH; Ho, TJ; Hsu, HH; Kuo, CH; Kuo, WW; Lin, YM; Tsai, FJ; Tsai, CH; Huang, CY				Chen, Ming-Cheng; Lee, Nien-Hung; Ho, Tsung-Jung; Hsu, Hsi-Hsien; Kuo, Chia-Hua; Kuo, Wei-Wen; Lin, Yueh-Min; Tsai, Fuu-Jen; Tsai, Chang-Hai; Huang, Chih-Yang			Resistance to irinotecan (CPT-11) activates epidermal growth factor receptor/nuclear factor kappa B and increases cellular metastasis and autophagy in LoVo colon cancer cells	CANCER LETTERS			English	Article						Chemoresistance; CPT-11; NF-kappa B; Metastasis; Autophagy	COLORECTAL-CANCER; INDUCIBLE CHEMORESISTANCE; ANTICANCER DRUGS; GEFITINIB IRESSA; INHIBITION; CHEMOTHERAPY; MECHANISMS; THERAPY; DEATH; 5-FLUOROURACIL	Chemotherapy is usually applied to treat colon cancer but leads to chemoresistance, and increased metastasis and invasion. The main focus of this study is to observe effects of resistance to irinotecan (CPT-11) on metastasis, invasion and autophagy in CPT-11 resistant (CPT-11-R) LoVo colon cancer cells. CPT-11, a topoisomerase I inhibitor and a first-line chemotherapeutic drug, is used to treat colon cancer. CPT-11-R cells were constructed in a step-wise fashion with increasing CPT-11 doses. The CPT-11-R strain had a significantly lower expression of Wnt/beta-catenin pathway, but induced an EGFR/IKK alpha/beta/NF-kappa B pathway with elevated cell cycle, metastasis and basal autophagy. C) 2014 Elsevier Ireland Ltd. All rights reserved.	[Chen, Ming-Cheng; Lee, Nien-Hung; Huang, Chih-Yang] China Med Univ, Grad Inst Basic Med Sci, Taichung, Taiwan; [Chen, Ming-Cheng] Taichung Vet Gen Hosp, Puli Branch, Nantou, Taiwan; [Ho, Tsung-Jung] China Med Univ, Beigang Hosp, Chinese Med Dept, Yunlin, Taiwan; [Hsu, Hsi-Hsien] Mackay Mem Hosp, Div Colorectal Surg, Taipei, Taiwan; [Hsu, Hsi-Hsien] Nursing & Management Coll, Mackay Jr Coll Med, Taipei, Taiwan; [Kuo, Chia-Hua] Univ Taipei, Dept Sports Sci, Taipei, Taiwan; [Kuo, Wei-Wen] China Med Univ, Dept Biol Sci & Technol, Taichung, Taiwan; [Lin, Yueh-Min] Changhua Christian Hosp, Dept Pathol, Changhua, Taiwan; [Lin, Yueh-Min] Jen Teh Jr Coll Med, Dept Med Technol, Miaoli, Taiwan; [Tsai, Fuu-Jen; Huang, Chih-Yang] China Med Univ, Grad Inst Chinese Med Sci, Taichung, Taiwan; [Tsai, Chang-Hai] Asia Univ, Dept Healthcare Adm, Taichung, Taiwan; [Huang, Chih-Yang] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung, Taiwan		Huang, CY (corresponding author), China Med Univ & Hosp, Sch Med, Grad Inst Basic Med Sci, 91 Hsueh Shih Rd, Taichung 404, Taiwan.	cyhuang@mail.cmu.edu.tw	Yuang, Chih-Yang/O-5111-2015; Tsai, Fuu-Jen/J-4140-2015	Lee, Nien-Hung/0000-0001-5423-8880; Kuo, Chia-Hua/0000-0002-1731-4984	Taiwan Department of Health Clinical Trial and Research Center of Excellence [DOH102-TD-B-111-004]	This study is supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004).	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JUL 10	2014	349	1					51	60		10.1016/j.canlet.2014.03.023			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AI8YW	WOS:000337213900007	24726344				2022-04-25	
J	Niklaus, M; Adams, O; Berezowska, S; Zlobec, I; Graber, F; Slotta-Huspenina, J; Nitsche, U; Rosenberg, R; Tschan, MP; Langer, R				Niklaus, Monique; Adams, Olivia; Berezowska, Sabina; Zlobec, Inti; Graber, Franziska; Slotta-Huspenina, Julia; Nitsche, Ulrich; Rosenberg, Robert; Tschan, Mario P.; Langer, Rupert			Expression analysis of LC3B and p62 indicates intact activated autophagy is associated with an unfavorable prognosis in colon cancer	ONCOTARGET			English	Article						colon cancer; autophagy; LC3; p62; immunohistochemistry	COLORECTAL-CANCER; P62/SEQUESTOSOME 1; CARCINOMA; CELLS; COMBINATION; PROGRESSION; INHIBITION; GUIDELINES; THERAPY; IMPACT	Autophagy is a lysosomal degradation and recycling process implicated in cancer progression and therapy resistance. We assessed the impact of basal autophagy in colon cancer (CC) in vitro and ex vivo. Functional autophagy was demonstrated in CC cell lines (LoVo; HT-29) showing a dose-dependent increase of the autophagy markers LC3B, p62 and autophagic vesciles upon increasing concentrations of the autophagy inhibitor chloroquine, which was demonstrated by immunoblotting, immunofluorescence and electron microscopy. Next, tissue microarrays with 292 primary resected CC, with cores from different tumor regions, and normal mucosa were analyzed by immunohistochemistry for LC3B and p62. CC tissue showed LC3B dot-like, p62 dot-like, cytoplasmic and nuclear staining in various levels without significant intratumoral heterogeneity. Tumoral LC3B and p62 expression was significantly higher than in normal tissue (p<0.001). No associations between staining patterns and pathological features (e.g. TNM categories; grading) were observed. Both low LC3B dot-like and low p62 dot-like-cytoplasmic staining were associated with worse overall survival (p=0.005 and p=0.002). The best prognostic discrimination, however, was seen for a combination of LC3B dot-like/p62 dot-like-cytoplasmic staining: high expression of both markers, indicative of impaired activated autophagy, was associated with the best overall survival. In contrast, high LC3B dot-like/low p62 dot-like-cytoplasmic expression, indicative of intact activated autophagy, was associated with the worst outcome (p<0.001 in univariate and HR=0.751; CI=0.6070.928; p=0.008 in multivariate analysis). These specific expression patterns of LC3B and p62 pointing to different states of autophagy associated with diverging clinical outcomes highlighte the potential significance of basal autophagy in CC biology.	[Niklaus, Monique; Adams, Olivia; Berezowska, Sabina; Zlobec, Inti; Graber, Franziska; Tschan, Mario P.; Langer, Rupert] Univ Bern, Inst Pathol, CH-3008 Bern, Switzerland; [Adams, Olivia; Zlobec, Inti; Tschan, Mario P.] Univ Bern, Grad Sch Cellular & Biomed Sci, CH-3008 Bern, Switzerland; [Slotta-Huspenina, Julia] Tech Univ Munich, Inst Pathol, D-81675 Munich, Germany; [Nitsche, Ulrich] Tech Univ Munich, Dept Surg, D-81675 Munich, Germany; [Rosenberg, Robert] Kantonsspital Liestal, Dept Surg, CH-4410 Liestal, Switzerland		Langer, R (corresponding author), Univ Bern, Inst Pathol, CH-3008 Bern, Switzerland.	rupert.langer@pathology.unibe.ch	Langer, Rupert/AAU-1174-2021; Berezowska, Sabina/AAJ-4557-2021	Langer, Rupert/0000-0001-9491-3609; Berezowska, Sabina/0000-0001-5442-9791; Zlobec, Inti/0000-0001-6741-3000	Swiss Cancer League [KFS-3083-02-2013]	The study has been funded by the Swiss Cancer League (KFS-3083-02-2013).	Adams O, 2016, ONCOTARGET, V7, P39241, DOI 10.18632/oncotarget.9649; Bauer K, 2012, CELL ONCOL, V35, P197, DOI 10.1007/s13402-012-0079-3; Boone BA, 2015, ANN SURG ONCOL, V22, P4402, DOI 10.1245/s10434-015-4566-4; Choi JH, 2014, GASTROENT RES PRACT, V2014, DOI 10.1155/2014/179586; Drecoll E, 2014, INT J COLORECTAL DIS, V29, P663, DOI 10.1007/s00384-014-1857-3; Duffy A, 2015, CANCER CHEMOTH PHARM, V75, P439, DOI 10.1007/s00280-014-2637-z; Fitzmaurice C, 2015, JAMA ONCOL, V1, P505, DOI 10.1001/jamaoncol.2015.0735; Galluzzi L, 2017, NAT REV CLIN ONCOL, V14, P247, DOI 10.1038/nrclinonc.2016.183; Galluzzi L, 2015, EMBO J, V34, P856, DOI 10.15252/embj.201490784; Gewirtz DA, 2016, CANCER RES, V76, P5610, DOI 10.1158/0008-5472.CAN-16-0722; Groulx JF, 2012, AUTOPHAGY, V8, P893, DOI 10.4161/auto.19738; Guo GF, 2011, WORLD J GASTROENTERO, V17, P4779, DOI 10.3748/wjg.v17.i43.4779; Jiang PD, 2015, METHODS, V75, P13, DOI 10.1016/j.ymeth.2014.11.021; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Liu JL, 2014, BRIT J CANCER, V111, P944, DOI 10.1038/bjc.2014.355; Mahalingam D, 2014, AUTOPHAGY, V10, P1403, DOI 10.4161/auto.29231; Park JM, 2013, CANCER BIOL THER, V14, P100, DOI 10.4161/cbt.22954; Ren F, 2014, MOL CELL BIOCHEM, V385, P95, DOI 10.1007/s11010-013-1818-0; Sasaki K, 2010, BMC CANCER, V10, DOI 10.1186/1471-2407-10-370; Sato K, 2007, CANCER RES, V67, P9677, DOI 10.1158/0008-5472.CAN-07-1462; Schlafli AM, 2015, EUR J HISTOCHEM, V59, P137, DOI 10.4081/ejh.2015.2481; Schlafli AM, 2016, ONCOTARGET, V7, P39544, DOI 10.18632/oncotarget.9647; Schmitz KJ, 2016, WORLD J SURG ONCOL, V14, DOI 10.1186/s12957-016-0946-x; Schmoll HJ, 2012, ANN ONCOL, V23, P2479, DOI 10.1093/annonc/mds236; Torre LA, 2015, CA-CANCER J CLIN, V65, P87, DOI 10.3322/caac.21262; Wong A, 2014, CLIN GASTROENTEROL H, V12, P139, DOI 10.1016/j.cgh.2013.08.040; Wu SH, 2015, INT J CLIN EXP PATHO, V8, P3882; Yang MP, 2015, ONCOTARGET, V6, P7084, DOI 10.18632/oncotarget.3054; Zhang Y, 2015, CURR MED RES OPIN, V31, P1009, DOI 10.1185/03007995.2015.1025731; Zheng Hai-yang, 2012, Cancer Biology Medicine, V9, P105, DOI 10.3969/j.issn.2095-3941.2012.02.004; Zlobec I, 2013, J TRANSL MED, V11, DOI 10.1186/1479-5876-11-104; Zlobec I, 2011, HISTOPATHOLOGY, V59, P482, DOI 10.1111/j.1365-2559.2011.03975.x	33	33	36	0	5	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	AUG	2017	8	33					54604	54615		10.18632/oncotarget.17554			12	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	FD9ER	WOS:000407826100059	28903368	Green Published, gold			2022-04-25	
J	Piao, SF; Ojha, R; Rebecca, VW; Samanta, A; Ma, XH; Mcafee, Q; Nicastri, MC; Buckley, M; Brown, E; Winkler, JD; Gimotty, PA; Amaravadi, RK				Piao, Shengfu; Ojha, Rani; Rebecca, Vito W.; Samanta, Arabinda; Ma, Xiao-hong; Mcafee, Quentin; Nicastri, Michael C.; Buckley, Meghan; Brown, Eric; Winkler, Jeffrey D.; Gimotty, Phyllis A.; Amaravadi, Ravi K.			ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells	AUTOPHAGY			English	Article						ALDH1; autophagy; chloroquine; HLTF; lysosome	ADVANCED SOLID TUMORS; PHASE-I TRIAL; RETINOIC ACID; CHROMOSOMAL INSTABILITY; COLORECTAL-CANCER; BRAIN-TUMORS; HYDROXYCHLOROQUINE; MELANOMA; GROWTH; BRAF(V600E)	Lysosomal autophagy inhibitors (LAI) such as hydroxychloroquine (HCQ) have significant activity in a subset of cancer cell lines. LAIs are being evaluated in cancer clinical trials, but genetic determinants of sensitivity to LAIs are unknown, making it difficult to predict which tumors would be most susceptible. Here we characterize differentially expressed genes in HCQ-sensitive (-S) and -resistant (-R) cancer cells. Notably, expression of canonical macroautophagy/autophagy genes was not associated with sensitivity to HCQ. Expression patterns of ALDH1A1 (aldehyde dehydrogenase 1 family member A1) and HLTF (helicase like transcription factor) identified HCQ-S (ALDH1A1(high) HLTFlow; ALDH1A1(low) HLTFlow) and HCQ-R (ALDH1A1(low) HLTFhigh) cells. ALDH1A1 overexpression was found to enhance LAI cell entry and cytotoxicity without directly affecting lysosome function or autophagic flux. Expression of HLTF allows repair of DNA damage caused by LAI-induced reactive oxygen species, leading to HCQ resistance. Sensitivity to HCQ is increased in cells where HLTF is silenced by promoter methylation. HLTF overexpression blunted the antitumor efficacy of chloroquine derivatives in vitro and in vivo. Analysis of tumor RNA sequencing data from >700 patients in the Cancer Genome Atlas identified cancers including colon cancer, renal cell carcinoma, and gastric cancers, that were enriched for the HCQ-S or HCQ-R signature. These results provide mechanistic insights into LAI efficacy, and guidance for LAI clinical development.	[Piao, Shengfu; Ojha, Rani; Rebecca, Vito W.; Samanta, Arabinda; Ma, Xiao-hong; Mcafee, Quentin; Amaravadi, Ravi K.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA; [Nicastri, Michael C.; Winkler, Jeffrey D.] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA; [Buckley, Meghan; Gimotty, Phyllis A.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA; [Brown, Eric] Univ Penn, Dept Canc Biol, Philadelphia, PA 19104 USA; [Brown, Eric; Winkler, Jeffrey D.; Gimotty, Phyllis A.; Amaravadi, Ravi K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA		Amaravadi, RK (corresponding author), Univ Penn, Dept Med, Abramson Canc Ctr, 777 South Tower PCAM 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA.; Gimotty, PA (corresponding author), Univ Penn, Dept Biostat & Epidemiol, Abramson Canc Ctr, 631 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA.	pgimotty@mail.med.upenn.edu; ravi.amaravadi@uphs.upenn.edu	Ojha, Rani/ABF-9507-2020		SPORE [P50 CA174523]; Pennsylvania Dept of Health;  [R01CA169134];  [P01 CA114046];  [P30 CA016520];  [1R01CA198015]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P01CA114046, P50CA174523, R01CA198015, P30CA016520, R01CA169134] Funding Source: NIH RePORTER	R01CA169134 (RA; PG); P01 CA114046 (RA, JW); P30 CA016520 (RA); SPORE P50 CA174523 (RA); 1R01CA198015 (RA); Pennsylvania Dept of Health (RA)	Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Amaravadi RK, 2015, J CLIN INVEST, V125, P1393, DOI 10.1172/JCI81504; Barnard RA, 2014, AUTOPHAGY, V10, P1415, DOI 10.4161/auto.29165; BENJAMINI Y, 1995, J R STAT SOC B, V57, P289, DOI 10.1111/j.2517-6161.1995.tb02031.x; Boone BA, 2015, ANN SURG ONCOL, V22, P4402, DOI 10.1245/s10434-015-4566-4; Carew JS, 2007, BLOOD, V110, P313, DOI 10.1182/blood-2006-10-050260; Chang DJ, 2009, NAT CHEM BIOL, V5, P82, DOI 10.1038/nchembio.139; Das S, 2010, CANCER RES, V70, P7874, DOI 10.1158/0008-5472.CAN-10-1534; 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Rebecca VW, 2016, ONCOGENE, V35, P1, DOI 10.1038/onc.2015.99; Rosenfeld MR, 2014, AUTOPHAGY, V10, P1359, DOI 10.4161/auto.28984; Selvakumaran M, 2013, CLIN CANCER RES, V19, P2995, DOI 10.1158/1078-0432.CCR-12-1542; Sheffer M, 2009, P NATL ACAD SCI USA, V106, P7131, DOI 10.1073/pnas.0902232106; Thorburn A, 2014, PLOS BIOL, V12, DOI 10.1371/journal.pbio.1001967; Tomita H, 2016, ONCOTARGET, V7, P11018, DOI 10.18632/oncotarget.6920; Unk I, 2010, DNA REPAIR, V9, P257, DOI 10.1016/j.dnarep.2009.12.013; Vogl DT, 2014, AUTOPHAGY, V10, P1380, DOI 10.4161/auto.29264; Wang YN, 2016, MOL CELL, V63, P34, DOI 10.1016/j.molcel.2016.05.027; Wei YJ, 2013, CELL, V154, P1269, DOI 10.1016/j.cell.2013.08.015; White E, 2012, NAT REV CANCER, V12, P401, DOI 10.1038/nrc3262; Yang A, 2014, AUTOPHAGY, V10, P1683, DOI 10.4161/auto.29961; Yang SH, 2011, GENE DEV, V25, P717, DOI 10.1101/gad.2016111; Zhang Y, 2014, J CELL BIOCHEM, V115, P1528, DOI 10.1002/jcb.24807	53	14	16	0	11	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	1554-8627	1554-8635		AUTOPHAGY	Autophagy		2017	13	12					2056	2071		10.1080/15548627.2017.1377377			16	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	FT5TJ	WOS:000423215800005	28981387	Bronze, Green Published			2022-04-25	
J	Han, J; Li, J; Tang, KJ; Zhang, HH; Guo, B; Hou, N; Huang, C				Han, Jia; Li, Jie; Tang, Kaijie; Zhang, Huahua; Guo, Bo; Hou, Ni; Huang, Chen			miR-338-3p confers 5-fluorouracil resistance in p53 mutant colon cancer cells by targeting the mammalian target of rapamycin	EXPERIMENTAL CELL RESEARCH			English	Article						miR-338-3p; 5-FU resistance; Colon cancer cell; p53; mTOR	COLORECTAL-CANCER; AUTOPHAGY; CHEMORESISTANCE; MECHANISMS; APOPTOSIS; MICRORNA; MTOR	Evidence demonstrate that p53 mutations and microRNAs (miRs) are important components of 5-FU resistance in colorectal cancer (CRC). miR-338-3p has been reported associated with cancer prognosis. However whether or not it influences chemotherapy sensitivity and the underlying mechanisms have not been elucidated. Here, three types of human colon cancer cell lines, HT29 (mutant p53), HCT116 (wild-type p53), and HCT116 p53(-/-) (deficient p53), were treated with 5-FU. We showed that expression of miR-338-3p was correlated with apoptosis and 5-FU resistance in colon cancer cells. Ectopic expression of miR-338-3p conferred resistance to 5-FU in HCT116 cells. Further experiments indicated that miR-338-3p mediated 5-FU resistance through down-regulation of mTOR expression. Moreover, inhibition of miR-338-3p in HT29 and HCT116 p53(-/-) cells increased their sensitivity to 5-FU treatment. Furthermore, we detected autophagy changes in our experiment because mTOR was known prominently regulating autophagy and the competition between autophagy and apoptosis in response to 5-FU was a mechanism influencing 5-FU sensitivity. Our results reveal a critical and novel role of miR-338-3p in the correlation of 5-FU resistance with p53 status. Moreover, the miR-338-3p inhibitor has the potential to overcome 5-FU resistance in p53 mutant colon cancer cells.	[Han, Jia; Tang, Kaijie; Zhang, Huahua; Guo, Bo; Hou, Ni; Huang, Chen] Xi An Jiao Tong Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Hlth Sci Ctr, 76 Western Yanta Rd, Xian 710061, Shaanxi, Peoples R China; [Li, Jie] Xi An Jiao Tong Univ, Affiliated Hosp 2, Dept Gen Surg, Xian, Shaanxi, Peoples R China; [Zhang, Huahua] Yanan Univ, Med Coll, Yanan, Peoples R China; [Huang, Chen] Xi An Jiao Tong Univ, Coll Stomatol, Key Lab Shaanxi Prov Craniofacial Precis Med Res, Xian, Shaanxi, Peoples R China		Hou, N; Huang, C (corresponding author), Xi An Jiao Tong Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Hlth Sci Ctr, 76 Western Yanta Rd, Xian 710061, Shaanxi, Peoples R China.	houni@mail.xjtu.edu.cn; hchen@mail.xjtu.edu.cn	Tang, Kaijie/AAE-8848-2019	Tang, Kaijie/0000-0002-8138-0206	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81172358, 31100969]; Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education MinistryScientific Research Foundation for the Returned Overseas Chinese Scholars [2013-09]; Shaanxi Province Scientific Research and Sharing Platform Construction Project [2015FWPT-14]	We thank Prof. Mian Wu for providing HCT116 p53<SUP>-/-</SUP> cell line. This work was supported by the grant from the National Natural Science Foundation of China (81172358) to Jie Li, the grants from the National Natural Science Foundation of China (31100969) and the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry (2013-09) to Ni Hou, and the grant from the Shaanxi Province Scientific Research and Sharing Platform Construction Project (2015FWPT-14) to Chen Huang.	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Cell Res.	NOV 15	2017	360	2					328	336		10.1016/j.yexcr.2017.09.023			9	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	FM3EV	WOS:000414888000031	28928082				2022-04-25	
J	Habeeb, BS; Kitayama, J; Nagawa, H				Habeeb, Baker S.; Kitayama, Joji; Nagawa, Hirokazu			Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells	CANCER SCIENCE			English	Article							PLASMA ADIPONECTIN; PROSTATE-CANCER; ENDOMETRIAL CANCER; GROWTH; ASSOCIATION; RISK; EXPRESSION; RECEPTORS; OBESITY; DEATH	Adiponectin is known to have suppressive effects on tumor growth and is thought to be a key molecule in the positive correlation between obesity and cancer. However, the detailed mechanisms regulating tumor cell activity have not been elucidated. In this study, we found that both full-length (f-Ad) and globular adiponectin (g-Ad) inhibited cell growth in colon cancer cell lines in glucose-containing medium, whereas it supported cell survival in glucose-deprived medium, with an increase in AdipoR1 and AdipoR2 expression. The latter effect of adiponectin in glucose deprivation was significantly inhibited by adding autophagy inhibitors, chloroquine, 3-methyl adenine or a combination of pepstatin A and E-64d, suggesting that the effect of supporting cell growth was dependent, at least in part, on the induction of autophagy. The enhancement of autophagy was confirmed morphologically using green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) fusion proteins under a fluorescence microscope using stably transfected DLD-1 cells expressing GFP-LC3. Western blot analysis revealed that adiponectin increased the expression of LC3-1, LC3-2, phosphorylated AMPK alpha and PPAR alpha but decreased that of phosphorylated mTOR, insulin like growth factor (IGF)-1, phosphorylated serine/threonine kinase (Akt) and phosphorylated phosphatidylinositol 3-kinase (PI3K) in glucose-deprived medium. We conclude that adiponectin supports cell survival in glucose deprivation through enhancement of the autophagic machinery by AMPK alpha and PPAR alpha activation and IGF-1/PI3k/Akt/mTOR pathway inhibition. The bimodal effects of adiponectin are thought to be clinically important in the pathophysiology of tumor development and progression. (Cancer Sci 2011; 102: 999-1006).	[Habeeb, Baker S.; Kitayama, Joji; Nagawa, Hirokazu] Univ Tokyo, Dept Surg Oncol, Tokyo, Japan		Habeeb, BS (corresponding author), Univ Tokyo, Dept Surg Oncol, Tokyo, Japan.	bakershalal@gmail.com		Habeeb, Baker/0000-0001-8070-8532	Ministry of Education, Culture, Sports, Science and Technology of JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [20591563]; Ministry of Health, Labor and Welfare of JapanMinistry of Health, Labour and Welfare, Japan	This work was funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 20591563), and the Ministry of Health, Labor and Welfare of Japan.	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MAY	2011	102	5					999	1006		10.1111/j.1349-7006.2011.01902.x			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	751PP	WOS:000289630300012	21299716	Bronze			2022-04-25	
J	Chen, XP; Xu, H; Yu, XH; Wang, X; Zhu, XH; Xu, XF				Chen, Xiaping; Xu, Hang; Yu, Xinhua; Wang, Xue; Zhu, Xiaohu; Xu, Xiaofeng			Apigenin inhibits in vitro and in vivo tumorigenesis in cisplatin-resistant colon cancer cells by inducing autophagy, programmed cell death and targeting m-TOR/PI3K/Akt signalling pathway	JOURNAL OF BUON			English	Article						autophagy; apoptosis; cell cycle; apigenin; colon cancer	DIETARY FLAVONOID FISETIN; ANTICANCER ACTIVITY; PI3K/AKT/MTOR; APOPTOSIS; QUERCETIN; CURCUMIN; GROWTH	Purpose: Colon cancer is one of the deadly malignancies and the second most frequent cancer in the world. The development of drug resistance and dearth of the viable drug options forms an obstacle in the treatment of colon cancer. Herein, the anticancer potential of Apigenin was examined against cisplatin-resistant colon cancer cells. Methods: The proliferation rate of the cisplatin-resistant colon cancer cell line HT-29 was assessed by WST-1 assay. Autophagy was detected by electron microscopy. Apoptotic cell death was analysed by propidium iodide (PI) staining. Cell cycle analysis was performed by flow cytometry. Protein expression was determined by immuno blotting. Xenografted mice models were used for in vivo evaluation of Apigenin. Results: The results showed that Apigenin could considerably inhibit the proliferation of colon cancer cells. The anticancer activity of Apigenin against the HT-29 colon cancer cells was found to be due to induction of autophagy and apoptosis. The Apigenin-triggered apoptosis and autophagy were also linked with alteration in the apoptosis and autophagy-related protein expression. Furthermore, it was found that Apigenin could inhibit the m-TOR/PI3K/AKT signalling pathway in the cisplatin-resistant colon cancer cells. The effects of Apigenin were also examined in vivo in xenografted mice models and it was revealed that Apigenin inhibited the growth of xenografted tumors. Conclusions: Taken together, these results indicate that Apigenin could inhibit the growth of cisplatin-resistant colon cancer cells in vitro and in vivo and may be used for the improvement of therapy of colon cancer.	[Chen, Xiaping] Hubei Univ Med, Taihe Hosp, Dept Sci Res, Shiyan 442000, Hubei, Peoples R China; [Xu, Hang] Hubei Univ Med, Taihe Hosp, Dept Phys Examinat Ctr, Shiyan 442000, Hubei, Peoples R China; [Yu, Xinhua; Zhu, Xiaohu] Hubei Univ Med, Taihe Hosp, Dept Orthopaed Rehabil Ward, Shiyan 442000, Hubei, Peoples R China; [Wang, Xue] Hubei Univ Med, Taihe Hosp, Dept Obstet & Gynaecol, Shiyan 442000, Hubei, Peoples R China; [Xu, Xiaofeng] Hubei Univ Med, Renmin Hosp, Dept Pharm, Shiyan 442000, Hubei, Peoples R China		Xu, XF (corresponding author), Hubei Univ Med, Shiyan Renmin Hosp, Dept Pharm, 37 Chaoyang Middle Rd, Shiyan 442000, Hubei, Peoples R China.	Alejandrinerhaj@yahoo.com					Adhami VM, 2012, BIOCHEM PHARMACOL, V84, P1277, DOI 10.1016/j.bcp.2012.07.012; Barrett D, 2012, PEDIATR DRUGS, V14, P299, DOI 10.2165/11594740-000000000-00000; Caltagirone S, 2000, INT J CANCER, V87, P595, DOI 10.1002/1097-0215(20000815)87:4&lt;595::AID-IJC21&gt;3.0.CO;2-5; Chahar Maheep K, 2011, Pharmacogn Rev, V5, P1, DOI 10.4103/0973-7847.79093; Choudhury D, 2013, BIOCHIMIE, V95, P1297, DOI 10.1016/j.biochi.2013.02.010; Del Follo-Martinez A, 2013, NUTR CANCER, V65, P494, DOI 10.1080/01635581.2012.725194; GOLDWASSER F, 1995, CANCER RES, V55, P2116; Jayaprakasha GK, 2007, BIOORGAN MED CHEM, V15, P4923, DOI 10.1016/j.bmc.2007.04.044; Kumar D, 2014, CANCER LETT, V343, P179, DOI 10.1016/j.canlet.2013.10.003; Liu HL, 2010, RECENT PAT ANTI-CANC, V5, P152, DOI 10.2174/157489210790936261; Manfredi GI, 2015, ENDOCRINE, V48, P363, DOI 10.1007/s12020-014-0380-1; Mao F, 2011, MED ONCOL, V28, P121, DOI 10.1007/s12032-009-9415-5; Ren WY, 2003, MED RES REV, V23, P519, DOI 10.1002/med.10033; Santhosh RS, 2014, PLANTA MED, V80, P9, DOI 10.1055/s-0033-1350978; Su CC, 2006, ANTICANCER RES, V26, P4379; Su ZY, 2015, MOL CANCER, V14, DOI 10.1186/s12943-015-0321-5; Tapia O, 2014, VIRCHOWS ARCH, V465, P25, DOI 10.1007/s00428-014-1588-4; Wang F, 2015, DRUG DES DEV THER, V9, P575, DOI 10.2147/DDDT.S75221; Wang YC, 2013, INT J PHARMACEUT, V441, P728, DOI 10.1016/j.ijpharm.2012.10.021; Yang PM, 2012, INT J ONCOL, V40, P469, DOI 10.3892/ijo.2011.1203; Yu FS, 2016, ENVIRON TOXICOL, V31, P395, DOI 10.1002/tox.22053	21	34	34	2	10	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	MAR-APR	2019	24	2					488	493					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	HT3JW	WOS:000464461100011	31127995				2022-04-25	
J	Rikiishi, H				Rikiishi, Hidemi			Autophagic action of new targeting agents in head and neck oncology	CANCER BIOLOGY & THERAPY			English	Review						head and neck squamous cell carcinoma; molecular targeted agents; epidermal growth factor; autophagy; autophagic cell death; autophagic resistance; apoptosis	SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR-RECEPTOR; AND/OR METASTATIC HEAD; SIGNAL-TRANSDUCTION PATHWAYS; MAMMALIAN TARGET; CANCER-CELLS; PHASE-II; MALIGNANT GLIOMA; ZD1839 IRESSA; TUMOR-CELLS	The survival rates of patients with squamous cell carcinoma of the head and neck (HNSCC) have not improved significantly despite multi-modality therapy, including surgery, radiation therapy and chemotherapy. Recently, molecular targeted agents have shown significant improvement in clinical outcomes; for example, in chronic myelogeneous leukemia with imatinib, breast cancer with trastuzumab, colon cancer with bevacizumab and cetuximab, and renal cell cancer with sorafenib and sunitinib. In HNSCC, the epidermal growth factor receptor antibody cetuximab has shown promising results in combination with radiation. Targeted agents including cetuximab induce stresses to activate prosurvival autophagy. Combining autophagy inhibitors with agents that induce autophagy as a prosurvival response may therefore increase their therapeutic efficacy. Whether autophagy contributes to the prosurvival response or to the antitumor effect of chemotherapeutic drugs is largely unknown. This review will discuss the possible role of autophagy as a novel target for anticancer therapy agents in HNSCC.	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Ther.	SEP	2012	13	11					978	991		10.4161/cbt.21079			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	004PT	WOS:000308694300002	22825332	hybrid, Green Published			2022-04-25	
J	Dimitrova, EG; Chaushev, BG; Conev, NV; Kashlov, JK; Zlatarov, AK; Petrov, DP; Popov, HB; Stefanova, NT; Klisarova, AD; Bratoeva, KZ; Donev, IS				Dimitrova, Eleonora G.; Chaushev, Borislav G.; Conev, Nikolay V.; Kashlov, Javor K.; Zlatarov, Aleksandar K.; Petrov, Dilyan P.; Popov, Hristo B.; Stefanova, Nadezhda T.; Klisarova, Anelia D.; Bratoeva, Kameliya Z.; Donev, Ivan S.			Role of the pretreatment F-18-fluorodeoxyglucose positron emission tomography maximal standardized uptake value in predicting outcomes of colon liver metastases and that value's association with Beclin-1 expression	BIOSCIENCE TRENDS			English	Article						Maximum standardized uptake value (SUVmax); Beclin-1; colon cancer	CELL LUNG-CANCER; COLORECTAL-CANCER; F-18-FDG PET/CT; FAVORABLE PROGNOSIS; CLINICAL-PRACTICE; FDG-PET/CT; CHEMOTHERAPY; AUTOPHAGY; ACCUMULATION; MUTATIONS	The current study sought to evaluate the predictive and prognostic performance of the maximum standardized uptake value (SUVmax) prior to treatment in 43 patients with colon cancer and unresectable liver metastases. Patients with colon cancer who underwent F-18-FDG-PET/computed tomography (CT) scans for staging before the start of first-line 5-fluorouracil-based chemotherapy were retrospectively analyzed. Expression of Beclin-1 in cancer cells was evaluated in primary tumors using immunohistochemical staining. The pretreatment SUVmax for liver metastases was not able to predict progression-free survival but was significantly associated with poorer overall survival, with a hazard ratio of 2.05 (95 % CI, 1.016-4.155). Moreover, a negative correlation was noted between SUVmax and expression of a marker of autophagy-Beclin-1 (rho=-0.42, p=0.006). This suggests that the pretreatment SUVmax in F-18-FDG PET/CT is a useful tool to help predict survival outcome in patients with colon cancer and unresectable liver metastases and may significantly distinguish between patients with low and high levels of Beclin-1 expression (AUC = 0.809, 95% CI: 0.670-0.948, p = 0.001).	[Dimitrova, Eleonora G.; Conev, Nikolay V.; Donev, Ivan S.] UMHAT St Marina, Clin Med Oncol, Varna, Bulgaria; [Dimitrova, Eleonora G.; Conev, Nikolay V.; Kashlov, Javor K.; Donev, Ivan S.] Med Univ Varna, Dept Propedeut Internal Dis, Marin Drinov Str 55, Varna 9000, Bulgaria; [Chaushev, Borislav G.; Klisarova, Anelia D.] UMHAT St Marina, Dept Nucl Med, Varna, Bulgaria; [Zlatarov, Aleksandar K.; Petrov, Dilyan P.] UMHAT St Marina, Surg Clin, Varna, Bulgaria; [Zlatarov, Aleksandar K.; Petrov, Dilyan P.] Med Univ Varna, Dept Gen & Operat Surg, Varna, Bulgaria; [Popov, Hristo B.; Stefanova, Nadezhda T.] UMHAT St Marina, Ctr Clin Pathol, Varna, Bulgaria; [Bratoeva, Kameliya Z.] Med Univ Varna, Div Pathophysiol, Varna, Bulgaria		Donev, IS (corresponding author), Med Univ Varna, Dept Propedeut Internal Dis, Marin Drinov Str 55, Varna 9000, Bulgaria.	ivan_donev75@abv.bg	Popov, Hristo/AAS-2552-2020; Donev, Ivan Shterev/AAE-7011-2020	Donev, Ivan Shterev/0000-0003-3045-3775; Popov, Hristo/0000-0002-5891-1494; Conev, Nikolay/0000-0001-5267-0354; Kashlov, Yavor/0000-0002-2465-8734			Avallone A, 2012, EUR J NUCL MED MOL I, V39, P1848, DOI 10.1007/s00259-012-2229-2; De Bruyne S, 2012, BRIT J CANCER, V106, P1926, DOI 10.1038/bjc.2012.184; de Geus-Oei LF, 2008, ANN ONCOL, V19, P348, DOI 10.1093/annonc/mdm470; Eberhard DA, 2008, J CLIN ONCOL, V26, P983, DOI 10.1200/JCO.2007.12.9858; Fendler WP, 2013, J NUCL MED, V54, P1202, DOI 10.2967/jnumed.112.116426; Goldsmith J, 2014, METHOD ENZYMOL, V542, P25, DOI 10.1016/B978-0-12-416618-9.00002-9; Guo GF, 2011, WORLD J GASTROENTERO, V17, P4779, DOI 10.3748/wjg.v17.i43.4779; Guo JY, 2011, GENE DEV, V25, P460, DOI 10.1101/gad.2016311; Han Y., 2014, J ADV SIGNAL PROCESS, V2014, P1, DOI DOI 10.1097/PAT.0000000000000125; Hendlisz A, 2012, ANN ONCOL, V23, P1687, DOI 10.1093/annonc/mdr554; Iwamoto M, 2014, J NUCL MED, V55, P2038, DOI 10.2967/jnumed.114.142927; Jemal A, 2011, CA-CANCER J CLIN, V61, P69, DOI [10.3322/caac.20107, 10.3322/caac.20115]; Juweid ME, 2006, NEW ENGL J MED, V354, P496, DOI 10.1056/NEJMra050276; Kawada K, 2012, CLIN CANCER RES, V18, P1696, DOI 10.1158/1078-0432.CCR-11-1909; Kinahan PE, 2010, SEMIN ULTRASOUND CT, V31, P496, DOI 10.1053/j.sult.2010.10.001; Koukourakis MI, 2010, BRIT J CANCER, V103, P1209, DOI 10.1038/sj.bjc.6605904; Krikelis D, 2014, ANTICANCER RES, V34, P2571; Li BX, 2009, AUTOPHAGY, V5, P303, DOI 10.4161/auto.5.3.7491; Mertens J, 2013, EUR J NUCL MED MOL I, V40, P1214, DOI 10.1007/s00259-013-2421-z; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Moruno Felix, 2012, Cells, V1, P372, DOI 10.3390/cells1030372; Muralidharan V, 2012, J NUCL MED, V53, P1345, DOI 10.2967/jnumed.112.102749; Riedl CC, 2007, J NUCL MED, V48, P771, DOI 10.2967/jnumed.106.037291; Sadahiro S, 2004, CANCER, V100, P590, DOI 10.1002/cncr.11945; Schmitz KJ, 2016, WORLD J SURG ONCOL, V14, DOI 10.1186/s12957-016-0946-x; Tsikitis VL, 2009, J CLIN ONCOL, V27, P3671, DOI 10.1200/JCO.2008.20.7050; Van Cutsem E, 2014, ANN ONCOL, V25, P1, DOI 10.1093/annonc/mdu260; Van den Abbeele AD, 2008, ONCOLOGIST, V13, P8, DOI 10.1634/theoncologist.13-S2-8; Vansteenkiste JF, 1999, J CLIN ONCOL, V17, P3201, DOI 10.1200/JCO.1999.17.10.3201; Vivanco I, 2014, BRIT J CANCER, V111, P2033, DOI 10.1038/bjc.2014.461; WEISS L, 1986, J PATHOL, V150, P195, DOI 10.1002/path.1711500308; Xia Q, 2015, CANCER IMAGING, V15, P1, DOI 10.1186/s40644-015-0055-z; Yang ZL, 2015, CLIN RES HEPATOL GAS, V39, P98, DOI 10.1016/j.clinre.2014.06.014; Zerizer I, 2012, EUR J NUCL MED MOL I, V39, P1391, DOI 10.1007/s00259-012-2149-1	34	1	1	2	5	IRCA-BSSA	TOKYO	PEARL CITY KOISHIKAWA 603, 2-4-5 KASUGA, BUNKYO-KU, TOKYO, 112-0003, JAPAN	1881-7815	1881-7823		BIOSCI TRENDS	BioSci. Trends	APR	2017	11	2					221	228		10.5582/bst.2016.01205			8	Biology	Science Citation Index Expanded (SCI-EXPANDED)	Life Sciences & Biomedicine - Other Topics	EY2OD	WOS:000403806900016	28250335	Bronze			2022-04-25	
J	Tang, JC; Feng, YL; Liang, X; Cai, XJ				Tang, Jia-Cheng; Feng, Yi-Li; Liang, Xiao; Cai, Xiu-Jun			Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer: Trends and Challenges	CHINESE MEDICAL JOURNAL			English	Review						5-Fluorouracil; Autophagy; Gastrointestinal Cancer; Tumor	CARCINOMA EC9706 CELLS; HEPATOCELLULAR-CARCINOMA; COLON-CANCER; PANCREATIC ADENOCARCINOMA; TARGETING AUTOPHAGY; COLORECTAL-CANCER; PHASE-II; IN-VITRO; BECLIN 1; GALLBLADDER CARCINOMA	Objective: 5-Fluorouracil (5-FU)-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice. This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system. Data Sources: All articles published in English from 1996 to date those assess the synergistic effect of autophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed. The search terms were "autophagy" and "5-FU" and ("colorectal cancer" or "hepatocellular carcinoma" or "pancreatic adenocarcinoma" or "esophageal cancer" or "gallbladder carcinoma" or "gastric cancer"). Study Selection: Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency of autophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized. The exclusion criteria for the articles were as follows: (1) new materials (e.g., nanomaterial)-induced autophagy; (2) clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers; and (3) immunogenic cell death for anticancer chemotherapy. Results: Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death. Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce. The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials. Conclusion: Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in gastrointestinal cancer.	[Tang, Jia-Cheng; Feng, Yi-Li; Liang, Xiao; Cai, Xiu-Jun] Zhejiang Univ, Sir Run Run Shaw Hosp, Zhejiang Prov Key Lab Laparosop Technol, Dept Gen Surg, Hangzhou 310016, Zhejiang, Peoples R China		Cai, XJ (corresponding author), Zhejiang Univ, Sir Run Run Shaw Hosp, Hangzhou 310016, Zhejiang, Peoples R China.	cxjzu@hotmail.com			Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LY13H180001]	This study was supported by a grant of Zhejiang Provincial Natural Science Foundation of China (No. LY13H180001).	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Zhu BS, 2015, MOL MED REP, V11, P1891, DOI 10.3892/mmr.2014.2926	104	32	33	2	38	MEDKNOW PUBLICATIONS & MEDIA PVT LTD	MUMBAI	B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA	0366-6999			CHINESE MED J-PEKING	Chin. Med. J.	FEB 20	2016	129	4					456	463		10.4103/0366-6999.176069			8	Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	General & Internal Medicine	DF0MC	WOS:000371032200012	26879020	Green Published, gold			2022-04-25	
J	Taniguchi, K; Sugito, N; Kumazaki, M; Shinohara, H; Yamada, N; Nakagawa, Y; Ito, Y; Otsuki, Y; Uno, B; Uchiyama, K; Akao, Y				Taniguchi, Kohei; Sugito, Nobuhiko; Kumazaki, Minami; Shinohara, Haruka; Yamada, Nami; Nakagawa, Yoshihito; Ito, Yuko; Otsuki, Yoshinori; Uno, Bunji; Uchiyama, Kazuhisa; Akao, Yukihiro			MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer	CANCER LETTERS			English	Article						miR-124; PTB1; PKM; Warburg effect; Colorectal cancer	PYRUVATE-KINASE; DOWN-REGULATION; MIR-124; EXPRESSION; METABOLISM; APOPTOSIS; RCK/P54; PROTEIN; GENE	Altered levels and functions of microRNAs (miRs) have been associated with carcinogenesis. In this study, we investigated the role of miR-124 in colorectal adenoma (CRA) and cancer (CRC). The expression levels of miR-124 were decreased in CRA (81.8%) and CRC (57.6%) in 55 clinical samples. The ectopic expression of miR-124 induced apoptosis and autophagy in colon cancer cells. Also, miR-124 targeted polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of pyruvate kinase muscles I and 2 (PKM1 and PKM2) and induced the switching of PKM isoform expression from PKM2 to PKM1. Also, siR-PTB1 induced drastic apoptosis in colon cancer cells. Furthermore, we found that the ectopic expression of miR-124 enhanced oxidative stress and the miR-124/PTB1/PKM1/PKM2 axis constituted a feedback cascade. Finally, we showed that intratumor injection of miR-124 and siR-PTB1 induced a tumor-suppressive effect in xenografted mice. The axis was established by both in vitro and in vivo experiments to function in human colorectal cancer cells. These findings suggest that miR-124 acts as a tumor-suppressor and a modulator of energy metabolism through a PTB1/PKM1/PKM2 feedback cascade in human colorectal tumor cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved.	[Taniguchi, Kohei; Sugito, Nobuhiko; Kumazaki, Minami; Shinohara, Haruka; Yamada, Nami; Uno, Bunji; Akao, Yukihiro] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Gifu 5011193, Japan; [Taniguchi, Kohei; Uchiyama, Kazuhisa] Osaka Med Coll, Dept Gen & Gastroenterol Surg, Takatsuki, Osaka 5698686, Japan; [Nakagawa, Yoshihito] Fujita Hlth Univ, Sch Med, Dept Gastroenterol, Toyoake, Aichi 4701192, Japan; [Ito, Yuko; Otsuki, Yoshinori] Osaka Med Coll, Div Life Sci, Dept Anat & Cell Biol, Takatsuki, Osaka 5698686, Japan		Akao, Y (corresponding author), Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, 1-1 Yanagido, Gifu 5011193, Japan.	yakao@gifu-u.ac.jp		Shinohara, Haruka/0000-0001-8326-1203; Taniguchi, Kohei/0000-0003-0648-1370; Yamada, Nami/0000-0002-1220-0814	Ministry of Education, Science, Sports, and Culture of JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [YA-24659157]	This work was supported by a Grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan (YA-24659157).	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JUL 10	2015	363	1					17	27		10.1016/j.canlet.2015.03.026			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CJ3AN	WOS:000355355900003	25818238				2022-04-25	
J	Qian, J; Cao, Y; Zhang, JF; Li, LC; Wu, J; Wei, GL; Yu, JL; Huo, JG				Qian, Jun; Cao, Yi; Zhang, Junfeng; Li, Lingchang; Wu, Juan; Wei, Guoli; Yu, Jialin; Huo, Jiege			Tanshinone IIA induces autophagy in colon cancer cells through MEK/ERK/mTOR pathway	TRANSLATIONAL CANCER RESEARCH			English	Article						Tanshinone IIA; autophagy; colon cancer cells; MEK/ERK/mTOR pathway	DOWN-REGULATION; APOPTOSIS; GROWTH; ANGIOGENESIS	Background: Colon cancer is a common malignancy of the digestive tract. The search for effective drugs to treat colon cancer has become the focus of current researches. Tanshinone IIA (Tan IIA) is a fat-soluble component extracted from tanshinone, a traditional Chinese medicine. Tan IIA can modulate the occurrence and development of tumors, but its effect on autophagy in colon cancer cells has not been reported. Methods: Two types of colon cancer cell lines were selected and different concentrations of Tan IIA were used to treat cells at different time points. Cell Counting Kit-8 assay (CCK-8) was used to detect the effect of Tan IIA on cell proliferation; transmission electron microscopy was used to observe the formation of autophagosomes; reverse transcription-polymerase chain reaction (RT-qPCR) and western blot were used to detect the expression of autophagy related genes and proteins. Cell transfection was used to interfere with MEK (mitogen-activated extracellular signal-regulated kinase) expression, and RT-qPCR and western blot were used to detect the expression of MEK/ERK/mTOR pathway-related proteins. Results: Tan IIA resulted in a significant reduction in the viability of the two kinds of colon cancer cells. The number of autophagosomes increased significantly after the treatment of Tan IIA into these cells. Addition of autophagy inhibitor 3-MA (3-Methyladenine) improved the increase of autophagosomes in cells induced by Tan IIA. At the same time, Tan IIA induced the expression of autophagy-related proteins in the two colon cancer cell lines. When Tan IIA induced autophagy in colon cancer cells, the expression of MEK/ ERK/mTOR pathway-related proteins increased significantly. After interfering with the expression of MEK, the expression of autophagy decreased significantly, indicating that Tan IIA promoted autophagy of colon cancer cells through MEK/ERK/mTOR pathway. Conclusions: Tan IIA stimulates autophagy in colon cancer cells through MEK/ERK/mTOR pathway, hence inhibiting the growth of colon cancer cells.	[Qian, Jun] Nanjing Univ Chinese Med, Sch Chinese Med, Sch Integrated Chinese & Western Med, Dept Diagnost Chinese Med, Nanjing, Peoples R China; [Cao, Yi] Nanjing Univ Chinese Med, Inst Literature Chinese Med, Res Off Herbal Literature, Nanjing, Peoples R China; [Zhang, Junfeng] Nanjing Univ Chinese Med, Sch Med & Holist Integrat Med, Dept Pathogen & Immunol, Nanjing, Peoples R China; [Li, Lingchang; Wei, Guoli; Yu, Jialin; Huo, Jiege] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Dept Oncol, Nanjing, Peoples R China; [Wu, Juan] Nanjing Univ Chinese Med, Sch Med & Holist Integrat Med, Dept Publ Hlth, Nanjing, Peoples R China		Qian, J (corresponding author), 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China.; Huo, JG (corresponding author), 100 Shizi St, Nanjing 210028, Jiangsu, Peoples R China.	junqian_njucm@163.com; huojiege@jsatcm.com	Li, Lingchang/AAL-4850-2021	Li, Lingchang/0000-0001-5520-7023	Project of National Clinical Research Base of Traditional Chinese Medicine in Jiangsu Province, China [JD2019SZXYB04]; Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine); Leading Talents Project of Chinese Medicine in Jiangsu Province [SLJ0211]	This work was supported by Project of National Clinical Research Base of Traditional Chinese Medicine in Jiangsu Province, China (No. JD2019SZXYB04); a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine); the Leading Talents Project of Chinese Medicine in Jiangsu Province (No. SLJ0211).	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Cancer Res.	NOV	2020	9	11					6919	6928		10.21037/tcr-20-1963			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	OX4WB	WOS:000593565600029	35117300	Green Published, gold			2022-04-25	
J	Shao, LN; Zhu, BS; Xing, CG; Yang, XD; Young, W; Cao, JP				Shao, Le-Ning; Zhu, Bao-Song; Xing, Chun-Gen; Yang, Xiao-Dong; Young, Wu; Cao, Jian-Ping			Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells	MOLECULAR MEDICINE REPORTS			English	Article						tumor-associated macrophages; autophagy; colorectal cancer; radiosensitivity	LYMPH-NODE METASTASIS; INDUCED APOPTOSIS; POOR-PROGNOSIS; MICROENVIRONMENT; COLON; PROGRESSION; BIOMARKERS; SURVIVIN; TARGET; MODEL	Tumor-associated macrophages (TAMs), a major component of the tumor microenvironment, are crucial to the processes of tumor growth, infiltration and metastasis, and contribute to drug resistance. The importance of TAMs in radiation resistance of colorectal cancer remains unclear. To investigate the effects of autophagy regulation of TAMs on the radiosensitivity of colorectal cancer cells, the current study induced TAM formation from THP-1 monocyte cells. Sequential treatment of THP-1 cells with PMA for 72 h and human recombinant interleukin-4 for 24 h was used to stimulate THP-1 differentiation to TAMs. Expression of the cell surface markers CD68, CD204 and CD206, and changes to cell morphology were used to confirm successful differentiation. The TAMs were stimulated to promote or inhibit autophagy during co-culture with LoVo colorectal adenocarcinoma cells. The cells were irradiated, with subsequent measurement of LoVo colony formation and apoptosis. Additionally, the expression of p53, Bcl-2, survivin and Smac proteins was assessed by western blotting. Monodansylcadaverin staining was used to analyze the presence of autophagic vacuoles in TAM, and western blot analysis was used to assess the expression of Beclin-1, LC3B I and II, ATG-3, -5 and -7. The results demonstrated TAM autophagy to be markedly altered by rapamycin and bafilomycin A1 treatment. Following co-culture with TAMs, the colony formation rate and survival fraction of LoVo cells were significantly higher than those in the control group (P<0.05). It was further demonstrated that the regulation of autophagy in TAMs was able to inhibit the colony formation of LoVo colorectal cancer cells. Upregulation of TAM autophagy using rapamycin exhibited more effective inhibition of LoVo colony formation than autophagy downregulation. Notably, apoptosis was significantly increased in LoVo cells when co-cultured with TAMs only, or with rapamycin-mediated autophagy upregulated TAMs, compared with LoVo cells cultured alone (P<0.01). Expression of Bcl-2, survivin and p53 were reduced in LoVo cells co-cultured with TAMs, compared with the control group (P<0.05), whereas Smac expression was increased in the co-culture groups (P<0.01). It was demonstrated that rapamycin-mediated autophagy stimulation in TAMs led to reduced expression levels of survivin and Bcl-2, however, Smac expression was increased. The upregulation of autophagy in TAMs inhibited proliferation and induced apoptosis in colon cancer cells, and altered the expression of radiosensitivity-associated proteins. This data indicated that the radiosensitivity of colorectal cancer cells is associated with autophagy of TAM, and that stimulating TAM autophagy may increase the radiosensitivity of colorectal cancer cells.	[Shao, Le-Ning; Zhu, Bao-Song; Xing, Chun-Gen; Yang, Xiao-Dong; Young, Wu] Soochow Univ, Affiliated Hosp 2, Dept Gen Surg, 1055 Sanxian Rd, Suzhou 215004, Jiangsu, Peoples R China; [Cao, Jian-Ping] Soochow Univ, Jiangsu Prov Key Lab Radiat Med & Protect, Suzhou 215123, Jiangsu, Peoples R China		Xing, CG (corresponding author), Soochow Univ, Affiliated Hosp 2, Dept Gen Surg, 1055 Sanxian Rd, Suzhou 215004, Jiangsu, Peoples R China.	xingcg@126.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81172348]; Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection [KJS1334]; Suzhou Science and Education Guardian Youth Science and Technology Project [2011010]	The present study was supported by grants from the National Natural Science Foundation of China (no. 81172348), the Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection (no. KJS1334) and Suzhou Science and Education Guardian Youth Science and Technology Project (no. 2011010).	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Med. Rep.	MAR	2016	13	3					2661	2670		10.3892/mmr.2016.4820			10	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	DF8TS	WOS:000371633000094	26821367	Bronze			2022-04-25	
J	Yu, HY; Yin, SS; Zhou, SY; Shao, YY; Sun, JC; Pang, X; Han, LF; Zhang, Y; Gao, XM; Jin, CY; Qiu, YL; Wang, T				Yu, Haiyang; Yin, Shuangshuang; Zhou, Shiyue; Shao, Yingying; Sun, Jiachen; Pang, Xu; Han, Lifeng; Zhang, Yi; Gao, Xiumei; Jin, Chengyun; Qiu, Yuling; Wang, Tao			Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers	CELL DEATH & DISEASE			English	Article							SIGNALING PATHWAY; IN-VITRO; PROGRESSION; CARCINOMA; TRANSFORMATION; METASTASIS; METABOLISM; ACTIVATION; EXPRESSION; APOPTOSIS	Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.	[Yu, Haiyang; Yin, Shuangshuang; Zhou, Shiyue; Shao, Yingying; Sun, Jiachen; Pang, Xu; Han, Lifeng; Zhang, Yi; Gao, Xiumei; Wang, Tao] Tianjin Univ Tradit Chinese Med, Tianjin State Key Lab Modern Chinese Med, Tianjin 300193, Peoples R China; [Jin, Chengyun] Zhengzhou Univ, Sch Pharmaceut Sci, Key Lab Henan Prov Drug Qual Control & Evaluat, Key Lab,State Minist Educ, Zhengzhou 450001, Henan, Peoples R China; [Qiu, Yuling] Tianjin Med Univ, Sch Pharm, Tianjin 300070, Peoples R China		Wang, T (corresponding author), Tianjin Univ Tradit Chinese Med, Tianjin State Key Lab Modern Chinese Med, Tianjin 300193, Peoples R China.; Jin, CY (corresponding author), Zhengzhou Univ, Sch Pharmaceut Sci, Key Lab Henan Prov Drug Qual Control & Evaluat, Key Lab,State Minist Educ, Zhengzhou 450001, Henan, Peoples R China.; Qiu, YL (corresponding author), Tianjin Med Univ, Sch Pharm, Tianjin 300070, Peoples R China.	cyjin@zzu.edu.cn; qiuyuling@tmu.edu.cn; wangt@263.net			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81603253, 21711540293, 81673703, 81602614]; Natural Science Foundation of Tianjin CityNatural Science Foundation of Tianjin [15JCYBJC54900, 15PTCYSY00030]	We thank Dr. Yuhong Hu (Hebei Normal University) for her technical assistance in electron microscope analysis. This work was supported by grants from National Natural Science Foundation of China (Nos. 81603253 and 21711540293 to H. Yu, No. 81673703 to T. Wang, No. 81602614 to Y. Qiu), Natural Science Foundation of Tianjin City (No. 15JCYBJC54900 to H. Yu, No. 15PTCYSY00030 to Z. Li).	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JUN 13	2018	9								702	10.1038/s41419-018-0660-4			13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	GK9NV	WOS:000436579400007	29899555	Green Published, gold			2022-04-25	
J	Ou, JJ; Miao, HM; Ma, YY; Guo, F; Deng, J; Wei, X; Zhou, J; Xie, GF; Shi, H; Xue, BZ; Liang, HJ; Yu, LQ				Ou, Juanjuan; Miao, Hongming; Ma, Yinyan; Guo, Feng; Deng, Jia; Wei, Xing; Zhou, Jie; Xie, Ganfeng; Shi, Hang; Xue, Bingzhong; Liang, Houjie; Yu, Liqing			Loss of Abhd5 Promotes Colorectal Tumor Development and Progression by Inducing Aerobic Glycolysis and Epithelial-Mesenchymal Transition	CELL REPORTS			English	Article							ADIPOSE TRIGLYCERIDE LIPASE; ACTIVATED PROTEIN-KINASE; LIPID STORAGE DISEASE; GENE-TRANSCRIPTION; ENERGY-METABOLISM; HEPATIC STEATOSIS; CANCER; CGI-58; GROWTH; AUTOPHAGY	How cancer cells shift metabolism to aerobic glycolysis is largely unknown. Here, we show that deficiency of alpha/beta-hydrolase domain-containing 5 (Abhd5), an intracellular lipolytic activator that is also known as comparative gene identification 58 (CGI- 58), promotes this metabolic shift and enhances malignancies of colorectal carcinomas (CRCs). Silencing of Abhd5 in normal fibroblasts induces malignant transformation. Intestine- specific knockout of Abhd5 in Apc(Min/+) mice robustly increases tumorigenesis and malignant transformation of adenomatous polyps. In colon cancer cells, Abhd5 deficiency induces epithelial-mesenchymal transition by suppressing the AMPK alpha-p53 pathway, which is attributable to increased aerobic glycolysis. In human CRCs, Abhd5 expression falls substantially and correlates negatively with malignant features. Our findings link Abhd5 to CRC pathogenesis and suggest that cancer cells develop aerobic glycolysis by suppressing Abhd5-mediated intracellular lipolysis.	[Ou, Juanjuan; Miao, Hongming; Ma, Yinyan; Wei, Xing; Yu, Liqing] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA; [Ou, Juanjuan; Miao, Hongming; Deng, Jia; Wei, Xing; Zhou, Jie; Xie, Ganfeng; Liang, Houjie] Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing 400038, Peoples R China; [Ou, Juanjuan; Miao, Hongming; Deng, Jia; Wei, Xing; Zhou, Jie; Xie, Ganfeng; Liang, Houjie] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China; [Guo, Feng] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Winston Salem, NC 27157 USA; [Shi, Hang; Xue, Bingzhong] Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA		Liang, HJ (corresponding author), Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing 400038, Peoples R China.	lianghoujie@sina.com; lyu123@umd.edu	miao, hongming/AAV-8561-2020		National Institute of Diabetes and Digestive and Kidney DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK085176, R01DK084172]; National Heart, Lung and Blood InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL107500]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81370063, 81172115]; China National Natural Science Foundation, Oversea, Hong Kong & Macao Scholars Collaborated Research Fund [510025]; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL107500] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK085176, R01DK084172] Funding Source: NIH RePORTER	We thank Jianbing Zhang, Xianfeng Wang, Rongbin Zhou, and Shun Lei for technical assistance.This work was supported in part by grants R01DK085176 (L.Y.) and R01DK084172 (H.S.) from the National Institute of Diabetes and Digestive and Kidney Diseases; grant R01HL107500 (B.X.) from the National Heart, Lung and Blood Institute; grants 81370063 (J.O.) and 81172115 (H.L.) from the National Natural Science Foundation of China; and grant 510025 (L.Y.) from the China National Natural Science Foundation, Oversea, Hong Kong & Macao Scholars Collaborated Research Fund.	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J	Symonds, EL; Konczak, I; Fenech, M				Symonds, Erin L.; Konczak, Izabela; Fenech, Michael			The Australian fruit Illawarra plum (Podocarpus elatus Endl., Podocarpaceae) inhibits telomerase, increases histone deacetylase activity and decreases proliferation of colon cancer cells	BRITISH JOURNAL OF NUTRITION			English	Article						Colon cancer; Anthocyanins; Autophagy; Histone deacetylase; Proliferation	ANTHOCYANINS; EXTRACTS; GROWTH; MICRONUCLEUS; ANTIOXIDANTS; EXPRESSION; APOPTOSIS; SURVIVAL; SIRT1; LINES	Fruit antioxidants have many health benefits including prevention of cancer development. The native Australian bush fruit Illawarra plum (Podocarpus elatus Endl., Podocarpaceae) has a high content of anthocyanin-rich phenolics, with an antioxidant capacity at levels higher than most fruits. In the present study the molecular mechanisms of the anti-proliferative activity of Illawarra plum on colorectal cancer cells were investigated. Non-tumorigenic young adult mouse colonic (YAMC) cells and tumorigenic human colonic (HT-29) cells were treated with a polyphenolic-rich Illawarra plum extract (0-1000 mu g/ml). Illawarra plum had anti-proliferative properties in only the cancer cells, with growth suppressed in a dose- and time-dependent manner. Treatment of HT-29 cells with Illawarra plum extract (500 mu g/ml; 24 h) was also associated with a 2-fold increase in apoptosis, and a cell cycle delay in the S phase (P<0.01). Assessment of biomarkers for DNA damage revealed that plum treatment caused a 93% down-regulation of telomerase activity (P<0.001) and a decrease in telomere length (up to 75 %; P<0.01). Treatment with Illawarra plum extract also induced morphological alterations to HT-29 cells that were suggestive of induction of autophagy, as the formation of cytoplasmic vacuoles was observed in many cells. This could be induced by the increased (6-fold) histone deacetylase (HDAC) activity (P<0.001) and the trend for increased expression of the class III HDAC sirtuin 1. The present study has shown that Illawarra plum extract is able to reduce the proliferation of colon cancer cells by altering the cell cycle, increasing apoptosis and possibly inducing autophagy. The active ingredients in Illawarra plum may provide an alternative chemo-prevention strategy to conventional chemotherapy.	[Symonds, Erin L.; Fenech, Michael] CSIRO Food & Nutr Sci, Adelaide, SA 5000, Australia; [Konczak, Izabela] CSIRO Food & Nutr Sci, N Ryde, NSW 1670, Australia		Symonds, EL (corresponding author), CSIRO Food & Nutr Sci, Adelaide, SA 5000, Australia.	erinsymonds@yahoo.com	Konczak, Izabela/AAF-7476-2021	Konczak, Izabela/0000-0002-1712-9754; Symonds, Erin/0000-0003-2451-0358	National Health and Medical Research Council of AustraliaNational Health and Medical Research Council (NHMRC) of Australia [357702]	E. L. S. was supported by a CJ Martin post-doctoral fellowship (salary) awarded by the National Health and Medical Research Council of Australia (no. 357702). The research project received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. E. L. S., I. K. and M. F. designed the research; I. K. provided methodology and essential reagents; E. L. S. conducted the research; E. L. S. and M. F. analysed the data; E. L. S. wrote the paper and had primary responsibility for final content. All authors read and approved the final manuscript. The authors have no conflicts of interest.	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J	Giannopoulou, E; Antonacopoulou, A; Matsouka, P; Kalofonos, HP				Giannopoulou, Efstathia; Antonacopoulou, Anna; Matsouka, Panagiota; Kalofonos, Haralabos P.			Autophagy: Novel Action of Panitumumab in Colon Cancer	ANTICANCER RESEARCH			English	Article						Panitumumab; autophagy; redox status	METASTATIC COLORECTAL-CANCER; GROWTH-FACTOR RECEPTOR; MONOCLONAL-ANTIBODY; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; EGFR INHIBITORS; THERAPY; KRAS; CELLS; PROTEIN	Background: Panitumumab, a fully-human monoclonal antibody raised against epidermal growth factor receptor (EGFR), has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of patients with EGFR expressing metastatic colorectal carcinoma (mCRC) after failure of standard chemotherapy. Additionally, the guideline of the EMEA includes the use of panitumumab in patients with wild-type KRAS. The goal of the current study was to evaluate the effect of panitumumab oil colon cancer cells, proliferation, apoptosis, necrosis, cell cycle arrest and autophagy. The effect Of panitumumab oil the redox status of the cells was also studied. Materials and Methods: The cell lines Caco-2, DLD-1 and HT-29 which differ in their expression of EGFR and HER-2 were used. Cell proliferation and apoptosis/necrosis were measured by methyl tetrazolium (MTT) assay and annexin V/propidium iodide assay, respectively. Cell cycle arrest was estimated by propidium iodide assay and autophagy was detected using Western blot analysis. Spectrophotometrical quantification of glutathione (GSH) levels and an analysis, of KRAS sequence were applied. Results: Panitumumab reduced proliferation only in the DLD-1 cells despite the mutated KRAS in this cell line. However, panitumumab did not affect DLD-1 cell apoptosis, necrosis or cell cycle progression. Interestingly, immunoblotting analysis revealed that panitumumab increased protein levels of beclin-1, a marker of autophagy. In addition, an increase in the GSH level was noted following panitumumab treatment reflecting an imbalance in the redox status of the cells. Conclusion: Panitumumab affects colon cancer cell proliferation independently of KRAS mutations and EGFR protein levels, possibly through the induction of autophagy.	[Giannopoulou, Efstathia; Antonacopoulou, Anna; Matsouka, Panagiota; Kalofonos, Haralabos P.] Univ Hosp Patras, Patras Med Sch, Div Oncol, Clin Oncol Lab,Dept Med, Rion 26504, Greece		Kalofonos, HP (corresponding author), Univ Hosp Patras, Patras Med Sch, Div Oncol, Rion 26504, Greece.	kalofon@med.upatras.gr		Kalofonos, Haralabos/0000-0002-3286-778X	Oncological Research Fund (EOGE); Hellenic Cooperative Oncology Group (HECOG)	This work was supported by the Oncological Research Fund (EOGE) and Efstathia Giannopoulou and Anna Antonacopoulou were supported by the Hellenic Cooperative Oncology Group (HECOG). We would like to thank Amgen Inc. for providing panitumumab and Mr. Kostas Polimenous for study support.	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J	Jin, Y; Hong, Y; Park, CY; Hong, Y				Jin, Yunho; Hong, Yunkyung; Park, Chan Young; Hong, Yonggeun			Molecular Interactions of Autophagy with the Immune System and Cancer	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Review						autophagy; immune system; cancer; cell death; metabolic homeostasis	DOUBLE-EDGED-SWORD; TOLL-LIKE RECEPTORS; CHAPERONE-MEDIATED AUTOPHAGY; T-CELL HOMEOSTASIS; COLORECTAL-CANCER; INNATE IMMUNITY; THERAPY; TUMOR; GENE; MACROAUTOPHAGY	Autophagy is a highly conserved catabolic mechanism that mediates the degradation of damaged cellular components by inducing their fusion with lysosomes. This process provides cells with an alternative source of energy for the synthesis of new proteins and the maintenance of metabolic homeostasis in stressful environments. Autophagy protects against cancer by mediating both innate and adaptive immune responses. Innate immune receptors and lymphocytes (T and B) are modulated by autophagy, which represent innate and adaptive immune responses, respectively. Numerous studies have demonstrated beneficial roles for autophagy induction as well as its suppression of cancer cells. Autophagy may induce either survival or death depending on the cell/tissue type. Radiation therapy is commonly used to treat cancer by inducing autophagy in human cancer cell lines. Additionally, melatonin appears to affect cancer cell death by regulating programmed cell death. In this review, we summarize the current understanding of autophagy and its regulation in cancer.	[Jin, Yunho; Hong, Yonggeun] Inje Univ, Dept Rehabil Sci, Grad Sch, Gimhae 50834, South Korea; [Jin, Yunho; Hong, Yunkyung; Hong, Yonggeun] Inje Univ, Ubiquitous Healthcare & Antiaging Res Ctr U HARC, Gimhae 50834, South Korea; [Jin, Yunho; Hong, Yunkyung; Hong, Yonggeun] Inje Univ, BPRC, Gimhae 50834, South Korea; [Hong, Yunkyung; Hong, Yonggeun] Inje Univ, Dept Phys Therapy, Coll Biomed Sci & Engn, Gimhae 50834, South Korea; [Park, Chan Young] UNIST, Dept Life Sci, Ulsan 44919, South Korea		Hong, Y (corresponding author), Inje Univ, Dept Rehabil Sci, Grad Sch, Gimhae 50834, South Korea.; Hong, Y (corresponding author), Inje Univ, Ubiquitous Healthcare & Antiaging Res Ctr U HARC, Gimhae 50834, South Korea.; Hong, Y (corresponding author), Inje Univ, BPRC, Gimhae 50834, South Korea.; Hong, Y (corresponding author), Inje Univ, Dept Phys Therapy, Coll Biomed Sci & Engn, Gimhae 50834, South Korea.; Park, CY (corresponding author), UNIST, Dept Life Sci, Ulsan 44919, South Korea.	jynh33@naver.com; dangmoo777@naver.com; cypark@unist.ac.kr; yonghong@inje.ac.kr	Park, Chan Young/F-5696-2010	Park, Chan Young/0000-0002-5183-3665	National Research Foundation [2015R1A1A1A05027490, NRF-2015R1C1A2A01055691, NRF-2017R1A2A2A01067169]; KRIBB Research Initiative Program, Republic of Korea [KGM4611714]; Inje University	We thank Sookyoung Park, Jinyoung Won, and Jeonghyun Choi for critically reading the manuscript, and Jongwon Kim for critical comments and useful suggestions. This work was supported by grants from the National Research Foundation (2015R1A1A1A05027490 to Chan Young Park, NRF-2015R1C1A2A01055691 to Yunkyung Hong, NRF-2017R1A2A2A01067169 to Yonggeun Hong,), and by the KRIBB Research Initiative Program (KGM4611714), Republic of Korea. This work was also supported by the 2016 Creative Research Program of Inje University.	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J. Mol. Sci.	AUG	2017	18	8							1694	10.3390/ijms18081694			10	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	FF4HB	WOS:000408897400095	28771183	Green Published, gold, Green Submitted			2022-04-25	
J	Wang, X; Xu, YM; Li, T; Chen, B; Yang, WQ				Wang, Xu; Xu, Yuanmin; Li, Ting; Chen, Bo; Yang, Wenqi			Development of prognosis model for colon cancer based on autophagy-related genes	WORLD JOURNAL OF SURGICAL ONCOLOGY			English	Article						Autophagy-related genes; Prognosis model; Colon cancer; TCGA	COLORECTAL-CANCER; YOUNGER	\Background: Autophagy is an orderly catabolic process for degrading and removing unnecessary or dysfunctional cellular components such as proteins and organelles. Although autophagy is known to play an important role in various types of cancer, the effects of autophagy-related genes (ARGs) on colon cancer have not been well studied. Methods: Expression profiles from ARGs in 457 colon cancer patients were retrieved from the TCGA database (https://portal.gdc.cancer.gov). Differentially expressed ARGs and ARGs related to overall patient survival were identified. Cox proportional-hazard models were used to investigate the association between ARG expression profiles and patient prognosis. Results: Twenty ARGs were significantly associated with the overall survival of colon cancer patients. Five of these ARGs had a mutation rate >= 3%. Patients were divided into high-risk and low-risk groups based on Cox regression analysis of 8 ARGs. Low-risk patients had a significantly longer survival time than high-risk patients (p < 0.001). Univariate and multivariate Cox regression analysis showed that the resulting risk score, which was associated with infiltration depth and metastasis, could be an independent predictor of patient survival. A nomogram was established to predict 1-, 3-, and 5-year survival of colon cancer patients based on 5 independent prognosis factors, including the risk score. The prognostic nomogram with online webserver was more effective and convenient to provide information for researchers and clinicians. Conclusion: The 8 ARGs can be used to predict the prognosis of patients and provide information for their individualized treatment.	[Wang, Xu; Xu, Yuanmin; Li, Ting; Chen, Bo; Yang, Wenqi] Anhui Med Univ, Affiliated Hosp 1, Dept Gen Surg, Hefei 230032, Anhui, Peoples R China		Yang, WQ (corresponding author), Anhui Med Univ, Affiliated Hosp 1, Dept Gen Surg, Hefei 230032, Anhui, Peoples R China.	doctoryangwenqi@sina.com			Key Research and Development Plan Projects of Anhui Province [201904a07020055]	The Key Research and Development Plan Projects of Anhui Province (No. 201904a07020055).	Balachandran VP, 2015, LANCET ONCOL, V16, pE173, DOI 10.1016/S1470-2045(14)71116-7; Bhandari A, 2017, J INVEST MED, V65, P311, DOI 10.1136/jim-2016-000229; Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI 10.3322/caac.21492; Burada F, 2015, WORLD J GASTRO ONCOL, V7, P271, DOI 10.4251/wjgo.v7.i11.271; D'Arcangelo D, 2018, OXID MED CELL LONGEV, V2018, DOI 10.1155/2018/1471682; Devenport SN, 2019, CELLS-BASEL, V8, DOI 10.3390/cells8111349; Doonan BB, 2017, IN VITRO CELL DEV-AN, V53, P575, DOI 10.1007/s11626-017-0174-x; Dulak AM, 2013, NAT GENET, V45, P478, DOI 10.1038/ng.2591; Gil J, 2018, MED ONCOL, V35, DOI 10.1007/s12032-018-1220-6; Goruppi S, 2017, CELL REP, V20, P2468, DOI 10.1016/j.celrep.2017.08.048; Hu WW, 2007, NATURE, V450, P721, DOI 10.1038/nature05993; Iasonos A, 2008, J CLIN ONCOL, V26, P1364, DOI 10.1200/JCO.2007.12.9791; Kamburov A, 2015, P NATL ACAD SCI USA, V112, pE5486, DOI 10.1073/pnas.1516373112; Kwon CH, 2015, ONCOTARGET, V6, P20312, DOI 10.18632/oncotarget.3964; Lee SJ, 2014, ANN SURG ONCOL, V21, pS634, DOI 10.1245/s10434-014-3729-z; Lenz Heinz-Josef, 2008, Gastrointest Cancer Res, V2, P203; Levine B, 2007, NATURE, V446, P745, DOI 10.1038/446745a; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Russo AG, 2019, CANCER EPIDEMIOL, V60, P134, DOI 10.1016/j.canep.2019.03.015; Salemi M, 2014, HUM CELL, V27, P172, DOI 10.1007/s13577-013-0076-5; Schroll MM, 2016, NUTR RES, V36, P1068, DOI 10.1016/j.nutres.2016.08.002; Tian XQ, 2015, ONCOTARGETS THER, V8, P1691, DOI 10.2147/OTT.S81621; Yuan WZ, 2019, J MOL MED, V97, P89, DOI 10.1007/s00109-018-1716-8; Yun CW, 2018, INT J MOL SCI, V19, DOI 10.3390/ijms19113466	24	4	4	0	3	BMC	LONDON	CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND		1477-7819		WORLD J SURG ONCOL	World J. Surg. Oncol.	OCT 30	2020	18	1							285	10.1186/s12957-020-02061-w			8	Oncology; Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Surgery	OP4NN	WOS:000588058700003	33126898	gold, Green Submitted, Green Published			2022-04-25	
J	Xu, JS; Dai, SQ; Yuan, Y; Xiao, Q; Ding, KF				Xu, Jiasheng; Dai, Siqi; Yuan, Ying; Xiao, Qian; Ding, Kefeng			A Prognostic Model for Colon Cancer Patients Based on Eight Signature Autophagy Genes	FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY			English	Article						colon cancer; autophagy genes; prognostic model; TCGA; prognostic markers	COLORECTAL-CANCER; STATISTICS; SURVIVAL; THERAPY; DEATH; CELLS	Objective: To screen key autophagy genes in colon cancer and construct an autophagy gene model to predict the prognosis of patients with colon cancer. Methods: The colon cancer data from the TCGA were downloaded as the training set, data chip of GSE17536 as the validation set. The differential genes of the training set were obtained and were analyzed for enrichment and protein network. Acquire autophagy genes from Human Autophagy Database . Autophagy genes in differentially expressed genes were extracted using R-packages limma. Using LASSO/Cox regression analysis combined with clinical information to construct the autophagy gene risk scoring model and divide the samples into high and low risk groups according to the risk value. The Nomogram assessment model was used to predict patient outcomes. CIBERSORT was used to calculate the infiltration of immune cells in the samples and study the relationship between high and low risk groups and immune checkpoints. Results: Nine hundred seventy-six differentially expressed genes were screened from training set, including five hundred sixty-eight up-regulated genes and four hundred eight down regulated genes. These differentially expressed genes were mainly involved: the regulation of membrane potential, neuroactive ligand-receptor interaction. We identified eight autophagy genes CTSD, ULK3, CDKN2A, NRG1, ATG4B, ULK1, DAPK1, and SERPINA1 as key prognostic genes and constructed the model after extracting the differential autophagy genes in the training set. Survival analysis showed significant differences in sample survival time after grouping according to the model. Nomogram assessment showed that the model had high reliability for predicting the survival of patients with colon cancer in the 1, 3, 5 years. In the high-risk group, the infiltration degrees of nine types of immune cells are different and the samples can be well distinguished according to these nine types of immune cells. Immunological checkpoint correlation results showed that the expression levels of CTLA4, IDO1, LAG3, PDL1, and TIGIT increased in high-risk groups. Conclusion: The prognosis prediction model based on autophagy gene has a good evaluation effect on the prognosis of colon cancer patients. Eight key autophagy genes can be used as prognostic markers for colon cancer.	[Xu, Jiasheng; Dai, Siqi; Xiao, Qian; Ding, Kefeng] Zhejiang Univ, Affiliated Hosp 2, Dept Colorectal Surg & Oncol, Minist Educ,Key Lab Canc Prevent & Intervent,Sch, Hangzhou, Peoples R China; [Xu, Jiasheng; Dai, Siqi; Yuan, Ying; Xiao, Qian; Ding, Kefeng] Zhejiang Univ, Canc Ctr, Hangzhou, Peoples R China; [Yuan, Ying] Zhejiang Univ, Affiliated Hosp 2, Dept Med Oncol, Sch Med, Hangzhou, Peoples R China		Ding, KF (corresponding author), Zhejiang Univ, Affiliated Hosp 2, Dept Colorectal Surg & Oncol, Minist Educ,Key Lab Canc Prevent & Intervent,Sch, Hangzhou, Peoples R China.; Ding, KF (corresponding author), Zhejiang Univ, Canc Ctr, Hangzhou, Peoples R China.	dingkefeng@zju.edu.cn			National Key R&D Program of China [2017YFC0908200]; Key Technology Research and Development Program of Zhejiang Province [2017C03017]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81772545]; Project of the regional diagnosis and treatment center of the Health Planning Committee [JBZX-201903]	The authors' research was supported by the research fund of the National Key R&D Program of China (2017YFC0908200), the Key Technology Research and Development Program of Zhejiang Province (No. 2017C03017), Project of the regional diagnosis and treatment center of the Health Planning Committee (No. JBZX-201903), and National Natural Science Foundation of China (No. 81772545).	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Cell. Dev. Biol.	NOV 26	2020	8								602174	10.3389/fcell.2020.602174			13	Cell Biology; Developmental Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Developmental Biology	PC2RO	WOS:000596854500001	33324651	gold, Green Published			2022-04-25	
J	Wang, R; Xiao, X; Wang, PY; Wang, L; Guan, QN; Du, CG; Wang, XJ				Wang, Rong; Xiao, Xin; Wang, Peng-Yuan; Wang, Lin; Guan, Qiunong; Du, Caigan; Wang, Xiao-Juan			Stimulation of autophagic activity in human glioma cells by anti-proliferative ardipusilloside I isolated from Ardisia pusilla	LIFE SCIENCES			English	Article						Ardipusilloside I; Natural compound; Triterpenoid saponin; Ardisia pusilla; Human glioblastoma; Autophagy; Apoptosis	GLIOBLASTOMA U251MG CELLS; COLON-CANCER CELLS; TRITERPENOID SAPONINS; SIGNALING PATHWAYS; APOPTOSIS; DEATH; INHIBITION; MACROAUTOPHAGY; PROLIFERATION; MECHANISMS	Aims: Ardipusilloside I (ADS-I), a triterpenoid saponin isolated from Ardisia pusilla A. DC (Myrsinaceae), has been recently tested for cancer treatment including brain cancer. However, the mechanism of its action remains elusive. The present study was to investigate the role of autophagy activation in the anti-tumor activities of ADS-I in human glioma cells. Main methods: The tetrazolium dye (MTT) colorimetric assay was used for the measurement of cell proliferation in cultured glioma cells, transmission electron microscopy (TEM) for the examination of autophagic activity, flow cytometric analysis for the determination of cell cycle and apoptotic cells, and immunocytochemistry and Western blot for protein expression of microtubule-associated protein light-chain 3 (LC3) and Beclin 1. Key findings: ADS-I significantly inhibited the proliferation of both U373 and T98G glioma cells in cultures in a dose-dependent manner. The cytotoxic activity of ADS-I against glioma cell growth was associated not only with the induction of cell cycle arrest at G(2)/M phase and cell apoptosis in flow cytometric analysis, but also with the activation of autophagy, indicated by the formation of autophagosomes and up-regulated expression of both autophagic protein Beclin 1 and LC3 in glioma cells. Additionally, the treatment with chloroquine, an autophagy inhibitor, reduced ADS-1-mediated cell death. Significance: These data suggest that the anti-proliferative activity of ADS-I in human glioma cells is associated with the activation of autophagy in addition to cell cycle arrest and apoptosis, and the antagonistic effect of chloroquine suggests an important role of autophagy in ADS-I-mediated cell death against tumor growth. (C) 2014 Elsevier Inc. All rights reserved.	[Wang, Rong; Xiao, Xin; Wang, Peng-Yuan; Wang, Lin; Wang, Xiao-Juan] Fourth Mil Med Univ, Sch Stomatol, Dept Pharm, Xian 710032, Shaanxi, Peoples R China; [Wang, Rong] Xi An Jiao Tong Univ, Dept Pharmacol, Coll Med, Xian 710061, Shaanxi, Peoples R China; [Guan, Qiunong; Du, Caigan] Univ British Columbia, Dept Urol Sci, Vancouver, BC V6H 3Z6, Canada		Du, CG (corresponding author), Jack Bell Res Ctr, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada.	caigan@mail.ubc.ca; wxjyh231@fmmu.edu.cn			National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30973623]; Shaanxi Science and Technology Innovation project plan as a whole project [2011KTCL03-01]; project of the Administration of Traditional Chinese Medicine of Shaanxi [13-ZY041]	The authors greatly appreciate the financial support from the National Science Foundation of China (grant no. 30973623), Shaanxi Science and Technology Innovation project plan as a whole project (grant no. 2011KTCL03-01) and project of the Administration of Traditional Chinese Medicine of Shaanxi (grant no. 13-ZY041).	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AUG 6	2014	110	1					15	22		10.1016/j.lfs.2014.06.016			8	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	AL6QS	WOS:000339258300003	24984215				2022-04-25	
J	Skarkova, V; Kralova, V; Vitovcova, B; Rudolf, E				Skarkova, Veronika; Kralova, Vera; Vitovcova, Barbora; Rudolf, Emil			Selected Aspects of Chemoresistance Mechanisms in Colorectal CarcinomaA Focus on Epithelial-to-Mesenchymal Transition, Autophagy, and Apoptosis	CELLS			English	Review						colorectal carcinoma (CRC); chemoresistance; epithelial-to-mesenchymal transition (EMT); autophagy; apoptosis	III COLON-CANCER; ABERRANT CRYPT FOCI; DRUG-RESISTANCE; E-CADHERIN; PROGNOSTIC-SIGNIFICANCE; SMAC/DIABLO EXPRESSION; PROTEIN EXPRESSION; ADJUVANT THERAPY; BETA-CATENIN; TUMOR-GROWTH	Chemoresistance has been found in all malignant tumors including colorectal carcinoma (CRC). Nowadays chemoresistance is understood as a major reason for therapy failure, with consequent tumor growth and spreading leading ultimately to the patient's premature death. The chemotherapy-related resistance of malignant colonocytes may be manifested in diverse mechanisms that may exist both prior to the onset of the therapy or after it. The ultimate function of this chemoresistance is to ensure the survival of malignant cells through continuing adaptation within an organism, therefore, the nature and spectrum of cell-survival strategies in CRC represent a highly significant target of scientific inquiry. Among these survival strategies employed by CRC cells, three unique but significantly linked phenomena stand outepithelial-to-mesenchymal transition (EMT), autophagy, and cell death. In this mini-review, current knowledge concerning all three mechanisms including their emergence, timeline, regulation, and mutual relationships will be presented and discussed.	[Skarkova, Veronika; Kralova, Vera; Vitovcova, Barbora; Rudolf, Emil] Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Zborovska 2089, Hradec Kralove 50003, Czech Republic		Rudolf, E (corresponding author), Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Zborovska 2089, Hradec Kralove 50003, Czech Republic.	hanusovav@lfhk.cuni.cz; kralovav@lfhk.cuni.cz; vitovcob@lfhk.cuni.cz; rudolf@lfhk.cuni.cz	Rudolf, Emil/B-5956-2017; Králová, Věra/B-6608-2017	Rudolf, Emil/0000-0002-9526-3174; Králová, Věra/0000-0001-5971-4110	 [GACR 17-10331S]	This research was funded by the research project GACR 17-10331S.	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J	Zhang, P; Pan, Y; Sun, JJ; Pan, GY				Zhang, Peng; Pan, Yan; Sun, Jujun; Pan, Gaiyan			Aberrant expression of LncRNA CASC2 mediated the cell viability, apoptosis and autophagy of colon cancer cells by sponging miR-19a via NF-kappa B signaling pathway	INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY			English	Article						apoptosis; autophagy; cell viability; colon cancer; lncRNA CASC2; NF&#8208; &#954; B	COLORECTAL-CANCER; RNA; PROLIFERATION; PROGRESSION	Abnormal and rapid proliferation of colon cancer cells is a severe problem that can be regulated by non-coding RNAs. Thus, our study focused on effects of lncRNA CASC2 and miR-19a on colon cancer cells. Expressions of lncRNA CASC2, miR-19a, Bcl-2, Bax and NF-kappa B/p65 were examined by RT-qPCR. Cell viabilities were detected by CCK-8. A luciferase report assay was used for measuring binding conditions between lncRNA CASC2 and miR-19a. Western blotting was used to evaluate expression of LC3-I, LC3-II and p62 related to autophagy. Expression of lncRNA CASC2 lower in cancer cell lines and the overexpression reduced the cell viability of HT29 and SW480. Furthermore, Bcl-2 was suppressed by overexpressed lncRNA CASC2, while Bax was upregulated. LC3-? and p62 were both inhibited, but LC3-II was promoted. MiR-19a was predicted to bind lncRNA CASC2 and expressed higher in cancer cell lines. Overexpressed miR-19a reduced expression of lncRNA CASC2 and increased cell viability. This was repressed by upregulated lncRNA CASC2. Bcl-2 and Bax expression and proteins implicated in autophagy that are regulated by lncRNA CASC2 upregulation were reversed by miR-19a overexpression. NF-kappa B was upregulated in colon cancer cell lines, while inhibition of NF-kappa B reversed functions of lncRNA CASC2 and magnified roles of miR-19a. Our findings showed that lncRNA CASC2 inhibited cell viability in colon cancer cell lines and miR-19a reversed its functions through the NF-kappa B signalling pathway, suggesting that these could be factors in treating colon cancer in the future.	[Zhang, Peng] Xian Union Hosp, Xian, Shaanxi, Peoples R China; [Pan, Yan] Xian Cent Hosp, Xian, Shaanxi, Peoples R China; [Sun, Jujun] Xian XD Grp Hosp, Xian, Shaanxi, Peoples R China; [Pan, Gaiyan] Shaanxi Univ Chinese Med, Affiliated Hosp, Xian 710000, Shaanxi, Peoples R China		Pan, GY (corresponding author), Shaanxi Univ Chinese Med, Affiliated Hosp, Xian 710000, Shaanxi, Peoples R China.	naiikai812984@163.com					Barkett M, 1999, ONCOGENE, V18, P6910, DOI 10.1038/sj.onc.1203238; Becker H, 1995, Praxis (Bern 1994), V84, P1371; Braconi C, 2011, ONCOGENE, V30, P4750, DOI 10.1038/onc.2011.193; Brosnan CA, 2009, CURR OPIN CELL BIOL, V21, P416, DOI 10.1016/j.ceb.2009.04.001; Buttner R, 2019, PATHOLOGE, V40, P584, DOI 10.1007/s00292-019-0643-y; Calin GA, 2007, CANCER CELL, V12, P215, DOI 10.1016/j.ccr.2007.07.027; Chiang AC, 2008, NEW ENGL J MED, V359, P2814, DOI 10.1056/NEJMra0805239; Ellis BC, 2014, BBA-MOL CELL RES, V1843, P372, DOI 10.1016/j.bbamcr.2013.10.016; Epinat JC, 1999, ONCOGENE, V18, P6896, DOI 10.1038/sj.onc.1203218; Graham Lloyd D, 2011, Genes Cancer, V2, P829, DOI 10.1177/1947601911431081; He L, 2004, NAT REV GENET, V5, P522, DOI 10.1038/nrg1379; He XZ, 2016, TUMOR BIOL, V37, P9503, DOI 10.1007/s13277-016-4787-6; Huang GL, 2016, SCI REP-UK, V6, DOI 10.1038/srep26524; Huxley RR, 2009, INT J CANCER, V125, P171, DOI 10.1002/ijc.24343; Ju BL, 2020, AM J TRANSL RES, V12, P2695; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Li YX, 2018, BIOMED PHARMACOTHER, V108, P1775, DOI 10.1016/j.biopha.2018.09.181; Liu YM, 2018, J CELL BIOCHEM, V119, P358, DOI 10.1002/jcb.26188; Liu YQ, 2017, MOL CANCER, V16, DOI 10.1186/s12943-017-0625-8; Liu ZY, 2020, J CELL PHYSIOL, V235, P1494, DOI 10.1002/jcp.29069; Luo Sheng-lan, 2013, Zhonghua Liu Xing Bing Xue Za Zhi, V34, P1194; Marques AC, 2009, GENOME BIOL, V10, DOI 10.1186/gb-2009-10-11-r124; Mu P, 2009, GENE DEV, V23, P2806, DOI 10.1101/gad.1872909; Nissan A, 2012, INT J CANCER, V130, P1598, DOI 10.1002/ijc.26170; OBRIEN JM, 2000, NEW ENGL J MED, V45, P167; Olive V, 2009, GENE DEV, V23, P2839, DOI 10.1101/gad.1861409; Rinn JL, 2007, CELL, V129, P1311, DOI 10.1016/j.cell.2007.05.022; Rong L, 2020, BIOMED PHARMACOTHER, V122, DOI 10.1016/j.biopha.2019.109726; SEN R, 1986, CELL, V46, P705, DOI 10.1016/0092-8674(86)90346-6; Siegel RL, 2019, CA-CANCER J CLIN, V69, P7, DOI 10.3322/caac.21551; Sun K, 2019, CELL BIOSCI, V9, DOI 10.1186/s13578-019-0353-4; Tong JF, 2019, BIOSCIENCE REP, V39, DOI 10.1042/BSR20190452; Tsai HL, 2009, INT J COLORECTAL DIS, V24, P177, DOI 10.1007/s00384-008-0594-x; Xiao T, 2018, CELL DEATH DIS, V9, DOI 10.1038/s41419-018-1113-9; Xu DF, 2020, INT J ONCOL, V56, P494, DOI 10.3892/ijo.2019.4937; Zhang B, 2019, ONCOL LETT, V17, P414, DOI 10.3892/ol.2018.9592; Zhang SX, 2018, BIOMED PHARMACOTHER, V102, P302, DOI 10.1016/j.biopha.2018.03.071; Zhang YK, 2019, ONCOL RES, V27, P371, DOI 10.3727/096504018X15178740729367; Zhao L, 2018, J CELL PHYSIOL, V233, P6661, DOI 10.1002/jcp.26446; Zhou JF, 2017, MOL MED REP, V16, P5235, DOI 10.3892/mmr.2017.7233; Zhou PP, 2017, BMC CANCER, V17, DOI 10.1186/s12885-017-3829-9	41	0	0	1	1	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0959-9673	1365-2613		INT J EXP PATHOL	Int. J. Exp. Pathol.	JUN	2021	102	3					163	171		10.1111/iep.12393		MAY 2021	9	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	SF3JV	WOS:000649822900001	33983643				2022-04-25	
J	Ouyang, GQ; Xiong, L; Liu, ZP; Lam, B; Bui, B; Ma, L; Chen, X; Zhou, P; Wang, KP; Zhang, ZJ; Huang, H; Miao, XY; Chen, W; Wen, Y				Ouyang, Guoqing; Xiong, Li; Liu, Zhipeng; Lam, Brandon; Bui, Brian; Ma, Lun; Chen, Xiang; Zhou, Pan; Wang, Kunpeng; Zhang, Zijian; Huang, He; Miao, Xiongying; Chen, Wei; Wen, Yu			Inhibition of autophagy potentiates the apoptosis-inducing effects of photodynamic therapy on human colon cancer cells	PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY			English	Article						Apoptosis; Autophagy; Colorectal cancer; Photodynamic therapy; Porphyrin IX	COLORECTAL-CANCER; STATISTICS; RESPONSES; BCL-2; PHOTOSENSITIZERS; ACCUMULATION; MECHANISMS; RESISTANCE; PATHWAY; DEATH	Background: Photodynamic therapy (PDT) has been reported to be a promising therapy for colon cancer because of its substantial safety features and its ability to induce a systematic reaction rather than local effects on the focal lesion in the intestine. Autophagy and apoptosis play important roles in the response to PDT. However, the role of autophagy after PDT treatment has not yet been clarified. Methods: In this study, we investigated the relationship between apoptosis and autophagy in porphyrin IX (PpIX)-mediated PDT (PpIX-PDT) in HCT116 colon cancer cells. PpIX-PDT decreased cell viability in a concentration-and light dose-dependent manner. Results: PpIX-PDT results in nuclear condensation, increased the expression of Caspase-3, Bax, and PARP, and decreased expression of Bcl-2. PpIX-PDT also induces the double membrane autophagosome, up-regulates LC3B, Atg7, Beclin-1, and Bcl-2 expression and down-regulates P62 expression. Inhibition of autophagy using chloroquine (CQ) or Atg7 knockdown with a shRNA enhances apoptotic cell death. Based on these findings, autophagy plays a self-protective role in HCT116 cells in response to PpIX-PDT treatment. Discussion: Both autophagy and apoptosis were induced by PpIX-PDT in HCT116 cells, and the inhibition of autophagy strengthened the proapoptotic effect of PpIX-PDT. Thus, the appropriate modulation of autophagy may be as a potential therapeutic target for colon cancer cells treated with PpIX-PDT.	[Ouyang, Guoqing; Xiong, Li; Liu, Zhipeng; Chen, Xiang; Zhou, Pan; Wang, Kunpeng; Zhang, Zijian; Miao, Xiongying; Wen, Yu] Cent South Univ, Xiangya Hosp 2, Dept Gen Surg, Changsha 410011, Hunan, Peoples R China; [Lam, Brandon; Bui, Brian; Ma, Lun; Chen, Wei] Univ Texas Arlington, Dept Phys, Arlington, TX 76019 USA; [Lam, Brandon; Bui, Brian; Ma, Lun; Chen, Wei] Univ Texas Arlington, SAVANT Ctr, Arlington, TX 76019 USA; [Ouyang, Guoqing] Liuzhou Peoples Hosp, Dept Hepatobiliary Surg, Liuzhou 545000, Guangxi, Peoples R China; [Huang, He] Cent South Univ, Xiangya Sch Med, Changsha 410078, Hunan, Peoples R China		Wen, Y (corresponding author), Cent South Univ, Xiangya Hosp 2, Dept Gen Surg, Changsha 410011, Hunan, Peoples R China.; Chen, W (corresponding author), Univ Texas Arlington, Dept Phys, Arlington, TX 76019 USA.; Chen, W (corresponding author), Univ Texas Arlington, SAVANT Ctr, Arlington, TX 76019 USA.	weichen@uta.edu; wenyu2861@csu.edu.cn	wen, yu/AAJ-7482-2021		Chinese National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773293]; Keypoint Research and Invention Program of Hunan Province [2017DK2010]; Development and Reform Commission of Hunan [201583]; Fundamental Research Funds for the Central South University [2016zzts537]; Furong Scholarship from Central South University; U.S. Army Medical Research Acquisition Activity (USAMRAA) [W81XWH-10-1-0279, W81XWH-10-1-0234]	This work was supported by the Chinese National Natural Science Foundation of China(Grant 81773293), the Keypoint Research and Invention Program of Hunan Province (2017DK2010), Development and Reform Commission of Hunan (Grant 201583), the Fundamental Research Funds for the Central South University (grant 2016zzts537), the Furong Scholarship from Central South University, the support from the U.S. Army Medical Research Acquisition Activity (USAMRAA) under Contracts of W81XWH-10-1-0279 and W81XWH-10-1-0234.	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Ther.	MAR	2018	21						396	403		10.1016/j.pdpdt.2018.01.010			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GD6UP	WOS:000430644200063	29355734				2022-04-25	
J	Wang, WH; Xu, L; Liu, PY; Jairam, K; Yin, YB; Chen, K; Sprengers, D; Peppelenbosch, MP; Pan, QW; Smits, R				Wang, Wenhui; Xu, Lei; Liu, Pengyu; Jairam, Kiran; Yin, Yuebang; Chen, Kan; Sprengers, Dave; Peppelenbosch, Maikel P.; Pan, Qiuwei; Smits, Ron			Blocking Wnt Secretion Reduces Growth of Hepatocellular Carcinoma Cell Lines Mostly Independent of beta-Catenin Signaling	NEOPLASIA			English	Article							COLON-CANCER CELLS; COLORECTAL-CANCER; GAMMA-CATENIN; ADHERENS JUNCTIONS; GENE-EXPRESSION; PATHWAY; KNOCKDOWN; PORCUPINE; TUMORIGENESIS; INHIBITORS	Aberrant activation of Wnt/beta-catenin signaling plays a key role in the onset and development of hepatocellular carcinomas (HCC), with about half of them acquiring mutations in either CTNNB1 or AXIN1. However, it remains unclear whether these mutations impose sufficient beta-catenin signaling or require upstream Wnt ligand activation for sustaining optimal growth, as previously suggested for colorectal cancers. Using a panel of nine HCC cell lines, we show that siRNA-mediated knockdown of beta-catenin impairs growth of all these lines. Blocking Wnt secretion, by either treatment with the IWP12 porcupine inhibitor or knockdown of WLS, reduces growth of most of the lines. Unexpectedly, interfering with Wnt secretion does not clearly affect the level of beta-catenin signaling in the majority of lines, suggesting that other mechanisms underlie the growth-suppressive effect. However, IWP12 treatment did not induce autophagy or endoplasmic reticulum (ER) stress, which may have resulted from the accumulation of Wnt ligands within the ER. Similar results were observed for colorectal cancer cell lines used for comparison in various assays. These results suggest that most colorectal and liver cancers with mutations in components of the beta-catenin degradation complex do not strongly rely on extracellular Wnt ligand exposure to support optimal growth. In addition, our results also suggest that blocking Wnt secretion may aid in tumor suppression through alternative routes currently unappreciated.	[Wang, Wenhui; Xu, Lei; Liu, Pengyu; Jairam, Kiran; Yin, Yuebang; Chen, Kan; Sprengers, Dave; Peppelenbosch, Maikel P.; Pan, Qiuwei; Smits, Ron] Erasmus MC, Univ Med Ctr, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands		Smits, R (corresponding author), Dept Gastroenterol & Hepatol, S Gravendijkwal 230, NL-3015 CE Rotterdam, Netherlands.	m.j.m.smits@erasmusmc.nl	Peppelenbosch, Maikel P./U-5304-2019	Pan, Qiuwei/0000-0001-9982-6184; Peppelenbosch, Maikel/0000-0001-9112-6028; liu, pengyu/0000-0001-6600-6139	China Scholarship Council PhD fellowshipChina Scholarship Council [201306190123]; Erasmus Trustfonds [III A 97095.78/16.0366/evt]	The authors gratefully thank Dr. Francois Helle (Centre Universitaire de Recherche en Sante, Amiens, France) for providing the SNU182, SNU398, SNU449, and PLC/PRF/5 cell lines. This research is sponsored by a China Scholarship Council PhD fellowship (file no. 201306190123) and Erasmus Trustfonds travel grant (reference: III A 97095.78/16.0366/evt) to Wenhui Wang.	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J	Chen, JC; Hsieh, YY; Lo, HL; Li, A; Chou, CJ; Yang, PM				Chen, Jung-Chien; Hsieh, Yao-Yu; Lo, Hsiang-Ling; Li, Albert; Chou, Chia-Jung; Yang, Pei-Ming			In Vitro and In Silico Mechanistic Insights into miR-21-5p-Mediated Topoisomerase Drug Resistance in Human Colorectal Cancer Cells	BIOMOLECULES			English	Article						autophagy; colorectal cancer; Connectivity Map; drug resistance; microRNA	CONNECTIVITY MAP; INHIBITING AUTOPHAGY; THERAPEUTIC TARGET; MICRORNA-21; MIR-21; EXPRESSION; ENCYCLOPEDIA; COMBINATION; DOXORUBICIN; SENSITIVITY	Although chemotherapy for treating colorectal cancer has had some success, drug resistance and metastasis remain the major causes of death for colorectal cancer patients. MicroRNA-21-5p (hereafter denoted as miR-21) is one of the most abundant miRNAs in human colorectal cancer. A Kaplan-Meier survival analysis found a negative prognostic correlation of miR-21 and metastasis-free survival in colorectal cancer patients (The Cancer Genome Atlas Colon Adenocarcinoma/TCGA-COAD cohort). To explore the role of miR-21 overexpression in drug resistance, a stable miR-21-overexpressing clone in a human DLD-1 colorectal cancer cell line was established. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell viability assay found that miR-21 overexpression induced drug resistance to topoisomerase inhibitors (SN-38, doxorubicin, and etoposide/VP-16). Mechanistically, we showed that miR-21 overexpression reduced VP-16-induced apoptosis and concomitantly enhanced pro-survival autophagic flux without the alteration of topoisomerase expression and activity. Bioinformatics analyses suggested that miR-21 overexpression induced genetic reprogramming that mimicked the gene signature of topoisomerase inhibitors and downregulated genes related to the proteasome pathway. Taken together, our results provide a novel insight into the role of miR-21 in the development of drug resistance in colorectal cancer.	[Chen, Jung-Chien; Hsieh, Yao-Yu; Lo, Hsiang-Ling; Li, Albert; Chou, Chia-Jung; Yang, Pei-Ming] Taipei Med Univ, Coll Med Sci & Technol, PhD Program Canc Mol Biol & Drug Discovery, Taipei 111, Taiwan; [Chen, Jung-Chien; Hsieh, Yao-Yu; Lo, Hsiang-Ling; Li, Albert; Chou, Chia-Jung; Yang, Pei-Ming] Acad Sinica, Taipei 111, Taiwan; [Chen, Jung-Chien] Min Sheng Gen Hosp, Dept Surg, Taoyuan 168, Taiwan; [Chen, Jung-Chien] Cent Clin & Hosp, Taipei 106, Taiwan; [Hsieh, Yao-Yu] Taipei Med Univ, Shuang Ho Hosp, Div Hematol & Oncol, New Taipei 235, Taiwan; [Hsieh, Yao-Yu] Taipei Med Univ, Div Hematol & Oncol, Sch Med, Dept Internal Med,Coll Med, Taipei 111, Taiwan; [Lo, Hsiang-Ling; Li, Albert; Chou, Chia-Jung; Yang, Pei-Ming] Taipei Med Univ, Coll Med Sci & Technol, Grad Inst Canc Biol & Drug Discovery, Taipei 111, Taiwan; [Li, Albert] Taipei Med Univ, Sch Med, Taipei 111, Taiwan; [Yang, Pei-Ming] TMU Res Ctr Canc Translat Med, Taipei 111, Taiwan; [Chou, Chia-Jung; Yang, Pei-Ming] Taipei Med Univ, Wan Fang Hosp, Canc Ctr, Taipei 111, Taiwan		Yang, PM (corresponding author), Taipei Med Univ, Coll Med Sci & Technol, PhD Program Canc Mol Biol & Drug Discovery, Taipei 111, Taiwan.; Yang, PM (corresponding author), Acad Sinica, Taipei 111, Taiwan.; Yang, PM (corresponding author), Taipei Med Univ, Coll Med Sci & Technol, Grad Inst Canc Biol & Drug Discovery, Taipei 111, Taiwan.; Yang, PM (corresponding author), TMU Res Ctr Canc Translat Med, Taipei 111, Taiwan.; Yang, PM (corresponding author), Taipei Med Univ, Wan Fang Hosp, Canc Ctr, Taipei 111, Taiwan.	yangpm@tmu.edu.tw	; Chen, Jung-Chien/J-5386-2015	Li, Albert/0000-0002-4590-3268; Chen, Jung-Chien/0000-0001-8634-1145	health and welfare surcharge of tobacco products (WanFang Hospital, Chi-Mei Medical Center) [MOHW108-TDU-B-212-124020]; health and welfare surcharge of tobacco products (Hualien Tzu-Chi Hospital Joing Cancer Center Grant-Focus on Colon Cancer Research) [MOHW108-TDU-B-212-124020]; Ministry of Science and Technology [MOST103-2320-B-038-052, MOST104-2320-B-038-005, MOST105-2320-B-038-002, MOST108-2314-B-038-010]; Ministry of Education [DP2-108-21121-01-C-03-05]; Taipei Medical University [TMU103-AE2-I04-4, TMU104-AE2-I02-4, TMU105-AE2-I03-4, TMU105-U-32, TMU106-F-005]; Taipei Medical University - Shuang Ho Hospital [108TMU-SHH-19]	This research was funded by the health and welfare surcharge of tobacco products (WanFang Hospital, Chi-Mei Medical Center, and Hualien Tzu-Chi Hospital Joing Cancer Center Grant-Focus on Colon Cancer Research), grant number MOHW108-TDU-B-212-124020; the Ministry of Science and Technology, grant numbers MOST103-2320-B-038-052, MOST104-2320-B-038-005, MOST105-2320-B-038-002, MOST108-2314-B-038-010; the Ministry of Education, grant number DP2-108-21121-01-C-03-05; the Taipei Medical University, grant numbers TMU103-AE2-I04-4, TMU104-AE2-I02-4, TMU105-AE2-I03-4, TMU105-U-32, TMU106-F-005; and the Taipei Medical University - Shuang Ho Hospital, grant number 108TMU-SHH-19.	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J	Zhu, J; Zhao, L; Luo, B; Sheng, W				Zhu, Jing; Zhao, Lei; Luo, Bin; Sheng, Wang			Shikonin regulates invasion and autophagy of cultured colon cancer cells by inhibiting yes-associated protein	ONCOLOGY LETTERS			English	Article						colon cancer; shikonin; autophagy; yes-associated protein	DEGRADATION; STATISTICS; YAP/TAZ; PATHWAY; YAP	Colon cancer is a common malignancy, and its morbidity and mortality have been increasing in recent years in China. Shikonin (Shi), a naturally occurring naphthoquinone, exhibits anticancer activity. However, the mechanisms of action of Shi remain unclear. The aim of the present study was to investigate the antitumor mechanism of Shi in colon cancer cells. The effects of different Shi concentrations on the viability of colon cancer cells using MTT, colony formation and wound-healing assays were assessed. Western blot analysis was performed to detect the expression of LC3-II, p62. Shi effectively suppressed viability and cell migration, and induced autophagy in colon cancer cells. Yes-associated protein (YAP) increases cell viability, and inhibits cell apoptosis and cell contact. Expression of YAP is downregulated by Shi. The cytotoxic effects of Shi were further investigated on YAP overexpression and on YAP knockout cell lines. The findings revealed that Shi suppressed the viability and induced autophagy of colon cancer cells. Additionally, YAP expression reversed the effects of Shi. The results of the present study suggest that Shi may be a promising anticancer treatment for colon cancer, and YAP may be a potential diagnostic marker for colon cancer.	[Zhu, Jing; Sheng, Wang] Beijing Univ Technol, Coll Life Sci & Bioengn, Canc Lab, 100 Pingleyuan, Beijing 100124, Peoples R China; [Zhu, Jing; Luo, Bin] Hubei Univ Med, Dept Basic Med Sci, Shiyan 442000, Hubei, Peoples R China; [Zhao, Lei] Hubei Univ Med, Taihe Hosp, Reprod Med Ctr, Shiyan 442000, Hubei, Peoples R China		Zhu, J; Sheng, W (corresponding author), Beijing Univ Technol, Coll Life Sci & Bioengn, Canc Lab, 100 Pingleyuan, Beijing 100124, Peoples R China.	jing_Zhu0719@163.com; shengwang@bjut.edu.en		Zhu, Jing/0000-0002-2860-3685	National Natural Technology Foundation of China (Beijing, China) [81428016]; Key Program for Science and Technology Development of Beijing (Beijing, China) [Z151100003915073]	This study was supported by the National Natural Technology Foundation of China (Beijing, China; grant no. 81428016) and the Key Program for Science and Technology Development of Beijing (Beijing, China; grant no. Z151100003915073).	DeSantis CE, 2014, CA-CANCER J CLIN, V64, P252, DOI 10.3322/caac.21235; Fridlender M, 2015, FRONT PLANT SCI, V6, DOI 10.3389/fpls.2015.00799; Gao Y, 2014, INT J MOL SCI, V15, P15173, DOI 10.3390/ijms150915173; He GD, 2016, BIOCHEM BIOPH RES CO, V469, P1075, DOI 10.1016/j.bbrc.2015.12.100; Jouffret L, 2015, ANZ J SURG, V85, P860, DOI 10.1111/ans.13277; Kim HJ, 2017, J TRANSL MED, V15, DOI 10.1186/s12967-017-1223-7; Klionsky DJ, 2008, AUTOPHAGY, V4, P151, DOI 10.4161/auto.5338; Li YJ, 2017, CHIN J CANCER, V52, DOI 10.1186/s40880-017-0219-2; Liu ZM, 2017, AM J TRANSL RES, V9, P3212; Mo JS, 2014, EMBO REP, V15, P642, DOI 10.15252/embr.201438638; Moroishi T, 2015, NAT REV CANCER, V15, P73, DOI 10.1038/nrc3876; Oku Y, 2015, FEBS OPEN BIO, V5, P542, DOI 10.1016/j.fob.2015.06.007; Petherick KJ, 2013, EMBO J, V32, P1903, DOI 10.1038/emboj.2013.123; Qian HR, 2016, ONCOTARGET, V7, P17641, DOI 10.18632/oncotarget.7508; Shi SQ, 2014, ONCOL LETT, V8, P1087, DOI 10.3892/ol.2014.2293; Singh KE, 2014, J ADOLESC YOUNG ADUL, V3, P176, DOI 10.1089/jayao.2014.0006; Torre LA, 2015, CA-CANCER J CLIN, V65, P87, DOI 10.3322/caac.21262; Wang SP, 2016, OPEN BIOL, V6, DOI 10.1098/rsob.160119; Wang XD, 2012, EUR J CANCER, V48, P1227, DOI 10.1016/j.ejca.2011.10.001; Wang YP, 2015, INT J CLIN EXP MED, V8, P1080; Wang Z, 2017, CANCER RES, V77, P2413, DOI 10.1158/0008-5472.CAN-16-3229; Wu H, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0052706; XU TA, 1995, DEVELOPMENT, V121, P1053; Zhou W, 2011, BIOMED CHROMATOGR, V25, P1067, DOI 10.1002/bmc.1570	24	8	10	0	3	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-1074	1792-1082		ONCOL LETT	Oncol. Lett.	DEC	2019	18	6					6117	6125		10.3892/ol.2019.10980			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	KA1RN	WOS:000505576300049	31788086	gold, Green Published			2022-04-25	
J	Chen, L; Zhang, KZ; Sun, J; Tang, JT; Zhou, JP				Chen, Lin; Zhang, Kunzi; Sun, Jian; Tang, Jingtong; Zhou, Jianping			Development and Validation of an Autophagy-Stroma-Based Microenvironment Gene Signature for Risk Stratification in Colorectal Cancer	ONCOTARGETS AND THERAPY			English	Article						autophagy; stroma; tumor microenvironment; colorectal cancer; TNS1; TAGLN; SFRP4	COLON-CANCER; OXIDATIVE STRESS; TUMOR-STROMA; FIBROBLASTS; INHIBITION; METABOLISM; CELLS; HYDROXYCHLOROQUINE; POLYMORPHISM; INSTABILITY	Background: Colorectal cancer is the fourth most common cancer and the second leading cause of cancer-related death in the USA. The aim of this study was to establish a tumor gene signature based on tumor stromal cell and autophagy for predicting the risk of recurrence in patients with colorectal cancer. Methods: We used "Rtsne" and "xCell" R packages to estimate autophagy and stroma status, respectively. The discovery cohort used microarray gene expression data retrieved from the GSE39582 dataset. The Cox regression model and Least Absolute Shrinkage and Selection Operator (LASSO) were used to identify prognostic genes and to construct an autophagy-stroma-based gene signature. Moreover, external validation was conducted using GSE17538, GSE38832, TCGA database, and patient data obtained from the First Hospital of China Medical University (CMU). Results: The LASSO model identified three genes (TNS1, TAGLN, and SFRP4) which were used to develop a risk stratification gene signature. The autophagy-stroma-based gene signature was identified as an independent prognostic factor by multivariate analysis (p=0.0023). The results were validated in GSE17538 (p=0.0062), GSE38832 (p=0.028), TCGA (p=0.046) database, and patient data obtained from the First Hospital of China Medical University (CMU) (p=0.027). Conclusion: We have established and verified a feasible prognostic model of colorectal cancer based on autophagy and stromal cell characteristics of patients. The model can be used to evaluate recurrence risk of cancer patients, and the hub genes in the model provide potential targets for targeted colorectal cancer treatment.	[Chen, Lin; Zhang, Kunzi; Sun, Jian; Tang, Jingtong; Zhou, Jianping] China Med Univ, Dept Gastrointestinal Surg, Hosp 1, Shenyang 110001, Peoples R China		Zhou, JP (corresponding author), China Med Univ, Dept Gastrointestinal Surg, Hosp 1, Shenyang 110001, Peoples R China.	zjphama@163.com		Chen, Lin/0000-0001-5602-7139	Department of gastrointestinal surgery of the First Hospital of China Medical University	We acknowledge the support from the Department of gastrointestinal surgery of the First Hospital of China Medical University.	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J	Kim, JY; Cho, TJ; Woo, BH; Choi, KU; Lee, CH; Ryu, MH; Park, HR				Kim, Ji Young; Cho, Tae Jin; Woo, Bok Hee; Choi, Kyung Un; Lee, Chang Hun; Ryu, Mi Heon; Park, Hae Ryoun			Curcumin-induced autophagy contributes to the decreased survival of oral cancer cells	ARCHIVES OF ORAL BIOLOGY			English	Article						Curcumin; Autophagy; Apoptosis; Oral squamous cell carcinoma	NF-KAPPA-B; CARCINOMA-CELLS; JURKAT CELLS; COLON-CANCER; APOPTOSIS; DEATH; ACTIVATION; INDUCTION; CHEMOPREVENTION; CASPASE-3	Curcumin, a major active component of turmeric Curcuma longa, has been shown to have inhibitory effects on cancers. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying the anticancer effects of curcumin is unclear. Recently, it has been suggested that autophagy may play an important role in cancer therapy. However, little data are available regarding the role of autophagy in oral cancers. In this study, we have shown that curcumin has anticancer activity against oral squamous cell carcinoma (OSCC). Induction of autophagy, marked by autophagic vacuoles formation, was detected by acridine orange staining and monodansylcadaverine (MDC) dye after exposure to curcumin. Conversion of LC3-I to LC3-II, a marker of active autophagosome formation, was also detectable by Western blot following curcumin treatment We have also observed that curcumin induced reactive oxygen species (ROS) production and autophagic vacuoles formation by curcumin was almost completely blocked in the presence of N-acetylcystein (NAC), an antioxidant. Rescue experiments using an autophagy inhibitor suppressed curcumin-induced cell death in OSCC, confirming that autophagy acts as a pro-death signal. Furthermore, curcumin shows anticancer activity against OSCC via both autophagy and apoptosis. These findings suggest that curcumin may potentially contribute to oral cancer treatment and provide useful information for the development of a new therapeutic agent. (C) 2012 Elsevier Ltd. All rights reserved.	[Kim, Ji Young; Cho, Tae Jin; Woo, Bok Hee; Ryu, Mi Heon; Park, Hae Ryoun] Pusan Natl Univ, Sch Dent, Dept Oral Pathol, Yangsan 626870, South Korea; [Choi, Kyung Un; Lee, Chang Hun] Pusan Natl Univ, Sch Med, Dept Pathol, Yangsan 626870, South Korea		Park, HR (corresponding author), Pusan Natl Univ, Sch Dent, Dept Oral Pathol, Yangsan 626870, South Korea.	parkhr@pusan.ac.kr		Park, Hae Ryoun/0000-0003-1908-0824	National research Foundation of Korea (NRF)National Research Foundation of Korea; Ministry of Education, Science and technologyMinistry of Education, Science and Technology, Republic of Korea [2011-0005931, 2011-0016183]	This research was supported by Basic Science Research Program through the National research Foundation of Korea (NRF) funded by the Ministry of Education, Science and technology (2011-0005931) and by NRF funded by MEST (2011-0016183).	Aoki H, 2007, MOL PHARMACOL, V72, P29, DOI 10.1124/mol.106.033167; Bursch W, 2000, ANN NY ACAD SCI, V926, P1, DOI 10.1111/j.1749-6632.2000.tb05594.x; Chang KW, 2010, INT J CANCER, V127, P9, DOI 10.1002/ijc.25220; Choudhuri T, 2002, FEBS LETT, V512, P334, DOI 10.1016/S0014-5793(02)02292-5; Dalby KN, 2010, AUTOPHAGY, V6, P322, DOI 10.4161/auto.6.3.11625; Duvoix A, 2003, ANN NY ACAD SCI, V1010, P389, DOI 10.1196/annals.1299.071; Goel A, 2008, BIOCHEM PHARMACOL, V75, P787, DOI 10.1016/j.bcp.2007.08.016; Hussain AR, 2008, MOL CANCER THER, V7, P3318, DOI 10.1158/1535-7163.MCT-08-0541; Johnson JJ, 2007, CANCER LETT, V255, P170, DOI 10.1016/j.canlet.2007.03.005; Kanzawa T, 2003, CANCER RES, V63, P2103; Kroemer G, 2008, NAT REV MOL CELL BIO, V9, P1004, DOI 10.1038/nrm2529; Lee EJ, 2005, EXP MOL MED, V37, P379, DOI 10.1038/emm.2005.48; Lee YJ, 2011, KOREAN J PHYSIOL PHA, V15, P1, DOI 10.4196/kjpp.2011.15.1.1; Levine B, 2007, NATURE, V446, P745, DOI 10.1038/446745a; Mizushima N, 2007, AUTOPHAGY, V3, P542, DOI 10.4161/auto.4600; Nonaka M, 2006, INT J ORAL MAX SURG, V35, P649, DOI 10.1016/j.ijom.2006.01.011; O'Sullivan-Coyne G, 2009, BRIT J CANCER, V101, P1585, DOI 10.1038/sj.bjc.6605308; Paglin S, 2001, CANCER RES, V61, P439; Piwocka K, 2002, ANN NY ACAD SCI, V973, P250, DOI 10.1111/j.1749-6632.2002.tb04643.x; Piwocka K, 1999, EXP CELL RES, V249, P299, DOI 10.1006/excr.1999.4480; Ravindran J, 2009, AAPS J, V11, P495, DOI 10.1208/s12248-009-9128-x; Reuter S, 2008, BIOCHEM PHARMACOL, V76, P1340, DOI 10.1016/j.bcp.2008.07.031; Shin HK, 2010, PHYTOTHER RES, V24, P577, DOI 10.1002/ptr.2989; Sikora E, 2006, MOL CANCER THER, V5, P927, DOI 10.1158/1535-7163.MCT-05-0360; Singh M, 2009, MOL CELL BIOCHEM, V325, P107, DOI 10.1007/s11010-009-0025-5; SINGH S, 1995, J BIOL CHEM, V270, P24995, DOI 10.1074/jbc.270.42.24995; Singh Sarvjeet, 2006, Anti-Cancer Agents in Medicinal Chemistry, V6, P259, DOI 10.2174/187152006776930918; Su CC, 2006, ANTICANCER RES, V26, P4379; Tan TW, 2006, ANTICANCER RES, V26, P4361; William BM, 2008, HEMATOLOGY, V13, P333, DOI 10.1179/102453308X343437; Wright TI, 2006, J AM ACAD DERMATOL, V54, P933, DOI 10.1016/j.jaad.2005.08.062; Yu SW, 2008, MOL CANCER THER, V7, P2609, DOI 10.1158/1535-7163.MCT-07-2400	32	91	96	2	25	PERGAMON-ELSEVIER SCIENCE LTD	OXFORD	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND	0003-9969	1879-1506		ARCH ORAL BIOL	Arch. Oral Biol.	AUG	2012	57	8					1018	1025		10.1016/j.archoralbio.2012.04.005			8	Dentistry, Oral Surgery & Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Dentistry, Oral Surgery & Medicine	992RO	WOS:000307797600003	22554995				2022-04-25	
J	Ryan, D; Carberry, S; Murphy, AC; Lindner, AU; Fay, J; Hector, S; McCawley, N; Bacon, O; Concannon, CG; Kay, EW; McNamara, DA; Prehn, JHM				Ryan, Deborah; Carberry, Steven; Murphy, Aine C.; Lindner, Andreas U.; Fay, Joanna; Hector, Suzanne; McCawley, Niamh; Bacon, Orna; Concannon, Caoimhin G.; Kay, Elaine W.; McNamara, Deborah A.; Prehn, Jochen H. M.			Calnexin, an ER-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer	JOURNAL OF TRANSLATIONAL MEDICINE			English	Article						Colorectal cancer; ER Stress; Calnexin; GRP78; GRP94; UPR (unfolded protein response)	ENDOPLASMIC-RETICULUM STRESS; ADJUVANT CHEMOTHERAPY; GRP78; PROGRESSION; AUTOPHAGY; CELLS; FLUOROURACIL; RESISTANCE; CARCINOMA; APOPTOSIS	Background: Colorectal cancer (CRC) is a leading cause of cancer mortality in the Western world and commonly treated with genotoxic chemotherapy. Stress in the endoplasmic reticulum (ER) was implicated to contribute to chemotherapeutic resistance. Hence, ER stress related protein may be of prognostic or therapeutic significance. Methods: The expression levels of ER stress proteins calnexin, calreticulin, GRP78 and GRP94 were determined in n = 23 Stage II and III colon cancer fresh frozen tumour and matched normal tissue samples. Data were validated in a cohort of n = 11 rectal cancer patients treated with radiochemotherapy in the neoadjuvant setting. The calnexin gene was silenced using siRNA in HCT116 cells. Results: There were no increased levels of ER stress proteins in tumour compared to matched normal tissue samples in Stage II or III CRC. However, increased calnexin protein levels were predictive of poor clinical outcome in the patient cohort. Data were validated in the rectal cancer cohort treated in the neoadjuvant setting. Calnexin gene-silencing significantly reduced cell survival and increased cancer cell susceptibility to 5FU chemotherapy. Conclusion: Increased tumour protein levels of calnexin may be of prognostic significance in CRC, and calnexin may represent a potential target for future therapies.	[Ryan, Deborah; Carberry, Steven; Murphy, Aine C.; Lindner, Andreas U.; Hector, Suzanne; McCawley, Niamh; Bacon, Orna; Concannon, Caoimhin G.; Prehn, Jochen H. M.] Royal Coll Surgeons Ireland, Ctr Syst Med, Dept Physiol & Med Phys, 123 St Stephens Green, Dublin 2, Ireland; [Ryan, Deborah; McCawley, Niamh; Bacon, Orna; Concannon, Caoimhin G.; McNamara, Deborah A.] Beaumont Hosp, Dept Colorectal Surg, Dublin 9, Ireland; [Fay, Joanna; Kay, Elaine W.] Beaumont Hosp, Dept Pathol, Dublin 9, Ireland; [Fay, Joanna; Kay, Elaine W.] Royal Coll Surgeons Ireland, Dublin 9, Ireland		Prehn, JHM (corresponding author), Royal Coll Surgeons Ireland, Ctr Syst Med, Dept Physiol & Med Phys, 123 St Stephens Green, Dublin 2, Ireland.	prehn@rcsi.ie	Prehn, Jochen HM/A-3928-2010	Prehn, Jochen HM/0000-0003-3479-7794; Fay, Joanna/0000-0001-6294-2886; Lindner, Andreas/0000-0003-1590-3547	Health Research Board [TRA/2007/26]; Science Foundation IrelandScience Foundation IrelandEuropean Commission [13/IA/1881]; European UnionEuropean Commission [306021]	This research was supported by grants from the Health Research Board (TRA/2007/26), Science Foundation Ireland (13/IA/1881) and the European Union (FP7 APO-DECIDE Contract 306021) to JHMP.	Arnaudeau S, 2002, J BIOL CHEM, V277, P46696, DOI 10.1074/jbc.M202395200; Blachere NE, 1997, J EXP MED, V186, P1315, DOI 10.1084/jem.186.8.1315; Corazzari M, 2015, CELL DEATH DIFFER, V22, P946, DOI 10.1038/cdd.2014.183; de Gramont A, 2000, J CLIN ONCOL, V18, P2938, DOI 10.1200/JCO.2000.18.16.2938; Delom F, 2007, CELL DEATH DIFFER, V14, P586, DOI 10.1038/sj.cdd.4402012; Feldman DE, 2005, MOL CANCER RES, V3, P597, DOI 10.1158/1541-7786.MCR-05-0221; Fernandez PM, 2000, BREAST CANCER RES TR, V59, P15, DOI 10.1023/A:1006332011207; Figueredo A, 2008, COCHRANE DB SYST REV, DOI 10.1002/14651858.CD005390.pub2; Fu Y, 2006, CANCER BIOL THER, V5, P741, DOI 10.4161/cbt.5.7.2970; Gray R, 2007, LANCET, V370, P2020, DOI 10.1016/s0140-6736(07)61866-2; Hardy B, 2012, CELL ONCOL, V35, P345, DOI 10.1007/s13402-012-0094-4; Jamora C, 1996, P NATL ACAD SCI USA, V93, P7690, DOI 10.1073/pnas.93.15.7690; Li XM, 2011, J HEMATOL ONCOL, V4, DOI 10.1186/1756-8722-4-8; Nakamura K, 2000, J CELL BIOL, V150, P731, DOI 10.1083/jcb.150.4.731; Ni M, 2007, FEBS LETT, V581, P3641, DOI 10.1016/j.febslet.2007.04.045; PARSONS R, 1993, CELL, V75, P1227, DOI 10.1016/0092-8674(93)90331-J; Ragnhammar P, 2001, ACTA ONCOL, V40, P282, DOI 10.1080/02841860151116367; Ribic CM, 2003, NEW ENGL J MED, V349, P247, DOI 10.1056/NEJMoa022289; Schild H, 2000, NAT IMMUNOL, V1, P100, DOI 10.1038/77770; Schonthal AH, 2009, CANCER LETT, V275, P163, DOI 10.1016/j.canlet.2008.07.005; Shuda M, 2003, J HEPATOL, V38, P605, DOI 10.1016/S0168-8278(03)00029-1; Singh-Jasuja H, 2000, EUR J IMMUNOL, V30, P2211, DOI 10.1002/1521-4141(2000)30:18<2211::AID-IMMU2211>3.0.CO;2-H; Takizawa T, 2004, J BIOCHEM, V136, P399, DOI 10.1093/jb/mvh133; Tamura Y, 1997, SCIENCE, V278, P117, DOI 10.1126/science.278.5335.117; Ullman E, 2008, CELL DEATH DIFFER, V15, P422, DOI 10.1038/sj.cdd.4402234; Wang GH, 2010, AM J TRANSL RES, V2, P65; Yang SY, 2009, TRENDS MOL MED, V15, P225, DOI 10.1016/j.molmed.2009.03.003; Zhuang LQ, 2009, HISTOPATHOLOGY, V54, P462, DOI 10.1111/j.1365-2559.2009.03242.x	28	31	32	0	2	BMC	LONDON	CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	1479-5876			J TRANSL MED	J. Transl. Med.	JUL 1	2016	14								196	10.1186/s12967-016-0948-z			10	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	DR3MW	WOS:000379808300002	27369741	Green Published, gold			2022-04-25	
J	Tang, Y; Li, M; Wang, YL; Threadgill, MD; Xiao, M; Mou, CF; Song, GL; Kuang, J; Yang, X; Yang, L; Gao, XJ; Wang, YP; Meng, YP				Tang, Yi; Li, Ming; Wang, Ya-Lan; Threadgill, Michael D.; Xiao, Ming; Mou, Chun-Feng; Song, Guang-Lin; Kuang, Jing; Yang, Xi; Yang, Li; Gao, Xing-Jie; Wang, Ya-Ping; Meng, Yun-Peng			ART1 promotes starvation-induced autophagy: a possible protective role in the development of colon carcinoma	AMERICAN JOURNAL OF CANCER RESEARCH			English	Article						Autophagy; colon carcinoma; ART1; proliferation; apoptosis	ARGININE ADP-RIBOSYLTRANSFERASE; COLORECTAL-CANCER CELLS; POLY(ADP-RIBOSE) POLYMERASE-1; INTEGRIN ALPHA-7; DUAL ROLE; RIBOSYLATION; INHIBITION; APOPTOSIS; MIGRATION; NECROSIS	Autophagy plays a protective role in colorectal carcinoma. Arginine ADP-ribosyltransferase 1 (ART1) is an important mono-ADP-ribose transferase, which has been shown to play a role in biological processes such as proliferation and invasion of cancer cells. Interestingly, the role of ART1 in the regulation of autophagy is still not clear. We examined effects of overexpression or knockdown of ART1 by lentiviral transfection on starvation-induced autophagy of colon carcinoma CT26 cell lines in vivo and in vitro. The formation of autophagosome was detected by electron microscopy, acridine orange staining and expression of LC3 B. The molecular contributions of ART1 in regulation of autophagy were detected by western blotting or by co-immunoprecipitation. Additionally, inhibitors were used to study further the signaling pathway of ART1 in the regulation of autophagy. CCK8 assay, plate cloning assay, soft agar assay, examination of subcutaneous transplanted carcinoma in BALB/c mice, flow cytometry and Hoechst33342 staining were used to assess survival and apoptotic ability when starvation-induced autophagy modulated by ART1 was inhibited by 3-MA. Overexpression of ART1 promoted starvation-induced autophagy, which related to increases in the expression of Rac1, NF-kappa B, PARP-1, LKB1 and p-AMPK and a decrease in the expression of p-P70S6K. Correspondingly, knockdown of ART1 caused the opposite effects. ART1 also interacted with integrin alpha 7. Additionally, changes of protein expressions were further validated following inhibition of Rac1 and PARP-1 in the starvation-induced ART1-GFP CT26 cells. Inhibition of ART1-stimulated starvation-induced autophagy restrained the growth and promoted apoptosis. ART1 is thus relevant in starvation-induced autophagy in colorectal carcinoma and may play essential roles in therapeutic anticancer strategies.	[Tang, Yi; Li, Ming; Wang, Ya-Lan; Xiao, Ming; Song, Guang-Lin; Kuang, Jing; Yang, Xi] Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Pathol, Chongqing 400016, Peoples R China; [Threadgill, Michael D.] Univ Bath, Sch Pharm & Pharmacol, Bath BA2 7AY, Avon, England; [Mou, Chun-Feng; Yang, Li] Chongqing Med Univ, Fac Basic Med Sci, Chongqing 400016, Peoples R China; [Gao, Xing-Jie; Wang, Ya-Ping; Meng, Yun-Peng] Chongqing Med Univ, Clin Med Coll, Chongqing 400016, Peoples R China		Wang, YL (corresponding author), Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Pathol, Chongqing 400016, Peoples R China.	wangyalan074@126.com			Ministry of Education Specialized Research Fund for the Doctoral Program of Higher Education [20105503110009]; Science and Technology Program of Chongqing Municipal Education Commission [KJ110322]; National Nature Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [30870946]	This study was supported by the Ministry of Education Specialized Research Fund for the Doctoral Program of Higher Education (Grant No. 20105503110009), the Science and Technology Program of Chongqing Municipal Education Commission (Grant No. KJ110322) and the National Nature Science Foundation of China (NSFC: 30870946).	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J	Khandia, R; Dadar, M; Munjal, A; Dhama, K; Karthik, K; Tiwari, R; Yatoo, MI; Iqbal, HMN; Singh, KP; Joshi, SK; Chaicumpa, W				Khandia, Rekha; Dadar, Maryam; Munjal, Ashok; Dhama, Kuldeep; Karthik, Kumaragurubaran; Tiwari, Ruchi; Yatoo, Mohd Iqbal; Iqbal, Hafiz M. N.; Singh, Karam Pal; Joshi, Sunil K.; Chaicumpa, Wanpen			A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy	CELLS			English	Review						autophagy mechanism; autophagy-associated diseases; macroautophagy; chaperone-mediated autophagy; apoptosis; necroptosis; necrosis; iron homeostasis; autophagy inhibition; AKT/mTOR signaling pathway; autosis	HEPATITIS-C VIRUS; CHAPERONE-MEDIATED AUTOPHAGY; ENDOPLASMIC-RETICULUM STRESS; STARVATION-INDUCED AUTOPHAGY; ACTIVATED PROTEIN-KINASE; COLORECTAL-CANCER CELLS; TUMOR-SUPPRESSOR GENE; X-LINKED MYOPATHY; ALPHA-SYNUCLEIN; SELECTIVE AUTOPHAGY	Autophagy (self-eating) is a conserved cellular degradation process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Autophagy dysfunction can have various pathological consequences, including tumor progression, pathogen hyper-virulence, and neurodegeneration. This review describes the mechanisms of autophagy and its associations with other cell death mechanisms, including apoptosis, necrosis, necroptosis, and autosis. Autophagy has both positive and negative roles in infection, cancer, neural development, metabolism, cardiovascular health, immunity, and iron homeostasis. Genetic defects in autophagy can have pathological consequences, such as static childhood encephalopathy with neurodegeneration in adulthood, Crohn's disease, hereditary spastic paraparesis, Danon disease, X-linked myopathy with excessive autophagy, and sporadic inclusion body myositis. Further studies on the process of autophagy in different microbial infections could help to design and develop novel therapeutic strategies against important pathogenic microbes. This review on the progress and prospects of autophagy research describes various activators and suppressors, which could be used to design novel intervention strategies against numerous diseases and develop therapeutic drugs to protect human and animal health.	[Khandia, Rekha; Munjal, Ashok] Barkatullah Univ, Dept Genet, Bhopal 462026, Madhya Pradesh, India; [Dadar, Maryam] AREEO, Razi Vaccine & Serum Res Inst, Karaj 31975148, Iran; [Dhama, Kuldeep; Singh, Karam Pal] ICAR Indian Vet Res Inst, Div Pathol, Bareilly 243122, Uttar Pradesh, India; [Karthik, Kumaragurubaran] Tamil Nadu Vet & Anim Sci Univ, Cent Univ Lab, Chennai 600051, Tamil Nadu, India; [Tiwari, Ruchi] UP Pandit Deen Dayal Upadhayay Pashu Chikitsa Vig, Coll Vet Sci, Dept Vet Microbiol & Immunol, Mathura 281001, Uttar Pradesh, India; [Yatoo, Mohd Iqbal] Sher E Kashmir Univ Agr Sci & Technol Kashmir, Srinagar 190025, Jammu & Kashmir, India; [Iqbal, Hafiz M. N.] Tecnol Monterrey, Sch Engn & Sci, Campus Monterrey,Ave Eugenio Garza Sada 2501, Monterrey 64849, NL, Mexico; [Joshi, Sunil K.] Univ Miami, Sch Med, Div Hematol Oncol & Bone Marrow Transplantat, Dept Pediat, Miami, FL 33136 USA; [Chaicumpa, Wanpen] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Parasitol,Ctr Res Excellence Therapeut Prot, Bangkok 10700, Thailand		Munjal, A (corresponding author), Barkatullah Univ, Dept Genet, Bhopal 462026, Madhya Pradesh, India.; Dhama, K (corresponding author), ICAR Indian Vet Res Inst, Div Pathol, Bareilly 243122, Uttar Pradesh, India.; Joshi, SK (corresponding author), Univ Miami, Sch Med, Div Hematol Oncol & Bone Marrow Transplantat, Dept Pediat, Miami, FL 33136 USA.	ak.munjal@bubhopal.ac.in; kdhama@rediffmail.com; sunil.joshi@med.miami.edu	Dadar, Maryam/D-3660-2017; Yatoo, Mohd Iqbal/AAT-1624-2020; Khandia, Rekha/AAE-6122-2022; Karthik, K/AAN-5411-2020; Kumaragurubaran, Karthik/ABF-9301-2021; Dhama, Kuldeep/B-7852-2015; Tiwari, Ruchi/ABG-9049-2021; Iqbal, Hafiz M.N./J-5423-2014	Dadar, Maryam/0000-0001-5831-801X; Khandia, Rekha/0000-0002-9961-3127; Kumaragurubaran, Karthik/0000-0002-9215-6306; Dhama, Kuldeep/0000-0001-7469-4752; Tiwari, Ruchi/0000-0001-7763-5547; Iqbal, Hafiz M.N./0000-0003-4855-2720; Munjal, Ashok/0000-0001-6294-1584; Yatoo, Dr. Mohd. 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J	Wang, HW; Yang, SH; Huang, GD; Lin, JK; Chen, WS; Jiang, JK; Lan, YT; Lin, CC; Hwang, WL; Tzeng, CH; Li, AFY; Yen, CC; Teng, HW				Wang, Hsei-Wei; Yang, Shung-Haur; Huang, Guan-Da; Lin, Jen-Kou; Chen, Wei-Shone; Jiang, Jeng-Kai; Lan, Yuan-Tzu; Lin, Chun-Chi; Hwang, Wei-Lun; Tzeng, Cheng-Hwai; Li, Anna Fen-Yau; Yen, Chueh-Chuan; Teng, Hao-Wei			Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism	JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY			English	Article						utophagy; mTOR; AKT; Erk	METASTATIC COLORECTAL-CANCER; SIGNALING PATHWAYS; HUMAN MALIGNANCIES; 1ST-LINE THERAPY; PROGNOSTIC ROLE; GASTRIC-CANCER; PHOSPHATASE 2A; PHASE-III; CIP2A; CHEMOTHERAPY	Purpose A dozen clinical trials examining a combination of temsirolimus and cetuximab in treating metastatic colon cancer are currently underway. We investigated the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in the synergism between temsirolimus and cetuximab in colon cancer. Methods Five colon cancer cell lines were used for in vitro studies. Signal transduction pathways were assessed by immunoblotting. The synergism between studied drugs was analyzed with combination indexes. Gene silencing was performed using small interfering RNAs. The efficacies of temsirolimus and cetuximab were tested in nude mice with colon cancer xenografts. Transcriptional activity was assessed using a reporter assay. The inhibitors leupeptin, chloroquine, and MG132 were used to assess protein degradation. The association between CIP2A, clinicopathological parameters, and survival was examined by immunohistochemical staining using a tumor tissue microarray. Results Temsirolimus decreased the resistance of cells to cetuximab by both inhibiting transcription of CIP2A and increasing degradation of CIP2A through the lysosomal-autophagy pathway. The mammalian target of rapamycin (mTOR) protein immunoprecipitated along with CIP2A. Temsirolimus decreased expression of phosphorylated extracellular regulated protein kinase (pErk) and phosphorylated v-akt murine thymoma viral oncogene (pAKT) and decreased the interaction of CIP2A and mTOR in cell lines without the K-ras codon 12 mutation. CIP2A was a prognostic marker only in colon cancer patients with weak expression of pErk or pAKT. Conclusions Temsirolimus decreases cellular resistance to cetuximab by regulating CIP2A expression in colon cancer cells. Potential biomarkers for CIP2A inhibitors include pErk and pAKT.	[Wang, Hsei-Wei; Yang, Shung-Haur; Lin, Jen-Kou; Chen, Wei-Shone; Jiang, Jeng-Kai; Lan, Yuan-Tzu; Lin, Chun-Chi; Hwang, Wei-Lun; Tzeng, Cheng-Hwai; Li, Anna Fen-Yau; Yen, Chueh-Chuan; Teng, Hao-Wei] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan; [Wang, Hsei-Wei; Hwang, Wei-Lun] Natl Yang Ming Univ, Inst Microbiol & Immunol, Taipei 112, Taiwan; [Wang, Hsei-Wei; Hwang, Wei-Lun] Natl Taiwan Univ Hosp, Natl Ctr Excellence Clin Trial & Res, Taipei, Taiwan; [Yang, Shung-Haur; Lin, Jen-Kou; Chen, Wei-Shone; Jiang, Jeng-Kai; Lan, Yuan-Tzu; Lin, Chun-Chi] Taipei Vet Gen Hosp, Dept Surg, Div Colon & Rectal Surg, Taipei 112, Taiwan; [Huang, Guan-Da; Tzeng, Cheng-Hwai; Yen, Chueh-Chuan; Teng, Hao-Wei] Taipei Vet Gen Hosp, Dept Med, Div Hematol & Oncol, Taipei 112, Taiwan; [Tzeng, Cheng-Hwai; Yen, Chueh-Chuan; Teng, Hao-Wei] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan; [Li, Anna Fen-Yau] Gen Hosp, Dept Pathol, Taipei, Taiwan		Teng, HW (corresponding author), Taipei Vet Gen Hosp, Dept Med, Div Hematol & Oncol, 201,Sec 2,Shih Pai Rd, Taipei 112, Taiwan.	danny_teng@yahoo.com.tw		Hwang, Wei-Lun/0000-0002-8694-877X	Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General HospitalTaipei Veterans General Hospital; Taipei Veterans General Hospital, Taiwan Clinical Oncology Research Foundation, Department of Health, Taiwan (Center of Excellence for Cancer Research at Taipei Veterans General Hospital [102DHA0100184, 101DHA0100369]	This work was supported in part by the Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital, and by the Taipei Veterans General Hospital, Taiwan Clinical Oncology Research Foundation, Department of Health, Taiwan (Center of Excellence for Cancer Research at Taipei Veterans General Hospital (102DHA0100184, 101DHA0100369).	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J	Gandesiri, M; Chakilam, S; Ivanovska, J; Benderska, N; Ocker, M; Di Fazio, P; Feoktistova, M; Gali-Muhtasib, H; Rave-Frank, M; Prante, O; Christiansen, H; Leverkus, M; Hartmann, A; Schneider-Stock, R				Gandesiri, Muktheshwar; Chakilam, Saritha; Ivanovska, Jelena; Benderska, Natalya; Ocker, Matthias; Di Fazio, Pietro; Feoktistova, Maria; Gali-Muhtasib, Hala; Rave-Fraenk, Margret; Prante, Olaf; Christiansen, Hans; Leverkus, Martin; Hartmann, Arndt; Schneider-Stock, Regine			DAPK plays an important role in panobinostat-induced autophagy and commits cells to apoptosis under autophagy deficient conditions	APOPTOSIS			English	Article						Panobinostat; LBH589; DAPK; Autophagy; Apoptosis; Colon cancer	HISTONE DEACETYLASE INHIBITOR; ENDOPLASMIC-RETICULUM STRESS; PROTEIN-KINASE DAPK; COLON-CANCER; DNA METHYLATION; TUMOR-CELLS; DEATH; LBH589; RESISTANCE; LINES	The histone deacetylase inhibitor (HDACi) LBH589 has been verified as an effective anticancer agent. The identification and characterization of new targets for LBH589 action would further enhance our understanding of the molecular mechanisms involved in HDACi therapy. The role of the tumor suppressor death-associated protein kinase (DAPK) in LBH589-induced cytotoxicity has not been investigated to date. Stable DAPK knockdown (shRNA) and DAPK overexpressing (DAPK+++) cell lines were generated from HCT116 wildtype colon cancer cells. LBH589 inhibited cell proliferation, reduced the long-term survival, and up-regulated and activated DAPK in colorectal cancer cells. Moreover, LBH589 significantly suppressed the growth of colon tumor xenografts and in accordance with the in vitro studies, increased DAPK levels were detected immunohistochemically. LBH589 induced a DAPK-dependent autophagy as assessed by punctuate accumulation of LC3-II, the formation of acidic vesicular organelles, and degradation of p62 protein. LBH589-induced autophagy seems to be predominantly caused by DAPK protein interactions than by its kinase activity. Caspase inhibitor zVAD increased autophagosome formation, decreased the cleavage of caspase 3 and PARP but didn't rescue the cells from LBH589-induced cell death in crystal violet staining suggesting both caspase-dependent as well as caspase-independent apoptosis pathways. Pre-treatment with the autophagy inhibitor Bafilomycin A1 caused caspase 3-mediated apoptosis in a DAPK-dependent manner. Altogether our data suggest that DAPK induces autophagy in response to HDACi-treatment. In autophagy deficient cells, DAPK plays an essential role in committing cells to HDACi-induced apoptosis.	[Gandesiri, Muktheshwar; Chakilam, Saritha; Ivanovska, Jelena; Benderska, Natalya; Hartmann, Arndt; Schneider-Stock, Regine] Univ Erlangen Nurnberg, Dept Pathol, D-91054 Erlangen, Germany; [Ocker, Matthias; Di Fazio, Pietro] Univ Marburg, Inst Surg Res, Marburg, Germany; [Feoktistova, Maria; Leverkus, Martin] Univ Heidelberg, Mol Dermatol Sect, Dept Dermatol Venereol & Allergol, Med Fac Mannheim, Heidelberg, Germany; [Gali-Muhtasib, Hala] Amer Univ Beirut, Dept Biol, Beirut, Lebanon; [Rave-Fraenk, Margret; Christiansen, Hans] Univ Hosp Gottingen, Dept Radiat Oncol, Gottingen, Germany; [Prante, Olaf] Clin Nucl Med, Lab Mol Imaging, Erlangen, Germany; [Christiansen, Hans] Med Sch Hanover, Hannover, Germany		Schneider-Stock, R (corresponding author), Univ Erlangen Nurnberg, Dept Pathol, Univ Str 22, D-91054 Erlangen, Germany.	regine.schneider-stock@uk-erlangen.de	Schneider-Stock, Regine/H-8863-2012; Di Fazio, Pietro/ABC-1524-2020; Di Fazio, Pietro/AAU-4575-2020	Di Fazio, Pietro/0000-0003-0091-8498; 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Zalckvar E, 2009, AUTOPHAGY, V5, P720, DOI 10.4161/auto.5.5.8625; Zhang F, 2009, CANCER BIOL THER, V8, P823, DOI 10.4161/cbt.8.9.8143; Zhang XT, 2006, ONCOL REP, V16, P563	63	47	49	0	15	SPRINGER	DORDRECHT	VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS	1360-8185			APOPTOSIS	Apoptosis	DEC	2012	17	12					1300	1315		10.1007/s10495-012-0757-7			16	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	042XG	WOS:000311504800006	23011180				2022-04-25	
J	Yang, PY; Cartwright, C; Efuet, E; Hamilton, SR; Wistuba, II; Menter, D; Addington, C; Shureiqi, I; Newman, RA				Yang, Peiying; Cartwright, Carrie; Efuet, Ekem; Hamilton, Stanley R.; Wistuba, Ignacio Ivan; Menter, David; Addington, Crandell; Shureiqi, Imad; Newman, Robert A.			Cellular location and expression of Na+, K+-ATPase alpha subunits affect the anti-proliferative activity of oleandrin	MOLECULAR CARCINOGENESIS			English	Article						CaCO-2 cells; oleandrin; Na, K-ATPase alpha 3 isoform; colon tissues; cardiac glycoside	CARDIAC-GLYCOSIDES; 15-LIPOXYGENASE-1 EXPRESSION; CANCER-CELLS; BETA-SUBUNIT; SODIUM-PUMP; NA,K-ATPASE; APOPTOSIS; DEATH; THERAPY; DIFFERENTIATION	The purpose of this study was to investigate whether intracellular distribution of Na+, K+-ATPase alpha 3 subunit, a receptor for cardiac glycosides including oleandrin, is differentially altered in cancer versus normal cells and whether this altered distribution can be therapeutically targeted to inhibit cancer cell survival. The cellular distribution of Na+, K+-ATPase alpha 3 isoform was investigated in paired normal and cancerous mucosa biopsy samples from patients with lung and colorectal cancers by immunohistochemical staining. The effects of oleandrin on alpha 3 subunit intracellular distribution, cell death, proliferation, and EKR phosphorylation were examined in differentiated and undifferentiated human colon cancer CaCO-2 cells. While Na+, K+-ATPase alpha 3 isoform was predominantly located near the cytoplasmic membrane in normal human colon and lung epithelia, the expression of this subunit in their paired cancer epithelia was shifted to a peri-nuclear position in both a qualitative and quantitative manner. Similarly, distribution of alpha 3 isoform was also shifted from a cytoplasmic membrane location in differentiated human colon cancer CaCO-2 cells to a peri-nuclear position in undifferentiated CaCO-2 cells. Intriguingly, oleandrin exerted threefold stronger anti-proliferative activity in undifferentiated CaCO-2 cells (IC50, 8.25 nM) than in differentiated CaCO-2 cells (IC50, >25 nM). Oleandrin (10 to 20 nM) caused an autophagic cell death and altered ERK phosphorylation in undifferentiated but not in differentiated CaCO-2 cells. These data demonstrate that the intracellular location of Na+, K+-ATPase alpha 3 isoform is altered in human cancer versus normal cells. These changes in alpha 3 cellular location and abundance may indicate a potential target of opportunity for cancer therapy. (c) 2012 Wiley Periodicals, Inc.	[Yang, Peiying; Cartwright, Carrie; Efuet, Ekem] Univ Texas MD Anderson Canc Ctr, Dept Gen Oncol, Houston, TX 77030 USA; [Yang, Peiying; Menter, David] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA; [Hamilton, Stanley R.; Wistuba, Ignacio Ivan] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA; [Addington, Crandell] Phoenix Biotechnol Inc, San Antonio, TX USA; [Shureiqi, Imad] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA; [Shureiqi, Imad] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA; [Newman, Robert A.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA		Newman, RA (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, 112 Whale Rock Lane, Surry, ME 04684 USA.		Shureiqi, imad/T-6214-2019	Shureiqi, Imad/0000-0003-2019-938X	Phoenix Biotechnology, Inc. (San Antonio, TX); NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016672, P01CA091844] Funding Source: NIH RePORTER	The research work was in part supported by Phoenix Biotechnology, Inc. (San Antonio, TX). We thank Kennith Burner Jr. for his expert technical support with respect to transmission electron microscopy.	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J	Wirawan, E; Berghe, TV; Lippens, S; Agostinis, P; Vandenabeele, P				Wirawan, Ellen; Vanden Berghe, Tom; Lippens, Saskia; Agostinis, Patrizia; Vandenabeele, Peter			Autophagy: for better or for worse	CELL RESEARCH			English	Review						autophagy; autophagosome; vesicle; degradation; cell death	PROGRAMMED CELL-DEATH; BECLIN 1-DEPENDENT AUTOPHAGY; ENDOGENOUS VIRAL-ANTIGENS; INNATE IMMUNE-RESPONSE; LIFE-SPAN EXTENSION; COLON-CANCER CELLS; MICROSATELLITE INSTABILITY; MITOCHONDRIAL CLEARANCE; ENDOPLASMIC-RETICULUM; MEDIATED AUTOPHAGY	Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.	[Wirawan, Ellen; Vanden Berghe, Tom; Lippens, Saskia; Vandenabeele, Peter] VIB, Dept Mol Biomed Res, Unit Mol Signaling & Cell Death, B-9052 Ghent, Zwijnaarde, Belgium; [Wirawan, Ellen; Vanden Berghe, Tom; Lippens, Saskia; Vandenabeele, Peter] Univ Ghent, Dept Biomed Mol Biol, Unit Mol Signaling & Cell Death, B-9052 Ghent, Belgium; [Agostinis, Patrizia] KULeuven, Lab Cell Death & Therapy, Dept Mol & Cell Biol, B-3000 Louvain, Belgium		Vandenabeele, P (corresponding author), VIB, Dept Mol Biomed Res, Unit Mol Signaling & Cell Death, Technol Pk 927, B-9052 Ghent, Zwijnaarde, Belgium.	Peter.Vandenabeele@dmbr.vib-UGent.be	Vandenabeele, Peter/AAD-5793-2022; Agostinis, Patrizia/AAO-2468-2020; Agostinis, Patrizia/ABI-1177-2020; Berghe, Tom Vanden/C-4916-2009; Vandenabeele, Peter/C-8597-2009; Berghe, Tom Vanden/N-2902-2019	Vandenabeele, Peter/0000-0002-6669-8822; Agostinis, Patrizia/0000-0003-1314-2115; Berghe, Tom Vanden/0000-0002-1633-0974; Berghe, Tom Vanden/0000-0002-1633-0974; Lippens, Saskia/0000-0002-8261-3462	Flanders Institute for Biotechnology (VIB); European grants [MRTN-CT-035624, FP7-200767]; Belgian grants [IAP 6/18]; Fonds Wetenschappelijk Onderzoek VlaanderenFWO [FWO G.0875.11, FWO G.0973.11]; Ghent UniversityGhent University; Flemish GovernmentEuropean Commission [BOF09/01M00709]; Ghent UniversityGhent University [BOF 2001-GOA 12050502 en BOF 2005-GOA 01GC0205]; Methusalem project [BOF09/01M00709]; FWOFWO [G.0661.09, G.0728.10]; Catholic University of LeuvenKU Leuven [GOA/11/009]	This research has been supported by Flanders Institute for Biotechnology (VIB), by European grants (FP6 ApopTrain, MRTN-CT-035624; FP7 EC RTD Integrated Project, Apo-Sys, FP7-200767; Euregional PACT II), Belgian grants (Interuniversity Attraction Poles, IAP 6/18), Flemish grants (Fonds Wetenschappelijk Onderzoek Vlaanderen, FWO G.0875.11 and FWO G.0973.11), and Ghent University grants (MRP, GROUP-ID). PV is holder of a Methusalem grant (BOF09/01M00709) from the Flemish Government. The doctoral fellowship of EW has been supported by Ghent University grants (BOF 2001-GOA 12050502 en BOF 2005-GOA 01GC0205) and by the Methusalem project BOF09/01M00709. SL and TV are postdoctoral fellows with the FWO. Research in PA's laboratory is supported by FWO G.0661.09 and G.0728.10, the Catholic University of Leuven (GOA/11/009) and the Stichting tegen Kanker. We thank Dr Amin Bredan (DMBR-VIB, Ghent) for editing the manuscript.	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JAN	2012	22	1					43	61		10.1038/cr.2011.152			19	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	879EQ	WOS:000299312900009	21912435	Green Published, Bronze			2022-04-25	
J	Du, BY; Guo, Y; Jin, L; Xiong, MY; Liu, DD; Xi, XY				Du, Boyu; Guo, Yang; Jin, Lan; Xiong, Mengyuan; Liu, Dandan; Xi, Xueyan			Targeting autophagy promote the 5-fluorouracil induced apoptosis in human colon cancer cells	INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY			English	Article						Chloroquine; 5-fluorouracil; colon cancer; autophagy; apoptosis	DRUG-RESISTANCE; CHLOROQUINE; INHIBITION; CYTOTOXICITY; MECHANISMS; CISPLATIN; OVERCOME; STRESS; DEATH	Colon cancer is a leading cause of cancer-related death in developed countries. Although 5-fluorouracil (5-FU) has traditionally been studied for its potential to induce apoptosis, its clinical use had been greatly limited as a result of the development of drug resistance in patients. Besides the medicines that could induce apoptosis in cancer cells, several other alternative treatments, which had different mechanisms of action (such as autophagy), had gained more and more attention recently. As for colon cancer, autophagy appeared to have certain protective effects in tumor cells by antagonizing the inhibition caused by chemotherapy and radiotherapy. Therefore, autophagy inhibition seemed to be an effective mean for cancer treatment. In this study, HT29 and SW480 cells were treated with autophagy inhibitors together with/without 5-FU, the proliferation rate, apoptosis and autophagy induction effects were then evaluated. The proliferation rate of cancer cells was analyzed by MTT assay. Apoptosis was quantified by flow-cytometry after the cells were double-stained with Annexin V/PI. Autophagy and apoptosis were both further confirmed by western blot analysis. Finally, to confirm the effects of combinational use of 5-FU with 3-methyladenine (3-MA) and Chloroquine (CQ), the colony formation assay was also performed. Our results demonstrated that 5-FU could induce apoptosis and autophagy in colon cancer cells. Both 3-MA and CQ could enhance the apoptosis induced by 5-FU in colon cancer cells, while CQ had better inhibitory effect against the proliferation of colon cancer cells. Meanwhile, CQ could induce a caspase-dependent apoptosis in colon cancer cells. Cathepins might function in the synergistic interaction between 5-FU and CQ. Based on the above results, we proposed the combinational use of 5-FU and CQ might be a novel therapeutic method for the treatment of colon cancer.	[Du, Boyu; Guo, Yang; Jin, Lan; Xiong, Mengyuan; Liu, Dandan; Xi, Xueyan] Hubei Univ Med, Sch Basic Med Sci, Shiyan, Peoples R China		Xi, XY (corresponding author), Hubei Univ Med, Sch Basic Med Sci, Dept Immunol, 30 Renmin Nanlu, Shiyan 442000, Hubei Province, Peoples R China.	xixueyan2001@126.com			Science and Technology Research Project of Education Department of Hubei Province [D20162104, B2016504]; Faculty Development Grant of Hubei University of Medicine [2015QDJZR07, 2015QDJZR10]	This work was supported by grants from Science and Technology Research Project of Education Department of Hubei Province (D20162104 to Xueyan Xi and B2016504 to Dandan Liu) and Faculty Development Grant of Hubei University of Medicine (2015QDJZR07 to Xueyan Xi and 2015QDJZR10 to Boyu Du).	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J. Clin. Exp. Pathol.		2017	10	5					6071	6081					11	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	EW1UG	WOS:000402279600130					2022-04-25	
J	Prasad, AR; Prasad, S; Nguyen, H; Facista, A; Lewis, C; Zaitlin, B; Bernstein, H; Bernstein, C				Prasad, Anil R.; Prasad, Shilpa; Nguyen, Huy; Facista, Alexander; Lewis, Cristy; Zaitlin, Beryl; Bernstein, Harris; Bernstein, Carol			Novel diet-related mouse model of colon cancer parallels human colon cancer	WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY			English	Article						Diet; Deoxycholate; Mouse model; Colon cancer; Histology; Chlorogenic acid; 8-OH-dG; Beclin 1; Beta-catenin		AIM: To investigate the close parallels between our novel diet-related mouse model of colon cancer and human colon cancer. METHODS: Twenty-two wild-type female mice (ages 6-8 wk) were fed the standard control diet (AIN-93G) and an additional 22 female mice (ages 6-8 wk) were fed the control diet supplemented with 0.2% deoxycholic acid [diet + deoxycholic acid (DOC)] for 10 mo. Tumors occurred in the colons of mice fed diet + DOC and showed progression to colon cancer [adenocarcinoma (AC)]. This progression is through the stages of tubular adenoma (TA), TA with high grade dysplasia or adenoma with sessile serrated morphology, intramucosal AC, AC stage T1, and AC stage T2. The mouse tumors were compared to human tumors at the same stages by histopathological analysis. Sections of the small and large intestines of mice and humans were evaluated for glandular architecture, cellular and nuclear morphology including cellular orientation, cellular and nuclear atypia, pleomorphism, mitotic activity, frequency of goblet cells, crypt architecture, ulceration, penetration of crypts through the muscularis mucosa and presence of malignant crypts in the muscularis propria. In addition, preserved colonic tissues from genetically similar male mice, obtained from a prior experiment, were analyzed by immunohistochemistry. The male mice had been fed the control diet or diet + DOC. Four molecular markers were evaluated: 8-OH-dG, DNA repair protein ERCC1, autophagy protein beclin-1 and the nuclear location of beta-catenin in the stem cell region of crypts. Also, male mice fed diet + DOC plus 0.007% chlorogenic acid (diet + DOC + CGA) were evaluated for ERCC1, beclin-1 and nuclear location of beta-catenin. RESULTS: Humans with high levels of diet-related DOC in their colons are at a substantially increased risk of developing colon cancer. The mice fed diet + DOC had levels of DOC in their colons comparable to that of humans on a high fat diet. The 22 mice without added DOC in their diet had no colonic tumors while 20 of the 22 mice (91%) fed diet + DOC developed colonic tumors. Furthermore, the tumors in 10 of these mice (45% of mice) included an adenocarcinoma. All mice were free of cancers of the small intestine. Histopathologically, the colonic tumor types in the mice were virtually identical to those in humans. In humans, characteristic aberrant changes in molecular markers can be detected both in field defects surrounding cancers (from which cancers arise) and within cancers. In the colonic tissues of mice fed diet + DOC similar changes in biomarkers appeared to occur. Thus, 8-OH-dG was increased, DNA repair protein ERCC1 was decreased, autophagy protein beclin-1 was increased and, in the stem cell region at the base of crypts there was substantial nuclear localization of beta-catenin as well as increased cytoplasmic beta-catenin. However, in mice fed diet + DOC + CGA (with reduced frequency of cancer) and evaluated for ERCC1, beclin-1, and beta-catenin in the stem cell region of crypts, mouse tissue showed amelioration of the aberrancies, suggesting that chlorogenic acid is protective at the molecular level against colon cancer. This is the first diet-related model of colon cancer that closely parallels human progression to colon cancer, both at the histomorphological level as well as in its molecular profile. CONCLUSION: The diet-related mouse model of colon cancer parallels progression to colon cancer in humans, and should be uniquely useful in model studies of prevention and therapeutics. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.	[Prasad, Anil R.] Northwest Med Ctr, Dept Pathol, Tucson, AZ 85741 USA; [Prasad, Anil R.] Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85724 USA; [Prasad, Shilpa] Boston Univ, Coll Arts & Sci, Boston, MA USA; [Nguyen, Huy; Facista, Alexander; Lewis, Cristy; Bernstein, Harris; Bernstein, Carol] Univ Arizona, Coll Med, Dept Cellular & Mol Med, Tucson, AZ 85724 USA; [Zaitlin, Beryl] Matrix Solut Inc, Calgary, AB T2R 0V2, Canada		Bernstein, C (corresponding author), Univ Arizona, Coll Med, Dept Cellular & Mol Med, 2639 E 4th St, Tucson, AZ 85716 USA.	bernstein324@yahoo.com			National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5 R01 CA119087]; Arizona Biomedical Research Commission [0803]; Veterans Affairs Merit ReviewUS Department of Veterans Affairs [0142]	Supported by National Institutes of Health, No. 5 R01 CA119087; Arizona Biomedical Research Commission, No. 0803; and Veterans Affairs Merit Review, No. 0142; administered by the Southern Arizona Veterans Affairs Health Care System	Bernstein C., 2013, NEW RES DIRECTIONS D; 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Gastrointest. Oncol.	JUL 15	2014	6	7					225	243		10.4251/wjgo.v6.i7.225			19	Oncology; Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Gastroenterology & Hepatology	V9A4H	WOS:000422132600003	25024814	Green Published, hybrid			2022-04-25	
J	Sipos, F; Firneisz, G; Muzes, G				Sipos, Ferenc; Firneisz, Gabor; Muzes, Gyorgyi			Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases	WORLD JOURNAL OF GASTROENTEROLOGY			English	Review						c-MYC; Therapy; Apoptosis; Autophagy; Colon; Inflammation; Colorectal cancer	MESENCHYMAL STEM-CELLS; COLORECTAL-CANCER; INDUCED APOPTOSIS; BOWEL-DISEASE; TRANSCRIPTION FACTORS; GENE-EXPRESSION; SELECTIVE-INHIBITION; INTESTINAL CRYPTS; EPITHELIAL-CELLS; BETA-CATENIN	Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host's protective immunity. In cells upon DNA damage several protooncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and microRNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be selected for combined regiments. However, due to its context-dependent cellular function, it is clinically essential to consider which cytotoxic drugs are used in combination with c-MYC targeted agents in various tissues. Increasing our knowledge about MYC-dependent pathways might provide direction to novel anti-inflammatory and colorectal cancer therapies.	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Gastroenterol.	SEP 21	2016	22	35					7938	7950		10.3748/wjg.v22.i35.7938			13	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	DW9LT	WOS:000383981800007	27672289	hybrid, Green Published, Green Submitted			2022-04-25	
J	Liu, TT; Liu, SM				Liu, Ting-ting; Liu, Shu-min			Prediction of Prognostic Biomarkers and Construction of an Autophagy Prognostic Model for Colorectal Cancer Using Bioinformatics	TECHNOLOGY IN CANCER RESEARCH & TREATMENT			English	Article						autophagy; prognostic model; colorectal cancer; bioinformatics; markers		Objective: The incidence of colorectal cancer is increasing every year, and autophagy may be related closely to the pathogenesis of colorectal cancer. Autophagy is a natural catabolic mechanism that allows the degradation of cellular components in eukaryotic cells. However, autophagy plays a dual role in tumorigenesis. It not only promotes normal cell survival and tumor growth but also induces cell death and suppresses tumors survival. In addition, the pathogenesis of various conditions, including inflammation, neurodegenerative diseases, or tumors, is associated with abnormal autophagy. The present work aimed to examine the significance of autophagy-related genes (ARGs) in prognosis prediction, to construct an autophagy prognostic model, and to identify independent prognostic factors for colorectal cancer (CRC). Methods: This study discovered a total of 36 ARGs in CRC cases using The Cancer Genome Atlas (TCGA) and Human Autophagy-dedicated (HADd) databases along with functional enrichment analysis. Then, an autophagy prognostic model was constructed using univariate Cox regression analysis, and the key prognostic genes were screened. Finally, independent prognostic markers were determined through independent prognostic analysis and clinical correlation analysis of key genes. Results: Of the 36 differentially expressed ARGs, 13 were related to prognosis, as determined by univariate Cox regression analysis. A total of 6 key genes were obtained by a multivariate Cox regression analysis. Independent prognostic values were shown by 3 genes, namely, microtubule-associated protein 1 light chain 3 (MAP1LC3C), small GTPase superfamily and Rab family (RAB7A), and WD-repeat domain phosphoinositide-interacting protein 2 (WIPI2) by independent prognostic analysis and clinical correlation. Conclusions: In this study, molecular bioinformatics technology was employed to determine and construct a prognostic model of autophagy for colon cancer patients, which revealed 3 autophagy-related features, namely, MAP1LC3C, WIPI2, and RAB7A.	[Liu, Ting-ting; Liu, Shu-min] Heilongjiang Univ Chinese Med, Grad Sch, Harbin, Heilongjiang, Peoples R China; [Liu, Shu-min] Heilongjiang Univ Chinese Med, Inst Tradit Chinese Med, 24 Heping Rd, Harbin 150040, Heilongjiang, Peoples R China		Liu, SM (corresponding author), Heilongjiang Univ Chinese Med, Inst Tradit Chinese Med, 24 Heping Rd, Harbin 150040, Heilongjiang, Peoples R China.	keji-liu@163.com					Bakula D, 2013, BIOCHEM SOC T, V41, P962, DOI 10.1042/BST20130039; Bathe OF, 2014, GENES-BASEL, V5, P536, DOI 10.3390/genes5030536; Bell ES, 2020, AUTOPHAGY, V16, P959, DOI 10.1080/15548627.2020.1728099; Brody H, 2015, NATURE, V521, pS1, DOI 10.1038/521S1a; Chen C, 2020, PLOS ONE, V15, DOI 10.1371/journal.pone.0232832; Devenport SN, 2019, CELLS-BASEL, V8, DOI 10.3390/cells8111349; Dooley HC, 2014, MOL CELL, V55, P238, DOI 10.1016/j.molcel.2014.05.021; Dorayappan KDP, 2018, ONCOGENE, V37, P3806, DOI 10.1038/s41388-018-0189-0; Gafar AA, 2016, PEERJ, V4, DOI 10.7717/peerj.2445; Gonzalez-Gaitan Marcos, 2003, Cell, V115, P513, DOI 10.1016/S0092-8674(03)00932-2; Grimmel M, 2015, CELLS-BASEL, V4, P202, DOI 10.3390/cells4020202; Guerra F, 2019, CANCERS, V11, DOI 10.3390/cancers11081096; Guerra F, 2016, CELLS-BASEL, V5, DOI 10.3390/cells5030034; He Y, 2020, BIOSCI BIOTECH BIOCH, V84, P1645, DOI 10.1080/09168451.2020.1760784; Kuchitsu Y, 2018, CELLS-BASEL, V7, DOI 10.3390/cells7110215; Liang XH, 2001, CANCER RES, V61, P3443; Liao CC, 2013, AUTOPHAGY, V9, P5, DOI 10.4161/auto.22379; Liu PF, 2014, AUTOPHAGY, V10, P1454, DOI 10.4161/auto.29556; Mo SB, 2019, CARCINOGENESIS, V40, P861, DOI 10.1093/carcin/bgz031; Mowers EE, 2017, ONCOGENE, V36, P1619, DOI 10.1038/onc.2016.333; Polson HEJ, 2010, AUTOPHAGY, V6, P506, DOI 10.4161/auto.6.4.11863; Proikas-Cezanne T, 2004, ONCOGENE, V23, P9314, DOI 10.1038/sj.onc.1208331; Snider MD, 2003, MOL CELL, V12, P796, DOI 10.1016/S1097-2765(03)00401-5; Tian S, 2017, ONCOTARGET, V8, P11071, DOI 10.18632/oncotarget.14360; Towers CG, 2020, J CELL BIOL, V219, DOI 10.1083/jcb.201909033; Towers CG, 2016, EBIOMEDICINE, V14, P15, DOI 10.1016/j.ebiom.2016.10.034; Weiser MR, 2011, J CLIN ONCOL, V29, P4796, DOI 10.1200/JCO.2011.36.5080; Yang Z, 2020, INT J ONCOL, V56, P1442, DOI 10.3892/ijo.2020.5027; Yu J., 2019, MODERN ONCOL MED, V27, P2055; Zhang CR, 2020, FRONT GENET, V11, DOI 10.3389/fgene.2020.00245; Zhong ZY, 2016, CELL, V166, P288, DOI 10.1016/j.cell.2016.05.051; Zhou HY, 2016, CANCER BIOMARK, V17, P1, DOI 10.3233/CBM-160613	32	0	0	3	4	SAGE PUBLICATIONS INC	THOUSAND OAKS	2455 TELLER RD, THOUSAND OAKS, CA 91320 USA	1533-0346	1533-0338		TECHNOL CANCER RES T	Technol. Cancer Res. Treat.	DEC 24	2020	19								1533033820984177	10.1177/1533033820984177			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	PM1FL	WOS:000603554100001	33357130	Green Published, gold			2022-04-25	
J	Zhai, H; Song, B; Xu, X; Zhu, W; Ju, J				Zhai, H.; Song, B.; Xu, X.; Zhu, W.; Ju, J.			Inhibition of autophagy and tumor growth in colon cancer by miR-502	ONCOGENE			English	Article						miR-502; autophagy; p53; colon cancer	CELL-CYCLE; GENE-EXPRESSION; SMALL RNAS; TRANSCRIPTIONAL ACTIVATION; P53; MICRORNAS; MIR-34A; PROLIFERATION; CHEMORESISTANCE; 5-FLUOROURACIL	Autophagy is a catabolic process that allows cellular macromolecules to be broken down and recycled as metabolic precursors. The influence of non-coding microRNAs in autophagy has not been explored in colon cancer. In this study, we discover a novel mechanism of autophagy regulated by hsa-miR-502-5p (miR-502) by suppression of Rab1B, a critical mediator of autophagy. A number of other miR-502 suppressed mRNA targets (for example, dihydroorotate dehydrogenase) are also identified by microarray analysis. Ectopic expression of miR-502 inhibited autophagy, colon cancer cell growth and cell-cycle progression of colon cancer cells in vitro. miR-502 also inhibited in-vivo colon cancer growth in a mouse tumor xenografts model. In addition, the expression of miR-502 was regulated by p53 via a negative feedback regulatory mechanism. The expression of miR-502 was downregulated in colon cancer patient specimens compared with the paired normal control samples. These results suggest that miR-502 may function as a potential tumor suppressor and therefore be a novel candidate for developing miR-502-based therapeutic strategies. Oncogene (2013) 32, 1570-1579; doi:10.1038/onc.2012.167; published online 14 May 2012	[Zhai, H.; Ju, J.] SUNY Stony Brook, Dept Pathol, Translat Res Lab, Stony Brook, NY 11794 USA; [Song, B.] Dalian Med Univ, Dept Pathol, Dalian, Peoples R China; [Xu, X.; Zhu, W.] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA		Ju, J (corresponding author), SUNY Stony Brook, Dept Pathol, Translat Res Lab, BST L9,Room 185, Stony Brook, NY 11794 USA.	jingfang.ju@stonybrookmedicine.edu	zhai, haiyan/K-4659-2014	Ju, Jingfang/0000-0002-4821-7458	Stony Brook University Translational Research Laboratory [R01CA155019, R33CA147966]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA155019, R33CA147966] Funding Source: NIH RePORTER	We appreciate the critical review by Ms Sonya R Lorrain. We thank Dr Stella E Tsirka for technical support in animal experiments. This study was supported in part by Stony Brook University Translational Research Laboratory Start-up Fund (J Ju), R01CA155019 (J Ju) and R33CA147966 (J Ju).	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Oncology; Cell Biology; Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity	110PC	WOS:000316456000010	22580605	Green Accepted, Bronze			2022-04-25	
J	Zhang, HZ; Cui, ZH; Cheng, D; Du, YY; Guo, XL; Gao, R; Chen, JW; Sun, WW; He, RR; Ma, XJ; Peng, QW; Martin, RAL; Yan, W; Rong, YG; Wang, CH				Zhang, Huazhi; Cui, Zhihui; Cheng, Du; Du, Yanyun; Guo, Xiaoli; Gao, Ru; Chen, Jianwen; Sun, Wanwei; He, Ruirui; Ma, Xiaojian; Peng, Qianwen; Martin, Bradley N.; Yan, Wei; Rong, Yueguang; Wang, Chenhui			RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis	AUTOPHAGY			English	Article						Autophagy; EPHB2; ephrin B1; RNF186; ulcerative colitis	INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION; COLORECTAL-CANCER; EPHB RECEPTORS; ULCERATIVE-COLITIS; SUSCEPTIBILITY; PROLIFERATION; DEGRADATION; PREVALENCE; EXPRESSION	Although genome-wide association studies have identified the gene RNF186 encoding an E3 ubiquitin-protein ligase as conferring susceptibility to ulcerative colitis, the exact function of this protein remains unclear. In the present study, we demonstrate an important role for RNF186 in macroautophagy/autophagy activation in colonic epithelial cells and intestinal homeostasis. Mechanistically, RNF186 acts as an E3 ubiquitin-protein ligase for EPHB2 and regulates the ubiquitination of EPHB2. Upon stimulation by ligand EFNB1 (ephrin B1), EPHB2 is ubiquitinated by RNF186 at Lys892, and further recruits MAP1LC3B for autophagy. Compared to control mice, rnf186(-/-) and ephb2(-/-) mice have a more severe phenotype in the DSS-induced colitis model, which is due to a defect in autophagy in colon epithelial cells. More importantly, treatment with ephrin-B1-Fc recombinant protein effectively relieves DSS-induced mouse colitis, which suggests that ephrin-B1-Fc may be a potential therapy for human inflammatory bowel diseases.	[Zhang, Huazhi; Cui, Zhihui; Du, Yanyun; Guo, Xiaoli; Gao, Ru; Chen, Jianwen; Sun, Wanwei; He, Ruirui; Ma, Xiaojian; Peng, Qianwen; Wang, Chenhui] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Natl Engn Res Ctr Nanomed, Key Lab Mol Biophys,Minist Educ, 1037th Luoyu Ave, Wuhan 430074, Peoples R China; [Cheng, Du] Wuhan Univ, Dept Gastroenterol, Renmin Hosp, Wuhan, Peoples R China; [Martin, Bradley N.] Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Boston, MA USA; [Yan, Wei] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Gastroenterol, Wuhan, Peoples R China; [Rong, Yueguang] Huazhong Univ Sci & Technol, Sch Basic Med, Dept Pathogen Biol, Wuhan, Peoples R China; [Wang, Chenhui] Wuhan Inst Biotechnol, Dept Bioinformat, Wuhan, Peoples R China		Wang, CH (corresponding author), Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Natl Engn Res Ctr Nanomed, Key Lab Mol Biophys,Minist Educ, 1037th Luoyu Ave, Wuhan 430074, Peoples R China.; Rong, YG (corresponding author), Huazhong Univ Sci & Technol, Sch Basic Med, Dept Pathogen Biol, Wuhan, Peoples R China.	rongyueguang@hust.edu.cn; wangchenhui@hust.edu.cn		Martin, Bradley/0000-0002-8902-8805; RONG, YUEGUANG/0000-0001-6661-9664; Wang, Chenhui/0000-0002-3186-3066	Huazhong University of Science Technology [2017KFYXJJ163]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81871280]; Junior Thousand Talents Program of China	This investigation was supported by the independent innovation grant from Huazhong University of Science & Technology [grant 2017KFYXJJ163]; and the grant from the National Natural Science Foundation of China [grants 81871280]; and the Junior Thousand Talents Program of China [to C.H.W.].	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J	Wen, J; Zhao, YY; Guo, L				Wen, Jing; Zhao, Yuyan; Guo, Lei			Orexin A induces autophagy in HCT-116 human colon cancer cells through the ERK signaling pathway	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE			English	Article						orexin A; autophagy; extracellular signal-regulated kinase signaling pathway; HCT-116 human colon cancer cells	INHIBITION; BECLIN-1; GROWTH; SUPPRESSES; APOPTOSIS; PROTEIN; GENE; MACROAUTOPHAGY; TUMORIGENESIS; ACTIVATION	Orexins are a class of peptides which have a potent influence on a broad variety of cancer cells. Autophagy is closely associated with tumors; however, its function is not yet completely understood. In this study, we aimed to determine whether orexin A induces autophagy in HCT-116 human colon cancer cells and to elucidate the molecular mechanisms involved. For this purpose, HCT-116 cells were treated with orexin A, and cell viability was then measured by MTT assay, and apoptosis was determined by flow cytometry. The expression levels of autophagy-related proteins were measured by western blot analysis. Quantitative analysis of autophagy following acridine orange (AO) staining was performed using fluorescence microscopy, and cellular morphology was observed under a transmission electron microscope. In addition, the HCT-116 cells were treated with the extracellular signal-regulated kinase (ERK) inhibitor, U0126, or the autophagy inhibitor, chloroquine, in combination with orexin A in order to examine the activation of ERK. We found that orexin A significantly inhibited the viability of the HCT-116 cells. Both autophagy and apoptosis were activated during the orexin A-induced death of HCT-116 cells. When the HCT-116 cells were treated with orexin A for 24 h, an accumulation of punctate microtubule-associated protein-1 light chain 3 (LC3) and an increase in LC3-II protein levels were also detected, indicating the activation of autophagy. Moreover, orexin A upregulated ERK phosphorylation; however, U0126 or chloroquine abrogated ERK phosphorylation and decreased autophagy, compared to treatment with orexin A alone. Therefore, our findings demonstratedm that orexin A induced autophagy through the ERK pathway in HCT-116 human colon cancer cells. The inhibition of autophagy may thus prove to be an effective strategy for enhancing the antitumor potential of orexin A as a treatment for colon cancer.	[Wen, Jing; Zhao, Yuyan] China Med Univ, Affiliated Hosp 1, Dept Endocrinol, Shenyang 110001, Liaoning, Peoples R China; [Guo, Lei] China Med Univ, Affiliated Hosp 1, Dept Orthoped Surg, Shenyang 110001, Liaoning, Peoples R China		Zhao, YY (corresponding author), China Med Univ, Affiliated Hosp 1, Dept Endocrinol, 155 Nanjing North St, Shenyang 110001, Liaoning, Peoples R China.	g572@sina.com; 15241818899@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81470998, 81071460, 81271996]; Natural Science Foundation of Liaoning ProvinceNatural Science Foundation of Liaoning Province [201202292]	The authors would like to thank The China Medical University Affiliated Hospital Laboratory Center for kindly providing the equipment. This study was supported by the National Natural Science Foundation of China (grant nos. 81470998, 81071460 and 81271996) and the Natural Science Foundation of Liaoning Province (grant no. 201202292).	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J. Mol. Med.	JAN	2016	37	1					126	132		10.3892/ijmm.2015.2409			7	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	DA5UB	WOS:000367867000015	26572581	Bronze			2022-04-25	
J	Shang, YY; Yao, M; Zhou, ZW; Jian-Cui; Li-Xia; Hu, RY; Yu, YY; Qiong-Gao; Biao-Yang; Liu, YX; Dang, J; Zhou, SF; Nan-Yu				Shang, Yuan-Yuan; Yao, Ming; Zhou, Zhi-Wei; Jian-Cui; Li-Xia; Hu, Rong-Ying; Yu, Ying-Yao; Qiong-Gao; Biao-Yang; Liu, Yu-Xi; Dang, Jie; Zhou, Shu-Feng; Nan-Yu			Alisertib promotes apoptosis and autophagy in melanoma through p38 MAPK-mediated aurora a signaling	ONCOTARGET			English	Article						alisertib; melanoma; AURKA; MAPK	PROSTATE-CANCER CELLS; COLON-CANCER; IN-VIVO; KINASE; PATHWAY; THERAPY; DEATH; INHIBITOR; CARCINOMA; OVEREXPRESSION	We investigated the efficacy of Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, in melanoma. We found that ALS exerts anti-proliferative, proapoptotic, and pro-autophagic effects on A375 and skmel-5 melanoma cells by inhibiting p38 MAPK signaling. SB202190, a p38 MAPK-selective inhibitor, enhanced ALS-induced apoptosis and autophagy in both cell lines. ALS induced cell cycle arrest in melanoma cells through activation of the p53/p21/cyclin B1 pathway. Knockdown of p38 MAPK enhanced ALS-induced apoptosis and reduced ALS-induced autophagy. Inhibition of autophagy sensitized melanoma cells to ALS-induced apoptosis. These data indicate ALS is a potential therapeutic agent for melanoma.	[Shang, Yuan-Yuan; Li-Xia; Hu, Rong-Ying; Yu, Ying-Yao; Qiong-Gao; Biao-Yang; Liu, Yu-Xi; Nan-Yu] NingXia Med Univ, Gen Hosp, Dept Dermatol, Yinchuan, Peoples R China; [Shang, Yuan-Yuan; Yao, Ming; Zhou, Zhi-Wei; Zhou, Shu-Feng] Univ S Florida, Dept Pharmaceut Sci, Coll Pharm, Tampa, FL 33620 USA; [Yao, Ming] NingXia Med Univ, Dept Burns & Plast Surg, Gen Hosp, Yinchuan, Peoples R China; [Jian-Cui] NingXia Med Univ, Gen Hosp, Dept Anesthesia, Yinchuan, Peoples R China; [Dang, Jie] Ningxia Med Univ, Dept Med Genet & Cell Biol, Yinchuan, Peoples R China		Nan-Yu (corresponding author), NingXia Med Univ, Gen Hosp, Dept Dermatol, Yinchuan, Peoples R China.; Zhou, SF (corresponding author), Univ S Florida, Dept Pharmaceut Sci, Coll Pharm, Tampa, FL 33620 USA.	szhou@health.usf.edu; syy23301@163.com	Zhou, Shu-Feng/E-3166-2013	Zhou, Shu-Feng/0000-0002-5542-6119	General Hospital of NingXia Medical University	This work is supported by General Hospital of NingXia Medical University.	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J	Xu, D; Yang, F; He, HY; Hu, J; Lv, XD; Ma, DL; Chen, YY				Xu, Dong; Yang, Fan; He, Huiying; Hu, Jia; Lv, Xiaodong; Ma, Dalong; Chen, Ying Yu			Expression of TMEM166 Protein in Human Normal and Tumor Tissues	APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY			English	Article						TMEM166; tissue microarrays; immunohistochemistry; normal human tissues; tumor tissues	CELL-DEATH; MOLECULAR-MECHANISMS; AUTOPHAGY GENE; SUPPRESSOR; BECLIN-1; CANCER; TUMORIGENESIS; APOPTOSIS; UVRAG	Transmembrane protein 166 (TMEM166) is a novel human regulator involved in both autophagy and apoptosis. In this study, we generated a specific rabbit polyclonal antibody against human TMEM166 and assessed the expression of this protein in various human normal and tumor tissue samples by tissue microarray-based immunohistochemical analysis. Varying TMEM166 protein levels were expressed in a cell-type and tissue-type-specific manner in detected tissues or organs. Strong TMEM166 expression was shown in the glomerular zona of the adrenal cortex, chromophil cells of the pituitary gland, islet cells, squamous epithelium of the esophagus mucosa, the fundic gland, and hepatocytes. Moderate or weak TMEM166 staining was identified in the parathyroid gland, the testis, vaginal stratified squamous cells, lung macrophages, hematopoietic cells, renal tubular epithelial cells, macrophages in the spleen red pulp, and neuronal cells in the cerebral cortex. Some tissues failed to stain for TMEM166, such as adipose tissue, colon, cerebellum, lymph node, mammary gland, ovary, prostate, rectum, skin, small intestine, thyroid gland, tonsil, and thymus. In comparing human normal and tumor tissues, TMEM166 expression was widely downregulated in the cancer tissues. Our studies provide the basis for future investigations into cell-type-specific functions of this protein in human normal and tumor tissues.	[Xu, Dong; Hu, Jia; Lv, Xiaodong; Ma, Dalong; Chen, Ying Yu] Peking Univ, Minist Hlth, Key Lab Med Immunol, Beijing 100083, Peoples R China; [Xu, Dong; Hu, Jia; Ma, Dalong; Chen, Ying Yu] Peking Univ, Ctr Human Dis Genom, Beijing 100083, Peoples R China; [Yang, Fan] Peking Univ, Peoples Hosp, Dept Thorac Surg, Beijing 100083, Peoples R China; [He, Huiying] Peking Univ, Sch Basic Med Sci, Dept Pathol, Beijing 100083, Peoples R China		Chen, YY (corresponding author), Peking Univ, Ctr Human Dis Genom, 38 Xue Yuan Rd, Beijing 100083, Peoples R China.	yingyu_chen@bjmu.edu.cn		Yang, Fan/0000-0002-1044-7821	National Key Project for Basic Research of China (973)National Basic Research Program of China [2011CB910103]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30771057]	Supported by the grants from the National Key Project for Basic Research of China (973, 2011CB910103) and the National Natural Science Foundation of China (30771057).	Ciavarra G, 2011, AUTOPHAGY, V7, P544, DOI 10.4161/auto.7.5.15056; Coppola D, 2008, CANCER-AM CANCER SOC, V113, P2665, DOI 10.1002/cncr.23892; Daido S, 2004, CANCER RES, V64, P4286, DOI 10.1158/0008-5472.CAN-03-3084; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Gozuacik D, 2006, AUTOPHAGY, V2, P74, DOI 10.4161/auto.2.2.2459; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Klionsky DJ, 2007, NAT REV MOL CELL BIO, V8, P931, DOI 10.1038/nrm2245; Klionsky DJ, 2005, J CELL SCI, V118, P7, DOI 10.1242/jcs.01620; Levine B, 2005, CELL, V120, P159, DOI 10.1016/j.cell.2005.01.005; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Liang CY, 2008, NAT CELL BIOL, V10, P776, DOI 10.1038/ncb1740; Liang C, 2006, NAT CELL BIOL, V8, P688, DOI 10.1038/ncb1426; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Maclean KH, 2008, J CLIN INVEST, V118, P79, DOI 10.1172/JCI33700; Maiuri MC, 2010, CURR OPIN CELL BIOL, V22, P181, DOI 10.1016/j.ceb.2009.12.001; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Mathew R, 2011, CURR OPIN GENET DEV, V21, P113, DOI 10.1016/j.gde.2010.12.008; Pimkina J, 2009, AUTOPHAGY, V5, P397, DOI 10.4161/auto.5.3.7782; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Rashmi R, 2008, ONCOGENE, V27, P1366, DOI 10.1038/sj.onc.1210783; Ravikumar B, 2010, PHYSIOL REV, V90, P1383, DOI 10.1152/physrev.00030.2009; Wang L, 2007, APOPTOSIS, V12, P1489, DOI 10.1007/s10495-007-0073-9; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	24	18	18	1	7	LIPPINCOTT WILLIAMS & WILKINS	PHILADELPHIA	530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA	1541-2016	1533-4058		APPL IMMUNOHISTO M M	Appl. Immunohistochem.	DEC	2013	21	6					543	552		10.1097/PAI.0b013e31824e93d1			10	Anatomy & Morphology; Medical Laboratory Technology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Anatomy & Morphology; Medical Laboratory Technology; Pathology	255AR	WOS:000327212100011	22495369				2022-04-25	
J	Zhang, N; Hu, XY; Du, YN; Du, J				Zhang, Ning; Hu, Xianyu; Du, Yinan; Du, Juan			The role of miRNAs in colorectal cancer progression and chemoradiotherapy	BIOMEDICINE & PHARMACOTHERAPY			English	Review						microRNA; Colorectal cancer; Chemoradiotherapy; Cancer therapy; Biomarkers	COLON-CANCER; CELL-PROLIFERATION; SIGNALING PATHWAY; DOWN-REGULATION; TUMOR-GROWTH; MESENCHYMAL TRANSITION; INHIBITS PROLIFERATION; TRANSCRIPTION FACTORS; RADIATION-RESISTANCE; TARGETING ZEB1	Colorectal cancer (CRC) is known as the third most common cancer as well as the fourth most deadly cancer worldwide. CRC accounts for approximately 10 % of all new cancer cases globally, remaining the second most frequent cause of cancer-related deaths. MicroRNAs (miRNAs) are a class of small noncoding RNAs that can affect a variety of cellular and molecular targets. Depending on the cell environment in which the information is expressed, miRNAs can serve as a CRC suppressor or promoter and play essential roles in several biological processes. In this review, we summarized the relationship between miRNAs and proliferation, metastasis, angiogenesis, autophagy, apoptosis, and the chemoradiotherapy of CRC, revealing that relevant miRNAs could serve as potential targets for CRC therapy.	[Du, Juan] Chinese Univ Hong Kong, Longgang Dist Peoples Hosp Shenzhen, Shenzhen 518172, Guangdong, Peoples R China; [Du, Juan] Chinese Univ Hong Kong, Affiliated Hosp Provis 3, Shenzhen 518172, Guangdong, Peoples R China; [Zhang, Ning; Hu, Xianyu; Du, Yinan; Du, Juan] Anhui Med Univ, Sch Basic Med Sci, Hefei 230032, Anhui, Peoples R China		Du, J (corresponding author), Chinese Univ Hong Kong, Longgang Dist Peoples Hosp Shenzhen, Shenzhen 518172, Guangdong, Peoples R China.; Du, J (corresponding author), Chinese Univ Hong Kong, Affiliated Hosp Provis 3, Shenzhen 518172, Guangdong, Peoples R China.; Du, YN (corresponding author), Anhui Med Univ, Sch Basic Med Sci, Hefei 230032, Anhui, Peoples R China.	duyinannan@163.com; dujuan@cuhk.edu.cn		Du, Yinan/0000-0002-7678-7546; Zhang, Ning/0000-0002-5892-2193	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31701162, 8197102295, U1732157]	This work was funded by the National Natural Science Foundation of China (No. 31701162, 8197102295 and U1732157).	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Pharmacother.	FEB	2021	134								111099	10.1016/j.biopha.2020.111099			10	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	PY7MT	WOS:000612226900008	33338745	gold			2022-04-25	
J	Wang, QY; Wang, P; Xiao, ZG				Wang, Qiuyu; Wang, Peng; Xiao, Zhigang			Resistant starch prevents tumorigenesis of dimethylhydrazine-induced colon tumors via regulation of an ER stress-mediated mitochondrial apoptosis pathway	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE			English	Article						resistant starch; tumorigenesis; colon tumor; apoptosis; endoplasmic reticulum stress	COLORECTAL-CANCER; CELL INVASION; UP-REGULATION; EXPRESSION; METASTASIS; AUTOPHAGY; METAANALYSIS; ACTIVATION; CARCINOMA; ANTITUMOR	Resistant starch is as common soluble fiber that escapes digestion in the small intestine and can regulate intestinal function, metabolism of blood glucose and lipids, and may prevent tumorigenesis of gastrointestinal cancer. Epidemiology and other evidence have suggested that resistant starch may prevent colon cancer development. The aim of the current study was to explore the ameliorative effects and potential mechanisms of resistant starch in the tumorigenesis of colon tumors induced by dimethylhydrazine in C57BL/6 mice. Western blot analysis, ELISA, microscopy, immunofluorescence and immunohistochemistry were used to analyze the efficacy of resistant starch on the metabolic balance in the colon and tumorigenesis of colon tumors. The results demonstrated that a diet containing resistant starch decreased the animal body weight and reduced free ammonia, pH and short chain fatty acids in feces compared with mice that received a standard diet. Resistant starch reduced the incidence of colon tumors and suppressed the expression of carcinogenesis-associated proteins, including heat shock protein 25, protein kinase C-d and gastrointestinal glutathione peroxidase in colon epithelial cells compared with standard starch and control groups. Colon tumor cells proliferation and dedifferentiation were significantly decreased by a resistant starch diet. The results also demonstrated that resistant starch increased the apoptosis of colon tumor cells through regulation of apoptosis-associated gene expression levels in colon tumor cells. Oxidative stress and endoplasmic reticulum stress were upregulated, and elevation eukaryotic translation initiation factor 2 (eIF2), activating transcription factor-4 and secretase- expression levels were increased in the resistant starch diet group. Additionally, the activity of eIF2 and PERK were increased in colon tumor cells from mice that had received resistant starch. Increasing DNA damage-inducible transcript 3 protein (CHOP), binding immunoglobulin protein (BIP) and caspase-12 expression levels upregulated by resistant starch diet may contribute to the resistant starch-induced apoptosis of colon tumor cells induced by 1,2-dimethylhydrazine. In vitro assays demonstrated that knockdown of eIF2 inhibited apoptosis of colon tumor cells isolated from mice fed with resistant starch, which also downregulated CHOP, BIP and caspase-3 expression levels compared with controls. Furthermore, long-term survival of experimental mice was prolonged by the resistant starch diet compared with the standard diet group. In conclusion, the results indicate that resistant starch in the diet may prevent carcinogenesis of colon epithelial cells, mediated by enhancing apoptosis through an endoplasmic reticulum stress-mediated mitochondrial apoptosis pathway.	[Wang, Qiuyu; Wang, Peng; Xiao, Zhigang] Northeast Agr Univ, Coll Food Sci, 59 Mucai St, Harbin 150030, Heilongjiang, Peoples R China		Xiao, ZG (corresponding author), Northeast Agr Univ, Coll Food Sci, 59 Mucai St, Harbin 150030, Heilongjiang, Peoples R China.	xiaozhigangprof@163.com					Atkins C, 2013, CANCER RES, V73, P1993, DOI 10.1158/0008-5472.CAN-12-3109; Baskaran R, 2016, BIOMED PHARMACOTHER, V83, P1407, DOI 10.1016/j.biopha.2016.08.063; Birt DF, 2014, TOXICOL PATHOL, V42, P182, DOI 10.1177/0192623313506791; Bukurova Iu A, 2010, Mol Biol (Mosk), V44, P375; Burness CB, 2016, DRUGS, V76, P1393, DOI 10.1007/s40265-016-0633-9; Chaveroux C, 2015, SCI SIGNAL, V8, DOI 10.1126/scisignal.aaa0549; Chibaudel B, 2015, LANCET ONCOL, V16, pE583, DOI 10.1016/S1470-2045(15)00448-9; Christova I, 2003, INT J IMMUNOPATH PH, V16, P261, DOI 10.1177/039463200301600312; Crespo I, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0050407; Dagistanli FK, 2018, EXP CLIN ENDOCR DIAB, V126, P168, DOI 10.1055/s-0042-107243; Dronamraju SS, 2009, GUT, V58, P413, DOI 10.1136/gut.2008.162933; Edagawa M, 2014, J BIOL CHEM, V289, P21544, DOI 10.1074/jbc.M114.558890; Fan ZY, 2015, ONCOTARGET, V6, P25266, DOI 10.18632/oncotarget.4457; Guo J, 2016, TUMOR BIOL, V37, P6371, DOI 10.1007/s13277-015-4504-x; Haigis KM, 2008, NAT GENET, V40, P600, DOI 10.1038/ng.115; Hawkins P, 2011, LAB ANIM-UK, V45, P1, DOI 10.1258/la.2010.010031; Hino M, 2012, BIOL PHARM BULL, V35, P2097, DOI 10.1248/bpb.b12-00633; Hirai HW, 2016, ALIMENT PHARM THER, V43, P755, DOI 10.1111/apt.13556; Ho Y, 2016, AM J PATHOL, V186, P1939, DOI 10.1016/j.ajpath.2016.03.004; Jang YM, 2016, FREE RADICAL BIO MED, V95, P190, DOI 10.1016/j.freeradbiomed.2016.03.018; Jiang N, 2014, TUMOR BIOL, V35, P9429, DOI 10.1007/s13277-014-2258-5; Khan I, 2016, BIOMED PHARMACOTHER, V84, P789, DOI 10.1016/j.biopha.2016.09.094; Le Leu RK, 2010, CARCINOGENESIS, V31, P246, DOI 10.1093/carcin/bgp197; Lee JS, 2012, INT J TOXICOL, V31, P70, DOI 10.1177/1091581811423845; Liu WL, 2016, INT J MOL MED, V37, P309, DOI 10.3892/ijmm.2015.2425; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Lopez NE, 2016, AM J SURG, V212, P700, DOI 10.1016/j.amjsurg.2016.06.019; Ma Z, 2016, CRIT REV FOOD SCI NU, DOI [10. 1080/10408398. 2016. 1230537 27646607, DOI 10.1080/10408398.2016.123053727646607]; Marin M, 2000, PARASITOL RES, V86, P431, DOI 10.1007/s004360050690; Mathers JC, 2012, LANCET ONCOL, V13, P1242, DOI 10.1016/S1470-2045(12)70475-8; Moilanen JM, 2015, HUM PATHOL, V46, P434, DOI 10.1016/j.humpath.2014.11.020; Molinari AJ, 2012, RADIAT RES, V177, P59, DOI 10.1667/RR2729.1; Moriarity A, 2016, THER ADV MED ONCOL, V8, P276, DOI 10.1177/1758834016646734; Nabizadeh A, 2016, IRAN J CANCER PREV, V9, DOI 10.17795/ijcp-3919; Ou JH, 2013, AM J CLIN NUTR, V98, P111, DOI 10.3945/ajcn.112.056689; Raigond P, 2015, J SCI FOOD AGR, V95, P1968, DOI 10.1002/jsfa.6966; Ridlon JM, 2006, CANCER BIOL THER, V5, P273, DOI 10.4161/cbt.5.3.2728; Shen DQ, 2017, INT J FOOD SCI NUTR, V68, P149, DOI 10.1080/09637486.2016.1226275; Stanton MJ, 2013, CANCER RES, V73, P160, DOI 10.1158/0008-5472.CAN-11-3635; Thompson BA, 2013, HUM MUTAT, V34, P200, DOI 10.1002/humu.22213; Wali VB, 2009, APOPTOSIS, V14, P1366, DOI 10.1007/s10495-009-0406-y; Xiao SH, 2016, INT J BIOL MARKER, V31, pE276, DOI 10.5301/jbm.5000199; Yamaoka Y, 2015, SURG CASE REP, V1, DOI 10.1186/s40792-015-0118-1; Yuan W, 2017, AM J TRANSL RES, V9, P5662; Yueh AE, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0148730; Zhai H, 2013, ONCOGENE, V32, P1570, DOI 10.1038/onc.2012.167; Zhang C, 2016, CELL STRESS CHAPERON, V21, P251, DOI 10.1007/s12192-015-0655-3; Zhang XB, 2016, TUMOR BIOL, V37, P8317, DOI 10.1007/s13277-015-4511-y	48	5	6	4	22	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1107-3756	1791-244X		INT J MOL MED	Int. J. Mol. Med.	APR	2018	41	4					1887	1898		10.3892/ijmm.2018.3423			12	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	FY9BQ	WOS:000427160600010	29393371	hybrid, Green Published, Green Submitted			2022-04-25	
J	Wu, YH; Yao, JL; Xie, JS; Liu, Z; Zhou, YB; Pan, HM; Han, WD				Wu, Yuhui; Yao, Junlin; Xie, Jiansheng; Liu, Zhen; Zhou, Yubin; Pan, Hongming; Han, Weidong			The role of autophagy in colitis-associated colorectal cancer	SIGNAL TRANSDUCTION AND TARGETED THERAPY			English	Review							INTESTINAL EPITHELIAL-CELLS; NATURAL-KILLER-CELLS; REGULATORY T-CELLS; COLON-CANCER; GENE ATG16L1; STEM-CELLS; IMPAIRED AUTOPHAGY; TUMOR ANGIOGENESIS; IMMUNE-RESPONSE; BECLIN 1	Autophagy is an evolutionarily conserved catabolic process that eliminates harmful components through lysosomal degradation. In addition to its role in maintaining cellular homeostasis, autophagy is critical to pathological processes, such as inflammation and cancer. Colitis-associated colorectal cancer (CAC) is a specific type of colorectal cancer that develops from long-standing colitis in inflammatory bowel disease (IBD) patients. Accumulating evidence indicates that autophagy of microenvironmental cells plays different but vital roles during tumorigenesis and CAC development. Herein, after summarizing the recent advances in understanding the role of autophagy in regulating the tumor microenvironment during different CAC stages, we draw the following conclusions: autophagy in intestinal epithelial cells inhibits colitis and CAC initiation but promotes CAC progression; autophagy in macrophages inhibits colitis, but its function on CAC is currently unclear; autophagy in neutrophils and cancer-associated fibroblasts (CAFs) promotes both colitis and CAC; autophagy in dendritic cells (DCs) and T cells represses both colitis and CAC; autophagy in natural killer cells (NKs) inhibits colitis, but promotes CAC; and autophagy in endothelial cells plays a controversial role in colitis and CAC. Understanding the role of autophagy in specific compartments of the tumor microenvironment during different stages of CAC may provide insight into malignant transformation, tumor progression, and combination therapy strategies for CAC.	[Wu, Yuhui; Yao, Junlin; Liu, Zhen; Pan, Hongming; Han, Weidong] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Med Oncol, Coll Med, Hangzhou 310016, Zhejiang, Peoples R China; [Xie, Jiansheng] Zhejiang Univ, Inst Clin Sci, Sir Run Run Shaw Hosp, Lab Canc Biol,Coll Med, Hangzhou 310016, Zhejiang, Peoples R China; [Zhou, Yubin] Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Ctr Translat Canc Res, Houston, TX 77030 USA		Pan, HM; Han, WD (corresponding author), Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Med Oncol, Coll Med, Hangzhou 310016, Zhejiang, Peoples R China.	panhongming@zju.edu.cn; hanwd@zju.edu.cn	Zhou, Yubin/D-4748-2011	Zhou, Yubin/0000-0001-7962-0517; Liu, Zhen/0000-0002-8910-9664	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81572361, 81772543, 81572592]; Zhejiang Province Preeminence Youth Fund [LR16H160001]; Zhejiang Medical Innovative Discipline Construction Project-2016	This work was supported by the National Natural Science Foundation of China (81572361, 81772543, and 81572592); the Zhejiang Province Preeminence Youth Fund (LR16H160001); and the Zhejiang Medical Innovative Discipline Construction Project-2016.	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Zhao J, 2015, INT IMMUNOPHARMACOL, V26, P221, DOI 10.1016/j.intimp.2015.03.033; Zhong ZY, 2016, CELL, V166, P288, DOI 10.1016/j.cell.2016.05.051; Zhu XR, 2015, J CLIN INVEST, V125, P1098, DOI 10.1172/JCI76344	120	29	31	5	17	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	2095-9907	2059-3635		SIGNAL TRANSDUCT TAR	Signal Transduct. Target. Ther.	NOV 30	2018	3								31	10.1038/s41392-018-0031-8			11	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	HG0EM	WOS:000454615200001	30510778	Green Published, gold			2022-04-25	
J	Yu, R; Zhang, ZQ; Wang, B; Jiang, HX; Cheng, L; Shen, LM				Yu, Rong; Zhang, Zhi-qing; Wang, Bin; Jiang, Hong-xin; Cheng, Lei; Shen, Li-ming			Berberine-induced apoptotic and autophagic death of HepG2 cells requires AMPK activation	CANCER CELL INTERNATIONAL			English	Article						Hepatocellular carcinoma; Berberine; AMPK; Apoptosis; Autophagy and mTOR	SKELETAL-MUSCLE CELLS; COLON-CANCER CELLS; PROTEIN-KINASE; HEPATOCELLULAR-CARCINOMA; SIGNALING PATHWAY; GROWTH; INHIBITION; MTOR; AKT; PHOSPHORYLATION	Background: Hepatocellular carcinoma (HCC), the primary liver cancer, is one of the most malignant human tumors with extremely poor prognosis. The aim of this study was to investigate the anti-cancer effect of berberine in a human hepatocellular carcinoma cell line (HepG2), and to study the underlying mechanisms by focusing on the AMP-activated protein kinase (AMPK) signaling cascade. Results: We found that berberine induced both apoptotic and autophagic death of HepG2 cells, which was associated with a significant activation of AMPK and an increased expression of the inactive form of acetyl-CoA carboxylase (ACC). Inhibition of AMPK by RNA interference (RNAi) or by its inhibitor compound C suppressed berberine-induced caspase-3 cleavage, apoptosis and autophagy in HepG2 cells, while AICAR, the AMPK activator, possessed strong cytotoxic effects. In HepG2 cells, mammalian target of rapamycin complex 1 (mTORC1) activation was important for cell survival, and berberine inhibited mTORC1 via AMPK activation. Conclusions: Together, these results suggested that berberine-induced both apoptotic and autophagic death requires AMPK activation in HepG2 cells.	[Yu, Rong; Wang, Bin; Jiang, Hong-xin] Nanjing Med Univ, Dept Oncol, Suzhou Municipal Hosp, Affiliated Suzhou Hosp, Suzhou 215000, Jiangsu, Peoples R China; [Yu, Rong; Cheng, Lei; Shen, Li-ming] Nanjing Med Univ, Dept Intervent Radiol, Suzhou Municipal Hosp, Affiliated Suzhou Hosp, Suzhou 215000, Jiangsu, Peoples R China; [Zhang, Zhi-qing] Soochow Univ, Inst Neurosci, Suzhou 215123, Jiangsu, Peoples R China		Cheng, L (corresponding author), Nanjing Med Univ, Dept Intervent Radiol, Suzhou Municipal Hosp, Affiliated Suzhou Hosp, Suzhou 215000, Jiangsu, Peoples R China.	2979701309@qq.com; limingshensz@163.com			Soochow University	This work is funded by the research start-up funds of Soochow University.	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JUN 11	2014	14								49	10.1186/1475-2867-14-49			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AK9YY	WOS:000338785700001	24991192	gold, Green Published			2022-04-25	
J	D'Onofrio, N; Martino, E; Mele, L; Colloca, A; Maione, M; Cautela, D; Castaldo, D; Balestrieri, ML				D'Onofrio, Nunzia; Martino, Elisa; Mele, Luigi; Colloca, Antonino; Maione, Martina; Cautela, Domenico; Castaldo, Domenico; Balestrieri, Maria Luisa			Colorectal Cancer Apoptosis Induced by Dietary delta-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						colon cancer; mitophagy; mitochondrial dysfunction; PINK1; Parkin	PARKIN; MITOCHONDRIA; AUTOPHAGY; CELLS	Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. delta-Valerobetaine (delta VB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of delta VB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that delta VB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with delta VB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that delta VB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by delta VB in SW480 and SW620 colon cancer cells.	[D'Onofrio, Nunzia; Martino, Elisa; Colloca, Antonino; Maione, Martina; Balestrieri, Maria Luisa] Univ Campania Luigi Vanvitelli, Dept Precis Med, Via L De Crecchio 7, I-80138 Naples, Italy; [Mele, Luigi] Univ Campania Luigi Vanvitelli, Dept Expt Med, Via Luciano Armanni 5, I-80138 Naples, Italy; [Cautela, Domenico; Castaldo, Domenico] Azienda Speciale CCIAA Reggio Calabria, Stn Sperimentale Ind Essenze & Derivati Dagli Agr, Via G Tommasini 2, I-89125 Reggio Di Calabria, Italy; [Castaldo, Domenico] Minist Sviluppo Econ MiSE, Via Molise 2, I-00187 Rome, Italy		D'Onofrio, N (corresponding author), Univ Campania Luigi Vanvitelli, Dept Precis Med, Via L De Crecchio 7, I-80138 Naples, Italy.	nunzia.donofrio@unicampania.it; elisa.martino@unicampania.it; luigi.mele@unicampania.it; antonino.colloca@studenti.unicampania.it; martina.maione@unicampania.it; dcautela@ssea.it; dcastaldo@ssea.it; marialuisa.balestrieri@unicampania.it	Mele, Luigi/AAC-9887-2019; D'Onofrio, Nunzia/M-2081-2019; Cautela, Domenico/J-5235-2013	Mele, Luigi/0000-0002-6008-0802; D'Onofrio, Nunzia/0000-0002-5300-9530; Balestrieri, Maria Luisa/0000-0001-6001-1789; Cautela, Domenico/0000-0003-4894-0299; Martino, Elisa/0000-0003-4070-2894	VALERE 2019 Program University of Campania L. Vanvitelli [PON I&C 2014-2020-TABAREZO-F/200085/01-03/X45]	This research was supported by VALERE 2019 Program University of Campania L. Vanvitelli and PON I&C 2014-2020-TABAREZO-F/200085/01-03/X45.	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J. Mol. Sci.	AUG	2021	22	15							8117	10.3390/ijms22158117			17	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	TV8IS	WOS:000681960700001	34360883	gold, Green Published			2022-04-25	
J	Liu, M; Sun, TY; Li, N; Peng, JJ; Fu, D; Li, W; Li, L; Gao, WQ				Liu, Min; Sun, Tongyu; Li, Ni; Peng, Junjie; Fu, Da; Li, Wei; Li, Li; Gao, Wei-Qiang			BRG1 attenuates colonic inflammation and tumorigenesis through autophagy-dependent oxidative stress sequestration	NATURE COMMUNICATIONS			English	Article							ULCERATIVE-COLITIS; CROHN-DISEASE; PANETH CELLS; CANCER; PROMOTES; SWI/SNF; GENE; HOMEOSTASIS; IMMUNITY; VARIANTS	Autophagy is a central component of integrated stress responses that influences many inflammatory diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). While the core machinery is known, the molecular basis of the epigenetic regulation of autophagy and its role in colon inflammation remain largely undefined. Here, we report that BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for the homeostatic maintenance of intestinal epithelial cells (IECs) to prevent the inflammation and tumorigenesis. BRG1 emerges as a key regulator that directly governs the transcription of Atg16l1, Ambra1, Atg7 and Wipi2, which are important for autophagosome biogenesis. Defective autophagy in BRG1-deficient IECs results in excess reactive oxygen species (ROS), which leads to the defects in barrier integrity. Together, our results establish that BRG1 may represent an autophagy checkpoint that is pathogenetically linked to colitis and is therefore likely a potential therapeutic target for disease intervention.	[Liu, Min; Li, Li; Gao, Wei-Qiang] Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Renji Med X Clin Stem Cell Res Ctr, Ren Ji Hosp,Sch Med, Shanghai, Peoples R China; [Liu, Min; Li, Li; Gao, Wei-Qiang] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai, Peoples R China; [Liu, Min; Li, Li; Gao, Wei-Qiang] Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai, Peoples R China; [Sun, Tongyu; Li, Ni] Univ Chinese Acad Sci, Chinese Acad Sci, CAS Key Lab Tissue Microenvironm & Tumor,Shanghai, CAS Ctr Excellence Mol Cell Sci,Shanghai Inst Nut, Shanghai, Peoples R China; [Peng, Junjie] Fudan Univ, Shanghai Canc Ctr, Dept Colorectal Surg, Shanghai, Peoples R China; [Fu, Da] Tongji Univ, Sch Med, Cent Lab Med Res, Shanghai Peoples Hosp 10, Shanghai, Peoples R China; [Li, Wei] Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing, Peoples R China		Li, L; Gao, WQ (corresponding author), Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Renji Med X Clin Stem Cell Res Ctr, Ren Ji Hosp,Sch Med, Shanghai, Peoples R China.; Li, L; Gao, WQ (corresponding author), Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai, Peoples R China.; Li, L; Gao, WQ (corresponding author), Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai, Peoples R China.	lil@sjtu.edu.cn; gao.weiqiang@sjtu.edu.cn		Li, Wei/0000-0001-7864-404X; Li, Li/0000-0003-2342-3658	Ministry of Science and Technology of the People's Republic of ChinaMinistry of Science and Technology, China [2017YFA0102900]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81872406, 81630073, 81772938]; State Key Laboratory of Oncogenes and Related Genes [KF01801]; Science and Technology Commission of Shanghai MunicipalityScience & Technology Commission of Shanghai Municipality (STCSM) [16JC1405700, 18140902700, 19140905500]; High Peak IV fund from Education Commission of Shanghai Municipality on Stem Cell Research; KC Wong foundation; Innovation Research Plan from Shanghai Municipal Education Commission [ZXGF082101]; Shanghai Jiao Tong University Medical Engineering Cross Fund [YG2016MS52]; Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University	This study was supported by funds from Ministry of Science and Technology of the People's Republic of China (2017YFA0102900 to W.Q.G.), National Natural Science Foundation of China (81872406 and 81630073 to W.Q.G., 81772938 to L.L.), State Key Laboratory of Oncogenes and Related Genes (KF01801 to L.L.), Science and Technology Commission of Shanghai Municipality (16JC1405700 to W.Q.G., 18140902700 and 19140905500 to L.L.), High Peak IV fund from Education Commission of Shanghai Municipality on Stem Cell Research (to W.Q.G.), KC Wong foundation (to W.Q.G.). L.L. is supported by Innovation Research Plan from Shanghai Municipal Education Commission (ZXGF082101), and Shanghai Jiao Tong University Medical Engineering Cross Fund (YG2016MS52). The study is also supported by Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University.	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Commun.	OCT 10	2019	10								4614	10.1038/s41467-019-12573-z			15	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	JC8WW	WOS:000489557800007	31601814	gold, Green Published			2022-04-25	
J	Kao, C; Chao, A; Tsai, CL; Chuang, WC; Huang, WP; Chen, GC; Lin, CY; Wang, TH; Wang, HS; Lai, CH				Kao, C.; Chao, A.; Tsai, C-L; Chuang, W-C; Huang, W-P; Chen, G-C; Lin, C-Y; Wang, T-H; Wang, H-S; Lai, C-H			Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation	CELL DEATH & DISEASE			English	Article							INDUCED PHOSPHOPROTEIN 1; PROTEASOME INHIBITOR; DECREASED EXPRESSION; CYSTEINE CATHEPSINS; MATURATION STEP; APOPTOSIS; DEGRADATION; CISPLATIN; PATHWAYS; RESISTANCE	The antitumor activity of an inhibitor of 26S proteasome bortezomib (Velcade) has been observed in various malignancies, including colon cancer, prostate cancer, breast cancer, and ovarian cancer. Bortezomib has been proposed to stimulate autophagy, but scientific observations did not always support this. Interactions between ERK activity and autophagy are complex and not completely clear. Autophagy proteins have recently been shown to regulate the functions of ERK, and ERK activation has been found to induce autophagy. On the other hand, sustained activation of ERK has also been shown to inhibit the maturation step of the autophagy process. In this study, we sought to identify the mechanism of autophagy regulation in cancer cells treated with bortezomib. Our results indicate that bortezomib blocked the autophagic flux without inhibiting the fusion of the autophagosome and lysosome. In ovarian cancer, as well as endometrial cancer and hepatocellular carcinoma cells, bortezomib inhibited protein degradation in lysosomes by suppressing cathepsins, which requires the participation of ERK phosphorylation, but not JNK or p38. Our findings that ERK phosphorylation reduced cathepsins further explain how ERK phosphorylation inhibits the autophagic flux. In conclusion, bortezomib may induce ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy in ovarian cancer and other solid tumors. The inhibition of cisplatin-induced autophagy by bortezomib can enhance chemotherapy efficacy in ovarian cancer. As we also found that bortezomib blocks the autophagic flux in other cancers, the synergistic cytotoxic effect of bortezomib by abolishing chemotherapy-related autophagy may help us develop strategies of combination therapies for multiple cancers.	[Kao, C.; Chao, A.; Tsai, C-L; Chuang, W-C; Lin, C-Y; Wang, T-H; Wang, H-S; Lai, C-H] Chang Gung Mem Hosp, Linkou Med Ctr, Dept Obstet & Gynecol, Taoyuan 333, Guishan, Taiwan; [Kao, C.; Chuang, W-C; Wang, T-H] Chang Gung Univ, Coll Med, Grad Inst Biomed Sci, Taoyuan, Taiwan; [Huang, W-P] Natl Taiwan Univ, Dept Life Sci, Taipei 10764, Taiwan; [Chen, G-C] Acad Sinica, Inst Biol Chem, Taipei 115, Taiwan; [Wang, T-H] Chang Gung Mem Hosp, Linkou Med Ctr, Genom Med Res Core Lab, Taoyuan 333, Guishan, Taiwan; [Wang, T-H] Chang Gung Univ, Coll Med, Sch Tradit Chinese Med, Taoyuan, Taiwan; [Wang, H-S] Chang Gung Univ, Coll Med, Grad Inst Clin Med Sci, Taoyuan, Taiwan		Wang, TH (corresponding author), Chang Gung Mem Hosp, Linkou Med Ctr, 5 Fushin St, Taoyuan 333, Guishan, Taiwan.	knoxtn@cgmh.org.tw	Lai, Chyong-Huey/AAE-5731-2022	HUANG, WEI-PANG/0000-0001-8410-6555; Lai, Chyong-Huey/0000-0002-9977-9645	 [MOHW102-TD-PB-111-NSC106];  [NSC100-2314-B182-016 MY3];  [CMRPG391461 similar to 4];  [CMRPG3C0281 similar to 3]	This work was supported by the grants: MOHW102-TD-PB-111-NSC106 (to T. H. Wang), NSC100-2314-B182-016 MY3 (to TH Wang), CMRPG391461 similar to 4 (to T. H. Wang), and CMRPG3C0281 similar to 3 (to TH Wang). We are grateful for the help from Microscope Core Laboratory, CGMH, and Molecular Imaging Center, CGMH, and English editing by Dr. Shihyee Mimi Wang (Department of Obstetrics and Gynecology, White Memorial Hospital, Los Angeles).	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NOV	2014	5								e1510	10.1038/cddis.2014.468			12	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	AU5JW	WOS:000345643900004	25375375	Green Published, gold			2022-04-25	
J	Sun, Y; Xing, X; Liu, Q; Wang, Z; Xin, YH; Zhang, P; Hu, CS; Liu, Y				Sun, Yong; Xing, Xing; Liu, Qi; Wang, Zheng; Xin, Yuhu; Zhang, Ping; Hu, Chaosu; Liu, Yong			Hypoxia-induced autophagy reduces. radiosensitivity by the HIF-1 alpha/miR-210/Bcl-2 pathway in colon cancer cells	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						autophagy; hypoxia; radiosensitivity; colon cancer	BREAST-CANCER; IONIZING-RADIATION; INDUCIBLE FACTORS; BCL-2 EXPRESSION; APOPTOSIS; RESISTANCE; MIR-210; HIF-1-ALPHA; INHIBITION; PROTEINS	Autophagy is an evolutionarily conserved cellular response to conditions of stress such as hypoxia, which induce radioresistance in cancer cells. We studied the mechanism of action of hypoxia on autophagy and radiosensitivity in colon cancer cells. In the human colon cancer cell lines SW480 and SW620, autophagosomes were analyzed to evaluate autophagy by flow cytometry. The expression of hypoxia inducible factor-la (HIF-1 alpha), Bcl-2, and miR-210 was detected by western blotting and quantitative real-time polymerase chain reaction (PCR). HIF-1 alpha and miR-210 inhibition was induced by siRNA transfections. Apoptosis detection and colony assays were performed to determine radiosensitivity. HIF-1 alpha and miR-210 showed a significant increase under hypoxic condition. The inhibition of HIF-1 alpha decreased miR-210 expression and autophagy. Silencing of miR-210 upregulated Bcl-2 expression and reduced the survival fraction of colon cancer cells after radiation treatment. Under hypoxia, HIF-1 alpha induces miRNA-210 which in turn enhances autophagy and reduces radiosensitivity by downregulating Bcl-2 expression in colon cancer cells. Our results imply that autophagy contributes to the reduction of radiosensitivity in hypoxic environment, and the process is mediated through the HIF-1 alpha/miR-210/Bcl-2 pathway in human colon cancer cells.	[Sun, Yong; Liu, Qi; Xin, Yuhu; Zhang, Ping; Liu, Yong] Fudan Univ, Shanghai Canc Ctr, Canc Res Inst, Shanghai 200032, Peoples R China; [Xing, Xing; Wang, Zheng; Hu, Chaosu; Liu, Yong] Fudan Univ, Shanghai Canc Ctr, Dept Radiat Oncol, Shanghai 200032, Peoples R China; [Sun, Yong; Xing, Xing; Liu, Qi; Wang, Zheng; Xin, Yuhu; Zhang, Ping; Hu, Chaosu; Liu, Yong] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China		Liu, Y (corresponding author), Fudan Univ, Shanghai Canc Ctr, Canc Res Inst, 270 Dong An Rd, Shanghai 200032, Peoples R China.	hucsu62@yahoo.com; drliuyong@fudan.edu.cn		Hu, Chaosu/0000-0002-6503-0951	Scientific Research Foundation for the Returned Overseas Chinese Scholars from China State Education MinistryScientific Research Foundation for the Returned Overseas Chinese Scholars [N130204]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81202148, 31370838]; Foundation of Fudan University 985 Project [985IIIYPT06]; Shanghai Pujiang ProgramShanghai Pujiang Program [13PJ1401600]; Foundation of Shanghai Committee of Science and Technology of China [12DZ2260100]	This study was supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars (no. N130204) from China State Education Ministry, the National Natural Science Foundation of China (nos. 81202148 and 31370838), the Foundation of Fudan University 985 Project (985IIIYPT06), the Shanghai Pujiang Program (no. 13PJ1401600), the Foundation of Shanghai Committee of Science and Technology of China (no. 12DZ2260100).	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J. Oncol.	FEB	2015	46	2					750	756		10.3892/ijo.2014.2745			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AY6IX	WOS:000347671200035	25385144	Bronze			2022-04-25	
J	Ji, YC; Liu, C; Zhang, X; Zhang, CS; Wang, D; Zhang, Y				Ji, Yan-Chao; Liu, Chang; Zhang, Xia; Zhang, Cheng-Sen; Wang, Dong; Zhang, Yan			Intestinal bacterium-derived cyp27a1 prevents colon cancer cell apoptosis	AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH			English	Article						Colon cancer; vitamin D; Cyp27a1; apoptosis	INNATE LYMPHOID-CELLS; INDUCE APOPTOSIS; COLORECTAL-CANCER; PROSTATE-CANCER; VITAMIN-D; AUTOPHAGY; PROGRESSION; MECHANISMS; PROTECTS; SURVIVAL	The pathogenesis of metastasis of colon cancer (Cca) is to be further investigated. The dysfunction of apoptotic mechanism plays a role in the cancer cell over growth. This study tests a hypothesis by which intestinal bacterium-derived cyp27a1 prevents apoptosis in colon cancer cells. In this study, the levels of cyp27a1 in human stool samples were assessed by enzyme-linked immunosorbent assay. The apoptosis of Cca cells was observed by flow cytometry. The expression of cyp27a1 was assessed by real time RT-PCR and Western blotting. We observed higher levels of cyp27a1 in the stool samples of Cca patients than that from healthy subjects. Cca colon epithelial biopsy contained high levels of cyp27a1 protein, but not the cyp27a1 mRNA. Cyp27a1 prevented Cca cell apoptosis induced by vitamin D3. In conclusion, intestinal bacterium-derived cyp27a1 facilitates Cca survival by inhibiting Cca cell apoptosis.	[Ji, Yan-Chao; Liu, Chang; Zhang, Xia; Zhang, Cheng-Sen; Wang, Dong; Zhang, Yan] Harbin Med Univ, Affiliated Hosp 4, Dept Gen Surg, 37 Yiyuan St, Harbin 150001, Peoples R China		Liu, C (corresponding author), Harbin Med Univ, Affiliated Hosp 4, Dept Gen Surg, 37 Yiyuan St, Harbin 150001, Peoples R China.	changrrliu@sina.com			Natural Science Foundation of Heilongjiang ProvinceNatural Science Foundation of Heilongjiang Province [H201384]; Harbin medical university scientific research innovation fund [2016LCZX26]; Heilongjiang provincial health and Family Planning Commission research subject [2016128]	This study was supported by grants of Natural Science Foundation of Heilongjiang Province (H201384); Harbin medical university scientific research innovation fund (2016LCZX26) and Heilongjiang provincial health and Family Planning Commission research subject (2016128).	Adler J, 2015, AM J GASTROENTEROL, V110, P1657, DOI 10.1038/ajg.2015.365; Ahmed K, 2015, APOPTOSIS, V20, P1411, DOI 10.1007/s10495-015-1168-3; Banks M, 2015, ANTICANCER RES, V35, P3773; Ben-Eltriki M, 2016, J STEROID BIOCHEM, V158, P207, DOI 10.1016/j.jsbmb.2015.12.002; Brzozowa M, 2015, WSPOLCZESNA ONKOL, V19, P265, DOI 10.5114/wo.2014.42173; Buchheit CL, 2014, NAT REV CANCER, V14, P632, DOI 10.1038/nrc3789; Chen JF, 2016, AM J TRANSL RES, V8, P2169; Chu KF, 2014, NAT REV CANCER, V14, P199, DOI 10.1038/nrc3672; Cotter TG, 2009, NAT REV CANCER, V9, P501, DOI 10.1038/nrc2663; Di Sabatino A, 2015, AUTOIMMUN REV, V14, P1161, DOI 10.1016/j.autrev.2015.08.004; Diesing D, 2006, ANTICANCER RES, V26, P2755; Feldman D, 2014, NAT REV CANCER, V14, P342, DOI 10.1038/nrc3691; Goc J, 2016, INT IMMUNOL, V28, P43, DOI 10.1093/intimm/dxv056; Gong X, 2016, AM J TRANSL RES, V8, P2127; Guo XH, 2015, J CLIN INVEST, V125, P3430, DOI 10.1172/JCI83823; Janknecht R, 2010, AM J TRANSL RES, V2, P223; Jones G, 2014, J LIPID RES, V55, P13, DOI 10.1194/jlr.R031534; Kalady MF, 2015, CLIN COLON RECT SURG, V28, P205, DOI 10.1055/s-0035-1564432; Lowe SW, 2000, CARCINOGENESIS, V21, P485, DOI 10.1093/carcin/21.3.485; Ma YY, 2016, VITAM HORM, V100, P395, DOI 10.1016/bs.vh.2015.11.003; Marignol L, 2013, NAT REV UROL, V10, P405, DOI 10.1038/nrurol.2013.110; Roos WP, 2016, NAT REV CANCER, V16, P20, DOI 10.1038/nrc.2015.2; Russo E, 2016, THER ADV GASTROENTER, V9, P594, DOI 10.1177/1756283X16635082; Sharma K, 2014, INT J MOL SCI, V15, P10034, DOI 10.3390/ijms150610034; Shen C, 2015, APOPTOSIS, V20, P1176, DOI 10.1007/s10495-015-1146-9; Steele SR, 2015, DIS COLON RECTUM, V58, P713, DOI 10.1097/DCR.0000000000000410; Szymczak I, 2016, SCAND J IMMUNOL, V83, P83, DOI 10.1111/sji.12403; Wang XM, 2015, GUT MICROBES, V6, P370, DOI 10.1080/19490976.2015.1103426; Wierzbicka JM, 2015, INT J ONCOL, V47, P1084, DOI 10.3892/ijo.2015.3088; Zhang S, 2016, AM J TRANSL RES, V8, P354	30	3	3	0	5	E-CENTURY PUBLISHING CORP	MADISON	40 WHITE OAKS LN, MADISON, WI 53711 USA	1943-8141			AM J TRANSL RES	Am. J. Transl. Res.		2016	8	10					4434	4439					6	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	EB8OI	WOS:000387650100040	27830027				2022-04-25	
J	Dai, CP; Zhang, XN; Xie, D; Tang, PP; Li, CM; Zuo, Y; Jiang, BF; Xue, CP				Dai, Cuiping; Zhang, Xuning; Xie, Da; Tang, Peipei; Li, Chunmei; Zuo, Yi; Jiang, Baofei; Xue, Caiping			Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells	ONCOTARGET			English	Article						protein phosphatase 2A (PP2A); LB-100; colorectal cancer (CRC); AMP-activated protein kinase (AMPK) and mTOR	PROTEIN PHOSPHATASE 2A; CARCINOMA CELLS; NONCODING RNA; GROWTH; KINASE; MTOR; PHOSPHORYLATION; AUTOPHAGY; PATHWAY; APOPTOSIS	LB-100 is a novel PP2A inhibitor. Its activity in human colorectal cancer (CRC) cells was tested. The in vitro studies demonstrated that LB-100 inhibited survival and proliferation of both established CRC cells (HCT-116 and HT-29 lines) and primary human colon cancer cells. Further, LB-100 activated apoptosis and induced G1-S cell cycle arrest in CRC cells. LB-100 inhibited PP2A activity and activated AMPK signaling in CRC cells. AMPKa1 dominant negative mutation, shRNA-mediated knockdown or complete knockout (by CRISPR/Cas9 method) largely attenuated LB-100-induced AMPK activation and HCT-116 cytotoxicity. Notably, microRNA-17-92-mediated silence of PP2A (regulatory B subunit) also activated AMPK and induced HCT-116 cell death. Such effects were again largely attenuated by AMPKa mutation, silence or complete knockout. In vivo studies showed that intraperitoneal injection of LB-100 inhibited HCT-116 xenograft growth in nude mice. Its anti-tumor activity was largely compromised against HCT-116 tumors-derived from AMPKa1-knockout cells. We conclude that targeting PP2A by LB-100 and microRNA-17-92 activates AMPK signaling to inhibit CRC cells.	[Dai, Cuiping] Jiangsu Food & Pharmaceut Sci Coll, Fac Hlth, Huaian, Peoples R China; [Zhang, Xuning; Tang, Peipei; Li, Chunmei; Xue, Caiping] Jiangsu Coll Nursing, Huaian Key Lab Gastrointestinal Canc, Huaian, Peoples R China; [Xie, Da] Nanjing Med Univ, Affiliated Hosp 2, Oncol Dept, Nanjing, Jiangsu, Peoples R China; [Zuo, Yi] Nantong Univ, Dept Med, Xinglin Coll, Nantong, Peoples R China; [Jiang, Baofei] First Peoples Hosp Huaian City, Gastrointestinal Surg, Huaian, Peoples R China		Xue, CP (corresponding author), Jiangsu Coll Nursing, Huaian Key Lab Gastrointestinal Canc, Huaian, Peoples R China.; Jiang, BF (corresponding author), First Peoples Hosp Huaian City, Gastrointestinal Surg, Huaian, Peoples R China.	slhjliangcq@163.com; xuecplwtg@163.com			"533 Talents Project" of Huaian City; Medical Technology Development Project of Health Department of Jiangsu Province [J200912]; Social Development Fund of Technology Project, in Huaian City, Jiangsu Province, China [HAS2009002-3]; Science and Technology Development Project, in Huaian City, Jiangsu Province, China [HAS2009002-3, HAS201605]	This study was supported in part by the "533 Talents Project" research project in 2011 of Huaian City (Hygiene category 78), by the Medical Technology Development Project of Health Department of Jiangsu Province (J200912), by the Social Development Fund of Technology Project, in Huaian City, Jiangsu Province, China (HAS2009002-3) and by the Science and Technology Development Project, in Huaian City, Jiangsu Province, China (HAS201605 and HAS2009002-3).	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Cell Biology	FM3VP	WOS:000414937900062	29221169	Green Published, gold, Green Submitted			2022-04-25	
J	Li, DD; Sun, T; Wu, XQ; Chen, SP; Deng, R; Jiang, S; Feng, GK; Pan, JX; Zhang, XS; Zeng, YX; Zhu, XF				Li, Dan-Dan; Sun, Ting; Wu, Xiao-Qi; Chen, Shu-Peng; Deng, Rong; Jiang, Shan; Feng, Gong-Kan; Pan, Jing-Xuan; Zhang, Xiao-Shi; Zeng, Yi-Xin; Zhu, Xiao-Feng			The Inhibition of Autophagy Sensitises Colon Cancer Cells with Wild-Type p53 but Not Mutant p53 to Topotecan Treatment	PLOS ONE			English	Article							ACTIVATED PROTEIN-KINASE; DEATH; MECHANISM; APOPTOSIS; SESTRIN2; DISEASE; STRESS; PHOSPHORYLATION; UPSTREAM; PATHWAYS	Background: Topotecan produces DNA damage that induces autophagy in cancer cells. In this study, sensitising topotecan to colon cancer cells with different P53 status via modulation of autophagy was examined. Methodology/Principal Findings: The DNA damage induced by topotecan treatment resulted in cytoprotective autophagy in colon cancer cells with wild-type p53. However, in cells with mutant p53 or p53 knockout, treatment with topotecan induced autophagy-associated cell death. In wild-type p53 colon cancer cells, topotecan treatment activated p53, upregulated the expression of sestrin 2, induced the phosphorylation of the AMPKa subunit at Thr172, and inhibited the mTORC1 pathway. Furthermore, the inhibition of autophagy enhanced the anti-tumour effect of topotecan treatment in wild-type p53 colon cancer cells but alleviated the anti-tumour effect of topotecan treatment in p53 knockout cells in vivo. Conclusions/Significance: These results imply that the wild-type p53-dependent induction of cytoprotective autophagy is one of the cellular responses that determines the cellular sensitivity to the DNA-damaging drug topotecan. Therefore, our study provides a potential therapeutic strategy that utilises a combination of DNA-damaging agents and autophagy inhibitors for the treatment of colon cancer with wild-type p53.	[Li, Dan-Dan; Sun, Ting; Wu, Xiao-Qi; Chen, Shu-Peng; Deng, Rong; Jiang, Shan; Feng, Gong-Kan; Zhang, Xiao-Shi; Zeng, Yi-Xin; Zhu, Xiao-Feng] Sun Yat Sen Univ, State Key Lab Oncol S China, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China; [Pan, Jing-Xuan] Sun Yat Sen Univ, Dept Pathophysiol, Zhongshan Sch Med, Guangzhou 510275, Guangdong, Peoples R China		Li, DD (corresponding author), Sun Yat Sen Univ, State Key Lab Oncol S China, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China.	zhuxfeng@mail.sysu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30873085, 30972882, 81101670]; Major Science and Technology Project of the National Basic Research Program (973 Program) of ChinaNational Basic Research Program of China [2011CB504300]; Natural Science Foundation of Guangdong in China [S2011020002759]	This work was supported by grants from the National Natural Science Foundation of China (30873085, 30972882, 81101670) (http://www.nsfc.gov.cn/Portal0/default106.htm), the Major Science and Technology Project of the National Basic Research Program (973 Program) of China (2011CB504300) and the Natural Science Foundation of Guangdong in China (S2011020002759). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Arisan, ED; Akkoc, Y; Akyuz, KG; Kerman, EM; Obakan, P; Coker-Gurkan, A; Unsal, NP				Arisan, Elif Damla; Akkoc, Yunus; Akyuz, Kaan Gencer; Kerman, Ezgi Melek; Obakan, Pinar; Coker-Gurkan, Ajda; Unsal, Narcin Palavan			Polyamines modulate the roscovitine-induced cell death switch decision autophagy vs. apoptosis in MCF-7 and MDA-MB-231 breast cancer cells	MOLECULAR MEDICINE REPORTS			English	Article						breast cancer; polyamines; roscovitine; apoptosis; autophagy	LYMPHOCYTIC-LEUKEMIA CELLS; COLON-CARCINOMA-CELLS; LIFE-SPAN EXTENSION; ORNITHINE-DECARBOXYLASE; CDK INHIBITORS; HISTONE ACETYLTRANSFERASE; THERAPEUTIC TARGET; SELICICLIB CYC202; R-ROSCOVITINE; CYCLE ARREST	Current clinical strategies against breast cancer mainly involve the use of anti-hormonal agents to decrease estrogen production; however, development of resistance is a major problem. The resistance phenotype depends on the modulation of cell-cycle regulatory proteins, cyclins and cyclin-dependent kinases. Roscovitine, a selective inhibitor of cyclin-dependent kinases, shows high therapeutic potential by causing cell-cycle arrest in various cancer types. Autophagy is a type of cell death characterized by the enzymatic degradation of macromolecules and organelles in double- or multi-membrane autophagic vesicles. This process has important physiological functions, including the degradation of misfolded proteins and organelle turnover. Recently, the switch between autophagy and apoptosis has been proposed to constitute an important regulator of cell death in response to chemotherapeutic drugs. The process is regulated by several proteins, such as the proteins of the Atg family, essential for the initial formation of the autophagosome, and PI3K, important at the early stages of autophagic vesicle formation. Polyamines (PAs) are small aliphatic amines that play major roles in a number of eukaryotic processes, including cell proliferation. The PA levels are regulated by ornithine decarboxylase (ODC), the rate-limiting enzyme in PA biosynthesis. In this study, we aimed to investigate the role of PAs in roscovitine-induced autophagic/apoptotic cell death in estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 breast cancer cells. We show that MDA-MB-231 cells are more resistant to roscovitine than MCF-7 cells. This difference was related to the regulation of autophagic key molecules in MDA-MB-231 cells. In addition, we found that exogenous PAs have a role in the cell death decision between roscovitine-induced apoptosis or autophagy in MCF-7 and MDA-MB-231 breast cancer cells.	[Arisan, Elif Damla; Akkoc, Yunus; Akyuz, Kaan Gencer; Kerman, Ezgi Melek; Obakan, Pinar; Coker-Gurkan, Ajda; Unsal, Narcin Palavan] Istanbul Kultur Univ, Dept Mol Biol & Genet, TR-34156 Istanbul, Turkey		Arisan, ED (corresponding author), Istanbul Kultur Univ, Dept Mol Biol & Genet, Atakoy Campus,E5 Highway Bakirkoy, TR-34156 Istanbul, Turkey.	d.arisan@iku.edu.tr	Arisan, Elif Damla/W-8682-2019; Arisan, ElifDamla/AAB-1173-2021; AKKOC, Yunus/AAK-8853-2020; OBAKAN, PINAR/D-2836-2015	Arisan, Elif Damla/0000-0002-4844-6381; AKKOC, Yunus/0000-0001-5379-6151; Gurkan, Ajda/0000-0003-1475-2417			Abedin MJ, 2007, CELL DEATH DIFFER, V14, P500, DOI 10.1038/sj.cdd.4402039; Al-Minawi AZ, 2008, NUCLEIC ACIDS RES, V36, P1, DOI 10.1093/nar/gkm888; Aldoss IT, 2009, EXPERT OPIN INV DRUG, V18, P1957, DOI 10.1517/13543780903418445; Ali S, 2002, NAT REV CANCER, V2, P101, DOI 10.1038/nrc721; Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Appleyard MVCL, 2009, INT J CANCER, V124, P465, DOI 10.1002/ijc.23938; 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Med. Rep.	JUN	2015	11	6					4532	4540		10.3892/mmr.2015.3303			9	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	CJ4ZL	WOS:000355497100076	25650699	Bronze			2022-04-25	
J	El Hasasna, H; Athamneh, K; Al Samri, H; Karuvantevida, N; Al Dhaheri, Y; Hisaindee, S; Ramadan, G; Al Tamimi, N; AbuQamar, S; Eid, A; Iratni, R				El Hasasna, Hussain; Athamneh, Khawlah; Al Samri, Halima; Karuvantevida, Noushad; Al Dhaheri, Yusra; Hisaindee, Soleiman; Ramadan, Gaber; Al Tamimi, Nedaa; AbuQamar, Synan; Eid, Ali; Iratni, Rabah			Rhus coriaria induces senescence and autophagic cell death in breast cancer cells through a mechanism involving p38 and ERK1/2 activation	SCIENTIFIC REPORTS			English	Article							COLON-CANCER; GROWTH ARREST; CYCLE ARREST; DNA-DAMAGE; APOPTOSIS; INDUCTION; L.; INHIBITION; THERAPY; G(1)	Here, we investigated the anticancer effect of Rhus coriaria on three breast cancer cell lines. We demonstrated that Rhus coriaria ethanolic extract (RCE) inhibits the proliferation of these cell lines in a time-and concentration-dependent manner. RCE induced senescence and cell cycle arrest at G1 phase. These changes were concomitant with upregulation of p21, downregulation of cyclin D1, p27, PCNA, c-myc, phospho-RB and expression of senescence-associated beta-galactosidase activity. No proliferative recovery was detected after RCE removal. Annexin V staining and PARP cleavage analysis revealed a minimal induction of apoptosis in MDA-MB-231 cells. Electron microscopy revealed the presence of autophagic vacuoles in RCE-treated cells. Interestingly, blocking autophagy by 3-methyladenine (3-MA) or chloroquine (CQ) reduced RCE-induced cell death and senescence. RCE was also found to activate p38 and ERK1/2 signaling pathways which coincided with induction of autophagy. Furthermore, we found that while both autophagy inhibitors abolished p38 phosphorylation, only CQ led to significant decrease in pERK1/2. Finally, RCE induced DNA damage and reduced mutant p53, two events that preceded autophagy. Our findings provide strong evidence that R. coriaria possesses strong anti-breast cancer activity through induction of senescence and autophagic cell death, making it a promising alternative or adjunct therapeutic candidate against breast cancer.	[El Hasasna, Hussain; Athamneh, Khawlah; Al Samri, Halima; Karuvantevida, Noushad; Al Dhaheri, Yusra; Ramadan, Gaber; Al Tamimi, Nedaa; AbuQamar, Synan; Iratni, Rabah] United Arab Emirates Univ, Coll Sci, Dept Biol, Al Ain, U Arab Emirates; [Hisaindee, Soleiman] United Arab Emirates Univ, Coll Sci, Dept Chem, Al Ain, U Arab Emirates; [Eid, Ali] Qatar Univ, Dept Biol & Environm Sci, Coll Arts & Sci, Doha, Qatar		Eid, A (corresponding author), Qatar Univ, Dept Biol & Environm Sci, Coll Arts & Sci, POB 2713, Doha, Qatar.	ali.eid@qu.edu.qa; R_iratni@uaeu.ac.ae	AbuQamar, Synan/AAV-1229-2021; Eid, Ali Hussein/ABD-6291-2021; Hisaindee, Soleiman/AAK-4862-2020	AbuQamar, Synan/0000-0002-2129-7689; Eid, Ali Hussein/0000-0003-3004-5675; Hisaindee, Soleiman/0000-0003-0084-8362; Karuvantevida, Noushad/0000-0002-9836-0316	UAEU Program for Advanced Research [31S111-UPAR]; Zayed Center for Health Sciences (ZCHS) [31R021]; College of Science Individual Research Grant [31S123]	This work was supported by UAEU Program for Advanced Research (Grant 31S111-UPAR) and by the Zayed Center for Health Sciences (ZCHS) research grant (grant 31R021) and College of Science Individual Research Grant (grant 31S123) to Rabah Iratni. We are thankful to Mr. Tariq Saeed, from the college of Medicine and health science, UAEU, for his precious technical help in electron microscopy. We also are thankful to Ms. Asma Al Rashedi for proofreading this manuscript.	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J	Li, J; Hou, N; Faried, A; Tsutsumi, S; Kuwano, H				Li, Jie; Hou, Ni; Faried, Ahmad; Tsutsumi, Soichi; Kuwano, Hiroyuki			Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model	EUROPEAN JOURNAL OF CANCER			English	Article						Colon cancer cells; 5-FU; Autophagy; Apoptosis	PROGRAMMED CELL-DEATH; ADJUVANT THERAPY; INDUCED CYTOTOXICITY; APOPTOSIS; PATHWAY; TARGET; EXPRESSION; RAPAMYCIN; P53	Although 5-fluorouracil (5-FU)-based adjuvant chemotherapy is widely used in the treatment of colorectal cancer, novel therapeutic strategies need to be explored. It has been reported that autophagy is extensively implicated in cancer. However, the function of autophagy is not fully understood. In the present study, apoptosis induced by 5-FU in 3 human colon cancer cell lines (HCT116, DLD-1, and DLD-1/5-FU (a specific 5-FU-resistant sub-line)) was measured using MTT assay, DNA fragmentation assay, Hoechst 33342 staining, and caspase-3 immunoblotting. The autophagy activation induced by 5-FU treatment was revealed by microtubule-associated protein 1 light chain 3 (LC3) immunofluorescence and immunoblotting and p62 immunoblotting. Inhibition of autophagy by 3-methyladenine (3-MA) or small interference RNA targeting Atg7 (Atg7 siRNA) significantly augmented 5-FU-induced apoptosis. This synergistic effect of 5-FU and 3-MA was further confirmed in the DLD-1 xenograft tumour model. Tumour growth was suppressed more significantly with combination treatment than 5-FU treatment alone. In conclusion, autophagy was activated as a protective mechanism against 5-FU-induced apoptosis and its inhibition could be a promising strategy for adjuvant chemotherapy in colon cancer. (C) 2010 Elsevier Ltd. All rights reserved.	[Li, Jie; Faried, Ahmad; Tsutsumi, Soichi; Kuwano, Hiroyuki] Gunma Univ, Dept Gen Surg Sci, Grad Sch Med, Maebashi, Gunma 3718511, Japan; [Hou, Ni] Gunma Univ, Dept Mol Med, Inst Mol & Cellular Regulat, Maebashi, Gunma 3718511, Japan; [Faried, Ahmad] Padjadjaran State Univ, Fac Med, Bandung, Indonesia		Li, J (corresponding author), Gunma Univ, Dept Gen Surg Sci, Grad Sch Med, 3-39-22 Showa Machi, Maebashi, Gunma 3718511, Japan.	lijie@med.gunma-u.ac.jp					ABEDIN MJ, 2006, CELL DEATH DIFFER, V22, P1; Albert JM, 2006, MOL CANCER THER, V5, P1183, DOI 10.1158/1535-7163.MCT-05-0400; Bauvy C, 2001, EXP CELL RES, V268, P139, DOI 10.1006/excr.2001.5285; BRATTAIN MG, 1981, CANCER RES, V41, P1751; BUYSE M, 1988, JAMA-J AM MED ASSOC, V259, P3571; Cao C, 2006, CANCER RES, V66, P10040, DOI 10.1158/0008-5472.CAN-06-0802; Danila DC, 2008, ACTA ENDOCRINOL-BUCH, V4, P75, DOI 10.4183/aeb.2008.75; Eisenberg-Lerner A, 2009, CELL DEATH DIFFER, V16, P966, DOI 10.1038/cdd.2009.33; Eisenberg-Lerner A, 2009, APOPTOSIS, V14, P376, DOI 10.1007/s10495-008-0307-5; Feng ZH, 2005, P NATL ACAD SCI USA, V102, P8204, DOI 10.1073/pnas.0502857102; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; Hippert MM, 2006, CANCER RES, V66, P9349, DOI 10.1158/0008-5472.CAN-06-1597; Hoyer-Hansen M, 2008, AUTOPHAGY, V4, P574, DOI 10.4161/auto.5921; Ju J, 2007, CLIN CANCER RES, V13, P4245, DOI 10.1158/1078-0432.CCR-06-2890; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kanzawa T, 2004, CELL DEATH DIFFER, V11, P448, DOI 10.1038/sj.cdd.4401359; Kim EH, 2007, CANCER RES, V67, P6314, DOI 10.1158/0008-5472.CAN-06-4217; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Komatsu M, 2007, P NATL ACAD SCI USA, V104, P14489, DOI 10.1073/pnas.0701311104; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Kondo Y, 2006, AUTOPHAGY, V2, P85, DOI 10.4161/auto.2.2.2463; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Meijer AJ, 2004, INT J BIOCHEM CELL B, V36, P2445, DOI 10.1016/j.biocel.2004.02.002; Meley D, 2006, J BIOL CHEM, V281, P34870, DOI 10.1074/jbc.M605488200; Ng G, 2005, MOL CARCINOGEN, V43, P183, DOI 10.1002/mc.20097; O'Connell MJ, 2009, J CLIN ONCOL, V27, P3082, DOI 10.1200/JCO.2009.22.2919; OConnell MJ, 1997, J CLIN ONCOL, V15, P246, DOI 10.1200/JCO.1997.15.1.246; Parkin DM, 2005, CA-CANCER J CLIN, V55, P74, DOI 10.3322/canjclin.55.2.74; Qadir MA, 2008, BREAST CANCER RES TR, V112, P389, DOI 10.1007/s10549-007-9873-4; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Shingu T, 2009, INT J CANCER, V124, P1060, DOI 10.1002/ijc.24030; Tolkovsky AM, 2002, BIOCHIMIE, V84, P233, DOI 10.1016/S0300-9084(02)01371-8; White E, 2009, CLIN CANCER RES, V15, P5308, DOI 10.1158/1078-0432.CCR-07-5023; Wolpin BM, 2008, GASTROENTEROLOGY, V134, P1296, DOI 10.1053/j.gastro.2008.02.098; Xie ZP, 2007, NAT CELL BIOL, V9, P1102, DOI 10.1038/ncb1007-1102; Yazawa S, 2002, GLYCOBIOLOGY, V12, P545, DOI 10.1093/glycob/cwf070; Yousefi S, 2006, NAT CELL BIOL, V8, P1124, DOI 10.1038/ncb1482	37	225	239	3	52	ELSEVIER SCI LTD	OXFORD	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND	0959-8049	1879-0852		EUR J CANCER	Eur. J. Cancer	JUL	2010	46	10					1900	1909		10.1016/j.ejca.2010.02.021			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	627JO	WOS:000280035500032	20231086				2022-04-25	
J	He, SS; Zhao, Z; Yang, YF; O'Connell, D; Zhang, XW; Oh, S; Ma, BY; Lee, JH; Zhang, T; Varghese, B; Yip, J; Pirooz, SD; Li, M; Zhang, Y; Li, GM; Martin, SE; Machida, K; Liang, CY				He, Shanshan; Zhao, Zhen; Yang, Yongfei; O'Connell, Douglas; Zhang, Xiaowei; Oh, Soohwan; Ma, Binyun; Lee, Joo-Hyung; Zhang, Tian; Varghese, Bino; Yip, Janae; Pirooz, Sara Dolatshahi; Li, Ming; Zhang, Yong; Li, Guo-Min; Martin, Sue Ellen; Machida, Keigo; Liang, Chengyu			Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers	NATURE COMMUNICATIONS			English	Article							MICROSATELLITE INSTABILITY; COLON-CANCER; CHROMOSOMAL INSTABILITY; GASTRIC-CANCER; TARGET GENES; CELL-GROWTH; IN-VITRO; TUMORIGENESIS; COMPLEX; PROTEIN	Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAGFS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAGFS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAGFS can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAGFS expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response.	[He, Shanshan; Zhao, Zhen; Yang, Yongfei; O'Connell, Douglas; Zhang, Xiaowei; Oh, Soohwan; Ma, Binyun; Lee, Joo-Hyung; Zhang, Tian; Yip, Janae; Pirooz, Sara Dolatshahi; Machida, Keigo; Liang, Chengyu] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA; [Varghese, Bino] Univ So Calif, Keck Sch Med, Dept Radiol, Los Angeles, CA 90033 USA; [Li, Ming] Peking Univ, Canc Hosp & Inst, Dept Colorectal Surg, Key Lab Carcinogenesis & Translat Res, Beijing 100142, Peoples R China; [Zhang, Yong] Xi An Jiao Tong Univ, Coll Med, Affiliated Hosp 1, Dept Surg Oncol, Xian 710061, Peoples R China; [Li, Guo-Min] Univ Kentucky, Grad Ctr Toxicol, Markey Canc Ctr, Coll Med, Lexington, KY 40506 USA; [Martin, Sue Ellen] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA		Liang, CY (corresponding author), Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA.	chengyu.liang@med.usc.edu	zhao, zhen/A-2080-2012; Lee, Joo-Hyung/ABB-7759-2021	zhao, zhen/0000-0001-8967-5570; Lee, Joo-Hyung/0000-0001-5345-1102; Machida, Keigo/0000-0002-9721-8553; Li, Guo-Min/0000-0002-9842-4578; yang, yongfei/0000-0002-1135-669X	National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [E14TG2a.4]; Margaret Early Trustee Foundation; American Cancer SocietyAmerican Cancer Society [RSG-11-121-01-CCG]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 CA140964]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA140964] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30DK048522] Funding Source: NIH RePORTER	The results shown here are in whole or part based on data generated by COSMIC (Catalogue of somatic mutations in cancer; http://cancer.sanger.ac.uk). We acknowledge the National Institutes of Health (NIH)-sponsored Mutant Mouse Regional Resource Center National System as the source of mouse embryonic stem cells (E14TG2a.4) for use in this study. We thank Victoria Bedell and the Cytogenetics Core of the City of Hope (Duarte, CA) for the SKY analysis. We thank Drs. J.U. Jung, M. Levine, T. Yoshimori, and Y. Ohsumi for providing reagents. We thank all the members of the Liang laboratory for helpful discussion. We thank Dr. Martine Torres for her editorial assistance. This work was supported by the Margaret Early Trustee Foundation, American Cancer Society (RSG-11-121-01-CCG), and NIH grant R01 CA140964 to C. Liang.	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J	Wang, QS; Shen, SQ; Sun, HW; Xing, ZX; Yang, HL				Wang, Qiu-Shuang; Shen, Shi-Qiang; Sun, Hua-Wen; Xing, Zhi-Xiang; Yang, Hou-Lai			Interferon-gamma induces autophagy-associated apoptosis through induction of cPLA2-dependent mitochondrial ROS generation in colorectal cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Interferon-gamma; Cytosolic phospholipase A2; Reactive oxygen species; Autophagy; Apoptosis; Colorectal cancer	OXIDATIVE STRESS; TUMOR-GROWTH; COLON; PATHWAY; INHIBITION; ACTIVATION; MECHANISM; THERAPY; DEATH	Colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and the third in males. In this work, we aim to investigate the possible anti-cancer effects of interferon-gamma (IFN-gamma) in CRC cells. We observed that IFN-gamma induced mitochondria-derived reactive oxygen species (ROS) production in a time-dependent manner in SW480 and HCT116 cell lines. The IFN-gamma-induced mitochondrial ROS generation was dependent on the activation of cytosolic phospholipase A2 (cPLA2). In addition, a mitochondria-targeted antioxidant SS31 and/or cPLA2 inhibitor AACOCF3 abolished the IFN-gamma-induced ROS production and subsequent autophagy and apoptosis. Moreover, suppression of autophagy by CQ was able to reduce IFN-gamma-induced cell apoptosis. Beclin-1 gene silencing resulted in caspase-3 inactivation, decreased Bax/Bcl-2 ratio and less population of apoptotic cells. Collectively, our results suggested that IFN-gamma induces autophagy-associated apoptosis in CRC cells via inducing cPLA2-dependent mitochondrial ROS production. (C) 2018 Elsevier Inc. All rights reserved.	[Wang, Qiu-Shuang; Shen, Shi-Qiang; Sun, Hua-Wen; Xing, Zhi-Xiang; Yang, Hou-Lai] Wuhan Univ, Renmin Hosp, Dept Gen Surg, 99 Zhangzhidong Rd, Wuhan 430060, Hubei, Peoples R China		Shen, SQ (corresponding author), Wuhan Univ, Renmin Hosp, Dept Gen Surg, 99 Zhangzhidong Rd, Wuhan 430060, Hubei, Peoples R China.	dr_sqshen@163.com					Aiken CT, 2011, MOL CELLULAR PROTEOM, V10, P744; Alexandre J, 2006, INT J CANCER, V119, P41, DOI 10.1002/ijc.21685; Bartsch H, 2006, LANGENBECK ARCH SURG, V391, P499, DOI 10.1007/s00423-006-0073-1; Billiau A, 1998, ANN NY ACAD SCI, V856, P22, DOI 10.1111/j.1749-6632.1998.tb08309.x; Brieger K, 2012, SWISS MED WKLY, V142, DOI 10.4414/smw.2012.13659; Chen PJ, 2017, FREE RADICAL BIO MED, V104, P280, DOI 10.1016/j.freeradbiomed.2017.01.033; Chen Y, 2008, CELL DEATH DIFFER, V15, P171, DOI 10.1038/sj.cdd.4402233; Giannopoulos A, 2003, CLIN CANCER RES, V9, P5550; Gough DJ, 2008, CYTOKINE GROWTH F R, V19, P383, DOI 10.1016/j.cytogfr.2008.08.004; Hanada T, 2006, J EXP MED, V203, P1391, DOI 10.1084/jem.20060436; HANNIGAN GE, 1991, SCIENCE, V251, P204, DOI 10.1126/science.1898993; Kalashnikova I, 2017, NANOSCALE, V9, P10375, DOI 10.1039/c7nr02770b; Ko CH, 2007, INT J CANCER, V121, P1670, DOI 10.1002/ijc.22910; LOLLINI PL, 1993, INT J CANCER, V55, P320, DOI 10.1002/ijc.2910550224; Miki H, 2012, INT J ONCOL, V40, P1020, DOI 10.3892/ijo.2012.1325; Pearl-Yafe M, 2003, BIOCHEM PHARMACOL, V65, P833, DOI 10.1016/S0006-2952(02)01620-9; Platanias LC, 2005, NAT REV IMMUNOL, V5, P375, DOI 10.1038/nri1604; PONZONI M, 1992, FEBS LETT, V310, P17, DOI 10.1016/0014-5793(92)81136-A; Saeidnia S., 2003, TOXICOL APPL PHARM, P49; Sakitani K, 2015, BMC CANCER, V15, DOI 10.1186/s12885-015-1789-5; Sawai N, 1999, INFECT IMMUN, V67, P279, DOI 10.1128/IAI.67.1.279-285.1999; Slattery ML, 2011, CARCINOGENESIS, V32, P1660, DOI 10.1093/carcin/bgr189; Sun GY, 2014, MOL NEUROBIOL, V50, P6, DOI 10.1007/s12035-014-8662-4; Supinski GS, 2016, AM J PHYSIOL-LUNG C, V310, pL975, DOI 10.1152/ajplung.00312.2015; Tjandra SS, 2007, CANCER RES, V67, P7124, DOI 10.1158/0008-5472.CAN-07-0686; Wang L, 2015, J INTERF CYTOK RES, V35, P273, DOI 10.1089/jir.2014.0132; Wang SQ, 2016, ONCOTARGET, V7, P72990, DOI 10.18632/oncotarget.12166; Watanabe Y, 2003, J CELL BIOCHEM, V89, P244, DOI 10.1002/jcb.10501; Wen SJ, 2013, FUTURE MED CHEM, V5, P53, DOI 10.4155/fmc.12.190; WIESENFELD M, 1995, J CLIN ONCOL, V13, P2324, DOI 10.1200/JCO.1995.13.9.2324; Windbichler GH, 2000, BRIT J CANCER, V82, P1138; WU T, 1994, J CLIN INVEST, V93, P571, DOI 10.1172/JCI117009; Xiao MJ, 2009, CANCER RES, V69, P2010, DOI 10.1158/0008-5472.CAN-08-3479; Yang D, 2007, EXP EYE RES, V85, P462, DOI 10.1016/j.exer.2007.06.013; Yu HG, 2003, REGUL PEPTIDES, V114, P101, DOI 10.1016/S0167-0115(03)00084-3; Zhu M, 2017, BIOCHEM BIOPH RES CO, V492, P373, DOI 10.1016/j.bbrc.2017.08.097; Ziech D, 2011, MUTAT RES-FUND MOL M, V711, P167, DOI 10.1016/j.mrfmmm.2011.02.015	37	14	14	0	13	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. 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J	Kim, TW; Lee, SJ; Kim, JT; Kim, SJ; Min, JK; Bae, KH; Jung, H; Kim, BY; Lim, JS; Yang, Y; Yoon, DY; Choe, YK; Lee, HG				Kim, Tae Woo; Lee, Seon-Jin; Kim, Jong-Tae; Kim, Sun Jung; Min, Jeong-Ki; Bae, Kwang-Hee; Jung, Haiyoung; Kim, Bo-Yeon; Lim, Jong-Seok; Yang, Young; Yoon, Do-Young; Choe, Yong-Kyung; Lee, Hee Gu			Kallikrein-related peptidase 6 induces chemotherapeutic resistance by attenuating auranofin-induced cell death through activation of autophagy in gastric cancer	ONCOTARGET			English	Article						kallikrein-related peptidase 6; autophagy; auranofin; cell death; chemoresistance	CLINICAL-SIGNIFICANCE; BREAST-CANCER; THIOREDOXIN REDUCTASE; MULTIDRUG-RESISTANCE; THERAPEUTIC TARGET; COLON-CANCER; APOPTOSIS; P53; EXPRESSION; INHIBITION	Kallikrein-related peptidase 6 (KLK6) is a biomarker of gastric cancer associated with poor prognosis. Mechanisms by which KLK6 could be exploited for chemotherapeutic use are unclear. We evaluated auranofin (AF), a compound with cytotoxic effects, in KLK6-deficient cells, and we investigated whether KLK6 expression induces autophagy and acquisition of drug resistance in gastric cancer. Using cultured human cells and a mouse xenograft model, we investigated how KLK6 affects antitumor-reagent-induced cell death and autophagy. Expression levels of KLK6, p53, and autophagy marker LC3B were determined in gastric cancer tissues. We analyzed the effects of knockdown/overexpression of KLK6, LC3B, and p53 on AF-induced cell death in cancer cells. Increased KLK6 expression in human gastric cancer tissues and cells inhibited AF-induced cell motility due to increased autophagy and p53 levels. p53 dependent induction of KLK6 expression increased autophagy and drug resistance, whereas KLK6 silencing decreased the autophagy level and increased drug sensitivity. During AF-induced cell death, KLK6 and LC3B colocalized to autophagosomes, associated with p53, and were then trafficked to the cytosol. In the xenograft model of gastric cancer, KLK6 expression decreased AF-induced cell death and KLK6-induced autophagy increased AF resistance. Taken together, the data suggest that the induction of autophagic processes through KLK6 expression may increase acquisition of resistance to AF. Our findings may contribute to a new paradigm for tumor therapeutics.	[Kim, Tae Woo; Lee, Seon-Jin; Kim, Jong-Tae; Jung, Haiyoung; Choe, Yong-Kyung; Lee, Hee Gu] Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, Daejeon, South Korea; [Kim, Tae Woo; Lee, Seon-Jin; Lee, Hee Gu] Univ Sci & Technol, Dept Biomol Sci, Daejeon, South Korea; [Kim, Sun Jung] Dongguk Univ Seoul, Dept Life Sci, Seoul, South Korea; [Min, Jeong-Ki] Korea Res Inst Biosci & Biotechnol, Biotherapeut Translat Res Ctr, Daejeon, South Korea; [Bae, Kwang-Hee] Korea Res Inst Biosci & Biotechnol, Res Ctr Metab Regulat, Daejeon, South Korea; [Kim, Bo-Yeon] Korea Res Inst Biosci & Biotechnol, World Class Inst, Ochang, Cheongwon, South Korea; [Lim, Jong-Seok; Yang, Young] Sookmyung Womens Univ, Dept Biol Sci, Seoul, South Korea; [Yoon, Do-Young] Konkuk Univ, Dept Biosci & Biotechnol, Seoul, South Korea		Choe, YK; Lee, HG (corresponding author), Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, Daejeon, South Korea.; Lee, HG (corresponding author), Univ Sci & Technol, Dept Biomol Sci, Daejeon, South Korea.	ykccoruk@kribb.re.kr; 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Zhou J, 2015, CARCINOGENESIS, V36, P441, DOI 10.1093/carcin/bgv014; Zou P, 2015, ONCOTARGET, V6, P36505, DOI 10.18632/oncotarget.5364	58	21	22	0	4	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA	1949-2553			ONCOTARGET	Oncotarget	DEC 20	2016	7	51					85332	85348		10.18632/oncotarget.13352			17	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	EG9BT	WOS:000391353200124	27863404	Green Submitted, Green Published, gold			2022-04-25	
J	Nagy, P; Kovacs, L; Sandor, GO; Juhasz, G				Nagy, Peter; Kovacs, Laura; Sandor, Gyongyver O.; Juhasz, Gabor			Stem-cell-specific endocytic degradation defects lead to intestinal dysplasia in Drosophila	DISEASE MODELS & MECHANISMS			English	Article						Autophagy; Drosophila; Endocytosis; UVRAG	PHOSPHATIDYLINOSITOL 3-KINASE COMPLEXES; HOPS COMPLEX; COLON-CANCER; AUTOPHAGY; UVRAG; HOMEOSTASIS; PROLIFERATION; REGENERATION; MAINTENANCE; MUTATIONS	UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy, endocytosis and DNA damage repair, but how its loss contributes to colorectal cancer is poorly understood. Here, we show that UVRAG deficiency in Drosophila intestinal stem cells leads to uncontrolled proliferation and impaired differentiation without preventing autophagy. As a result, affected animals suffer from gut dysfunction and short lifespan. Dysplasia upon loss of UVRAG is characterized by the accumulation of endocytosed ligands and sustained activation of STAT and JNK signaling, and attenuation of these pathways suppresses stem cell hyperproliferation. Importantly, the inhibition of early (dynamin-dependent) or late (Rab7-dependent) steps of endocytosis in intestinal stem cells also induces hyperproliferation and dysplasia. Our data raise the possibility that endocytic, but not autophagic, defects contribute to UVRAG-deficient colorectal cancer development in humans.	[Nagy, Peter; Kovacs, Laura; Sandor, Gyongyver O.; Juhasz, Gabor] Eotvos Lorand Univ, Dept Anat Cell & Dev Biol, Pazmany S 1-C, H-1117 Budapest, Hungary; [Juhasz, Gabor] Hungarian Acad Sci, Biol Res Ctr, Inst Genet, Temesvari Krt 62, H-6726 Szeged, Hungary		Juhasz, G (corresponding author), Eotvos Lorand Univ, Dept Anat Cell & Dev Biol, Pazmany S 1-C, H-1117 Budapest, Hungary.; Juhasz, G (corresponding author), Hungarian Acad Sci, Biol Res Ctr, Inst Genet, Temesvari Krt 62, H-6726 Szeged, Hungary.	szmrt@elte.hu	Juhasz, Gabor/G-5622-2013	Juhasz, Gabor/0000-0001-8548-8874; Nagy, Peter/0000-0002-5053-0646	Wellcome TrustWellcome TrustEuropean Commission [087518/Z/08/Z]; Hungarian Academy of Sciences (Magyar Tudoma'nyos Akade'mia) [LP-2014/2]; National Research, Development and Innovation Office (NKFIH) [PD115568]; Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences; Erdos Junior Research Fellowship [TAMOP4.2.4.A/1-11-1-2012-0001]	This work was supported by the Wellcome Trust [087518/Z/08/Z to G.J.]; the Hungarian Academy of Sciences (Magyar Tudoma'nyos Akade'mia) [grant number LP-2014/2 to G.J.]; the National Research, Development and Innovation Office (NKFIH) [PD115568 to P.N.]; the Bolyai Research Scholarship of the Hungarian Academy of Sciences to P.N.; and the Erdos Junior Research Fellowship [TAMOP4.2.4.A/1-11-1-2012-0001 to P.N.].	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Model. Mech.	MAY 1	2016	9	5					501	512		10.1242/dmm.023416			12	Cell Biology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Pathology	DN5DP	WOS:000377086800003	26921396	gold, Green Published, Green Accepted			2022-04-25	
J	Cheung, FWK; Che, CT; Sakagami, H; Kochi, M; Liu, WK				Cheung, F. W. K.; Che, C. T.; Sakagami, H.; Kochi, M.; Liu, W. K.			Sodium 5,6-Benzylidene-L-Ascorbate Induces Oxidative Stress, Autophagy, and Growth Arrest in Human Colon Cancer HT-29 Cells	JOURNAL OF CELLULAR BIOCHEMISTRY			English	Article						OXIDATIVE STRESS; GROWTH ARREST; P21 INHIBITOR; AUTOPHAGY	HUMAN PROSTATE-CANCER; CYCLE ARREST; MOLECULAR-MECHANISMS; LIPID-PEROXIDATION; HACAT CELLS; VITAMIN-C; IN-VITRO; APOPTOSIS; ASCORBATE; PHOSPHORYLATION	Our previous studies have demonstrated the oxidative stress properties of sodium ascorbate (SAA) and its benzaldehyde derivative (SBA) on cancer cell lines, but the molecular mechanisms mediating their cytotoxicity remain unclear. In this study, we treated human colon cancer HT-29 cells with SAA and SBA, and found a significant exposure time-dependent increase of cytotoxicity in both treatments, with a higher cytotoxicity for 24 h with SAA (IC50 = 5 mM) than SBA (IC50 = 10 mM). A short-term treatment of cells with 10 mM SAA for 2 h revealed a destabilization of the lysosomes and subsequent induction of cell death, whereas 10 mM SBA triggered a remarkable production of reactive oxidative species, phosphorylation of survival kinase AKT, expression of cyclin kinase-dependent inhibitor p21, and induction of transient growth arrest. The crucial role of p21 mediating this cytotoxicity was confirmed by isogenic derivatives of the human colon carcinoma HCT116 cell lines (p21(+/+) and p21(-/-)), and immunoprecipitation studies with p21 antibody. The SAA cytotoxicity was blocked by co-incubation with catalase, whereas the SBA cytotoxicity and its subsequent growth arrest were abolished by N-acetyl-L-cysteine (NAC), but was not affected by PI3K phosphorylation inhibitor LY294002, or catalase, suggesting two separated oxidative stress pathways were mediated by these two ascorbates. In addition, neither active caspase 3 nor apoptotic bodies but autophagic vacuoles associated with increased LC3-II were found in SBA-treated HT-29 cells; implicating that SBA induced AKT phosphorylation-autophagy and p21-growth arrest in colon cancer HT-29 cells through an NAC-inhibitable oxidative stress pathway. J. Cell. Biochem. 111: 412-424, 2010. (C) 2010 Wiley-Liss, Inc.	[Liu, W. K.] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China; [Cheung, F. W. K.; Che, C. T.] Chinese Univ Hong Kong, Sch Chinese Med, Shatin, Hong Kong, Peoples R China; [Sakagami, H.] Meikai Univ, Sch Dent, Div Pharmacol, Dept Diagnost & Therapeut Sci, Sakado, Saitama, Japan; [Kochi, M.] Ichijokai Hosp, Chiba, Japan		Liu, WK (corresponding author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China.	ken-liu@cuhk.edu.hk	Che, Chun-Tao/AAV-2795-2020				Altomare DA, 2004, ONCOGENE, V23, P5853, DOI 10.1038/sj.onc.1207721; Andreassen PR, 2001, MOL BIOL CELL, V12, P1315, DOI 10.1091/mbc.12.5.1315; Banhegyi G, 2003, BIOFACTORS, V17, P37, DOI 10.1002/biof.5520170105; Barnouin K, 2002, J BIOL CHEM, V277, P13761, DOI 10.1074/jbc.M111123200; Broker LE, 2005, CLIN CANCER RES, V11, P3155, DOI 10.1158/1078-0432.CCR-04-2223; Cerella C, 2009, ANN NY ACAD SCI, V1171, P583, DOI 10.1111/j.1749-6632.2009.04723.x; Chandra J, 2000, FREE RADICAL BIO MED, V29, P323, DOI 10.1016/S0891-5849(00)00302-6; Chen Q, 2005, P NATL ACAD SCI USA, V102, P13604, DOI 10.1073/pnas.0506390102; Cheung FWK, 2010, MAR DRUGS, V8, P80, DOI 10.3390/md8010080; Feng ZH, 2005, P NATL ACAD SCI USA, V102, P8204, DOI 10.1073/pnas.0502857102; Fiebig HH, 2004, EUR J CANCER, V40, P802, DOI 10.1016/j.ejca.2004.01.009; Gao N, 2003, BIOCHEM BIOPH RES CO, V310, P1124, DOI 10.1016/j.bbrc.2003.09.132; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; Kaap S, 2004, BIOCHEM PHARMACOL, V67, P919, DOI 10.1016/j.bcp.2003.10.001; Keeshan K, 2003, BRIT J HAEMATOL, V123, P34, DOI 10.1046/j.1365-2141.2003.04538.x; KOCHI M, 1980, CANCER TREAT REP, V64, P21; KOCHI M, 1988, PROGR CANCER RES THE, V35, P338; Kontopidis G, 2005, P NATL ACAD SCI USA, V102, P1871, DOI 10.1073/pnas.0406540102; KONTOPIDIS G, 2007, CELL DEATH DIFFER, V14, P230; Kouroku Y, 2007, CELL DEATH DIFFER, V14, P230, DOI 10.1038/sj.cdd.4401984; Lee JY, 2003, J NEUROSCI RES, V73, P156, DOI 10.1002/jnr.10647; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Li X, 2003, BIOCHEM BIOPH RES CO, V305, P656, DOI 10.1016/S0006-291X(03)00836-2; Lin SY, 2006, MELANOMA RES, V16, P509, DOI 10.1097/01.cmr.0000232297.99160.9e; Liu BPL, 2005, BIOCHEM PHARMACOL, V70, P287, DOI 10.1016/j.bcp.2005.04.024; Liu WK, 2008, J NAT PROD, V71, P842, DOI 10.1021/np8001223; Lockshin RA, 2004, INT J BIOCHEM CELL B, V36, P2405, DOI 10.1016/j.biocel.2004.04.011; Manning BD, 2007, CELL, V129, P1261, DOI 10.1016/j.cell.2007.06.009; MATSUIYUASA I, 1989, BIOCHEM INT, V18, P623; Olsson ME, 2004, J AGR FOOD CHEM, V52, P7264, DOI 10.1021/jf030479p; Paglin S, 2001, CANCER RES, V61, P439; Peterszegi G, 2002, EUR J CLIN INVEST, V32, P372, DOI 10.1046/j.1365-2362.2002.00992.x; Riviere J, 2006, FREE RADICAL BIO MED, V40, P2071, DOI 10.1016/j.freeradbiomed.2006.02.003; Sakagami H, 1997, ANTICANCER RES, V17, P4451; SAKAGAMI H, 1995, ANTICANCER RES, V15, P1269; Sakagami H, 2000, CELL MOL BIOL, V46, P129; SAKAGAMI H, 1991, ANTICANCER RES, V11, P1535; Savini I, 1999, FREE RADICAL BIO MED, V26, P1172, DOI 10.1016/S0891-5849(98)00311-6; Serbecic N, 2005, CELL TISSUE RES, V320, P465, DOI 10.1007/s00441-004-1030-3; Shen GX, 2006, CANCER CHEMOTH PHARM, V57, P317, DOI 10.1007/s00280-005-0050-3; Song JH, 2001, EXP NEUROL, V169, P425, DOI 10.1006/exnr.2001.7680; Thomas CG, 2005, J CELL PHYSIOL, V205, P310, DOI 10.1002/jcp.20405; Tse WP, 2006, J ETHNOPHARMACOL, V108, P133, DOI 10.1016/j.jep.2006.04.023; Wenzel U, 2004, CARCINOGENESIS, V25, P703, DOI 10.1093/carcin/bgh079; Xie SQ, 2001, J BIOL CHEM, V276, P36194, DOI 10.1074/jbc.M104157200; Yamamoto M, 2006, MOL CARCINOGEN, V45, P901, DOI 10.1002/mc.20204; Zafarullah M, 2003, CELL MOL LIFE SCI, V60, P6, DOI 10.1007/s000180300001	47	10	12	0	6	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0730-2312	1097-4644		J CELL BIOCHEM	J. Cell. Biochem.	OCT 1	2010	111	2					412	424		10.1002/jcb.22717			13	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	658HZ	WOS:000282482400017	20503249				2022-04-25	
J	Qian, K; Huang, HY; Jiang, J; Xu, DH; Guo, SN; Cui, Y; Wang, H; Wang, LQ; Li, KN				Qian, Kun; Huang, Huiying; Jiang, Jing; Xu, Dahua; Guo, Shengnan; Cui, Ying; Wang, Hao; Wang, Liqiang; Li, Kongning			Identifying autophagy gene-associated module biomarkers through construction and analysis of an autophagy-mediated ceRNA-ceRNA interaction network in colorectal cancer	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						autophagy; competing endogenous RNA; interaction network; colorectal cancer; prognostic biomarkers	B-CELL LYMPHOMA; SURVIVAL PREDICTION; COLON-CANCER; EXPRESSION; TUMOR; METASTASIS; SUPPRESSOR; MICROENVIRONMENT; ORGANIZATION; APOPTOSIS	Autophagy is crucial in cellular homeostasis and has been implicated in the development of malignant tumors. However, the regulatory function of autophagy in cancer remains to be fully elucidated. In the present study, the autophagy-mediated competing endogenous RNA (ceRNA)-ceRNA interaction networks in colorectal cancer (CRC) were constructed by integrating systematically expression profiles of long non-coding RNAs and mRNAs. It was found that a large proportion of autophagy genes were inclined to target hub nodes, including a fraction of autophagy genes, by comparing with other genes within ceRNA networks, and showed preferential interaction with themselves. The present study also revealed that autophagy genes may be used as prognostic markers for cancer therapy. A risk score model based on multivariable Cox regression analysis was then used to capture novel biomarkers in connection with lncRNA for the prognosis of CRC. These biomarkers were confirmed in the test dataset and an additional independent dataset. Furthermore, the prognostic value of biomarkers is independent of conventional clinical factors. These results provide improved understanding of autophagy-mediated ceRNA regulatory mechanisms in CRC and provide novel potential molecular therapeutic targets for the diagnosis and treatment of CRC.	[Qian, Kun; Huang, Huiying; Xu, Dahua; Guo, Shengnan; Cui, Ying; Wang, Liqiang; Li, Kongning] Harbin Med Univ, Coll Bioinformat Sci & Technol, 157 Baojian Rd, Harbin 150081, Heilongjiang, Peoples R China; [Jiang, Jing; Wang, Hao] Harbin Med Univ, Affiliated Hosp 2, Obstet & Gynaecol Dept, Harbin 150001, Heilongjiang, Peoples R China		Wang, LQ; Li, KN (corresponding author), Harbin Med Univ, Coll Bioinformat Sci & Technol, 157 Baojian Rd, Harbin 150081, Heilongjiang, Peoples R China.	wangliqiang0619@163.com; likongning@ems.hrbmu.edu.cn	; Li, Kongning/L-6188-2015	Wang, Hong/0000-0003-3524-0891; Li, Kongning/0000-0002-4928-6922	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31501075, 31301094]; Natural Science Foundation of Heilongjiang ProvinceNatural Science Foundation of Heilongjiang Province [B201302]; Education Department Foundation of Heilongjiang Province [12531227]; Health Department Foundation of Heilongjiang Province [2012-798]; Scientific Research Project of Heilongjiang Provincial Education Department [12541565]	This study was supported by the National Natural Science Foundation of China (grant nos. 31501075 and 31301094), the Natural Science Foundation of Heilongjiang Province (grant no. B201302), the Education Department Foundation of Heilongjiang Province (grant no. 12531227), the Health Department Foundation of Heilongjiang Province (grant no. 2012-798) and the Scientific Research Project of Heilongjiang Provincial Education Department (grant no. 12541565).	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J. Oncol.	SEP	2018	53	3					1083	1093		10.3892/ijo.2018.4443			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GP1NO	WOS:000440583100013	29916526	Green Submitted, hybrid, Green Published			2022-04-25	
J	Rodriguez, ME; Arevalo, DE; Sanabria, LM; Carrion, FDC; Fanelli, MA; Rivarola, VA				Exequiel Rodriguez, Matias; Elisa Arevalo, Daniela; Milla Sanabria, Laura; Cuello Carrion, Fernando Dario; Andrea Fanelli, Mariel; Alicia Rivarola, Viviana			Heat shock protein 27 modulates autophagy and promotes cell survival after photodynamic therapy	PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES			English	Article							INDUCED APOPTOSIS; CANCER-CELLS; RESISTANCE; HSP27; INDUCTION; DEATH; STRESS; PDT; ACTIVATION; MECHANISMS	Photodynamic therapy (PDT) is a clinically approved treatment that exerts a selective cytotoxic activity toward cancer cells. The procedure involves the administration of a photosensitizer drug followed by its activation by visible light. In the presence of oxygen, a series of events lead to tumor cell death. PDT releases different cell signals, some of these lead to death while others can lead to survival. The surviving or resistant cells contribute to the recurrence of tumors after treatment, from which the necessity to understand this molecular response induced by PDT arises. It has been shown that both Heat Shock Proteins (HSPs) and autophagy promote PDT resistance. Moreover, both of them can be stimulated by PDT treatment. However, the molecular interplay between HSPs and autophagy in the photodynamic therapy context is poorly understood. We studied whether PDT induces autophagic activity through HSPs. We demonstrated that PDT promoted HSP27 expression, which in turn triggered autophagic cell survival as well as inhibited apoptosis in colon cancer cells. In addition, an overexpression of the HSP27autophagy axis was observed in skin carcinoma cells resistant to PDT.	[Exequiel Rodriguez, Matias; Elisa Arevalo, Daniela; Milla Sanabria, Laura; Alicia Rivarola, Viviana] Natl Univ Rio Cuarto, Dept Mol Biol, Natl Route 36,Km 601, RA-5800 Rio Cuarto, Cordoba, Argentina; [Cuello Carrion, Fernando Dario; Andrea Fanelli, Mariel] IMBECU CRICYT, Inst Expt Med & Biol Cuyo, Oncol Lab, Boulogne Sur Mer 683, RA-5500 Mendoza, Argentina		Rodriguez, ME; Sanabria, LM (corresponding author), Natl Univ Rio Cuarto, Dept Mol Biol, Natl Route 36,Km 601, RA-5800 Rio Cuarto, Cordoba, Argentina.	exequiel198803@gmail.com; lmilla@exa.unrc.edu.ar	Rodriguez, Matias/Q-4760-2017	Rodriguez, Matias/0000-0002-5819-670X; Rivarola, v/0000-0001-7924-1445	Consejo Nacional de Investigacion Cientifica y Tecnologica (CONICET)Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Secretaria de Ciencia y Tecnica (SeCyT) at the National University of Rio Cuarto (UNRC); Agencia FONCYTFONCyT	This research was supported by Consejo Nacional de Investigacion Cientifica y Tecnologica (CONICET), Secretaria de Ciencia y Tecnica (SeCyT) at the National University of Rio Cuarto (UNRC), and Agencia FONCYT. Moreover, the authors thank Anca Mihaela Nichifor and Maria Julia Urbina.	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Photobiol. Sci.	FEB 1	2019	18	2					546	554		10.1039/c8pp00536b			9	Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics; Chemistry	HL2WG	WOS:000458569100027	30681107	hybrid			2022-04-25	
J	Katona, BW; Liu, YY; Ma, AQ; Jin, J; Hua, XX				Katona, Bryson W.; Liu, Yuanyuan; Ma, Anqi; Jin, Jian; Hua, Xianxin			EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells	CANCER BIOLOGY & THERAPY			English	Article						autophagy; colon cancer; EGFR; epigenetics; EZH2; gefitinib; UNC1999	GROWTH-FACTOR RECEPTOR; AUTOPHAGY; CHLOROQUINE; PROGRESSION; MUTATIONS; APOPTOSIS; ERLOTINIB; THERAPY	Metastatic colon cancer has a 5-year survival of less than 10% despite the use of aggressive chemotherapeutic regimens. As signaling from epidermal growth factor receptor (EGFR) is often enhanced and epigenetic regulation is often altered in colon cancer, it is desirable to enhance the efficacy of EGFR-directed therapy by co-targeting an epigenetic pathway. We showed that the histone methyltransferase EZH2, which catalyzes methylation of histone H3 lysine 27 (H3K27), was upregulated in colon cancers in The Cancer Genome Atlas (TCGA) database. Since co-inhibition of both EGFR and EZH2 has not been studied in colon cancer, we examined the effects of co-inhibition of EGFR and EZH2 on 2 colon cancer cell lines, HT-29 and HCT-15. Co-inhibition of EZH2 and EGFR with the small molecules UNC1999 and gefitinib, led to a significant decrease in cell number and increased apoptosis compared to inhibition of either pathway alone, and similar results were noted after EZH2 shRNA knockdown. Moreover, co-inhibition of EZH2 and EGFR also significantly induced autophagy, indicating that autophagy may play a role in the observed synergy. Together, these findings suggest that inhibition of both EZH2 and EGFR serves as an effective method to increase the efficacy of EGFR inhibitors in suppressing colon cancer cells.	[Katona, Bryson W.] Univ Penn, Div Gastroenterol, Perelman Sch Med, Philadelphia, PA 19104 USA; [Katona, Bryson W.; Liu, Yuanyuan; Hua, Xianxin] Univ Penn, Dept Canc Biol, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA; [Liu, Yuanyuan] Hubei Canc Hosp, Hubei Canc Res Inst, Wuhan, Hubei, Peoples R China; [Ma, Anqi; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA		Hua, XX (corresponding author), Univ Penn, Div Gastroenterol, Perelman Sch Med, Philadelphia, PA 19104 USA.	huax@mail.med.upenn.edu		Katona, Bryson/0000-0001-8186-9119	NIH/NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [T32-DK007066]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-DK085121, R01-GM103893]; Caring for Carcinoid Foundation-AACR Grant Care for Carcinoid Foundation [11-60-33]; TRP grant from the Leukemia and Lymphoma Society; ITMAT of the University of Pennsylvania; Hubei Province's Outstanding Medical Academic Leader Program; NIH/NIDDK Center for Molecular Studies in Digestive and Liver DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30DK050306]; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK085121, P30DK050306] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM103893] Funding Source: NIH RePORTER	We would like to acknowledge the following support: NIH/NIDDK T32-DK007066 (BK), NIH R01-DK085121 (XH), NIH R01-GM103893 (JJ), Caring for Carcinoid Foundation-AACR Grant Care for Carcinoid Foundation 11-60-33 (XH), TRP grant from the Leukemia and Lymphoma Society (XH), pilot grant from ITMAT of the University of Pennsylvania (XH), Hubei Province's Outstanding Medical Academic Leader Program-2013 (YL), and NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases (P30DK050306) and its core facilities.	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Ther.		2014	15	12					1677	1687		10.4161/15384047.2014.972776			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AZ7EP	WOS:000348382100012	25535899	Green Published, Bronze			2022-04-25	
J	Wang, SM; Gu, KS				Wang, Shuomin; Gu, Kangsheng			Insulin-like growth factor 1 inhibits autophagy of human colorectal carcinoma drug-resistant cells via the protein kinase B/mammalian target of rapamycin signaling pathway	MOLECULAR MEDICINE REPORTS			English	Article						insulin-like growth factor 1; human colorectal carcinoma cells; autophagy; protein kinase B; mammalian target of rapamycin	REGULATE AUTOPHAGY; CANCER CELLS; APOPTOSIS; EXPRESSION; PROGNOSIS; CLEAVAGE; BECLIN-1; RECEPTOR; DEATH	Insulin-like growth factor 1 (IGF-1) is reported to inhibit autophagy of human colorectal carcinoma cells (HCT); however, little is known regarding the mechanisms underlying the inhibitory effect of IGF-1 on autophagy in HCT resistant strains. The present study aimed to analyze the inhibitory effect of IGF-1 on the autophagy of HCT resistant strains and its potential underlying mechanisms. The viability and apoptosis of HCT-8 colon cancer cells were analyzed, and expression levels of relevant genes and proteins were investigated using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Treatment of cells with IGF-1 induced apoptosis. IGF-1 treatment activated protein kinase B (AKT), which may inhibit autophagy via the AKT/mammalian target of rapamycin signaling pathway. Following inhibition of autophagy, drug resistant cells became sensitive to apoptosis induced by 5-fluorouracil.	[Wang, Shuomin; Gu, Kangsheng] Anhui Med Univ, Affiliated Hosp 1, Dept Oncol, 218 Jixi Rd, Hefei 230022, Anhui, Peoples R China; [Wang, Shuomin] Anhui Med Univ, Affiliated Hosp 4, Dept Oncol, Hefei 230032, Anhui, Peoples R China		Gu, KS (corresponding author), Anhui Med Univ, Affiliated Hosp 1, Dept Oncol, 218 Jixi Rd, Hefei 230022, Anhui, Peoples R China.	kangshenggu11@sina.com					Betin VMS, 2009, J CELL SCI, V122, P2554, DOI 10.1242/jcs.046250; Cunningham D, 2010, LANCET, V375, P1030, DOI 10.1016/S0140-6736(10)60353-4; Galluzzi L, 2008, BIOCHEM SOC T, V36, P786, DOI 10.1042/BST0360786; Guo GF, 2011, WORLD J GASTROENTERO, V17, P4779, DOI 10.3748/wjg.v17.i43.4779; Hayashi-Nishino M, 2009, NAT CELL BIOL, V11, P1433, DOI 10.1038/ncb1991; Ikeda H, 2009, J MOL CELL CARDIOL, V47, P664, DOI 10.1016/j.yjmcc.2009.08.028; Jia GH, 2006, IMMUNOL CELL BIOL, V84, P448, DOI 10.1111/j.1440-1711.2006.01454.x; Klionsky DJ, 2003, DEV CELL, V5, P539, DOI 10.1016/S1534-5807(03)00296-X; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Lin CW, 2015, MOL PHARMACEUT, V12, P2858, DOI 10.1021/acs.molpharmaceut.5b00329; Liu WJ, 2015, CANCER BIOL THER, V16, P511, DOI 10.1080/15384047.2015.1017691; Lyu Q, 2015, BIOCHEM BIOPH RES CO, V462, P38, DOI 10.1016/j.bbrc.2015.04.102; Mizushima N, 2007, GENE DEV, V21, P2861, DOI 10.1101/gad.1599207; Nikoletopoulou V, 2013, BBA-MOL CELL RES, V1833, P3448, DOI 10.1016/j.bbamcr.2013.06.001; Oliveira CSF, 2015, CELL DEATH DIS, V6, DOI 10.1038/cddis.2015.157; Rubinsztein DC, 2012, NAT REV DRUG DISCOV, V11, P709, DOI 10.1038/nrd3802; Schmittgen TD, 2008, NAT PROTOC, V3, P1101, DOI 10.1038/nprot.2008.73; Schwartz-Roberts JL, 2015, CANCER RES, V75, P1046, DOI 10.1158/0008-5472.CAN-14-1851; Sekharam M, 2003, ANTICANCER RES, V23, P1517; Sobolewska A, 2009, EUR J CELL BIOL, V88, P117, DOI 10.1016/j.ejcb.2008.09.004; Troncoso R, 2012, CARDIOVASC RES, V93, P320, DOI 10.1093/cvr/cvr321; Yang MP, 2015, ONCOTARGET, V6, P7084, DOI 10.18632/oncotarget.3054; Yao W, 2016, OSTEOPOROSIS INT, V27, P283, DOI 10.1007/s00198-015-3308-6; Yousefi S, 2006, NAT CELL BIOL, V8, P1124, DOI 10.1038/ncb1482; Zhou WH, 2012, AUTOPHAGY, V8, P389, DOI 10.4161/auto.18641	25	9	9	0	4	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1791-2997	1791-3004		MOL MED REP	Mol. Med. Rep.	FEB	2018	17	2					2952	2956		10.3892/mmr.2017.8272			5	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	FT5WP	WOS:000423224300111	29257307	Green Published, hybrid, Green Submitted			2022-04-25	
J	Tylichova, Z; Strakova, N; Vondracek, J; Vaculova, AH; Kozubik, A; Hofmanova, J				Tylichova, Zuzana; Strakova, Nicol; Vondracek, Jan; Vaculova, Alena Hyrslova; Kozubik, Alois; Hofmanova, Jirina			Activation of autophagy and PPAR gamma protect colon cancer cells against apoptosis induced by interactive effects of butyrate and DHA in a cell type-dependent manner: The role of cell differentiation	JOURNAL OF NUTRITIONAL BIOCHEMISTRY			English	Article						Colon cancer; Butyrate; PPAR gamma; Autophagy; Differentiation; Docosahexaenoic acid	POLYUNSATURATED FATTY-ACIDS; DOCOSAHEXAENOIC ACID; COLORECTAL-CANCER; SODIUM-BUTYRATE; TERMINAL DIFFERENTIATION; DIETARY FIBER; EXPRESSION; METABOLISM; DEATH; CARCINOGENESIS	The short-chain and n-3 polyunsaturated fatty acids exhibit anticancer properties, and they may mutually interact within the colon. However, the molecular mechanisms of their action in colon cancer cells are still not fully understood. Our study focused on the mechanisms responsible for the diverse effects of sodium butyrate (NaBt), in particular when interacting with docosahexaenoic acid (DHA), in distinct colon cancer cell types, in which NaBt either induces cell differentiation or activates programmed cell death involving mitochondrial pathway. NaBt activated aufophagy both in HT-29 cells, which are sensitive to induction of differentiation, and in nondifferentiating HCT-116 cells. However, autophagy supported cell survival only in HT-29 cells. Combination of NaBt with DHA-promoted cell death, especially in HCT-116 cells and after longer time intervals. The inhibition of autophagy both attenuated differentiation and enhanced apoptosis in HT-29 cells treated with NaBt and DHA, but it had no effect in HCT-116 cells. NaBt, especially in combination with DHA, activated PPAR gamma in both cell types. PPAR gamma silencing decreased differentiation and increased apoptosis only in HT-29 cells, therefore we verified the role of caspases in apoptosis, differentiation and also PPAR gamma activity using a pan-caspase inhibitor. In summary, our data suggest that diverse responses of colon cancer cells to fatty acids may rely on their sensitivity to differentiation, which may in turn depend on distinct engagement of autophagy, caspases and PPAR gamma. These results contribute to understanding of mechanisms underlying differential effects of NaBt, when interacting with other dietary fatty acids, in colon cancer cells. (C) 2016 Elsevier Inc. All rights reserved.	[Tylichova, Zuzana; Strakova, Nicol; Vondracek, Jan; Vaculova, Alena Hyrslova; Kozubik, Alois; Hofmanova, Jirina] Czech Acad Sci, Inst Biophys, Dept Cytokinet, Brno, Czech Republic; [Tylichova, Zuzana; Vondracek, Jan; Kozubik, Alois; Hofmanova, Jirina] Masaryk Univ, Dept Expt Biol, Fac Sci, Brno, Czech Republic; [Strakova, Nicol] St Annes Univ Hosp Brno, Int Clin Res Ctr, Brno, Czech Republic		Hofmanova, J (corresponding author), Kralovopolska 135, Brno 61265, Czech Republic.	strakova@ibp.cz; hofmanova@ibp.cz	Straková, Nicol/E-9685-2019; Tylichova, Zuzana/AAX-9085-2021; Vondracek, Jan/J-3037-2012	Straková, Nicol/0000-0003-3874-3777; Vondracek, Jan/0000-0003-4071-1969; Hyrslova Vaculova, Alena/0000-0002-0445-8807	Czech Science FoundationGrant Agency of the Czech Republic [13-09766S]; Internal Grant Agency of Ministry of Health of the Czech Republic [NT 11201-5/2010]; National Program of Sustainability II (MEYS CR) [LQ1605]; project FNUSA-ICRC [CZ.1.05/1.1.00/02.0123]	This work was supported by grants No. 13-09766S of the Czech Science Foundation, NT 11201-5/2010 from Internal Grant Agency of Ministry of Health of the Czech Republic and no. LQ1605 from the National Program of Sustainability II (MEYS CR), the project FNUSA-ICRC no. CZ.1.05/1.1.00/02.0123 (OP VaVpI).	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Nutr. Biochem.	JAN	2017	39						145	155		10.1016/j.jnutbio.2016.09.006			11	Biochemistry & Molecular Biology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Nutrition & Dietetics	EE4IT	WOS:000389566200017	27840291				2022-04-25	
J	Hu, Q; Liang, B; Sun, Y; Guo, XL; Bao, YJ; Xie, DH; Zhou, M; Duan, YR; Yin, PH; Peng, ZH				Hu, Qiang; Liang, Bo; Sun, Ying; Guo, Xiao-Ling; Bao, Yi-Jie; Xie, Dong-Hao; Zhou, Ming; Duan, You-Rong; Yin, Pei-Hao; Peng, Zhi-Hai			Preparation of bufalin-loaded pluronic polyetherimide nanoparticles, cellular uptake, distribution, and effect on colorectal cancer	INTERNATIONAL JOURNAL OF NANOMEDICINE			English	Article						colon cancer; nanoparticles; tumor target; bufalin	APOPTOSIS; CELLS; AUTOPHAGY; DEATH	A large number of studies have shown that bufalin can have a significant antitumor effect in a variety of tumors. However, because of toxicity, insolubility in water, fast metabolism, short half-life, and other shortcomings, its application is limited in cancer therapy. In this study, we explored the anti-metastatic role of bufalin-loaded pluronic polyetherimide nanoparticles on HCT116 colon cancer-bearing mice. Nanoparticle size, shape, drug loading, encapsulation efficiency, and in vitro drug release were studied. Also, cellular uptake of nanoparticles, in vivo tumor targeting, and tumor metastasis were studied. The nanoparticles had a particle size of about 60 nm and an encapsulation efficiency of 75.71%, by weight. The in vitro release data showed that free bufalin was released faster than bufalin-loaded pluronic polyetherimide nanoparticles, and almost 80% of free bufalin was released after 32 hours. Nanoparticles had an even size distribution, were stable, and had a slow release and a tumor-targeting effect. Bufalin-loaded pluronic polyetherimide nanoparticles can significantly inhibit the growth and metastasis of colorectal cancer.	[Hu, Qiang; Peng, Zhi-Hai] Shandong Univ, Qianfoshan Hosp, Dept Hepatobiliary Surg, Jinan 250100, Peoples R China; [Liang, Bo; Guo, Xiao-Ling; Bao, Yi-Jie; Yin, Pei-Hao] Shanghai Univ Tradit Chinese Med, Dept Gen Surg, Putuo Hosp, Shanghai 200062, Peoples R China; [Hu, Qiang; Xie, Dong-Hao; Zhou, Ming] Shanghai Jiao Tong Univ, Dahua Hosp, Dept Gen Surg, Shanghai 200030, Peoples R China; [Sun, Ying; Duan, You-Rong] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes,Sch Med, Shanghai 200030, Peoples R China		Yin, PH (corresponding author), Shanghai Univ Tradit Chinese Med, Dept Gen Surg, Putuo Hosp, 164 Lanxi Rd, Shanghai 200062, Peoples R China.	yinpeihao1975@hotmail.com; zhihai.peng@hotmail.com			Shanghai Committee of Science and Technology, ChinaShanghai Science & Technology Committee [114119b3100]; Putuo District Committee of Science and Technology, Shanghai, China [201102]; State Administration of Traditional Chinese Medicine of People's Republic of China	This project was supported by the Shanghai Committee of Science and Technology, China (Number 114119b3100), and by the Putuo District Committee of Science and Technology, Shanghai, China (Number 201102). This research work was also supported by Construct Program of the Key Discipline of State Administration of Traditional Chinese Medicine of People's Republic of China. The four affiliations contributed equally to this work, thanks for the support of the four units.	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J. Nanomed.		2014	9						4035	4041		10.2147/IJN.S64708			7	Nanoscience & Nanotechnology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics; Pharmacology & Pharmacy	AN5CU	WOS:000340607800001	25187707	Green Published, Green Submitted, gold			2022-04-25	
J	Sun, PH; Zhu, LM; Qiao, MM; Zhang, YP; Jiang, SH; Wu, YL; Tu, SP				Sun, Ping Hu; Zhu, Li Ming; Qiao, Min Min; Zhang, Yong Ping; Jiang, Shi Hu; Wu, Yun Lin; Tu, Shui Ping			The XAF1 tumor suppressor induces autophagic cell death via upregulation of Beclin-1 and inhibition of Akt pathway	CANCER LETTERS			English	Article						XAF1; Autophagy; Apoptosis; Gastric cancer; Berlin 1	XIAP-ASSOCIATED FACTOR-1; HALF LIM PROTEIN-2; SIGNALING PATHWAYS; COLON-CANCER; APOPTOSIS; GENE; EXPRESSION; DEGRADATION; ACTIVATION; GROWTH	Autophagy is designated as type II programmed cell death and may confer a tumor-suppressive function. Our previous studies have shown that XIAP-associated factor 1 (XAF1) induced apoptosis and inhibited tumor growth in gastric cancer cells. In this study, we investigated the effect of XAF1 on the induction of autophagy in gastric cancer cells. We found that adenovirus vector-mediated XAF1 (adeno-XAF1) expression markedly induced autophagy, upregulated the level of Beclin-1 and inhibited phospho-Akt and phospho-p70S6K in gastric cancer cells. The downregulation of Beclin 1 or 3-methyladenine treatment suppressed adeno-XAF1-induced autophagy, but significantly enhanced adeno-XAF1-induced apoptosis. A pan-caspase inhibitor prevented adeno-XAF1-induced apoptosis, but significantly increased adeno-XAF1-induced autophagy. Furthermore, adeno-XAF1 induced autophagy in xenograft tumor and inhibited tumor growth. Our results document that adeno-XAF1 induces autophagy through upregulation of Beclin 1 expression and inhibition of Akt/p70S6K pathway, and reveal a new mechanism of XAF1 tumor suppression. (C) 2011 Elsevier Ireland Ltd. All rights reserved.	[Sun, Ping Hu; Zhu, Li Ming; Qiao, Min Min; Zhang, Yong Ping; Jiang, Shi Hu; Wu, Yun Lin; Tu, Shui Ping] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Gastroenterol, Shanghai, Peoples R China		Wu, YL (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Gastroenterol, Shanghai, Peoples R China.	wuyunlin1951@163.com; tushuiping@yahoo.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30572142, 30772518]	The project was supported by National Natural Science Foundation of China (Nos. 30572142, 30772518, S.P. Tu).	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NOV 28	2011	310	2					170	180		10.1016/j.canlet.2011.06.037			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	820DA	WOS:000294884500006	21788101				2022-04-25	
J	Wu, JN; Lin, L; Luo, SB; Qiu, XZ; Zhu, LY; Chen, D; Wei, ED; Fu, ZH; Qin, MB; Liang, ZH; Huang, JA; Liu, SQ				Wu, Jiang-Ni; Lin, Lan; Luo, Shi-Bo; Qiu, Xin-Ze; Zhu, Li-Ye; Chen, Da; Wei, Er-Dan; Fu, Zhen-Hua; Qin, Meng-Bin; Liang, Zhi-Hai; Huang, Jie-An; Liu, Shi-Quan			SphK1-driven autophagy potentiates focal adhesion paxillin-mediated metastasis in colorectal cancer	CANCER MEDICINE			English	Article						autophagy; colorectal cancer; metastases; paxillin; sphingosine kinase 1	CELL-MIGRATION; COLON-CANCER; P-PAXILLIN; EXPRESSION; FAK; TRANSITION; PATHWAY	Invasion and metastasis are the main causes of colorectal cancer (CRC)-related death. Accumulating evidence suggested that sphingosine kinase 1 (SphK1) promoted the metastasis of CRC and autophagy played an important role in SphK1 promoting the metastasis of malignancy. However, the mechanism by which SphK1-driven autophagy promotes invasion and metastasis in CRC remains to be clarified. In the present study, immunohistochemical detection showed the expression of SphK1 and paxillin was higher in human CRC tissues than those of normal colorectal mucosal tissues, they were both associated with TNM staging, lymphatic, and distance metastasis. In addition, study of in situ tumor transplantation model in nude mice showed that the suppression of SphK1 inhibited the growth of colonic orthotopic implantation tumors and the expression of paxillin, p-paxillin, LC3 in the tumor. So, SphK1 may promote CRC metastasis via inducing the expression of paxillin expression and its phosphorylation, in vivo. Furthermore, results of CCK8 assay, transwell and wound healing assays showed that SphK1 promoted the viability, invasion, and metastasis of CRC cells. Transmission electron microscopy detection showed that SphK1 is the key factor in autophagy induction in CRC cells. Moreover, western blot examination indicated that the expression of LC3II/I, paxillin, p-paxillin, MMP-2, and vimentin was enhanced in SphK1-overexpressed CRC cells and suppressed in SphK1 knockdown CRC cells, meanwhile, the expression of E-cadherin was suppressed in SphK1-overexpressed CRC cells and enhanced in SphK1 knockdown CRC cells. Suppression of autophagy by 3MA reversed the expression of paxillin and its phosphorylation in SphK1-overexpressed CRC cells, indicated that SphK1-driven autophagy induced the expression of paxillin and its phosphorylation in CRC cells. Together, these findings reveal that SphK1-driven autophagy may promote the invasion and metastasis of CRC via promoting the expression of focal adhesion paxillin and its phosphorylation.	[Wu, Jiang-Ni; Lin, Lan; Luo, Shi-Bo; Qiu, Xin-Ze; Zhu, Li-Ye; Chen, Da; Wei, Er-Dan; Fu, Zhen-Hua; Qin, Meng-Bin; Huang, Jie-An; Liu, Shi-Quan] Guangxi Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Nanning 530007, Guangxi, Peoples R China; [Liang, Zhi-Hai] Guangxi Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Nanning, Guangxi, Peoples R China		Liu, SQ (corresponding author), Guangxi Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Nanning 530007, Guangxi, Peoples R China.	poempower@163.com		WU, Jiangni/0000-0001-6514-226X	Natural Science Foundation of Guangxi ProvinceNational Natural Science Foundation of Guangxi Province [2017GXNSFAA198019, 2020GXNSFAA159056]; Natural Science Foundation Fostering Science Foundation of the Second Affiliated Hospital of Guangxi Medical University [GJPY2018010]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81460380]	Natural Science Foundation of Guangxi Province, Grant/Award Number: 2017GXNSFAA198019 and 2020GXNSFAA159056; Natural Science Foundation Fostering Science Foundation of the Second Affiliated Hospital of Guangxi Medical University, Grant/Award Number: GJPY2018010; National Natural Science Foundation of China, Grant/Award Number: 81460380	Amaravadi R, 2016, GENE DEV, V30, P1913, DOI 10.1101/gad.287524.116; Assar EA, 2020, FRONT CELL DEV BIOL, V8, DOI 10.3389/fcell.2020.00733; Benson AB, 2017, J NATL COMPR CANC NE, V15, P370, DOI 10.6004/jnccn.2017.0036; Birgisdottir AB, 2013, J CELL SCI, V126, P3237, DOI 10.1242/jcs.126128; Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI 10.3322/caac.21492; Chen GC, 2008, AUTOPHAGY, V4, P37, DOI 10.4161/auto.5141; Chen HT, 2019, MOL CANCER, V18, DOI 10.1186/s12943-019-1030-2; Chen J, 2012, CANCER RES, V72, P4130, DOI 10.1158/0008-5472.CAN-12-0655; Das J, 2019, EXP CELL RES, V381, P201, DOI 10.1016/j.yexcr.2019.04.037; Deakin NO, 2008, J CELL SCI, V121, P2435, DOI 10.1242/jcs.018044; Digman MA, 2008, BIOPHYS J, V94, P2819, DOI 10.1529/biophysj.107.104984; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Guo P, 2019, CANCER BIOL MED, V16, P377, DOI 10.20892/j.issn.2095-3941.2018.0386; Hong KO, 2019, MOLECULES, V24, DOI 10.3390/molecules24101928; Kenific CM, 2016, J CELL BIOL, V212, P577, DOI 10.1083/jcb.201503075; Lee BY, 2015, PHARMACOL THERAPEUT, V146, P132, DOI 10.1016/j.pharmthera.2014.10.001; Li XH, 2020, MOL CANCER, V19, DOI 10.1186/s12943-020-1138-4; Liu H, 2017, AUTOPHAGY, V13, P900, DOI 10.1080/15548627.2017.1291479; Liu SQ, 2019, INT J ONCOL, V54, P41, DOI 10.3892/ijo.2018.4607; Maceyka M, 2012, TRENDS CELL BIOL, V22, P50, DOI 10.1016/j.tcb.2011.09.003; Mantonakis E, 2017, J BUON, V22, P1097; Lopez-Colome AM, 2017, J HEMATOL ONCOL, V10, DOI 10.1186/s13045-017-0418-y; Mizushima N, 2007, AUTOPHAGY, V3, P542, DOI 10.4161/auto.4600; Pyne Nigel J., 2018, Advances in Biological Regulation, V68, P97, DOI 10.1016/j.jbior.2017.09.006; Sharifi MN, 2016, CELL REP, V15, P1660, DOI 10.1016/j.celrep.2016.04.065; Sukocheva OA, 2020, PHARMACOL THERAPEUT, V207, DOI 10.1016/j.pharmthera.2019.107464; Tanida I, 2004, INT J BIOCHEM CELL B, V36, P2503, DOI 10.1016/j.biocel.2004.05.009; Theocharis S, 2017, ANTICANCER RES, V37, P1313, DOI 10.21873/anticanres.11449; Turner CE, 2000, J CELL SCI, V113, P4139; Wang DP, 2019, BIOSCI BIOTECH BIOCH, V83, P836, DOI 10.1080/09168451.2019.1569496; Wang XW, 2020, CANCER CONTROL, V27, DOI 10.1177/1073274820976664; Webb DJ, 2002, NAT CELL BIOL, V4, pE97, DOI 10.1038/ncb0402-e97; Wen L, 2020, ONCOL REP, V44, P1105, DOI 10.3892/or.2020.7687; Xu CY, 2017, INT J MOL MED, V39, P1277, DOI 10.3892/ijmm.2017.2921; Xu CY, 2018, ONCOL LETT, V15, P9719, DOI 10.3892/ol.2018.8588; Yin SC, 2019, CANCER MED-US, V8, P1731, DOI 10.1002/cam4.2041; Young MM, 2016, CELL REP, V17, P1532, DOI 10.1016/j.celrep.2016.10.019; Zheng QS, 2018, J CANCER, V9, P959, DOI 10.7150/jca.22787; Zheng XJ, 2019, PHARMACOL THERAPEUT, V195, P85, DOI 10.1016/j.pharmthera.2018.10.011	39	0	0	1	1	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	2045-7634			CANCER MED-US	Cancer Med.	SEP	2021	10	17					6010	6021		10.1002/cam4.4129		JUL 2021	12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	UN2AV	WOS:000673964500001	34268882	Green Published, gold			2022-04-25	
J	Yang, Y; Bai, LL; Liao, WT; Feng, MY; Zhang, MX; Wu, QJ; Zhou, KX; Wen, F; Lei, WT; Zhang, N; Huang, JX; Li, Q				Yang, Yang; Bai, LiangLiang; Liao, Weiting; Feng, Mingyang; Zhang, Mengxi; Wu, Qiuji; Zhou, Kexun; Wen, Feng; Lei, Wanting; Zhang, Nan; Huang, Jiaxing; Li, Qiu			The role of non-apoptotic cell death in the treatment and drug-resistance of digestive tumors	EXPERIMENTAL CELL RESEARCH			English	Review						Digestive tumors; Autophagy; Pyroptosis; Ferroptosis; Treatment; Drug-resistance	PANCREATIC-CANCER CELLS; ERASTIN-INDUCED FERROPTOSIS; INHIBITS AUTOPHAGIC FLUX; COLON-CANCER; CYTOPLASMIC VACUOLATION; OBETICHOLIC ACID; CARCINOMA-CELLS; PYROPTOSIS; CISPLATIN; SENSITIVITY	Tumor cell apoptosis evasion is one of the main reasons for easy metastasis occurrence, chemotherapy resistance, and the low five-year survival rate of digestive system tumors. Current research has shown that non-apoptotic cell death plays an important role in tumors of the digestive system. Therefore, increasing the proportion of non-apoptotic tumor cells is one of the effective methods of improving therapeutic efficacies for digestive system tumors. Non-apoptotic cell death modes mainly include autophagic cell death, pyroptosis, ferroptosis, in addition to other cell death modes. This review covers a systematic review relating to the research progress made into autophagic cell death, pyroptosis, ferroptosis, and other cell death modes in the treatment of digestive system tumors. It also highlights how treatment is a reasonable prospect based on clinical experience and provides reliable guidance for the further development of digestive system tumor treatments.	[Yang, Yang; Bai, LiangLiang; Liao, Weiting; Feng, Mingyang; Zhang, Mengxi; Wu, Qiuji; Zhou, Kexun; Wen, Feng; Lei, Wanting; Zhang, Nan; Huang, Jiaxing; Li, Qiu] Sichuan Univ, West China Hosp, Canc Ctr, Dept Med Oncol, 37 GuoXue Xiang, Chengdu, Sichuan, Peoples R China; [Yang, Yang; Bai, LiangLiang; Liao, Weiting; Feng, Mingyang; Zhang, Mengxi; Wu, Qiuji; Zhou, Kexun; Wen, Feng; Lei, Wanting; Zhang, Nan; Huang, Jiaxing; Li, Qiu] Sichuan Univ, West China Biomed Big Data Ctr, 37 GuoXue Xiang, Chengdu, Sichuan, Peoples R China		Li, Q (corresponding author), Sichuan Univ, West China Hosp, Dept Canc Ctr, Chengdu, Peoples R China.	liqiu@scu.edu.cn					Ahechu P, 2018, FRONT IMMUNOL, V9, DOI 10.3389/fimmu.2018.02918; Alnuqaydan AM, 2020, AM J CANCER RES, V10, P799; Andrade-Tomaz M, 2020, CELLS-BASEL, V9, DOI 10.3390/cells9092140; Arai H, 2020, J IMMUNOTHER CANCER, V8, DOI 10.1136/jitc-2020-001714; Badgley MA, 2020, SCIENCE, V368, P85, DOI 10.1126/science.aaw9872; Bai T, 2020, J CELL PHYSIOL, V235, P5637, DOI 10.1002/jcp.29496; 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Cell Res.	AUG 15	2021	405	2							112678	10.1016/j.yexcr.2021.112678		JUL 2021	18	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	TS0HE	WOS:000679336700002	34171351				2022-04-25	
J	Chen, XL; Liu, P; Zhu, WL; Lou, LG				Chen, Xiang-ling; Liu, Peng; Zhu, Wei-liang; Lou, Li-guang			DCZ5248, a novel dual inhibitor of Hsp90 and autophagy, exerts antitumor activity against colon cancer	ACTA PHARMACOLOGICA SINICA			English	Article						DCZ5248; Hsp90; autophagy; lysosomal function; antitumor activity; colon cancer	PROTEIN 90 INHIBITORS; ADVANCED SOLID TUMORS; PHASE-I TRIAL; INDUCED APOPTOSIS; RESISTANCE; MUTANT; HYDROXYCHLOROQUINE; DEGRADATION; GANETESPIB; TEMOZOLOMIDE	Hsp90 is a potential therapeutic target for tumor, as it maintains the stability of a variety of proteins related to tumor development and progression. Autophagy is a self-degradation process to maintain cellular homeostasis and autophagy inhibitors can suppress tumor growth. In this study, we identified DCZ5248, a triazine derivative, was a dual inhibitor of both Hsp90 and late-autophagy with potent antitumor activity against colon cancer cells in vitro and in vivo. We showed that DCZ5248 (0.1-10 mu M) induced dose-dependent degradation of Hsp90 client proteins (AKT, CDK4, CDK6 and RAF-1) in HCT 116 colon cancer cells through a proteasome-dependent pathway. Meanwhile, DCZ5248 (0.3 mu M) induced cytoplasmic vacuole formation, LC3 II conversion, p62 protein upregulation, and inhibited autophagy at the late stage in the colon cancer cell lines tested. We further revealed that the inhibition of autophagy was achieved by impairing lysosomal functions through induction of lysosomal acidification and attenuation of lysosomal cathepsin activity. The modulation of autophagy by DCZ5248 was independent of Hsp90 inhibition as the autophagy inhibition was not blocked by Hsp90 knockdown. Importantly, inhibition of both Hsp90 function and autophagy by DCZ5248 induced G(1)-phase cell cycle arrest, apoptosis, and exerted potent antitumor activity against colon cancer cells both in vitro and in vivo. These findings demonstrate that DCZ5248 is a novel dual inhibitor of Hsp90 and autophagy with potential for colon cancer therapy.	[Chen, Xiang-ling; Liu, Peng; Zhu, Wei-liang; Lou, Li-guang] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; [Chen, Xiang-ling; Zhu, Wei-liang; Lou, Li-guang] Univ Chinese Acad Sci, Beijing 100049, Peoples R China		Lou, LG (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China.; Lou, LG (corresponding author), Univ Chinese Acad Sci, Beijing 100049, Peoples R China.	lglou@mail.shcnc.ac.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81273546]; Science and Technology Commission of Shanghai MunicipalityScience & Technology Commission of Shanghai Municipality (STCSM) [18DZ2293200]; Yunnan Province Sciences and Technology plan [2017ZF010]	This research was supported by grants from the National Natural Science Foundation of China (No. 81273546), the Science and Technology Commission of Shanghai Municipality (No. 18DZ2293200) and the Yunnan Province Sciences and Technology plan (No. 2017ZF010).	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Sin.	JAN	2021	42	1					132	141		10.1038/s41401-020-0398-2		MAY 2020	10	Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	PM9GU	WOS:000532622200003	32404982	Bronze, Green Published			2022-04-25	
J	Lee, YJ; Kim, NY; Suh, YA; Lee, C				Lee, Youn Ju; Kim, Nam-Yi; Suh, Young-Ah; Lee, ChuHee			Involvement of ROS in Curcumin-induced Autophagic Cell Death	KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY			English	Article						Autophagy; Curcumin; Microtubule-associated protein 1 light chain 3; Mitogen-activated protein kinase; Sequestome-1; Reactive oxygen species	MALIGNANT GLIOMA-CELLS; COLON-CANCER CELLS; OXIDATIVE STRESS; DOWN-REGULATION; APOPTOSIS; LC3; INHIBITION; ANTIOXIDANT; EXPRESSION; INDUCTION	Many anticancer agents as well as ionizing radiation have been shown to induce autophagy which is originally described as a protein recycling process and recently reported to play a crucial role in various disorders. In HCT116 human colon cancer cells, we found that curcumin, a polyphenolic phytochemical extracted from the plant Curcuma longa, markedly induced the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II and degradation of sequestome-1 (SQSTM1) which is a marker of autophagosome degradation. Moreover, we found that curcumin caused GFP-LC3 formation puncta, a marker of autophagosome, and decrease of GFP-LC3 and SQSTM1 protein level in GFP-LC3 expressing HCT116 cells. It was further confirmed that treatment of cells with hydrogen peroxide induced increase of LC3 conversion and decrease of GFP-LC3 and SQSTM1 levels, but these changes by curcumin were almost completely blocked in the presence of antioxidant, N-acetylcystein (NAC), indicating that curcumin leads to reactive oxygen species (ROS) production, which results in autophagosome development and autolysosomal degradation. In parallel with NAC, SQSTM1 degradation was also diminished by bafilomycin A, a potent inhibitor of autophagosome-lysosome fusion, and cell viability assay was further confirmed that cucurmin-induced cell death was partially blocked by bafilomycin A as well as NAC. We also observed that NAC abolished curcumin-induced activation of extracelluar signal-regulated kinases (ERK) 1/2 and p38 mitogen-activated protein kinases (MAPK), but not Jun N-terminal kinase (JNK). However, the activation of ERK1/2 and p38 MAPK seemed to have no effect on the curcumin-induced autophagy, since both the conversion of LC3 protein and SQSTM1 degradation by curcumin was not changed in the presence of NAC. Taken together, our data suggest that curcumin induced ROS production, which resulted in autophagic activation and concomitant cell death in HCT116 human colon cancer cell. However, ROS-dependent activation of ERK1/2 and p38 MAPK, but not JNK, might not be involved in the curcumin-induced autophagy.	[Kim, Nam-Yi; Lee, ChuHee] Yeungnam Univ, Dept Biochem & Mol Biol, Sch Med, Taegu 705717, South Korea; [Lee, Youn Ju] Catholic Univ, Coll Med, Dept Pharmacol, Taegu 705718, South Korea; [Suh, Young-Ah] Asan Med Ctr, Inst Innovat Canc Res, Seoul 138736, South Korea		Lee, C (corresponding author), Yeungnam Univ, Dept Biochem & Mol Biol, Sch Med, 317-1 Daemyung 5 Dong, Taegu 705717, South Korea.	chlee2@ynu.ac.kr			Ministry of Korean Government Education, Science and Technology [2010-0007352]	This work was supported by Fure-based Technology Development Program (Nano Fields, Grant No. 2010-0007352) through the National Research Foundation of Korea (NRF) funded by the Ministry of Korean Government Education, Science and Technology.	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PHYSIOL. PHARMACOL.	FEB	2011	15	1					1	7		10.4196/kjpp.2011.15.1.1			7	Pharmacology & Pharmacy; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Physiology	735LQ	WOS:000288416400001	21461234	Green Published			2022-04-25	
J	Hasan, M; Reddy, SM; Das, NK				Hasan, Mazen; Reddy, Sreedhar M.; Das, Nupur K.			Ferritinophagy is not required for colon cancer cell growth	CELL BIOLOGY INTERNATIONAL			English	Article						colon cancer; ferritin; ferritinophagy; iron homeostasis	COLORECTAL-CANCER; IRON HOMEOSTASIS; FERROPTOSIS; PROGRESSION; METABOLISM; MECHANISMS; DEATH; NCOA4	Ferritinophagy is a form of selective autophagy responsible for degrading intracellular ferritin, mediated by nuclear receptor coactivator 4 (NCOA4). NCOA4 plays significant roles in systemic iron homeostasis, and its disruption leads to simultaneous anemia and susceptibility to iron overload. The importance of iron colorectal cancer pathogenesis is well studied; however, the role of ferritinophagy in colon cancer cell growth has not been assessed. Disruption of ferritinophagy via NCOA4 knockout leads to only marginal differences in growth under basal and iron-restricted conditions. Moreover, NCOA4 played no significant role in cell death induced by 5-fluorouracil and erastin. Western blotting analysis for ferritin and transferrin receptor 1 found a dose-dependent effect on expression in both proteins in wild-type and NCOA4 knockout cell lines, but further investigation revealed no difference in growth response when treated at both high and low doses. Our data demonstrate a marginal role for ferritinophagy in growth both under normal and cytotoxic conditions in colon cancer cells, as well as a possible compensatory mechanism in colon cancer cells in response to ferroptosis induction.	[Hasan, Mazen; Reddy, Sreedhar M.; Das, Nupur K.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA		Das, NK (corresponding author), 7703,MS 2,E Catherine St, Ann Arbor, MI 48109 USA.	nkdas@umich.edu	Das, Nupur/AAK-7877-2020	Das, Nupur/0000-0002-5652-1134	University of Michigan Centre for Gastrointestinal Research (UMCGR); Undergraduate Research Opportunity Program (UROP), University of MichiganUniversity of Michigan System	The authors acknowledge the support of the University of Michigan Centre for Gastrointestinal Research (UMCGR) and the Undergraduate Research Opportunity Program (UROP), University of Michigan.	Andrews NC, 2008, BLOOD, V112, P219, DOI 10.1182/blood-2007-12-077388; Bellelli R, 2016, CELL REP, V14, P411, DOI 10.1016/j.celrep.2015.12.065; Bogaert J, 2014, ANN GASTROENTEROL, V27, P9; Bogdan AR, 2016, TRENDS BIOCHEM SCI, V41, P274, DOI 10.1016/j.tibs.2015.11.012; Cao JY, 2016, CELL MOL LIFE SCI, V73, P2195, DOI 10.1007/s00018-016-2194-1; Chifman J, 2014, ADV EXP MED BIOL, V844, P201, DOI 10.1007/978-1-4939-2095-2_10; Cui C, 2019, CANCER MANAG RES, V11, P6323, DOI 10.2147/CMAR.S198911; Ferreira C, 2001, BLOOD, V98, P525, DOI 10.1182/blood.V98.3.525; Gao GF, 2019, ADV EXP MED BIOL, V1173, P21, DOI 10.1007/978-981-13-9589-5_2; Gao MH, 2016, CELL RES, V26, P1021, DOI 10.1038/cr.2016.95; Gao XF, 2017, P NATL ACAD SCI USA, V114, P10107, DOI 10.1073/pnas.1711058114; Hou W, 2016, AUTOPHAGY, V12, P1425, DOI 10.1080/15548627.2016.1187366; Kawabata H, 2019, FREE RADICAL BIO MED, V133, P46, DOI 10.1016/j.freeradbiomed.2018.06.037; Krenn MA, 2015, FREE RADICAL BIO MED, V80, P48, DOI 10.1016/j.freeradbiomed.2014.12.007; Kurz T, 2011, FREE RADICAL BIO MED, V50, P1647, DOI 10.1016/j.freeradbiomed.2011.03.014; Longley DB, 2003, NAT REV CANCER, V3, P330, DOI 10.1038/nrc1074; Mancias JD, 2015, ELIFE, V4, DOI 10.7554/eLife.10308; Mancias JD, 2014, NATURE, V509, P105, DOI 10.1038/nature13148; Marley AR, 2016, INT J MOL EPIDEMIOL, V7, P105; Shah YM, 2009, CELL METAB, V9, P152, DOI 10.1016/j.cmet.2008.12.012; Shen Y, 2018, AM J CANCER RES, V8, P916; Xue X, 2016, CELL METAB, V24, P447, DOI 10.1016/j.cmet.2016.07.015; Xue X, 2013, NUTRIENTS, V5, P2333, DOI 10.3390/nu5072333; Xue X, 2012, CANCER RES, V72, P2285, DOI 10.1158/0008-5472.CAN-11-3836	24	4	4	0	9	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	1065-6995	1095-8355		CELL BIOL INT	Cell Biol. Int.	NOV	2020	44	11					2307	2314		10.1002/cbin.11439		AUG 2020	8	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	OC2LZ	WOS:000559437200001	32767706				2022-04-25	
J	Williams, JA; Hou, YF; Ni, HM; Ding, WX				Williams, Jessica A.; Hou, Yifeng; Ni, Hong-Min; Ding, Wen-Xing			Role of Intracellular Calcium in Proteasome Inhibitor-Induced Endoplasmic Reticulum Stress, Autophagy, and Cell Death	PHARMACEUTICAL RESEARCH			English	Article						autophagy; cell death; ER stress; intracellular calcium; proteasome inhibitor	TARGETING AUTOPHAGY; FUSION; CA2+; MACROAUTOPHAGY; THAPSIGARGIN; HOMEOSTASIS; MATURATION; LYSOSOMES; SURVIVAL; SYSTEM	Proteasome inhibition induces endoplasmic reticulum (ER) stress and compensatory autophagy to relieve ER stress. Disturbance of intracellular calcium homeostasis can lead to ER stress and alter the autophagy process. It has been suggested that inhibition of the proteasome disrupts intracellular calcium homeostasis. However, it is unknown if intracellular calcium affects proteasome inhibitor-induced ER stress and autophagy. Human colon cancer HCT116 Bax positive and negative cell lines were treated with MG132, a proteasome inhibitor. BAPTA-AM, a cell permeable free calcium chelator, was used to modulate intracellular calcium levels. Autophagy and cell death were determined by fluorescence microscopy and immunoblot analysis. MG132 increased intracellular calcium levels in HCT116 cells, which was suppressed by BAPTA-AM. MG132 suppressed proteasome activity independent of Bax and intracellular calcium levels in HCT116 cells. BAPTA-AM inhibited MG132-induced cellular vacuolization and ER stress, but not apoptosis. MG132 induced autophagy with normal autophagosome-lysosome fusion. BAPTA-AM seemed not to affect autophagosome-lysosome fusion in MG132-treated cells but further enhanced MG132-induced LC3-II levels and GFP-LC3 puncta formation, which was likely via impaired lysosome function. Blocking intracellular calcium by BAPTA-AM relieved MG132-induced ER stress, but it was unable to rescue MG132-induced apoptosis, which was likely due to impaired autophagic degradation.	[Williams, Jessica A.; Ni, Hong-Min; Ding, Wen-Xing] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA; [Hou, Yifeng] Fudan Univ, Canc Hosp, Breast Canc Inst, Dept Breast Surg, Shanghai 200433, Peoples R China		Ding, WX (corresponding author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, MS 1018 3901 Rainbow Blvd, Kansas City, KS 66160 USA.	wxding@kumc.edu			NIAAAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [R01 AA020518-01]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [5P20RR021940-07]; National Institute of Environmental Health SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [5T32 ES007079]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81072165]; Shanghai Science and Technology CommitteeShanghai Science & Technology Committee [09PJ1402700]; NATIONAL CENTER FOR RESEARCH RESOURCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [P20RR021940] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [T32ES007079] Funding Source: NIH RePORTER; NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISMUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [R37AA020518, R01AA020518] Funding Source: NIH RePORTER	Jessica A. Williams and Yifeng Hou contribute equally to this work. The research work in W. X Ding's lab was supported in part by the NIAAA funds R01 AA020518-01 and National Center for Research Resources (5P20RR021940-07). J. A. Williams was supported by the "Training Program in Environmental Toxicology" [grant 5T32 ES007079] from the National Institute of Environmental Health Sciences. Y.F. Hou was supported by the National Natural Science Foundation of China (# 81072165) and the Shanghai Science and Technology Committee (# 09PJ1402700). The authors are indebted to Dr. Bert Vogelstein (Johns Hopkins University) and Lin Zhang (University of Pittsburgh) for the HCT116 Bax-positive and Bax-negative cell lines.	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Res.	SEP	2013	30	9					2279	2289		10.1007/s11095-013-1139-8			11	Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	206EG	WOS:000323499900011	23893020	Green Accepted			2022-04-25	
J	Nishikawa, T; Tsuno, NH; Okaji, Y; Shuno, Y; Sasaki, K; Hongo, K; Sunami, E; Kitayama, J; Takahashi, K; Nagawa, H				Nishikawa, Takeshi; Tsuno, Nelson H.; Okaji, Yurai; Shuno, Yasutaka; Sasaki, Kazuhito; Hongo, Kumiko; Sunami, Eiji; Kitayama, Joji; Takahashi, Koki; Nagawa, Hirokazu			Inhibition of Autophagy Potentiates Sulforaphane-Induced Apoptosis in Human Colon Cancer Cells	ANNALS OF SURGICAL ONCOLOGY			English	Article							CASPASE-MEDIATED APOPTOSIS; CYTOCHROME-C; CYCLE ARREST; G(2)/M ARREST; INDUCTION; GROWTH; PHASE; ISOTHIOCYANATES; PROTECTION; ENZYMES	Background. Sulforaphane (SUL), an isothiocyanate naturally present in widely consumed vegetables, particularly broccoli, has recently attracted attention due to its inhibitory effects on tumor cell growth by inducing apoptosis. We investigated the ability of SUL to induce autophagy in human colon cancer cells and whether inhibition of autophagy could potentiate the proapoptotic effect of SUL. Methods. The proliferation of cells treated with SUL was assessed by MTS assay and colony-forming assay. Apoptosis and caspases activity were investigated by flow cytometry. The formation of acidic vesicular organelles (AVOs) was detected in acridine-orange-stained cells by flow cytometry. Western blotting was used for the detection of light chain 3 (LC3). Localizations of LC3 and cytochrome c were analyzed by immunocytochemistry. Results. The proapoptotic effect was observed by treatment of cells with relatively high concentrations of SUL for long periods of time. After 16 h of treatment, evident formation of AVOs and recruitment of LC3 to autophagosomes, features of autophagy, were observed. Treatment of cells with a specific autophagy inhibitor (3-methyladenine) potentiated the proapoptotic effect of SUL, which was dependent on the activation of caspases and the release of cytochrome c to the cytosol. Conclusion. The present results demonstrate induction of autophagy in colon cancer cells as a protective reaction against the proapoptotic effect of SUL, and consequently, the potentiation of the proapoptotic effect by autophagy inhibition. These findings provide a premise for use of autophagy inhibitors in combination with chemotherapeutic agents for treatment of colorectal cancer.	[Nishikawa, Takeshi; Tsuno, Nelson H.; Shuno, Yasutaka; Sasaki, Kazuhito; Hongo, Kumiko; Sunami, Eiji; Kitayama, Joji; Nagawa, Hirokazu] Univ Tokyo, Fac Med Sci, Dept Surg Oncol, Tokyo, Japan; [Tsuno, Nelson H.; Okaji, Yurai; Takahashi, Koki] Univ Tokyo, Dept Transfus Med, Fac Med Sci, Tokyo, Japan		Nishikawa, T (corresponding author), Univ Tokyo, Fac Med Sci, Dept Surg Oncol, Tokyo, Japan.	takn-tky@umin.ac.jp					Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Asakage Masahiro, 2006, Angiogenesis, V9, P83, DOI 10.1007/s10456-006-9034-0; Bonnesen C, 2001, CANCER RES, V61, P6120; Chiao JW, 2002, INT J ONCOL, V20, P631; Cho SD, 2005, NUTR CANCER, V52, P213, DOI 10.1207/s15327914nc5202_11; de Bruin EC, 2008, CANCER TREAT REV, V34, P737, DOI 10.1016/j.ctrv.2008.07.001; Fahey JW, 1997, P NATL ACAD SCI USA, V94, P10367, DOI 10.1073/pnas.94.19.10367; Gamet-Payrastre L, 2000, CANCER RES, V60, P1426; Gao XQ, 2001, P NATL ACAD SCI USA, V98, P15221, DOI 10.1073/pnas.261572998; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Herman-Antosiewicz A, 2007, MOL CANCER THER, V6, P1673, DOI 10.1158/1535-7163.MCT-06-0807; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; Ito H, 2005, INT J ONCOL, V26, P1401; Jakubikova J, 2005, BIOCHEM PHARMACOL, V69, P1543, DOI 10.1016/j.bcp.2005.03.015; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Kluck RM, 1997, SCIENCE, V275, P1132, DOI 10.1126/science.275.5303.1132; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Liang XH, 1998, J VIROL, V72, P8586, DOI 10.1128/JVI.72.11.8586-8596.1998; Matsuda K, 2002, CANCER RES, V62, P2883; Mizushima N, 2004, INT J BIOCHEM CELL B, V36, P2491, DOI 10.1016/j.biocel.2004.02.005; Nishikawa T, 2009, ANN SURG ONCOL, V16, P534, DOI 10.1245/s10434-008-0215-5; Pappa G, 2007, MOL NUTR FOOD RES, V51, P977, DOI 10.1002/mnfr.200700115; Pappa G, 2006, MUTAT RES-FUND MOL M, V599, P76, DOI 10.1016/j.mrfmmm.2006.01.007; Park SY, 2007, ONCOL REP, V18, P181; Pattingre S, 2005, CELL, V122, P927, DOI 10.1016/j.cell.2005.07.002; Sekine-Suzuki E, 2008, BIOCHEM BIOPH RES CO, V377, P341, DOI 10.1016/j.bbrc.2008.09.150; Shan Y, 2006, INT J ONCOL, V29, P883; Shen GX, 2006, CANCER CHEMOTH PHARM, V57, P317, DOI 10.1007/s00280-005-0050-3; Shimizu S, 1999, NATURE, V399, P483, DOI 10.1038/20959; Singh AV, 2004, CARCINOGENESIS, V25, P83, DOI 10.1093/carcin/bgg178; Singh SV, 2004, J BIOL CHEM, V279, P25813, DOI 10.1074/jbc.M313538200; Singletary K, 2008, CANCER EPIDEM BIOMAR, V17, P1596, DOI 10.1158/1055-9965.EPI-07-2917; Wang LG, 2004, INT J ONCOL, V24, P187; Yang YM, 2002, CANCER RES, V62, P2; ZHANG YS, 1992, P NATL ACAD SCI USA, V89, P2399, DOI 10.1073/pnas.89.6.2399	36	66	66	0	7	SPRINGER	NEW YORK	233 SPRING ST, NEW YORK, NY 10013 USA	1068-9265			ANN SURG ONCOL	Ann. Surg. Oncol.	FEB	2010	17	2					592	602		10.1245/s10434-009-0696-x			11	Oncology; Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Surgery	557SR	WOS:000274690900036	19830499				2022-04-25	
J	Zhang, Z; Shi, JY; Nice, EC; Huang, CH; Shi, Z				Zhang, Zhe; Shi, Jiayan; Nice, Edouard C.; Huang, Canhua; Shi, Zheng			The Multifaceted Role of Flavonoids in Cancer Therapy: Leveraging Autophagy with a Double-Edged Sword	ANTIOXIDANTS			English	Review						flavonoids; autophagy; cancer prevention; cancer therapy; nanotechnology	PROGRAMMED CELL-DEATH; PANCREATIC BETA-CELLS; NATURAL-PRODUCTS; PROTECTIVE AUTOPHAGY; INDUCED INJURY; COLON-CANCER; LUNG-CANCER; GREEN TEA; IN-VITRO; APOPTOSIS	Flavonoids are considered as pleiotropic, safe, and readily obtainable molecules. A large number of recent studies have proposed that flavonoids have potential in the treatment of tumors by the modulation of autophagy. In many cases, flavonoids suppress cancer by stimulating excessive autophagy or impairing autophagy flux especially in apoptosis-resistant cancer cells. However, the anti-cancer activity of flavonoids may be attenuated due to the simultaneous induction of protective autophagy. Notably, flavonoids-triggered protective autophagy is becoming a trend for preventing cancer in the clinical setting or for protecting patients from conventional therapeutic side effects in normal tissues. In this review, focusing on the underlying autophagic mechanisms of flavonoids, we hope to provide a new perspective for clinical application of flavonoids in cancer therapy. In addition, we highlight new research ideas for the development of new dosage forms of flavonoids to improve their various pharmacological effects, establishing flavonoids as ideal candidates for cancer prevention and therapy in the clinic.	[Zhang, Zhe; Shi, Jiayan; Huang, Canhua; Shi, Zheng] Chengdu Univ, Clin Med Coll, Chengdu 610106, Peoples R China; [Zhang, Zhe; Shi, Jiayan; Huang, Canhua; Shi, Zheng] Chengdu Univ, Affiliated Hosp, Chengdu 610106, Peoples R China; [Zhang, Zhe; Shi, Jiayan; Huang, Canhua] Sichuan Univ, Collaborat Innovat Ctr Biotherapy, Canc Ctr, West China Hosp, Chengdu 610041, Peoples R China; [Zhang, Zhe; Shi, Jiayan; Huang, Canhua] Sichuan Univ, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China; [Zhang, Zhe; Shi, Jiayan; Huang, Canhua] Sichuan Univ, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Peoples R China; [Nice, Edouard C.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia		Huang, CH; Shi, Z (corresponding author), Chengdu Univ, Clin Med Coll, Chengdu 610106, Peoples R China.; Huang, CH; Shi, Z (corresponding author), Chengdu Univ, Affiliated Hosp, Chengdu 610106, Peoples R China.; Huang, CH (corresponding author), Sichuan Univ, Collaborat Innovat Ctr Biotherapy, Canc Ctr, West China Hosp, Chengdu 610041, Peoples R China.; Huang, CH (corresponding author), Sichuan Univ, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China.; Huang, CH (corresponding author), Sichuan Univ, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Peoples R China.	scuzz@stu.scu.edu.cn; shijiayan@stu.scu.edu.cn; ed.nice@monash.edu; hcanhua@scu.edu.cn; shizheng@cdu.edu.cn		Nice, Edouard/0000-0001-5480-4715; Zhang, Zhe/0000-0001-7509-6965	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81821002, 81790251]; National Key Research and Development Project [2020YFA0509400, 2020YFC2002705]; Guangdong Basic and Applied Basic Research Foundation [2019B030302012]	This study was supported by grants from the National Natural Science Foundation of China (81821002 and 81790251), National Key Research and Development Project (2020YFA0509400, 2020YFC2002705), and Guangdong Basic and Applied Basic Research Foundation (2019B030302012).	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Chemistry, Medicinal; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Food Science & Technology	TN0SU	WOS:000675955300001	34356371	gold, Green Published			2022-04-25	
J	Xuan, Y; Zhao, S; Xiao, XJ; Xiang, LW; Zheng, HC				Xuan, Ying; Zhao, Shuang; Xiao, Xingjun; Xiang, Liwei; Zheng, Hua-Chuan			Inhibition of chaperone-mediated autophagy reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer	MOLECULAR MEDICINE REPORTS			English	Article						chaperone-mediated autophagy; lysosome-associated membrane protein 2A; colorectal cancer; drug resistance; NF-&#954; B p65 pathway; 5-fluorouracil		Chaperone-mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. The present study investigated the mechanisms underlying the response and resistance to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines. In engineered 5-FU-resistant CRC cell lines, a significant elevation of lysosome-associated membrane protein 2A (LAMP2A), which is the key molecule in the CMA pathway, was identified. High expression of LAMP2A was found to be responsible for 5-FU resistance and to enhance PLD2 expression through the activation of NF-kappa B pathway. Accordingly, loss or gain of function of LAMP2A in 5-FU-resistant CRC cells rendered them sensitive or resistant to 5-FU, respectively. Taken together, the results of the present study suggested that chemoresistance in patients with CRC may be mediated by enhancing CMA. Thus, CMA is a promising predictor of chemosensitivity to 5-FU treatment and anti-CMA therapy may be a novel therapeutic option for patients with CRC.	[Xuan, Ying; Zhao, Shuang; Xiao, Xingjun; Xiang, Liwei; Zheng, Hua-Chuan] China Med Univ, Dept Expt Oncol, Shengjing Hosp, 36 Sanhao St, Shenyang 110004, Liaoning, Peoples R China		Zheng, HC (corresponding author), China Med Univ, Dept Expt Oncol, Shengjing Hosp, 36 Sanhao St, Shenyang 110004, Liaoning, Peoples R China.	zheng_huachuan@hotmail.com			Liaoning BaiQianWan Talents Program; Key Scientific and Technological Project of Liaoning Province [2015408001]; National Natural Scientific Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472544, 81672700]	The present study was supported by Liaoning BaiQianWan Talents Program, Award for Liaoning Distinguished Professor, a Key Scientific and Technological Project of Liaoning Province (grant no. 2015408001) and National Natural Scientific Foundation of China (grant nos. 81472544 and 81672700).	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Med. Rep.	MAY	2021	23	5							360	10.3892/mmr.2021.11999			9	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	RA0JS	WOS:000631106200001	33760140	Green Published, hybrid			2022-04-25	
J	Burada, F; Nicoli, ER; Ciurea, ME; Uscatu, DC; Ioana, M; Gheonea, DI				Burada, Florin; Nicoli, Elena Raluca; Ciurea, Marius Eugen; Uscatu, Daniel Constantin; Ioana, Mihai; Gheonea, Dan Ionut			Autophagy in colorectal cancer: An important switch from physiology to pathology	WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY			English	Article						Colorectal cancer; Autophagy; Gene; Protein; Carcinogenesis	GENOME-WIDE ASSOCIATION; BECLIN 1 EXPRESSION; COLON-CANCER; CELL-DEATH; IN-VITRO; FAVORABLE PROGNOSIS; REGULATES AUTOPHAGY; SELECTIVE AUTOPHAGY; SUSCEPTIBILITY LOCI; DOWN-REGULATION	Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC.	[Burada, Florin; Ciurea, Marius Eugen; Ioana, Mihai; Gheonea, Dan Ionut] Univ Med & Pharm Craiova, Res Ctr Gastroenterol & Hepatol, 1 Mai 66, Craiova 200638, Romania; [Nicoli, Elena Raluca] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England; [Nicoli, Elena Raluca; Uscatu, Daniel Constantin] Univ Med & Pharm Craiova, Human Genom Lab, Craiova 200638, Romania		Burada, F (corresponding author), Univ Med & Pharm Craiova, Res Ctr Gastroenterol & Hepatol, 1 Mai 66, Craiova 200638, Romania.	buradaflorin@gmail.com	Nicoli, Elena-Raluca/F-3968-2011; Gheonea, Dan Ionut/C-3578-2012; Ioana, Mihai/N-4923-2016	Nicoli, Elena-Raluca/0000-0002-5545-630X; Ioana, Mihai/0000-0002-2186-1606	European Social Found, Human Resources Development Operational Programme [POSDRU/159/1.5/S/133377]	Supported by Grant POSDRU/159/1.5/S/133377, from European Social Found, Human Resources Development Operational Programme 2007-2013 (to Burada F).	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Gastrointest. Oncol.	NOV 15	2015	7	11					271	284		10.4251/wjgo.v7.i11.271			14	Oncology; Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Gastroenterology & Hepatology	V9A6T	WOS:000422139000002	26600927	hybrid, Green Published			2022-04-25	
J	Khaket, TP; Singh, MP; Khan, I; Bhardwaj, M; Kang, SC				Khaket, Tejinder Pal; Singh, Mahendra Pal; Khan, Imran; Bhardwaj, Monika; Kang, Sun Chul			Targeting of cathepsin C induces autophagic dysregulation that directs ER stress mediated cellular cytotoxicity in colorectal cancer cells	CELLULAR SIGNALLING			English	Article						Cathepsins; Autophag; Endoplasmic reticulum stress; Apoptosis	DIPEPTIDYL PEPTIDASE-I; UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; MONITORING AUTOPHAGY; CYSTEINE CATHEPSINS; SERINE PROTEASES; DEATH; ACTIVATION; INHIBITION; APOPTOSIS	As Autophagy is a pivotal mechanism of cancer cell survival and the development of chemotherapeutic resistance; therefore, new approaches are warranted for its targeting which may be fulfilled by cathepsins regulation. Amongst cathepsins, cathepsin C (CTSC) is highly expressed in various cancers and possesses significant therapeutic potential in autoimmune disorders; however, its role in colorectal cancer has not been explored. Herein, we aimed to investigate the role of CTSC in autophagy regulation mediated colorectal carcinoma cell proliferation. Cathepsin C targeting through inhibitors/siRNA leads to the accumulation of light chain 3 II and p62 without affecting the lysosomal integrity, revealed dysfunctional autolysosomal degradation which is also substantiated by proteolytic studies. Cathepsin C inhibition showed comparable autophagy blockade with E64d and augmented the autophagy blockade mediated by bafilomycin. Loss of CTSC function also induced ER stress mediated JNK phosphorylation accompanied by the translocation of mitochondrial cyt c followed by apoptotic cell death in colorectal carcinoma cells. Taken together, the study reveals that CTSC targeting plays a key role in the regulation of autophagy mediated colorectal cancer cell proliferation. Further investigations are required to determine the functional role of CTSC in other tumors also which may have implications for the therapeutic prevention of cancer in the future.	[Khaket, Tejinder Pal; Singh, Mahendra Pal; Khan, Imran; Bhardwaj, Monika; Kang, Sun Chul] Daegu Univ, Dept Biotechnol, Gyongsan 38453, Gyeongbuk, South Korea		Kang, SC (corresponding author), Daegu Univ, Coll Engn, Dept Biotechnol, Gyongsan 38453, Gyeongbuk, South Korea.	sckang@daegu.ac.kr	Singh, Mahendra Pal/J-8391-2019; Khaket, Tej/I-6260-2015		National Research Foundation of Korea (NRF) through Korea Research Fellowship Program [NRF 2016H1D3A1938249, NRF 2017R1D1A1B03036569, NRF 2016R1A2B4009227]	This work was supported by the National Research Foundation of Korea (NRF) through Korea Research Fellowship Program (NRF 2016H1D3A1938249, NRF 2017R1D1A1B03036569 and NRF 2016R1A2B4009227).	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J	Shi, Y; Han, Y; Xie, F; Wang, A; Feng, XK; Li, N; Guo, HL; Chen, DX				Shi, Ying; Han, Yue; Xie, Fang; Wang, Anna; Feng, Xiaokun; Li, Ning; Guo, Hongliang; Chen, Dexi			ASPP2 enhances Oxaliplatin (L-OHP)-induced colorectal cancer cell apoptosis in a p53-independent manner by inhibiting cell autophagy	JOURNAL OF CELLULAR AND MOLECULAR MEDICINE			English	Article						ASPP2; colorectal cancer; apoptosis; p53; autophagy	P53 GENE-MUTATIONS; TUMOR-SUPPRESSOR; STIMULATING PROTEIN; DNA-DAMAGE; EXPRESSION; PATHWAY; DEATH; DYSFUNCTION; DELETIONS; GROWTH	Inactivation of p53-mediated cell death pathways is a central component of cancer progression. ASPP2 (apoptosis stimulated protein of p53-2) is a p53 binding protein that specially stimulates pro-apoptosis function of p53. Down-regulation of ASPP2 is observed in many human cancers and is associated with poor prognosis and metastasis. In this study, ASPP2 was found to enhance L-OHP-induced apoptosis in HCT116 p53(-/-) cells in a p53-independent manner. Such apoptosis-promoting effect of ASPP2 was achieved by inhibiting autophagy. Further experiments with ASPP2 RNA interference and autophagy inhibitor (3-methyladenine, 3-MA) confirmed that ASPP2 enhanced HCT116 p53(-/-) cell apoptosis via inhibiting the autophagy. The association of cell death and autophagy was also found in ASPP2(+/-) mice, where colon tissue with reduced ASPP2 expression displayed more autophagy and less cell death. Finally, colorectal tumours and their adjacent normal tissues from 20 colorectal cancer patients were used to examine ASPP2 expression, p53 expression and p53 mutation, to understand their relationships with the patients' outcome. Three site mutations were found in p53 transcripts from 16 of 20 patients. ASPP2 mRNA expressions were higher, and autophagy level was lower in the adjacent normal tissues, compared with the tumour tissues, which was independent of both p53 mutation and expression level. Taken together, ASPP2 increased tumour sensitivity to chemotherapy via inhibiting autophagy in a p53-independent manner, which was associated with the tumour formation, suggesting that both p53 inactivation and ASPP2 expression level were involved in the sensitivity of colorectal cancer to chemotherapy.	[Shi, Ying; Wang, Anna; Li, Ning; Chen, Dexi] Capital Univ Med Sci, Beijing Youan Hosp, Beijing, Peoples R China; [Shi, Ying; Xie, Fang; Wang, Anna; Li, Ning; Chen, Dexi] Beijing Inst Hepatol, Beijing, Peoples R China; [Han, Yue; Feng, Xiaokun; Guo, Hongliang] Univ Jinan, Shandong Acad Med Sci, Sch Med & Life Sci, Shandong Tumor Hosp, Jinan, Peoples R China		Guo, HL (corresponding author), Univ Jinan, Shandong Acad Med Sci, Sch Med & Life Sci, Shandong Tumor Hosp, Jinan, Peoples R China.	hliangbb@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81100288, 81272266, 81361120401]; National Key Technology RD ProgramNational Key Technology R&D Program [2012BAI15B08]	This work was supported by National Natural Science Foundation of China (81100288, 81272266, 81361120401). This work is also supported by The National Key Technology R&D Program (2012BAI15B08).	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Cell. Mol. Med.	MAR	2015	19	3					535	543		10.1111/jcmm.12435			9	Cell Biology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Research & Experimental Medicine	CC4UD	WOS:000350348500003	25534115	gold, Green Published			2022-04-25	
J	Shu, W; Liu, G; Dai, Y; Feng, A; Chen, Z; Han, J; Li, X				Shu, Weibin; Liu, Guoqin; Dai, Yunpeng; Feng, Alei; Chen, Zheng; Han, Junqing; Li, Xinyu			The oncogenic role of NKAP in the growth and invasion of colon cancer cells	ONCOLOGY REPORTS			English	Article						colon cancer; NKAP; progression; metastasis; Akt; mTOR pathway	COLORECTAL-CANCER; SIGNALING PATHWAYS; E-CADHERIN; EXPRESSION; APOPTOSIS; STATISTICS; PI3K/AKT; PROTEIN; PROLIFERATION; AUTOPHAGY	It has been reported that NF-kappa B activating protein (NKAP) is a transcriptional repressor of the Notch signaling pathway and is involved in the proliferation and survival of hematopoietic stem cells. In the present study, we aimed to investigate the effect of NKAP on the progression and metastasis of colon cancer. The results of immunohistochemical staining and western blot analysis showed that NKAP was upregulated in colon cancer tissues, and its expression was associated with colon cancer stages. CCK-8, colony formation, Transwell, and flow cytometry assays were used to demonstrate that NKAP knockdown significantly suppressed the proliferation and invasion of HCT116 and HT-29 cells, and also induced apoptosis and autophagy. By contrast, NKAP overexpression markedly promoted the proliferation and invasion of HCT-15 cells, and inhibited cell apoptosis and autophagy. Moreover, we observed that NKAP knockdown inhibited the epithelial-mesenchymal transition (EMT) process in HCT116 and HT-29 cells, while NKAP overexpression promoted EMT in HCT-15 cells. Furthermore, NKAP knockdown inhibited activation of the Akt/mTOR signaling pathway by downregulating the phosphorylation of Akt and mTOR, as well as their downstream proteins, whereas NKAP overexpression promoted the Akt/mTOR signaling pathway. Additionally, expression of P65 was downregulated by silencing of NKAP and upregulated by NKAP overexpression. These data suggest that NKAP functions as an oncogene in the growth and invasion of colon cancer in vitro.	[Shu, Weibin; Feng, Alei; Chen, Zheng; Han, Junqing] Shandong Univ, Shandong Prov Hosp, Dept Oncol, 324 Jingwu Rd, Jinan 250021, Shandong, Peoples R China; [Liu, Guoqin] Shandong Univ, Jinan Cent Hosp, Dept Gen Surg, Jinan 250021, Shandong, Peoples R China; [Dai, Yunpeng; Li, Xinyu] Shandong Univ, Shandong Prov Hosp, Dept Pediat, 324 Jingwu Rd, Jinan 250021, Shandong, Peoples R China		Han, J (corresponding author), Shandong Univ, Shandong Prov Hosp, Dept Oncol, 324 Jingwu Rd, Jinan 250021, Shandong, Peoples R China.; Li, X (corresponding author), Shandong Univ, Shandong Prov Hosp, Dept Pediat, 324 Jingwu Rd, Jinan 250021, Shandong, Peoples R China.	hanjq19601960@163.com; lixinyu0627@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81502508, 81600121]; Natural Science Foundations of Shandong Province [ZR2016HQ46]	This study was supported by National Natural Science Foundation of China (nos. 81502508 and 81600121) and Natural Science Foundations of Shandong Province (no. ZR2016HQ46).	Alao JP, 2007, MOL CANCER, V6, DOI 10.1186/1476-4598-6-24; Amado NG, 2014, INT J MOL SCI, V15, P12094, DOI 10.3390/ijms150712094; Burgute BD, 2014, NUCLEIC ACIDS RES, V42, P3177, DOI 10.1093/nar/gkt1311; Burman C, 2010, SEMIN IMMUNOPATHOL, V32, P397, DOI 10.1007/s00281-010-0222-z; Chen DY, 2003, BIOCHEM BIOPH RES CO, V310, P720, DOI 10.1016/j.bbrc.2003.09.074; Cotter TG, 2009, NAT REV CANCER, V9, P501, DOI 10.1038/nrc2663; Croce CM, 2016, CANCER RES, V76, P5914, DOI 10.1158/0008-5472.CAN-16-1248; Fesik SW, 2005, NAT REV CANCER, V5, P876, DOI 10.1038/nrc1736; Gui DK, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0039824; He CC, 2009, ANNU REV GENET, V43, P67, DOI 10.1146/annurev-genet-102808-114910; Hsu FC, 2011, J EXP MED, V208, P1291, DOI 10.1084/jem.20101874; Huang Q, 2017, WORLD J GASTROENTERO, V23, P5018, DOI 10.3748/wjg.v23.i27.5018; Igney FH, 2002, NAT REV CANCER, V2, P277, DOI 10.1038/nrc776; Jiang BH, 2013, CURR CANCER DRUG TAR, V13, P233, DOI 10.2174/1568009611313030001; Jiang QG, 2014, MOL BIOL REP, V41, P3359, DOI 10.1007/s11033-014-3198-2; Kwak JM, 2007, DIS COLON RECTUM, V50, P1873, DOI 10.1007/s10350-007-9034-1; Li T, 2016, NAT COMMUN, V7, DOI 10.1038/ncomms12969; Liu JT, 2018, CANCER MANAG RES, V10, P5091, DOI 10.2147/CMAR.S178919; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Malinowsky K, 2014, BRIT J CANCER, V110, P2081, DOI 10.1038/bjc.2014.100; Martinou JC, 2011, DEV CELL, V21, P92, DOI 10.1016/j.devcel.2011.06.017; Murray L, 2010, ROLE E CADHERIN COLO; Oguma K, 2008, EMBO J, V27, P1671, DOI 10.1038/emboj.2008.105; Pajerowski AG, 2010, BLOOD, V116, P2684, DOI 10.1182/blood-2010-02-268391; Pajerowski AG, 2009, IMMUNITY, V30, P696, DOI 10.1016/j.immuni.2009.02.011; Parkin DM, 2005, CA-CANCER J CLIN, V55, P74, DOI 10.3322/canjclin.55.2.74; Parrish Amanda B, 2013, Cold Spring Harb Perspect Biol, V5, DOI 10.1101/cshperspect.a008672; Saito T, 2004, ONCOL REP, V11, P605; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Siegel RL, 2015, CA-CANCER J CLIN, V65, P5, DOI [10.3322/caac.21254, 10.3322/caac.21208, 10.1001/jamaoto.2014.2530, 10.1136/bmj.g1502]; Tan SF, 2016, INT J MOL MED, V37, P1030, DOI 10.3892/ijmm.2016.2492; Tang X, 2017, ONCOL REP, V38, P2023, DOI 10.3892/or.2017.5923; Thapa P, 2016, J IMMUNOL, V196, P4987, DOI 10.4049/jimmunol.1501653; Thapa P, 2013, NAT COMMUN, V4, DOI 10.1038/ncomms2580; Vatandoust S, 2015, WORLD J GASTROENTERO, V21, P11767, DOI 10.3748/wjg.v21.i41.11767; White E, 2015, J CLIN INVEST, V125, P42, DOI 10.1172/JCI73941; White E, 2012, NAT REV CANCER, V12, P401, DOI 10.1038/nrc3262; Wu QB, 2015, WORLD J GASTROENTERO, V21, P6206, DOI 10.3748/wjg.v21.i20.6206; Wu RD, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0167052	39	2	2	2	5	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	NOV	2019	42	5					2130	2138		10.3892/or.2019.7322			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JE9BA	WOS:000490982300046	31545474	Bronze			2022-04-25	
J	Hong, Y; Won, J; Lee, Y; Lee, S; Park, K; Chang, KT; Hong, Y				Hong, Yunkyung; Won, Jinyoung; Lee, Youngjeon; Lee, Seunghoon; Park, Kanghui; Chang, Kyu-Tae; Hong, Yonggeun			Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells	JOURNAL OF PINEAL RESEARCH			English	Article						apoptosis; autophagy; cardiotoxicity; melatonin; senescence	HISTONE-DEACETYLASE INHIBITOR; TRICHOSTATIN-A; CYCLE ARREST; CELLULAR SENESCENCE; PROLIFERATION; INDUCTION; DEATH; CHEMOTHERAPY; SUPPRESSION; DOXORUBICIN	In Asia, the incidence of colorectal cancer has been increasing gradually due to a more Westernized lifestyle. The aim of study is to determine the interaction between melatonin-induced cell death and cellular senescence. We treated HCT116 human colorectal adenocarcinoma cells with 10m melatonin and determined the levels of cell death-related proteins and evaluated cell cycle kinetics. The plasma membrane melatonin receptor, MT1, was significantly decreased by melatonin in a time-dependent manner, whereas the nuclear receptor, ROR, was increased only after 12hr treatment. HCT116 cells, which upregulated both pro-apoptotic Bax and anti-apoptotic Bcl-xL in the early response to melatonin treatment, activated autophagic as well as apoptotic machinery within 18hr. Melatonin decreased the S-phase population of the cells to 57% of the control at 48hr, which was concomitant with a reduction in BrdU-positive cells in the melatonin-treated cell population. We found not only marked attenuation of E- and A-type cyclins, but also increased expression of p16 and p-p21. Compared to the cardiotoxicity of Trichostatin A in vitro, single or cumulative melatonin treatment induced insignificant detrimental effects on neonatal cardiomyocytes. We found that 10m melatonin activated cell death programs early and induced G1-phase arrest at the advanced phase. Therefore, we suggest that melatonin is a potential chemotherapeutic agent for treatment of colon cancer, the effects of which are mediated by regulation of both cell death and senescence in cancerous cells with minimized cardiotoxicity.	[Hong, Yunkyung; Won, Jinyoung; Lee, Youngjeon; Lee, Seunghoon; Park, Kanghui; Hong, Yonggeun] Inje Univ, Dept Rehabil Sci, Grad Sch, 197 Inje Ro, Gimhae 621749, Gyeong Nam, South Korea; [Hong, Yunkyung; Won, Jinyoung; Lee, Seunghoon; Hong, Yonggeun] Inje Univ, Coll Biomed Sci & Engn, Cardiovasc & Metab Dis Ctr, Gimhae 621749, Gyeong Nam, South Korea; [Hong, Yunkyung; Won, Jinyoung; Lee, Seunghoon; Hong, Yonggeun] Inje Univ, Ubiquitous Healthcare Res Ctr, Gimhae 621749, Gyeong Nam, South Korea; [Lee, Youngjeon; Chang, Kyu-Tae] KRIBB, NPRC, Ochang 363883, Chung Buk, South Korea; [Park, Kanghui] Dongwei Med Ctr, Div Rehabil Med, Pusan, South Korea; [Hong, Yonggeun] Inje Univ, Coll Biomed Sci & Engn, Dept Phys Therapy, Gimhae 621749, Gyeong Nam, South Korea		Hong, Y (corresponding author), Inje Univ, Dept Rehabil Sci, Grad Sch, 197 Inje Ro, Gimhae 621749, Gyeong Nam, South Korea.	changkt@kribb.re.kr; yonghong@inje.ac.kr		Lee, Youngjeon/0000-0002-5387-3441	KRIBB Research Initiative Program [KGM4251314]; National Research Foundation, Republic of Korea [NRF-2012R1A1A200 5089]	This work was supported by grants from the KRIBB Research Initiative Program (KGM4251314 to YH) and by the National Research Foundation (NRF-2012R1A1A200 5089 to YH), Republic of Korea.	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Pineal Res.	APR	2014	56	3					264	274		10.1111/jpi.12119			11	Endocrinology & Metabolism; Neurosciences; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Endocrinology & Metabolism; Neurosciences & Neurology; Physiology	AC5YR	WOS:000332597400005	24484372				2022-04-25	
J	Wu, JB; Meng, XM; Gao, R; Jia, YB; Chai, JY; Zhou, Y; Wang, J; Xue, XH; Dang, T				Wu, Jinbao; Meng, Xianmei; Gao, Rui; Jia, Yanbin; Chai, Jianyuan; Zhou, Yi; Wang, Jing; Xue, Xiaohui; Dang, Tong			Long non-coding RNA LINC00858 inhibits colon cancer cell apoptosis, autophagy, and senescence by activating WNK2 promoter methylation	EXPERIMENTAL CELL RESEARCH			English	Article						Long non-coding RNA LINC00858; WNK lysine deficient protein kinase 2; Colon cancer; DNA methyltransferase	KINASE; GROWTH; PROLIFERATION; EXPRESSION	Accumulating evidence shows the involvement of long non-coding RNAs (lncRNAs) in tumorigenesis of many types of human cancers. However, the role of LINC00858 in colon cancer has not been fully elucidated. Therefore, we investigated the involvement of LINC00858 in the progression of colon cancer and identified its downstream targets. After examining the expression of LINC00858 in colon cancer tissues and cell lines, we then identified the possible interaction between LINC00858 and WNK lysine deficient protein kinase 2 (WNK2) by fluorescence in situ hybridization, RNA immunoprecipitation, chromatin immunoprecipitation, and RNA pulldown assays. Next, the role of the LINC00858/WNK2 axis was explored by evaluating the apoptosis, autophagy, and senescence of colon cancer cells in vitro after ectopic expression and depletion experiments in HCT116 cells. Moreover, a mouse xenograft model of HCT116 cells was established to verify the function of the LINC00858/WNK2 axis in vivo. There was high expression of LINC00858 and low expression of WNK2 in colon cancer tissues and cell lines. Silencing of LINC00858 promoted apoptosis, senescence, and autophagy in colon cancer cells. Additionally, the enrichment of WNK2 was promoted when LINC00858 bound to DNA methyltransferases. Furthermore, in vivo assays demonstrated that silencing of LINC00858 resulted in inhibited tumor growth by upregulating WNK2. In summary, LINC00858 acts as a tumor-promoting lncRNA in colon cancer by downregulating WNK2. Our results may provide novel targets for the treatment for colon cancer.	[Wu, Jinbao; Meng, Xianmei; Jia, Yanbin; Chai, Jianyuan; Zhou, Yi; Wang, Jing; Xue, Xiaohui; Dang, Tong] Inner Mongolia Univ Sci & Technol, Affiliated Hosp 2, Inner Mongolia Inst Digest Dis, Baotou Med Coll, Baotou 014030, Peoples R China; [Gao, Rui] Inner Mongolia Univ Sci & Technol, Affiliated Hosp 2, Anesthesiol Dept, Baotou Med Coll, Baotou 014030, Peoples R China; [Jia, Yanbin] Inner Mongolia Univ Sci & Technol, Baotou Med Coll, Nursing Coll, Baotou 014030, Peoples R China		Dang, T (corresponding author), Inner Mongolia Univ Sci & Technol, Affiliated Hosp 2, Inner Mongolia Inst Digest Dis, Baotou Med Coll, Baotou 014030, Peoples R China.	dtong@sina.com		Chai, Jianyuan/0000-0001-6975-6867	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81960445, 81550020]; Natural Science Foundation of Inner Mongolia Autonomous Region [2020LH08004, 2020LH08005, 2018LH08081, 2015MS0854]; Science and Technology Project of Baotou [2016X1030-11-01, 2017S2001-5-03, 2019Z3011-04, 2019P3078]	This study was supported by National Natural Science Foundation of China (81960445, 81550020), Natural Science Foundation of Inner Mongolia Autonomous Region (2020LH08004, 2020LH08005, 2018LH08081, 2015MS0854), and Science and Technology Project of Baotou (2016X1030-11-01, 2017S2001-5-03, 2019Z3011-04, 2019P3078).	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Cell Res.	NOV 1	2020	396	1							112214	10.1016/j.yexcr.2020.112214			11	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	OF9AO	WOS:000581491000020	32768499				2022-04-25	
J	Dong, Y; Wu, Y; Zhao, GL; Ye, ZY; Xing, CG; Yang, XD				Dong, Y.; Wu, Y.; Zhao, G. -L.; Ye, Z. -Y.; Xing, C. -G.; Yang, X. -D.			Inhibition of autophagy by 3-MA promotes hypoxia-induced apoptosis in human colorectal cancer cells	EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES			English	Article						Autophagy; Hypoxia; Apoptosis; Colorectal cancer	STRESS-INDUCED APOPTOSIS; STATISTICS; INTERPLAY	OBJECTIVE: Cell autophagy reduces the sensitivity of cancer cells to therapeutic reagents in various types of human cancer. Therefore, the aim of our study was to use human colorectal cancer HCT116 cells to explore whether inhibition of autophagy by 3-Methyladenine (3-MA, an autophagy inhibitor) is able to enhance hypoxia-induced apoptosis in vitro. MATERIALS AND METHODS: HCT116 cells were treated with 3-MA. hypoxia. or 3-MA plus hypoxia. and the autophagy. apoptosis and proliferation of the HCT116 cells were investigated. Western blot analysis was used to detect autophagy specificity protein microtubule-associated protein light chain 3 (LC3) expression. Effects on apoptosis were evaluated by using flow cytometry (JC-1 staining to measure mitochondrial membrane potential) and annexin V-propidium iodide (PI) staining. RESULTS: The results showed that the treatment of HCT116 cells in vitro with hypoxia alone increased autophagy as well as apoptosis, whereas combination treatment with 3-MA and hypoxia markedly inhibited hypoxia-induced autophagy. but increased hypoxia-induced cell apoptosis. CONCLUSIONS: Autophagy might play a role as a self-defense mechanism in hypoxia-treated colon cancer cells, and its inhibition could be a promising strategy for the adjuvant chemotherapy of colon cancer.	[Dong, Y.; Wu, Y.; Ye, Z. -Y.; Xing, C. -G.; Yang, X. -D.] Soochow Univ, Dept Gen Surg, Affiliated Hosp 2, Suzhou, Peoples R China; [Dong, Y.] Nanjing Univ Chinese Med, Dept Pathol, WuXi Hosp, Nanjing, Jiangsu, Peoples R China; [Zhao, G. -L.] Peoples Hosp Gaomi, Dept Gen Surg, Gaomi, Peoples R China		Xing, CG; Yang, XD (corresponding author), Soochow Univ, Dept Gen Surg, Affiliated Hosp 2, Suzhou, Peoples R China.	xingcg@126.com; wjyxd@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672970]; Projects of Suzhou Technology Bureau [SYS201552, SZS201618, SS201753]; focus of Clinical Disease Treatment Technology Special Funds of Suzhou City [LCZX201505]; Second Affiliated Hospital of Soochow University Preponderant Clinic Discipline Group Project Funding	This work was partially supported by the National Natural Science Foundation of China (Grant No.: 81672970), the Projects of Suzhou Technology Bureau (SYS201552, SZS201618, SS201753) and the focus of Clinical Disease Treatment Technology Special Funds of Suzhou City (LCZX201505), and the Second Affiliated Hospital of Soochow University Preponderant Clinic Discipline Group Project Funding.	Chen WQ, 2016, CA-CANCER J CLIN, V66, P115, DOI 10.3322/caac.21338; Cui Q, 2007, BIOL PHARM BULL, V30, P859, DOI 10.1248/bpb.30.859; Cui Q, 2006, J PHARMACOL SCI, V101, P230, DOI 10.1254/jphs.FPJ06003X; Du HL, 2012, ONCOL REP, V27, P143, DOI 10.3892/or.2011.1464; Fimia GM, 2010, CELL MOL LIFE SCI, V67, P1581, DOI 10.1007/s00018-010-0284-z; Jiang RY, 2014, EUR REV MED PHARMACO, V18, P806; Kroemer G, 2008, NAT REV MOL CELL BIO, V9, P1004, DOI 10.1038/nrm2529; Kumar D, 2014, CANCER LETT, V343, P179, DOI 10.1016/j.canlet.2013.10.003; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Li DY, 2017, EUR REV MED PHARMACO, V21, P5548, DOI 10.26355/eurrev_201712_13991; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Li MM, 2015, APOPTOSIS, V20, P769, DOI 10.1007/s10495-015-1110-8; Liao CS, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0082497; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; Mazure NM, 2010, CURR OPIN CELL BIOL, V22, P177, DOI 10.1016/j.ceb.2009.11.015; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Petiot A, 2000, J BIOL CHEM, V275, P992, DOI 10.1074/jbc.275.2.992; Sato K, 2007, CANCER RES, V67, P9677, DOI 10.1158/0008-5472.CAN-07-1462; Shen Yang, 2008, Ai Zheng, V27, P595; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Song LL, 2013, ONCOL LETT, V6, P1031, DOI 10.3892/ol.2013.1498; Ullman E, 2008, CELL DEATH DIFFER, V15, P422, DOI 10.1038/sj.cdd.4402234; Yousefi S, 2006, NAT CELL BIOL, V8, P1124, DOI 10.1038/ncb1482	23	15	19	2	15	VERDUCI PUBLISHER	ROME	VIA GREGORIO VII, ROME, 186-00165, ITALY	1128-3602			EUR REV MED PHARMACO	Eur. Rev. Med. Pharmacol. Sci.	FEB	2019	23	3					1047	1054					8	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	HM0ZX	WOS:000459178100020	30779071				2022-04-25	
J	Zhang, WL; Shi, HS; Zhang, MM; Liu, B; Mao, S; Li, L; Tong, F; Liu, GL; Yang, SL; Wang, HH				Zhang, Wenliang; Shi, Hongshun; Zhang, Mingming; Liu, Bin; Mao, Shuai; Li, Li; Tong, Fang; Liu, Guoliang; Yang, Shulan; Wang, Haihe			Poly C binding protein 1 represses autophagy through downregulation of LC3B to promote tumor cell apoptosis in starvation	INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY			English	Article						PCBP1; Autophagy; Apoptosis; LOB; Cancer	CANCER; CASPASE-8; BINDING-PROTEIN-1; EXPRESSION; CROSSTALK; COMPLEX; PCBP1; GENE; P62; RNA	Accumulating evidences indicate that poly C binding protein (PCBP1) is downregulated in various carcinomas as a tumor suppressor, but the underlying mechanism in suppression of tumorigenesis still remains elusive. Here, we found that PCBP1 overexpression attenuates tumor cell growth upon serum free starvation. Notably, the autophagic degradation inhibitor, chloroquine, could mimic this suppressive effect in tumor cell growth. Autophagy analyses demonstrated that PCBP1 overexpression blocked autophagic flux of tumor cells under starvation conditions, while PCBP1 downregulation in turn refueled this autophagic flux, protecting cells from death. Mechanistically, PCBP1 overexpression attenuated microtubule-associated protein Light chain 3 (LOB) mRNA stability to repress LC3B expression, resulting in the autophagy inhibition. Consequently, PCBP1 overexpression strongly triggered the caspase 3 and 8-mediated apoptosis of tumor cells and downregulated anti-apoptotic BcI-2 expression upon starvation, which could be further synergized by autophagic inhibitor, indicating that PCBP1 not only inhibits tumor cell autophagy, but also renders them to apoptosis. Taken together, our results uncovered a novel mechanism of PCBP1 in repressing autophagy-mediated cell survival and indicated that inhibition of tumor cell autophagy by PCBP1 upregulation or with autophagic inhibitors could be an effective therapeutical strategy to colon and ovary tumors with low PCBP1 expression. (C) 2016 Elsevier Ltd. All rights reserved.	[Zhang, Wenliang; Shi, Hongshun; Zhang, Mingming; Liu, Bin; Li, Li; Tong, Fang; Wang, Haihe] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem, CPZN, Guangzhou 510080, Guangdong, Peoples R China; [Zhang, Wenliang; Yang, Shulan] Sun Yat Sen Univ, Affiliated Hosp 1, Translat Med Ctr, CPZN, Guangzhou 510080, Guangdong, Peoples R China; [Mao, Shuai] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Hepat Surg, CPZN, Guangzhou 510080, Guangdong, Peoples R China; [Wang, Haihe] Sun Yat Sen Univ, Ctr Stem Cell Biol & Tissue Engn, CPZN, Guangzhou 510080, Guangdong, Peoples R China; [Liu, Guoliang] Jinxian Peoples Hosp Nanchang, Dept Internal Med, CPZN, Nanchang 331700, Jiangxi, Peoples R China		Yang, SL (corresponding author), CPZN, 74 Zhonshan Rd 2nd, Guangzhou 510080, Guangdong, Peoples R China.; Wang, HH (corresponding author), CPZN, 58 Zhonshan Rd 2nd, Guangzhou 510080, Guangdong, Peoples R China.	yangshl3@mail.sysu.edu.cn; wanghaih@mail.sysu.edu.cn	张, 文亮/AAM-6021-2020; Haihe, Wang/AAD-4036-2021	zhang, wenliang/0000-0003-0454-6935; LIU, BIN/0000-0003-0467-3678; , Haihe/0000-0002-9302-2334	National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31271481]; Guangzhou Science Technology and Innovation Commission [201510010144]	We thank our group members for the critical comments on this manuscript. This work was supported by National Science Foundation of China (grant no. 31271481) to W.H. and Guangzhou Science Technology and Innovation Commission (no. 201510010144) to Y.S.	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J. Biochem. Cell Biol.	APR	2016	73						127	136		10.1016/j.biocel.2016.02.009			10	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	EL2TI	WOS:000394472700012	26880484	Bronze			2022-04-25	
J	Ge, Y; Liu, BL; Cui, JP; Li, SQ				Ge, Yang; Liu, Bao-lin; Cui, Jun-peng; Li, Shu-qiang			Livin Regulates H2A.X-Y142 Phosphorylation and Promotes Autophagy in Colon Cancer Cells via a Novel Kinase Activity	FRONTIERS IN ONCOLOGY			English	Article						Livin; autophagy; colon cancer cells; H2A.X; phosphorylation	DNA-DAMAGE; HISTONE; INHIBITORS; EXPRESSION	Objective: To investigate Livin-mediated regulation of H2A.X-Y142 phosphorylation via a novel kinase activity and its effect on autophagy in colon cancer cells. Methods: The interaction between Livin and H2A.X was tested by immunoprecipitation. H2A.X-/- HCT116 cells were transfected with human influenza hemagglutinin (HA)-tagged WT or Y142F phospho-dead mutantH2A.X plasmids. GST-tagged recombinant Livin protein was used to perform in vitro pull-down experiment and kinase assay. H2A.X-/-Livin+/+ SW480 cells were co-transfected with H2A.X-WT/H2A.X-Y142F plasmid and LC3 EGFP-tagged plasmid to explore whether H2A.X-Y142F was involved in Livin-mediated autophagy induced by starvation in colon cancer cells. Results: Co-immunoprecipitation studies confirmed that Livin interacted with H2A.X and that it was phosphorylation dependent. In vitro kinase assay confirmed that Livin could phosphorylate H2A.X. Knockdown of Livin (Livin-/-) in SW480 cells or HCT116 cells canceled the starvation-induced autophagy in colon cancer cells; H2A.X-/-Livin+/+ SW480 cells transfected with H2A.X-WT activated autophagy induced by starvation while cells transfected with H2A.X-Y142F had no significant difference; Livin-H2A.X-Y142F axis activated autophagy in colon cancer cells through transcriptionally regulating ATG5 and ATG7. Conclusion: Livin promotes autophagy in colon cancer cells via regulating the phosphorylation of H2A.X-Y142.	[Ge, Yang; Liu, Bao-lin; Cui, Jun-peng; Li, Shu-qiang] China Med Univ, Dept Gen Surg 6, Shengjing Hosp, Shenyang, Liaoning, Peoples R China		Li, SQ (corresponding author), China Med Univ, Dept Gen Surg 6, Shengjing Hosp, Shenyang, Liaoning, Peoples R China.	lishuqiang_cmu@163.com					Beach TA, 2018, INT J RADIAT BIOL, V94, P1104, DOI 10.1080/09553002.2018.1516907; Castillo Josefa, 2017, Adv Exp Med Biol, V966, P65, DOI 10.1007/5584_2017_58; Chen SA, 2017, MOL CELL BIOCHEM, V434, P135, DOI 10.1007/s11010-017-3043-8; Chen YS, 2010, MOL BIOL REP, V37, P2241, DOI 10.1007/s11033-009-9711-3; Erdel F, 2017, BIOESSAYS, V39, DOI 10.1002/bies.201700053; Fan J, 2015, ACS CHEM BIOL, V10, P95, DOI 10.1021/cb500846u; Gimenez-Xavier P, 2008, INT J MOL MED, V22, P781, DOI 10.3892/ijmm_00000085; Kimmelman AC, 2017, CELL METAB, V25, P1037, DOI 10.1016/j.cmet.2017.04.004; Kimura T, 2013, CANCER RES, V73, P3, DOI 10.1158/0008-5472.CAN-12-2464; Kumar D, 2015, TOXICOL LETT, V235, P161, DOI 10.1016/j.toxlet.2015.04.006; Lawrence M, 2016, TRENDS GENET, V32, P42, DOI 10.1016/j.tig.2015.10.007; Lee J, 2017, BIOCHEMISTRY-US, V56, P977, DOI 10.1021/acs.biochem.6b01252; Liu S, 2018, ONCOL LETT, V15, P7707, DOI 10.3892/ol.2018.8282; Lorkovic ZJ, 2017, CURR BIOL, V27, P1192, DOI 10.1016/j.cub.2017.03.002; Pacaud R, 2015, THERANOSTICS, V5, P12, DOI 10.7150/thno.8799; Piquet S, 2018, MOL CELL, V72, P888, DOI 10.1016/j.molcel.2018.09.010; Rieux-Laucat F, 2017, CURR OPIN IMMUNOL, V49, P79, DOI 10.1016/j.coi.2017.10.001; Saleem M, 2013, CHEM BIOL DRUG DES, V82, P243, DOI 10.1111/cbdd.12176; Silke J, 2017, CURR TOP MICROBIOL, V403, P95, DOI 10.1007/82_2016_507; Silke J, 2014, METHOD ENZYMOL, V545, P35, DOI 10.1016/B978-0-12-801430-1.00002-0; Singh RK, 2011, EPIGENETICS-US, V6, P153, DOI 10.4161/epi.6.2.13589; Sofueva S, 2010, MOL CELL BIOL, V30, P4732, DOI 10.1128/MCB.00413-10; Stewart GS, 2003, NATURE, V421, P961, DOI 10.1038/nature01446; Tessarz P, 2014, NAT REV MOL CELL BIO, V15, P703, DOI 10.1038/nrm3890; Xu M, 2013, EUR J GYNAECOL ONCOL, V34, P152; Yoon TM, 2017, ONCOL REP, V37, P3667, DOI 10.3892/or.2017.5584; Zhan L, 2018, BIOCHEM BIOPH RES CO, V495, P60, DOI 10.1016/j.bbrc.2017.10.145; Zhang LP, 2019, AM J CANCER RES, V9, P406; Zhao CL, 2018, INT J MOL MED, V41, P2901, DOI 10.3892/ijmm.2018.3475; Zhuang L, 2015, MOL MED REP, V12, P547, DOI 10.3892/mmr.2015.3372	30	0	0	0	1	FRONTIERS MEDIA SA	LAUSANNE	AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND	2234-943X			FRONT ONCOL	Front. Oncol.	NOV 14	2019	9								1233	10.3389/fonc.2019.01233			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JT8RO	WOS:000501250900001	31799193	Green Published, gold			2022-04-25	
J	Song, X; Kim, SY; Zhang, L; Tang, D; Bartlett, DL; Kwon, YT; Lee, YJ				Song, X.; Kim, S-Y; Zhang, L.; Tang, D.; Bartlett, D. L.; Kwon, Y. T.; Lee, Y. J.			Role of AMP-activated protein kinase in cross-talk between apoptosis and autophagy in human colon cancer	CELL DEATH & DISEASE			English	Article							CASPASE-MEDIATED CLEAVAGE; BECLIN 1; LIVER METASTASES; MTOR INHIBITORS; CELLS; STIMULATION; COMBINATION; INDUCTION; COMPLEXES; RELEASE	Unresectable colorectal liver metastases remain a major unresolved issue and more effective novel regimens are urgently needed. While screening synergistic drug combinations for colon cancer therapy, we identified a novel multidrug treatment for colon cancer: chemotherapeutic agent melphalan in combination with proteasome inhibitor bortezomib and mTOR (mammalian target of rapamycin) inhibitor rapamycin. We investigated the mechanisms of synergistic antitumor efficacy during the multidrug treatment. All experiments were performed with highly metastatic human colon cancer CX-1 and HCT116 cells, and selected critical experiments were repeated with human colon cancer stem Tu-22 cells and mouse embryo fibroblast (MEF) cells. We used immunochemical techniques to investigate a cross-talk between apoptosis and autophagy during the multidrug treatment. We observed that melphalan triggered apoptosis, bortezomib induced apoptosis and autophagy, rapamycin caused autophagy and the combinatorial treatment-induced synergistic apoptosis, which was mediated through an increase in caspase activation. We also observed that mitochondrial dysfunction induced by the combination was linked with altered cellular metabolism, which induced adenosine monophosphate-activated protein kinase (AMPK) activation, resulting in Beclin-1 phosphorylated at Ser 93/96. Interestingly, Beclin-1 phosphorylated at Ser 93/96 is sufficient to induce Beclin-1 cleavage by caspase-8, which switches off autophagy to achieve the synergistic induction of apoptosis. Similar results were observed with the essential autophagy gene, autophagy-related protein 7, -deficient MEF cells. The multidrug treatment-induced Beclin-1 cleavage was abolished in Beclin-1 double-mutant (D133A/D146A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. These observations identify a novel mechanism for AMPK-induced apoptosis through interplay between autophagy and apoptosis.	[Song, X.; Kim, S-Y; Tang, D.; Bartlett, D. L.; Lee, Y. J.] Univ Pittsburgh, Dept Surg, Hillman Canc Ctr, Pittsburgh, PA 15213 USA; [Zhang, L.; Lee, Y. J.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA; [Kwon, Y. T.] Seoul Natl Univ, Coll Med, Prot Metab Med Res Ctr, Seoul 110799, South Korea; [Kwon, Y. T.] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 110799, South Korea		Lee, YJ (corresponding author), Univ Pittsburgh, Dept Surg, Hillman Canc Ctr, 497 Scaife Hall, Pittsburgh, PA 15213 USA.	leeyj@upmc.edu	Zhang, Lin/A-7389-2009; Tang, Daolin/ABD-5062-2021; Tang, Daolin/B-2905-2010	Zhang, Lin/0000-0003-0018-3903; Tang, Daolin/0000-0002-1903-6180; 	NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA140554, R01CA106348, R01CA172136, R01CA160417]; National Research Foundation of Korea Program [NRF-2013R1A2A2A01014170]; Nobel Laureates Invitation Program of Seoul National University;  [P30CA047904]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA160417, P30CA047904, R01CA140554, R01CA172136, R01CA106348] Funding Source: NIH RePORTER; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL083365] Funding Source: NIH RePORTER	This work was supported by the following grants: NCI R01CA140554 (YJL), R01CA106348 (LZ), R01CA172136 (LZ) and R01CA160417 (DT); National Research Foundation of Korea Program NRF-2013R1A2A2A01014170 (YTK); and Nobel Laureates Invitation Program of Seoul National University (YTK). This project used the UPCI Core Facility and was supported in part by award P30CA047904.	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OCT	2014	5								e1504	10.1038/cddis.2014.463			13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	AT5PG	WOS:000344994000075	25356873	gold, Green Published			2022-04-25	
J	Martyna, B; Malgorzata, MW; Nikola, Z; Beniamin, G; Urszula, M; Grazyna, J				Martyna, Bednarczyk; Malgorzata, Muc-Wierzgon; Nikola, Zmarzly; Beniamin, Grabarek; Urszula, Mazurek; Grazyna, Janikowska			Expression Profile of Genes Associated with the Proteins Degradation Pathways in Colorectal Adenocarcinoma	CURRENT PHARMACEUTICAL BIOTECHNOLOGY			English	Article						Autophagy; cancer; ubiquitination; colon; microarrays; lysosome	CELL-DEATH; CANCER; SYSTEM; RECRUITMENT; ACTIVATION; PROTEASOME; HOMEOSTASIS; OPTINEURIN; MITOPHAGY; CARCINOMA	Background: Changes in expression of genes associated with proteins or organelles degradation system in the cell may be a cause or signal to carcinogenesis. Thus, the aim of this study was to assess the profile of gene expression linked to the degradation systems of proteins or organelles in histo-pathologically confirmed colorectal adenocarcinoma in relation to normal colon tissue. Methods: Using oligonucleotide microarrays and GeneSpring 13.0, and PANTHER 13.1 software's we characterized 1095 mRNAs linked to the degradation system of proteins and organelles in sections of colorectal cancer from patients at various clinical stages of disease. Subsequent analyses with restrictive assumptions narrowed down the number of genes differentiating cancer, assuming a P-value of less than 0.05. Results: We found that most of the significant genes were silenced in the development of colorectal cancer. The FOXO1 had the lowest fold change value in the first clinical stage (CSI) comparing to the control. The HSPA8 was up-regulated in the two early clinical stages (CSI and CUE), and UBB only in the CSI. Only little-known PTPN22 showed increasing expression at all stages. Conclusion: In summary, the examined colorectal adenocarcinoma samples were characterized by almost complete silencing of the significant genes associated with the degradation of proteins and mitochondria in transcriptomic level. The FOXO1, HSPA8 and UBB genes may become potential diagnostic and/or therapeutic targets in the early stage of this cancer.	[Martyna, Bednarczyk; Malgorzata, Muc-Wierzgon] Med Univ Silesia, Sch Publ Hlth, Dept & Clin Internal Dis, Katowice, Poland; [Nikola, Zmarzly; Beniamin, Grabarek; Urszula, Mazurek] Med Univ Silesia, Sch Pharm, Dept Mol Biol, Katowice, Poland; [Nikola, Zmarzly; Beniamin, Grabarek; Urszula, Mazurek; Grazyna, Janikowska] Med Univ Silesia, Div Lab Med, Katowice, Poland; [Grazyna, Janikowska] Med Univ Silesia, Dept Analyt Chem, Sch Pharm, Katowice, Poland		Martyna, B (corresponding author), Med Univ Silesia, Sch Publ Hlth, Dept & Clin Internal Dis, Katowice, Poland.	martyna.bednarczyk@outlook.com	grabarek, beniamin/V-3630-2019	grabarek, beniamin/0000-0003-1633-7145; Zmarzly, Nikola/0000-0002-7833-6167; Mazurek, Urszula/0000-0003-1181-4934; Janikowska, Grazyna/0000-0002-2839-174X; Muc-Wierzgon, Malgorzata/0000-0001-6562-7072; Bednarczyk, Martyna/0000-0001-8360-9126	Medical University of Silesia [KNW-1-071/N/8/K]	The study was funded by the grant from Medical University of Silesia No. KNW-1-071/N/8/K.	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Pharm. Biotechnol.		2019	20	7					551	561		10.2174/1389201020666190516090744			11	Biochemistry & Molecular Biology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy	IP9FV	WOS:000480356500003	31096896				2022-04-25	
J	Lee, WY; Lee, WT; Cheng, CH; Chen, KC; Chou, CM; Chung, CH; Sun, MS; Cheng, HW; Ho, MN; Lin, CW				Lee, Wen-Ying; Lee, Wai-Theng; Cheng, Chia-Hsiung; Chen, Ku-Chung; Chou, Chih-Ming; Chung, Chu-Hung; Sun, Min-Siou; Cheng, Hung-Wei; Ho, Meng-Ni; Lin, Cheng-Wei			Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1	ONCOTARGET			English	Article						chlorpromazine; drug reposition; p53; apoptosis; SIRT1	HUMAN BREAST-CANCER; AUTOPHAGIC CELL-DEATH; P53 ACETYLATION; GENE-EXPRESSION; IN-VIVO; PROSTATE-CANCER; GLIOMA-CELLS; TUMOR-GROWTH; COLON-CANCER; MUTANT P53	Investigating existing drugs for repositioning can enable overcoming bottlenecks in the drug development process. Here, we investigated the effect and molecular mechanism of the antipsychotic drug chlorpromazine (CPZ) and identified its potential for treating colorectal cancer (CRC). Human CRC cell lines harboring different p53 statuses were used to investigate the inhibitory mechanism of CPZ. CPZ effectively inhibited tumor growth and induced apoptosis in CRC cells in a p53-dependent manner. Activation of c-jun N-terminal kinase (JNK) was crucial for CPZ-induced p53 expression and the subsequent induction of tumor apoptosis. Induction of p53 acetylation at lysine382 was involved in CPZ-mediated tumor apoptosis, and this induction was attenuated by sirtuin 1 (SIRT1), a class III histone deacetylase. By contrast, knocking down SIRT1 sensitized tumor cells to CPZ treatment. Moreover, CPZ induced the degradation of SIRT1 protein participating downstream of JNK, and JNK suppression abrogated CPZ-mediated SIRT1 downregulation. Clinical analysis revealed a significant association between high SIRT1 expression and poor outcome in CRC patients. These data suggest that SIRT1 is an attractive therapeutic target for CRC and that CPZ is a potential repositioned drug for treating CRC.	[Lee, Wen-Ying] Chi Mei Med Ctr, Dept Pathol, Tainan, Taiwan; [Lee, Wen-Ying] Taipei Med Univ, Sch Med, Dept Pathol, Coll Med, Taipei, Taiwan; [Lee, Wai-Theng; Cheng, Chia-Hsiung; Chen, Ku-Chung; Chou, Chih-Ming; Cheng, Hung-Wei; Ho, Meng-Ni; Lin, Cheng-Wei] Taipei Med Univ, Sch Med, Dept Biochem & Mol Cell Biol, Coll Med, Taipei, Taiwan; [Cheng, Chia-Hsiung; Chen, Ku-Chung; Chou, Chih-Ming; Lin, Cheng-Wei] Taipei Med Univ, Grad Inst Med Sci, Sch Med, Coll Med, Taipei, Taiwan; [Chung, Chu-Hung; Sun, Min-Siou] Acad Sinica, Inst Cellular & Organism Biol, Taipei 115, Taiwan		Lin, CW (corresponding author), Taipei Med Univ, Sch Med, Dept Biochem & Mol Cell Biol, Coll Med, Taipei, Taiwan.	cwlin@tmu.edu.tw	Cheng, Chia-Hsiung/A-6044-2019	Cheng, Chia-Hsiung/0000-0003-0307-9650	Taipei Medical University [TMU101-AE1-B24, TMUTOP103005-7]; Chi-Mei Medical Center [102CM-TMU-09, 103CM-TMU-03]	We thank the Zebrafish Core Facility of Taipei Medical University for assisting in the zebrafish toxicity test and the National RNAi Core Facility of Academia Sinica for providing shRNA clones. We also thank Dr. Michael Greenberg for providing the SIRT1 construct. This study was supported by grants from Taipei Medical University (TMU101-AE1-B24 and TMUTOP103005-7) and Chi-Mei Medical Center (102CM-TMU-09 and 103CM-TMU-03).	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J	Zhang, P; Lai, ZL; Chen, HF; Zhang, M; Wang, A; Jia, T; Sun, WQ; Zhu, XM; Chen, XF; Zhao, Z; Zhang, J				Zhang, Pan; Lai, Ze-Lin; Chen, Hui-Fen; Zhang, Min; Wang, An; Jia, Tao; Sun, Wen-Qin; Zhu, Xi-Min; Chen, Xiao-Feng; Zhao, Zheng; Zhang, Jun			Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice	JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH			English	Article						Curcumin; 5-fluorouracil; Autophagy; Colon cancer; Combination chemotherapy	STEM-LIKE CELLS; COLORECTAL-CANCER; SIGNALING PATHWAYS; HUMAN BREAST; IN-VIVO; TARGETS; ULK1; PHOSPHORYLATION; RESISTANCE; PROMOTES	Background: Chemoresistance is a major obstacle that limits the benefits of 5-Fluorouracil (5-Fu)-based chemotherapy for colon cancer patients. Autophagy is an important cellular mechanism underlying chemoresistance. Recent research advances have given new insights into the use of natural bioactive compounds to overcome chemoresistance in colon cancer chemotherapy. As one of the multitargeted and safer phytomedicines, curcumin has been reported to work as cancer-specific chemosensitizer, presumably via induction of autophagic signaling pathways. The precise therapeutic effect of curcumin on autophagy in determining tumorous cells' fate, however, remains unclear. This study was conducted to investigate the differential modulations of the treatments either with 5-Fu alone or 5-Fu combined with curcumin on cellular autophagic responses and viabilities in the human colon cancer cells HCT116 and HT29, and explore molecular signaling transductions underlying the curcumin-mediated autophagic changes and potentiation of 5-Fu's cytotoxicity in vitro and in vivo. Methods: Cell proliferation assay and morphology observation were used to identify the cytotoxicity of different combinations of curcumin and 5-Fu in HCT116 and HT29 cells. Cell immunofluorescence assay, Flow cytometry and Western blot were employed to detect changes of autophagy and the autophagy-related signaling pathways in the colon cancer cells and/or xenograft mice. Results: Curcumin could significantly augment the cytotoxicity of 5-Fu to the tumorous cells, and the pre-treatment with curcumin followed by 5-Fu (pre-Cur) proved to be the most effective one compared to other two combinations. The chemosensitizing role of curcumin might attribute to the autophagy turnover from being activated in 5-Fu mono-treatment to being inhibited in the pre-Cur treatment as indicated by the changes in expression of beclin-1, p62 and LC3II/LC3I and the intensity of Cyto-ID Green staining. The autophagic alterations appeared to be contributed by down-regulation of not only the phospho-Akt and phospho-mTOR expressions but the phospho-AMPK and phospho-ULK1 levels as well. The cellular activation of AMPK by addition of A-769662 to the pre-Cur combination resulted in reversed changes in expressions of the autophagy protein markers and apoptotic status compared to those of the pre-Cur combination treatment. The findings were validated in the xenograft mice, in which the tumor growth was significantly suppressed in the mice with 25-day combination treatment, and meanwhile expressions of the autophagy markers, P-AMPK and P-ULK1 were all reversely altered in line with those observed in HCT116 cells. Conclusion: Pre-treatment with curcumin followed by 5-Fu may mediate autophagy turnover both in vitro and in vivo via AMPK/ULK1-dependent autophagy inhibition and AKT modulation, which may account for the increased susceptibility of the colon cancer cells/xenograft to the cytotoxicity of 5-Fu.	[Zhang, Pan; Lai, Ze-Lin; Zhu, Xi-Min; Zhao, Zheng] East China Normal Univ, Sch Life Sci, Minist Educ, Key Lab Brain Funct Genom, Shanghai 200062, Peoples R China; [Chen, Hui-Fen; Sun, Wen-Qin; Zhang, Jun] Tongji Univ, Shanghai Matern & Infant Hosp 1, Dept Clin Lab, Sch Med, Shanghai 201204, Peoples R China; [Zhang, Min; Zhang, Jun] Fudan Univ, Dept Clin Lab, Shanghai Publ Hlth Clin Ctr, Shanghai 201508, Peoples R China; [Wang, An; Chen, Xiao-Feng] Fudan Univ, Huashan Hosp, Dept Thorac Surg, Shanghai 200040, Peoples R China; [Jia, Tao] CNRS, Inst Adv Biosci, INSERM UGA U1209, UMR5309, F-38700 La Tronche, France		Zhao, Z (corresponding author), East China Normal Univ, Sch Life Sci, Minist Educ, Key Lab Brain Funct Genom, Shanghai 200062, Peoples R China.; Zhang, J (corresponding author), Tongji Univ, Shanghai Matern & Infant Hosp 1, Dept Clin Lab, Sch Med, Shanghai 201204, Peoples R China.; Zhang, J (corresponding author), Fudan Univ, Dept Clin Lab, Shanghai Publ Hlth Clin Ctr, Shanghai 201508, Peoples R China.; Chen, XF (corresponding author), Fudan Univ, Huashan Hosp, Dept Thorac Surg, Shanghai 200040, Peoples R China.	dr_chenxiaofeng@126.com; zzhao@brain.ecnu.edu.cn; zhangjun@51mch.com	JIA, Tao/AAZ-1963-2020; Lai, Zelin/AGP-0626-2022	JIA, Tao/0000-0002-8358-6005; Lai, Zelin/0000-0002-5781-4780	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81,470,829, 31,171,019]; Key Laboratory of Brain Functional Genomics (ECNU), Ministry of Education	This work was supported in part by grants from the National Natural Science Foundation of China (81,470,829 to JZ and 31,171,019 to ZZ), and an opening grant from Key Laboratory of Brain Functional Genomics (ECNU), Ministry of Education (JZ).	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Exp. Clin. Cancer Res.	DEC 22	2017	36								190	10.1186/s13046-017-0661-7			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FR0FJ	WOS:000418736500002	29273065	Green Published, gold			2022-04-25	
J	Classen, F; Kranz, P; Riffkin, H; Pompsch, M; Wolf, A; Gopelt, K; Baumann, M; Baumann, J; Brockmeier, U; Metzen, E				Classen, Fabian; Kranz, Philip; Riffkin, Helena; Pompsch, Mosche; Wolf, Alexandra; Goepelt, Kirsten; Baumann, Melanie; Baumann, Jennifer; Brockmeier, Ulf; Metzen, Eric			Autophagy induced by ionizing radiation promotes cell death over survival in human colorectal cancer cells	EXPERIMENTAL CELL RESEARCH			English	Article						Autophagy; Atg7; Beclin1; Hypoxia; Glutamine starvation	TUMOR-CELLS; CHLOROQUINE; RESISTANCE; INHIBITION; MECHANISMS; GROWTH	Autophagy is commonly described as a cell survival mechanism and has been implicated in chemo- and radioresistance of cancer cells. Whether ionizing radiation induced autophagy triggers tumor cell survival or cell death still remains unclear. In this study the autophagy related proteins Beclinl and ATG7 were tested as potential targets to sensitize colorectal carcinoma cells to ionizing radiation under normoxic, hypoxic and starvation conditions. Colony formation, apoptosis and cell cycle analysis revealed that knockdown of Beclinl or ATG7 does not enhance radiosensitivity in HCT-116 cells. Furthermore, ATG7 knockdown led to an increased survival fraction under oxygen and glutamine starvation, indicating that ionizing radiation indeed induces autophagy which, however, leads to cell death finally. These results highlight that inhibition of autophagic pathways does not generally increase therapy success but may also lead to an unfavorable outcome especially under amino acid and oxygen restriction.	[Classen, Fabian; Kranz, Philip; Riffkin, Helena; Pompsch, Mosche; Wolf, Alexandra; Goepelt, Kirsten; Baumann, Melanie; Baumann, Jennifer; Brockmeier, Ulf; Metzen, Eric] Univ Duisburg Essen, Inst Physiol, Hufelandstr 55, D-45147 Essen, Germany		Metzen, E (corresponding author), Univ Duisburg Essen, Inst Physiol, Hufelandstr 55, D-45147 Essen, Germany.	eric.metzen@uni-due.de			Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [GRK1739]; IFORES program of the University of Duisburg-Essen	This study was funded by the research training group GRK1739 of the Deutsche Forschungsgemeinschaft and the IFORES program of the University of Duisburg-Essen. None of the funding bodies had an active role in the design of the study, in the collection, analysis and interpretation of data, in the preparation of the manuscript or in the publication process.	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Cell Res.	JAN 1	2019	374	1					29	37		10.1016/j.yexcr.2018.11.004			9	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	HI7KY	WOS:000456636300004	30412717	hybrid			2022-04-25	
J	Chen, SS; Fang, Y; Sun, LY; He, RN; He, BH; Zhang, S				Chen, Shanshan; Fang, Yi; Sun, Lingyu; He, Ruonan; He, Beihui; Zhang, Shuo			Long Non-Coding RNA: A Potential Strategy for the Diagnosis and Treatment of Colorectal Cancer	FRONTIERS IN ONCOLOGY			English	Review						long non-coding RNA; colorectal cancer; drug resistance; proliferation; metastasis; occurrence; invasion	EPITHELIAL-MESENCHYMAL-TRANSITION; COLON-CANCER; STEM-CELLS; PROGNOSTIC-FACTOR; HIPPO PATHWAY; EXPRESSION; PROMOTES; PROLIFERATION; PROTEIN; GROWTH	Colorectal cancer (CRC), being one of the most commonly diagnosed cancers worldwide, endangers human health. Because the pathological mechanism of CRC is not fully understood, there are many challenges in the prevention, diagnosis, and treatment of this disease. Long non-coding RNAs (lncRNAs) have recently drawn great attention for their potential roles in the different stages of CRC formation, invasion, and progression, including regulation of molecular signaling pathways, apoptosis, autophagy, angiogenesis, tumor metabolism, immunological responses, cell cycle, and epithelial-mesenchymal transition (EMT). This review aims to discuss the potential mechanisms of several oncogenic lncRNAs, as well as several suppressor lncRNAs, in CRC occurrence and development to aid in the discovery of new methods for CRC diagnosis, treatment, and prognosis assessment.</p>	[Chen, Shanshan; Fang, Yi; Sun, Lingyu; He, Beihui; Zhang, Shuo] Zhejiang Chinese Med Univ, Affiliated Hosp 1, Hangzhou, Peoples R China; [Fang, Yi; Sun, Lingyu; He, Ruonan] Zhejiang Chinese Med Univ, Clin Med Coll 1, Hangzhou, Peoples R China		He, BH; Zhang, S (corresponding author), Zhejiang Chinese Med Univ, Affiliated Hosp 1, Hangzhou, Peoples R China.	graf303@sina.com; zhangshuotcm@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81973598, 82074186, 82074214]; Medicine and Health Science and Technology Plan Projects in Zhejiang province [2021KY834]; Research Fund Project of Zhejiang Chinese Medical University [2019ZY02, 2020ZG41]	Funding This work was supported in part by the National Natural Science Foundation of China (81973598, 82074186, 82074214). Funding was also provided by the Medicine and Health Science and Technology Plan Projects in Zhejiang province (2021KY834), and Research Fund Project of Zhejiang Chinese Medical University (2019ZY02, 2020ZG41).	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Oncol.	OCT 27	2021	11								762752	10.3389/fonc.2021.762752			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	WW0AI	WOS:000717589400001	34778084	Green Published, gold			2022-04-25	
J	Benhalilou, N; Alsamri, H; Atneyadi, A; Athamneh, K; Alrashedi, A; Altamimi, N; Al Dhaheri, Y; Eid, AH; Iratni, R				Benhalilou, Nehia; Alsamri, Halima; Atneyadi, Aysha; Athamneh, Khawlah; Alrashedi, Asma; Altamimi, Nedaa; Al Dhaheri, Yusra; Eid, Ali H.; Iratni, Rabah			Origanum majorana Ethanolic Extract Promotes Colorectal Cancer Cell Death by Triggering Abortive Autophagy and Activation of the Extrinsic Apoptotic Pathway	FRONTIERS IN ONCOLOGY			English	Article						colon cancer; abortive autophagy; apoptosis; DNA damage; Origanum majorana; HPLC-MS	SURVIVIN; INHIBITION; ANTIOXIDANT; ANTICANCER; MARJORAM; IDENTIFICATION	Colorectal cancer is considered as the third leading cause of cancer death. In the present study, we investigated the potential anticancer effect and the molecular mechanism of Origanum majorana ethanolic extract (OME) against human colorectal cancer cells. We showed that OME exhibited strong anti-proliferative activity in a concentration- and time-dependent manner against two human colorectal cancer cell lines (HT-29 and Caco-2). OME inhibited cell viability, colony growth and induced mitotic arrest of HT-29 cells. Also, OME induced DNA damage, triggered abortive autophagy and activated a caspase 3 and 7-dependent extrinsic apoptotic pathway, most likely through activation of the TNF alpha pathway. Time-course analysis revealed that DNA damage occurred concomitantly with abortive autophagy after 4 h post-OME treatment while apoptosis was activated only 24 h later. Blockade of autophagy initiation, by 3-methyladenine, partially rescued OME-induced cell death. Cell viability arose from 37% in control group to 67% in group pre-treated with 3-MA before addition of OME. Inhibition of apoptosis, however, had a minimal effect on cell viability; it rose from 37% in control group to 43% in group pre-treated with Z-VAD-FMK. We also found that OME downregulated survivin in HT-29 cells. Our findings provide a strong evidence that O. majorana extract possesses strong anti-colon cancer potential, at least, through induction of autophagy and apoptosis. These finding provide the basis for therapeutic potential of O. majorana in the treatment of colon cancer.	[Benhalilou, Nehia; Alsamri, Halima; Atneyadi, Aysha; Athamneh, Khawlah; Alrashedi, Asma; Altamimi, Nedaa; Al Dhaheri, Yusra; Iratni, Rabah] United Arab Emirates Univ, Coll Sci, Dept Biol, Abu Dhabi, U Arab Emirates; [Eid, Ali H.] Amer Univ Beirut, Fac Med, Dep Pharmacol & Toxicol, Beirut, Lebanon		Iratni, R (corresponding author), United Arab Emirates Univ, Coll Sci, Dept Biol, Abu Dhabi, U Arab Emirates.	R_iratni@uaeu.ac.ae	Eid, Ali Hussein/ABD-6291-2021	Eid, Ali Hussein/0000-0003-3004-5675; Alneyadi, Aysha/0000-0002-6450-4713	Al Jalila FoundationAl Jalila Foundation (AJF) [21S102-AJF2018007]	This work was supported by Al Jalila Foundation research grant (Grant 21S102-AJF2018007) to RI.	Al Dhaheri Y, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0068808; Al Dhaheri Y, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0056649; Al-Howiriny T, 2009, AM J CHINESE MED, V37, P531, DOI 10.1142/S0192415X0900703X; Ambrosini G, 1997, NAT MED, V3, P917, DOI 10.1038/nm0897-917; Athamneh K, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-11202-3; Attoub S, 2011, EUR J PHARMACOL, V651, P18, DOI 10.1016/j.ejphar.2010.10.063; Benbrook D. 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Oncol.	AUG 21	2019	9								795	10.3389/fonc.2019.00795			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	IS2VU	WOS:000482012900002	31497536	Green Published, gold			2022-04-25	
J	Geng, YD; Zhang, L; Wang, GY; Feng, XJ; Chen, ZL; Jiang, L; Shen, AZ				Geng, Ya-di; Zhang, Lei; Wang, Guo-Yu; Feng, Xiao-Jun; Chen, Zhao-Lin; Jiang, Ling; Shen, Ai-Zong			Xanthatin mediates G(2)/M cell cycle arrest, autophagy and apoptosis via ROS/XIAP signaling in human colon cancer cells	NATURAL PRODUCT RESEARCH			English	Article						Xanthatin; cell cycle; apoptosis; autophagy; XIAP; colon cancer	XIAP; STRESS	Xanthatin is a natural plant bicyclic sesquiterpene lactone extracted fromXanthium plants (Asteraceae).In the present study, we demonstrated for the first time that Xanthatin inhibited cell proliferation and mediated G(2)/M phase arrest in human colon cancer cells. Xanthatin also activated caspase and mediated apoptosis in these cells. Concomitantly, Xanthatin triggered cell autophagic response. We found down-regulation of X-linked inhibitor of apoptosis protein (XIAP) contribute to the induction of apoptosis and autophagy. Moreover, reactive oxygen species (ROS) production was triggered upon exposure to Xanthatin in colon cancer cells. ROS inhibitor N-acetylcysteine (NAC) significantly reversed Xanthatin-mediated XIAP down-regulation, G(2)/M phase arrest, apoptosis and autophagosome accumulation. In summary, our findings demonstrated that Xanthatin caused G(2)/M phase arrest and mediated apoptosis and autophagy through ROS/XIAP in human colon cancer cells. We provided molecular bases for developing Xanthatin as a promising antitumor candidate for colon cancer therapy.	[Geng, Ya-di; Zhang, Lei; Wang, Guo-Yu; Feng, Xiao-Jun; Chen, Zhao-Lin; Jiang, Ling; Shen, Ai-Zong] Anhui Med Univ, Anhui Prov Hosp, Dept Pharm, Hefei, Anhui, Peoples R China		Jiang, L; Shen, AZ (corresponding author), Anhui Med Univ, Anhui Prov Hosp, Dept Pharm, Hefei, Anhui, Peoples R China.	ahslyyjl@126.com; ahslyysaz@126.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81603339, 81602344]; Natural Science Foundation of Anhui ProvinceNatural Science Foundation of Anhui Province [1708085QH175]	This work was co-supported by the National Natural Science Foundation of China (Program No. 81603339, 81602344) and Natural Science Foundation of Anhui Province (Program No. 1708085QH175).	Adams JM, 2003, GENE DEV, V17, P2481, DOI 10.1101/gad.1126903; Azad MB, 2009, ANTIOXID REDOX SIGN, V11, P777, DOI 10.1089/ARS.2008.2270; Barni S, 2007, ANN ONCOL, V18, P179, DOI 10.1093/annonc/mdm252; Crawford S, 2013, FRONT PHARMACOL, V4, DOI 10.3389/fphar.2013.00068; Eckelman BP, 2006, EMBO REP, V7, P988, DOI 10.1038/sj.embor.7400795; Hileman EO, 2004, CANCER CHEMOTH PHARM, V53, P209, DOI 10.1007/s00280-003-0726-5; Huang X, 2013, EMBO J, V32, P2204, DOI 10.1038/emboj.2013.133; Jiang H, 2020, NAT PROD RES, V34, P1743, DOI 10.1080/14786419.2018.1530229; Kim R, 2006, CANCER BIOL THER, V5, P1429, DOI 10.4161/cbt.5.11.3456; Kroemer G, 2010, MOL CELL, V40, P280, DOI 10.1016/j.molcel.2010.09.023; Linsalata M, 2008, NUTRITION, V24, P382, DOI 10.1016/j.nut.2007.12.014; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Mizushima N, 2007, AUTOPHAGY, V3, P542, DOI 10.4161/auto.4600; Mone A., 2013, ISSUES SCREENING SUR; Olivaro C, 2016, NATURAL PRODUCT RES, V30, P1; Schile AJ, 2008, GENE DEV, V22, P2256, DOI 10.1101/gad.1663108; Sharifi-Rad J, 2016, CELL MOL BIOL, V62, P69, DOI 10.14715/cmb/2016.62.9.11; Shi YS, 2015, J NAT PROD, V78, P1526, DOI 10.1021/np500951s; Trachootham D, 2009, NAT REV DRUG DISCOV, V8, P579, DOI 10.1038/nrd2803; Utz PJ, 2000, CELL DEATH DIFFER, V7, P589, DOI 10.1038/sj.cdd.4400696; Zhang L, 2012, PLANTA MED, V78, P890, DOI 10.1055/s-0031-1298481	21	7	7	2	23	TAYLOR & FRANCIS LTD	ABINGDON	2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND	1478-6419	1478-6427		NAT PROD RES	Nat. Prod. Res.	SEP 16	2020	34	18					2616	2620		10.1080/14786419.2018.1544976			5	Chemistry, Applied; Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	NL1BI	WOS:000567158900010	30587055				2022-04-25	
J	Wu, D; Zhou, WY; Lin, XT; Fang, L; Xie, CM				Wu, Di; Zhou, Wen-Yi; Lin, Xiao-Tong; Fang, Lei; Xie, Chuan-Ming			Bufalin induces apoptosis via mitochondrial ROS-mediated caspase-3 activation in HCT-116 and SW620 human colon cancer cells	DRUG AND CHEMICAL TOXICOLOGY			English	Article						Bufalin; apoptosis; ROS; colon cancer	DNA-DAMAGE; LEUKEMIA-CELLS; DEATH; AUTOPHAGY; CINOBUFAGIN; GENERATION; INHIBITION	Objective: Bufalin has been reported to kill various types of cancer including human colorectal cancer. Our previous study demonstrated that bufalin induced cell death via autophagy in HT-29 and Caco-2 colon cancer cells, but the action of bufalin remains unclear. This study was conducted to investigate the role of bufalin in other colon cancer HCT-116 and SW620 cells as well as its potential mechanism. Methods: The effect of bufalin in HCT-116 and SW620 colon cancer cells was detected by assessing cell viability and cell death. Apoptotic cells were analyzed by Western blot and trypan blue dye exclusion assay. Mitochondrial ROS production was analyzed by flow cytometry after DCFDA and DHR-123 staining. The potential mechanism was investigated via pharmacological inhibitors. Results: Bufalin had high potency against HCT-116 and SW620 cells with IC50 values of 12.823 +/- 1.792 nM and 26.303 +/- 2.498 nM in HCT-116 and SW620 cells, respectively. Bufalin decreased cell viability, increased cell death as well as caspase-3 downstream target (cleaved PARP) accumulation, and these actions were significantly blocked by pan-caspase inhibitor zVAD-FMK. Mechanistically, ROS production, but neither the NAD(P)H oxidase, AMPK, ERK nor p38, is responsible for bufalin-induced apoptotic cell death. Moreover, bufalin-induced ROS generation is derived from mitochondria. Conclusion: Bufalin significantly induces apoptosis in HCT-116 and SW620 colon cancer cells via mitochondrial ROS-mediated caspase-3 activation. We believe that our novel findings will greatly alter our current understanding on the anti-cancer mechanism of bufalin in colon cancer cells and will pave the way for further exploiting the clinical application.	[Wu, Di; Lin, Xiao-Tong; Fang, Lei; Xie, Chuan-Ming] Third Mil Med Univ, Inst Hepatobiliary Surg, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China; [Zhou, Wen-Yi] Essence Secur Co Ltd, Chongqing, Peoples R China		Xie, CM (corresponding author), Third Mil Med Univ, Inst Hepatobiliary Surg, Southwest Hosp, Army Med Univ, Chongqing, Peoples R China.	chuanming506@126.com	Xie, Chuan-Ming/AAT-9557-2021	Xie, Chuan-Ming/0000-0003-4362-6612	Southwest Hospital, Third Military Medical University (Army Medical University) [SWH2016JCYB-19]	This work was supported by the Direct Grant from Southwest Hospital, Third Military Medical University (Army Medical University) (SWH2016JCYB-19).	Bazhin AV, 2016, OXID MED CELL LONGEV, V2016, DOI 10.1155/2016/4197815; Chang YW, 2014, TUMOR BIOL, V35, P1075, DOI 10.1007/s13277-013-1143-y; Degli Esposti M, 1998, FEBS LETT, V430, P338, DOI 10.1016/S0014-5793(98)00688-7; Dikalov SI, 2014, ANTIOXID REDOX SIGN, V20, P372, DOI 10.1089/ars.2012.4886; Farah MA, 2016, COLLOID SURFACE B, V141, P158, DOI 10.1016/j.colsurfb.2016.01.027; Hu T, 2016, WORLD J GASTROENTERO, V22, P6876, DOI 10.3748/wjg.v22.i30.6876; Jiang YT, 2010, CYTOTECHNOLOGY, V62, P573, DOI 10.1007/s10616-010-9310-0; Kang XH, 2017, CELL PHYSIOL BIOCHEM, V41, P2067, DOI 10.1159/000475438; Liu F, 2016, ONCOTARGET, V7, P8896, DOI 10.18632/oncotarget.6840; Liu X, 2016, J ETHNOPHARMACOL, V193, P538, DOI 10.1016/j.jep.2016.09.047; Pelicano H, 2003, J BIOL CHEM, V278, P37832, DOI 10.1074/jbc.M301546200; Qi J, 2014, EVID-BASED COMPL ALT, V2014, DOI 10.1155/2014/312684; Qiu DZ, 2013, BMC COMPLEM ALTERN M, V13, DOI 10.1186/1472-6882-13-185; SCHERZSHOUVAL R, 2007, PROCEEDINGS OF THE N, V107, P18511, DOI DOI 10.1073/PNAS.1006124107; Sheng X, 2016, INT J ONCOL, V49, P1513, DOI 10.3892/ijo.2016.3667; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Sivaprasad U, 2008, J CELL MOL MED, V12, P1265, DOI 10.1111/j.1582-4934.2008.00282.x; Tian X, 2015, EVID-BASED COMPL ALT, V2015, DOI 10.1155/2015/546210; Wang J, 2015, GASTROENT RES PRACT, V2015, DOI 10.1155/2015/457193; WATABE M, 1957, CANCER RES, V57, P3097; Wu SH, 2014, AM J CHINESE MED, V42, P729, DOI 10.1142/S0192415X14500475; Xie CM, 2011, FREE RADICAL BIO MED, V51, P1365, DOI 10.1016/j.freeradbiomed.2011.06.016; Yan SC, 2014, ANTI-CANCER DRUG, V25, P683, DOI 10.1097/CAD.0000000000000095; Yeh JY, 2003, PROSTATE, V54, P112, DOI 10.1002/pros.10172; Yu CH, 2008, CANCER SCI, V99, P2467, DOI 10.1111/j.1349-7006.2008.00966.x; ZHAI X, 1934, PAN, V34, P678; Zhang X, 2017, BIOMED PHARMACOTHER, V94, P627, DOI 10.1016/j.biopha.2017.07.136; Zhu ZT, 2012, WORLD J SURG ONCOL, V10, DOI 10.1186/1477-7819-10-228; Zhu ZT, 2012, ACTA HAEMATOL-BASEL, V128, P144, DOI 10.1159/000339424	29	11	11	2	40	TAYLOR & FRANCIS LTD	ABINGDON	2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND	0148-0545	1525-6014		DRUG CHEM TOXICOL	Drug Chem. Toxicol.	JUL 4	2019	42	4					444	450		10.1080/01480545.2018.1512611			7	Chemistry, Multidisciplinary; Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy; Toxicology	HW7FB	WOS:000466854400013	30777466				2022-04-25	
J	Lei, C; Zhao, B; Liu, L; Zeng, XY; Yu, Z; Wang, XY				Lei, Cheng; Zhao, Bing; Liu, Lin; Zeng, Xiangyue; Yu, Zhen; Wang, Xiyan			Expression and clinical significance of p62 protein in colon cancer	MEDICINE			English	Article						colon cancer; immunohistochemistry; indicators; p62 protein	AUTOPHAGY; ACTIVATION; PHYSIOLOGY; PREDICTOR; CARCINOMA	p62 is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy-associated cancer cell growth. However, the role of p62 in colon cancer remains controversial. Here we investigated the expression of p62 protein in colon cancer and its clinical significance. Patients with colon adenocarcinoma who underwent resection at the Third Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital) were retrospectively analyzed. The expression of p62 protein in tumor tissues and adjacent normal tissues was detected by immunohistochemistry and western-blotting. Real-time quantitative polymerase chain reaction was used to detect the expression level of p62 messenger ribonucleic acid in specimens. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method and the log-rank test. A total of 85 colon cancer patients were enrolled, including 55 (64.71%) patients with high p62 expression, and 30 (35.29%) patients with low p62 expression. The transcription and expression level of p62 in colon cancer tissues were higher than those in adjacent normal tissues (P < .01). High expression of p62 was an independent risk factor for the poor prognosis (PFS and OS) of colon cancer. p62 may be a potential indicator of determining the progression and prognosis evaluation of colon cancer.	[Lei, Cheng; Liu, Lin; Zeng, Xiangyue; Yu, Zhen] Xinjiang Med Univ, Dept Gastrointestinal Surg, Affiliated Teaching Hosp 3, Affiliated Canc Hosp, Xinjiang, Peoples R China; [Zhao, Bing] Xinjiang Med Univ, Dept Day Oncol Unit, Affiliated Teaching Hosp 3, Affiliated Canc Hosp, Xinjiang, Peoples R China; [Wang, Xiyan] Xinjiang Med Univ, Affiliated Teaching Hosp 3, Affiliated Canc Hosp, Urumqi 830011, Xinjiang, Peoples R China		Wang, XY (corresponding author), Xinjiang Med Univ, Affiliated Teaching Hosp 3, Affiliated Canc Hosp, Urumqi 830011, Xinjiang, Peoples R China.	wangxiyan2415@163.com			Natural Science Foundation of Xinjiang Uygur Autonomous Region [2017D01C412]	The study was supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region (No. 2017D01C412).	Amin MB., 2017, AJCC CANC STAGING MA, V8th ed.; Burada F, 2015, WORLD J GASTRO ONCOL, V7, P271, DOI 10.4251/wjgo.v7.i11.271; Burdelski C, 2015, CLIN CANCER RES, V21, P3471, DOI 10.1158/1078-0432.CCR-14-0620; Charafe-Jaufrret E, 2004, J PATHOL, V202, P265, DOI 10.1002/path.1515; Chen HY, 2011, CANCER PREV RES, V4, P973, DOI 10.1158/1940-6207.CAPR-10-0387; De Rosa M, 2015, ONCOL REP, V34, P1087, DOI 10.3892/or.2015.4108; Eadens MJ, 2011, CURR ONCOL REP, V13, P168, DOI 10.1007/s11912-011-0157-0; Iwadate R, 2015, AM J PATHOL, V185, P2523, DOI 10.1016/j.ajpath.2015.05.008; Jin ZY, 2009, CELL, V137, P721, DOI 10.1016/j.cell.2009.03.015; Komatsu M, 2007, CELL, V131, P1149, DOI 10.1016/j.cell.2007.10.035; Komatsu M, 2012, PHARMACOL RES, V66, P457, DOI 10.1016/j.phrs.2012.07.004; Komatsu M, 2011, AUTOPHAGY, V7, P1088, DOI 10.4161/auto.7.9.16474; Kongara S, 2012, FRONT ONCOL, V2, DOI 10.3389/fonc.2012.00171; Lau A, 2010, MOL CELL BIOL, V30, P3275, DOI 10.1128/MCB.00248-10; Li SY, 2018, ONCOL LETT, V15, P9572, DOI 10.3892/ol.2018.8482; Liu JL, 2014, BRIT J CANCER, V111, P944, DOI 10.1038/bjc.2014.355; Liu WJ, 2016, CELL MOL BIOL LETT, V21, DOI 10.1186/s11658-016-0031-z; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Lu ML, 2001, AM J PATHOL, V159, P945, DOI 10.1016/S0002-9440(10)61770-1; Marinkovic M, 2018, OXID MED CELL LONGEV, V2018, DOI 10.1155/2018/8023821; Mathew R, 2009, CELL, V137, P1062, DOI 10.1016/j.cell.2009.03.048; Mizuno Y, 2018, SCI REP-UK, V8, DOI 10.1038/s41598-017-18323-9; Nakayama S, 2017, CANCER MED-US, V6, P1264, DOI 10.1002/cam4.1093; Niklaus M, 2017, ONCOTARGET, V8, P54604, DOI 10.18632/oncotarget.17554; Pankiv S, 2007, J BIOL CHEM, V282, P24131, DOI 10.1074/jbc.M702824200; Pugsley HR, 2017, JOVE-J VIS EXP, DOI 10.3791/55637; Sanz L, 2000, EMBO J, V19, P1576, DOI 10.1093/emboj/19.7.1576; SELBY JV, 1992, NEW ENGL J MED, V326, P653, DOI 10.1056/NEJM199203053261001; Siegel RL, 2016, CA-CANCER J CLIN, V66, P7, DOI 10.3322/caac.21332; Thompson HGR, 2003, ONCOGENE, V22, P2322, DOI 10.1038/sj.onc.1206325; Wu YH, 2018, SIGNAL TRANSDUCT TAR, V3, DOI 10.1038/s41392-018-0031-8; Xiang X, 2017, CANCER MED-US, V6, P2357, DOI 10.1002/cam4.1176; Yun CW, 2018, INT J MOL SCI, V19, DOI 10.3390/ijms19113466	33	9	9	0	0	LIPPINCOTT WILLIAMS & WILKINS	PHILADELPHIA	TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA	0025-7974	1536-5964		MEDICINE	Medicine (Baltimore)	JAN	2020	99	3							e18791	10.1097/MD.0000000000018791			6	Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	General & Internal Medicine	LB9LQ	WOS:000524950700048	32011477	Green Published, gold			2022-04-25	
J	Lim, MJ; Ahn, JY; Han, Y; Yu, CH; Kim, MH; Lee, SLO; Lim, DS; Song, JY				Lim, Min-Jin; Ahn, Ji-Yeon; Han, Youngsoo; Yu, Chi-ho; Kim, Mi-Hyoung; Lee, Sae-lo-oom; Lim, Dae-Seog; Song, Jie-Young			Acriflavine enhances radiosensitivity of colon cancer cells through endoplasmic reticulum stress-mediated apoptosis	INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY			English	Article						Acriflavine; Radiosensitivity; p53; ER stress	RADIATION-INDUCED AUTOPHAGY; NEGATIVE PROGNOSTIC-FACTOR; COLORECTAL-CANCER; CARCINOMA-CELLS; DEATH DECISIONS; LOW BAX; P53; PROTEIN; ACTIVATION; GROWTH	Radiotherapy (RT) is one of the most effective tools in the clinical treatment of cancer. Because the tumor suppressor p53 plays a central role in radiation-mediated responses, including cell cycle-arrest and apoptosis, a number of studies have suggested that p53 could be a useful therapeutic target of anti-cancer agents. Accordingly, we sought to discover a new agent capable of increasing p53 activity. HCT116 colon cancer cells, containing wild-type p53, were stably transfected with a p53 responsive-luciferase (p53-Luc) reporter gene. A cell-based high-throughput screen of 7920 synthetic small molecules was performed in duplicate. Of the screened compounds, acriflavine (ACF) significantly increased p53-Luc activity in a concentration-dependent manner without causing toxicity. Pretreatment with ACF enhanced the induction of p53 protein expression and phosphorylation on serine 15 by gamma-irradiation. Clonogenic assays showed that ACF pretreatment also potentiated radiation-induced cell death. The combination of irradiation and ACF treatment induced mitochondrial release of cytochrome c and significant activation of caspase-3 with PARP cleavage in colon cancer cells, demonstrating typical apoptotic cell death. Combined treatment with ACF and radiation increased the expression of Bax and Bad, while decreasing expression of Bcl-2. In addition, the ACF/radiation treatment combination induced endoplasmic reticulum (ER) stress responses mediated by IRE1 alpha (inositol-requiring transmembrane kinase and endonuclease 1 alpha), eIF-2 alpha (eukaryotic initiation factor 2 alpha), caspase-2/12, and CHOP (C/EBP homologous protein). The knockdown of IRE1 alpha by siRNA inhibited the apoptotic cell death induced by ACF/radiation treatment. In vivo studies showed that combined treatment with ACF and radiation significantly inhibited the growth of tumors in colorectal cancer xenografted mice. These results indicate that ACF acts through p53-dependent mitochondrial pathways and ER stress signals, and could be a promising radiosensitizer. (C) 2012 Elsevier Ltd. All rights reserved.	[Lim, Min-Jin; Ahn, Ji-Yeon; Yu, Chi-ho; Kim, Mi-Hyoung; Lee, Sae-lo-oom; Song, Jie-Young] Korea Inst Radiol & Med Sci, Dept Radiat Canc Sci, Seoul 139706, South Korea; [Han, Youngsoo] Sookmyung Womens Univ, Coll Sci, Div Biol Sci, Seoul 140742, South Korea; [Lim, Dae-Seog] CHA Univ, Dept Appl Biosci, Songnam 463836, Gyeonggi Do, South Korea		Song, JY (corresponding author), Korea Inst Radiol & Med Sci, Dept Radiat Canc Sci, 215-4 Gongneung Dong, Seoul 139706, South Korea.	dslim@cha.ac.kr; immu@kirams.re.kr	Song, Jie-Young/AAG-6684-2019; Song, Jie-Young/AAH-1254-2019	Song, Jie-Young/0000-0002-5769-3886; Song, Jie-Young/0000-0003-2434-7511	Nuclear Research & Development Program of the Korea Science and Engineering Foundation (KOSEF)Korea Science and Engineering Foundation; Korean Government (MEST)Ministry of Education, Science and Technology, Republic of KoreaKorean Government	This work was supported by a grant from the Nuclear Research & Development Program of the Korea Science and Engineering Foundation (KOSEF), funded by the Korean Government (MEST).	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J. Biochem. Cell Biol.	AUG	2012	44	8					1214	1222		10.1016/j.biocel.2012.04.022			9	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	974QE	WOS:000306450600002	22564437				2022-04-25	
J	Qi, WC; Zhou, XT; Wang, JQ; Zhang, K; Zhou, YJ; Chen, SP; Nie, SP; Xie, MY				Qi, Wucheng; Zhou, Xingtao; Wang, Junqiao; Zhang, Ke; Zhou, Yujia; Chen, Shuping; Nie, Shaoping; Xie, Mingyong			Cordyceps sinensis polysaccharide inhibits colon cancer cells growth by inducing apoptosis and autophagy flux blockage via mTOR signaling	CARBOHYDRATE POLYMERS			English	Article						Cordyceps sinensis polysaccharide; Autophagy; Apoptosis; Colon cancer cell; mTOR signaling	PROTEIN; MODULATION; DEATH	Cordyceps sinensis is thought to have anti-cancer effects, but its mechanisms remain elusive. In this study, we aimed to investigate the anti-cancer effect of Cordyceps sinensis polysaccharide (CSP) on human colon cancer cell line (HCT116) and its mechanism. Results indicated that CSP significantly inhibited the proliferation of HCT116 cells, increased autophagy and apoptosis, while blocked autophagy flux and lysosome formation. Further experiments showed that CSP decreased the expression of PI3K and phosphorylation level of AKT and mTOR, increased the expression of AMPKa and phosphorylation level of ULK1. In addition, repression of CSP-induced autophagy by bafilomycin (autophagy inhibitor) enhanced apoptosis and cell death of HCT116 cells. Hence, our findings suggested that CSP inhibited the proliferation of HCT116 cells by inducing apoptosis and autophagy flux blockage, which might be achieved through PI3K-AKT-mTOR and AMPK-mTOR-ULK1 signaling. CSP may be a potential therapeutic agent for colon cancer.	[Qi, Wucheng; Zhou, Xingtao; Wang, Junqiao; Zhang, Ke; Zhou, Yujia; Chen, Shuping; Nie, Shaoping; Xie, Mingyong] Nanchang Univ, State Key Lab Food Sci & Technol, China Canada Joint Lab Food Sci & Technol Nanchan, 235 Nanjing East Rd, Nanchang 330047, Jiangxi, Peoples R China; [Xie, Mingyong] Jiangxi Normal Univ, Natl R&D Ctr Freshwater Fish Proc, Nanchang 330022, Jiangxi, Peoples R China		Zhou, XT; Xie, MY (corresponding author), Nanchang Univ, State Key Lab Food Sci & Technol, China Canada Joint Lab Food Sci & Technol Nanchan, 235 Nanjing East Rd, Nanchang 330047, Jiangxi, Peoples R China.	13576019586@163.com; myxie@ncu.edu.cn	周, 兴涛/F-2927-2019	周, 兴涛/0000-0002-1902-9677; Nie, Shao-Ping/0000-0002-2412-4679	National Key Research and Development Program of China [2017YFC1600405, 2017YFD0400705-2]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31571826]; Jiangxi Provincial Major Program of Research and Development Foundation [20165ABC28004]	The financial support from the National Key Research and Development Program of China (2017YFC1600405); The National Natural Science Foundation of China (31571826); The National Key Research and Development Program of China (2017YFD0400705-2); Jiangxi Provincial Major Program of Research and Development Foundation (Agriculture field) (20165ABC28004) are gratefully acknowledged. ptfLC3 was a gift from Tamotsu Yoshimori (Addgene plasmid #21074).	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Polym.	JUN 1	2020	237								116113	10.1016/j.carbpol.2020.116113			11	Chemistry, Applied; Chemistry, Organic; Polymer Science	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Polymer Science	KY2FV	WOS:000522387000013	32241434				2022-04-25	
J	Coker-Gurkan, A; Arisan, ED; Obakan, P; Palavan-Unsal, N				Coker-Gurkan, Ajda; Arisan, Elif Damla; Obakan, Pinar; Palavan-Unsal, Narcin			Lack of functional p53 renders DENSpm-induced autophagy and apoptosis in time dependent manner in colon cancer cells	AMINO ACIDS			English	Article						Colon cancer; Apoptosis; Autophagy; Polyamine analogues; DENSpm; p53	HUMAN-MELANOMA CELLS; POLYAMINE ANALOG N-1,N-11-DIETHYLNORSPERMINE; SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE; INHIBITION; INDUCTION; DEATH; CATABOLISM; MODULATORS; MECHANISM; CARCINOMA	Polyamines (PAs), such as putrescine, spermidine and spermine, are alkyl-amines that are essential for cell growth, proliferation, differentiation and cancer progression in eukaryotic cells. A designed PA analogue; DENSpm, induces cell cycle arrest, inhibits proliferation and induces apoptosis in melanoma, breast, prostate, lung and colon cancer cells. Although the mechanism by which DENSpm induces apoptosis has been examined, the effect of DENSpm on autophagy has not been investigated yet. Therefore, in this study, our objective was to determine the role of p53 in the DENSpm-induced autophagy/apoptotic regulation in a time-dependent manner in colon cancer cells. Exposure of HCT 116 colon cancer cells to DENSpm decreased cell viability in a dose- and time-dependent manner. However, the p53 mutant, SW480, and deficient HCT 116 p53(-/-) cells were more resistant to DENSpm treatment compared to HCT 116 p53(+/+) cells. The resistant profile caused by p53 defect also caused a cell type-specific response to PA pool depletion and SSAT overexpression. In addition to PA depletion, DENSpm induced apoptosis by activating the mitochondria-mediated pathway in a caspase-dependent manner regardless of p53 expression in colon cancer cells. Concomitantly, we determined that DENSpm also affected autophagy in HCT 116 p53(+/+), SW480 and HCT 116 p53(-/-) colon cancer cells for different periods of exposure to DENSpm. Therefore, this study revealed that effect of DENSpm on cell death differs due to p53 protein expression profile. In addition, DENSpm-induced autophagy may be critical in drug resistance in colon cancer cells.	[Coker-Gurkan, Ajda; Arisan, Elif Damla; Obakan, Pinar; Palavan-Unsal, Narcin] Istanbul Kultur Univ, Sci & Literature Fac, Mol Biol & Genet Dept, TR-34156 Istanbul, Turkey		Coker-Gurkan, A (corresponding author), Istanbul Kultur Univ, Sci & Literature Fac, Mol Biol & Genet Dept, Atakoy Campus, TR-34156 Istanbul, Turkey.	a.coker@iku.edu.tr	OBAKAN, PINAR/D-2836-2015; Arisan, Elif Damla/W-8682-2019	Arisan, Elif Damla/0000-0002-4844-6381; Unsal Palavan, Narcin/0000-0002-2945-540X; Gurkan, Ajda/0000-0003-1475-2417	TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [TBAG-212T227]; Istanbul Kultur University Scientific Projects Support CenterIstanbul Kultur University	This work was supported by the grant from TUBITAK (TBAG-212T227) and funded in part by Istanbul Kultur University Scientific Projects Support Center.	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J	Zhang, Z				Zhang, Zhuo			Trefoil factor 3 knock-down prevents autophagy-related gene 12 elevation in colon adenocarcinoma	JOURNAL OF HISTOTECHNOLOGY			English	Article						TFF3; ATG12; colon adenocarcinoma; autophagy; immunohistochemistry; Western blot; siRNA	EXPRESSION; PROTEIN; SURVIVAL; YEAST	Colon cancer, which is considered a common gastrointestinal cancer, has been the third leading cause of cancer mortality in the United States. Colon cancer has various histological sub-types and 90% of them are adenocarcinoma. In recent years, autophagy, the process by which cells are self-cannibalized, has been implicated in pathophysiology of various diseases including colon adenocarcinoma and thus, has become a strong research focus. This has also been true for trefoil factor 3 (TFF3). TFF3 is a small secreted peptide that is present in almost all mucin-secreting tissues, it is most abundant in goblet cells of the gastrointestinal tract and expressed at high protein levels in colon cancer. The present study analyzed the expression of TFF3 and autophagy-related gene ATG12 in cancerous and normal tissue samples collected from patients with colon adenocarcinoma. The expression of both proteins was shown to be increased in cancerous as compared to adjacent non-cancerous tissues. Furthermore, these proteins were shown to be positively correlated using the Pearson's Correlation test in cancerous tissues. Finally, TFF3 was shown to regulate ATG12 in human colon adenocarcinoma cells in vitro. Thus, the data presented here suggest that both TFF3 and ATG12 may be promising potential therapeutic targets to develop novel treatment strategies for patients with colon adenocarcinoma.	[Zhang, Zhuo] China Med Univ, Coll Basic Med Sci, Dept Cell Biol, Taichung, Taiwan		Zhang, Z (corresponding author), China Med Univ, Coll Basic Med Sci, Dept Cell Biol, Taichung, Taiwan.	549652114@qq.com			Key discipline of China Medical University [3110116002]	This work was supported by the promotion project funds from Key discipline of China Medical University (Project Number: 3110116002).	Ahmed ARH, 2012, AM J PATHOL, V180, P904, DOI 10.1016/j.ajpath.2011.11.022; Aiping D, 2013, PLOS ONE, V8; BABA M, 1994, J CELL BIOL, V124, P903, DOI 10.1083/jcb.124.6.903; Cufi S, 2012, ONCOTARGET, V3, P1600; Dong CY, 2016, ONCOTARGET, V7, P8850, DOI 10.18632/oncotarget.7091; Gu JC, 2015, TUMOR BIOL, V36, P3001, DOI 10.1007/s13277-014-2933-6; Kannan N, 2010, NEOPLASIA, V12, P1041, DOI 10.1593/neo.10916; Levine B, 2007, NATURE, V446, P745, DOI 10.1038/446745a; Maibritt N, 2017, INT J MOL SCI, V18, P1; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Mizushima N, 1998, NATURE, V395, P395, DOI 10.1038/26506; Mizushima N, 1999, EMBO J, V18, P3888, DOI 10.1093/emboj/18.14.3888; Morito K, 2015, INT J ONCOL, V46, P563, DOI 10.3892/ijo.2014.2755; Pandey V, 2014, BREAST CANCER RES, V16, DOI 10.1186/s13058-014-0429-3; Parlato M, 2014, INT J MOL SCI, V15, P9594, DOI 10.3390/ijms15069594; Regalo G, 2005, CELL MOL LIFE SCI, V62, P2910, DOI 10.1007/s00018-005-5478-4; Rosenfeldt MT, 2011, CARCINOGENESIS, V32, P955, DOI 10.1093/carcin/bgr031; Rosenfeldt MT, 2009, EXPERT REV MOL MED, V11, DOI 10.1017/S1462399409001306; SEGLEN PO, 1992, EXPERIENTIA, V48, P158, DOI 10.1007/BF01923509; Sophie P, 2003, J BIOL CHEM, V275, P39090; Taheshige K, 1992, J CELL BIOL, V119, P301; Tamura H, 2010, J HISTOCHEM CYTOCHEM, V58, P443, DOI 10.1369/jhc.2010.955690; Vestergaard EM, 2010, INT J CANCER, V127, P1857, DOI 10.1002/ijc.25209; Wilkinson S, 2010, CURR OPIN GENET DEV, V20, P57, DOI 10.1016/j.gde.2009.12.004; William A, 1994, TRENDS CELL BIOL, V4, P139; Xu M, 2017, NEOPLASMA, V64, P56, DOI 10.4149/neo_2017_107; Zhou ST, 2012, CANCER LETT, V323, P115, DOI 10.1016/j.canlet.2012.02.017	27	0	0	0	2	TAYLOR & FRANCIS LTD	ABINGDON	2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND	0147-8885	2046-0236		J HISTOTECHNOL	J. Histotechnol.	OCT 2	2019	42	4			SI		169	176		10.1080/01478885.2019.1633088		AUG 2019	8	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	KB3WD	WOS:000479371800001	31362594				2022-04-25	
J	Zheng, A; Li, H; Wang, X; Feng, ZH; Xu, J; Cao, K; Zhou, B; Wu, J; Liu, JK				Zheng, Adi; Li, Hao; Wang, Xun; Feng, Zhihui; Xu, Jie; Cao, Ke; Zhou, Bo; Wu, Jing; Liu, Jiankang			Anticancer Effect of a Curcumin Derivative B63: ROS Production and Mitochondrial Dysfunction	CURRENT CANCER DRUG TARGETS			English	Article						Colon cancer cells; curcumin; curcumin derivative; ER stress; mitochondrial dysfunction; ROS	CANCER-CELLS; APOPTOSIS; BIM; INHIBITION; ACTIVATION; AUTOPHAGY; ANALOGS; DEATH; PUMA	Curcumin, a polyphenol isolated from the plant Curcuma longa, displays chemotherapeutic and chemo-preventive effects in diverse cancers, including colorectal cancer. A mono-carbonyl analogue B63 was synthesized through several chemical modifications of the basic structure of curcumin to increase its biological activity and bioavailability. In vitro assays showed potent anti-proliferative effects of B63 on colon cancer cells (about 2 fold more effective than curcumin based on IC50). B63 treatment also induced significant necrosis, apoptosis, and S phase cell cycle arrest in SW620 colon cancer cells. The pro-apoptotic proteins Bad and Bim were up-regulated, and cytochrome c release from the mitochondria into the cytosol was enhanced, resulting in pro-caspase-3 and PARP-1 cleavage. Furthermore, the anticancer activity of B63 was dependent on intracellular ROS from damaged mitochondrial function and induced endoplasmic reticulum (ER) stress. In vivo, 50 mg/kg of B63 inhibit tumor growth similarly to 100 mg/kg curcumin in a mouse xenograft model using SW620 cells. These results suggest that the curcumin derivative B63 has a greater anticancer capacity than the parent curcumin in colon cancer cells and that the necrotic and apoptotic effects of B63 are mediated by ROS resulting from ER stress and mitochondrial dysfunction.	[Zheng, Adi; Li, Hao; Wang, Xun; Feng, Zhihui; Xu, Jie; Cao, Ke; Wu, Jing; Liu, Jiankang] Xi An Jiao Tong Univ, Sch Life Sci & Technol, Key Lab Biomed Informat Engn, Ctr Mitochondrial Biol & Med,Minist Educ, Xian 710049, Peoples R China; [Zheng, Adi; Li, Hao; Wang, Xun; Feng, Zhihui; Xu, Jie; Cao, Ke; Wu, Jing; Liu, Jiankang] Xi An Jiao Tong Univ, Frontier Inst Life Sci, FIST, Xian 710049, Peoples R China; [Zhou, Bo] Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Gansu, Peoples R China		Wu, J (corresponding author), Xi An Jiao Tong Univ, Sch Life Sci & Technol, Inst Mitochondrial Biol & Med, Xian 710049, Peoples R China.	Jing_wu@mail.xjtu.edu.cn; j.liu@mail.xjtu.edu.cn	Li, Hao/K-7001-2017; Liu, Jiankang/A-1610-2011; Feng, Zhihui/E-7408-2011	Li, Hao/0000-0001-5677-3377; Feng, Zhihui/0000-0002-2448-6565; Wang, Xun/0000-0001-5172-0305	National Natural Science Foundation of China, Key ProgramNational Natural Science Foundation of China (NSFC) [30930105]; National 12-5 Support Plan Project of the Ministry of Science and Technology of China [2012BAH30F03]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31070740, 21172101]; Xi'an Jiaotong UniversityXi'an Jiaotong University	The authors thank Prof. JianJian Li at University of California at Davis for his critical reading and ideas to this work. This study was partially supported by the National Natural Science Foundation of China, Key Program 30930105, National 12-5 Support Plan Project of the Ministry of Science and Technology of China (2012BAH30F03), the National Natural Science Foundation of China (No. 31070740 and No. 21172101), and the 985 and 211 Projects of Xi'an Jiaotong University.	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Cancer Drug Targets		2014	14	2					156	166		10.2174/1568009613666131126115444			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AN8UE	WOS:000340879400005	24274397				2022-04-25	
J	Dukel, M; Tavsan, Z; Erdogan, D; Gok, DE; Kayali, HA				Dukel, Muzaffer; Tavsan, Zehra; Erdogan, Duygu; Gok, Deniz Erkan; Kayali, Hulya Ayar			Protein kinase C Inhibitors selectively modulate dynamics of cell adhesion molecules and cell death in human colon cancer cells	CELL ADHESION & MIGRATION			English	Article						Colon cancer; protein kinase C; cell adhesion molecules; reactive oxygen species; cell death	COLORECTAL-CANCER; EXPRESSION; ALPHA; APOPTOSIS; ACTIVATION; TIGHT; BETA; PKC; METASTASIS; INDUCTION	During development of colon cancer, Protein Kinase Cs (PKCs) are involved in regulation of many genes controlling several cellular mechanisms. Here, we examined the changes in cell adhesion molecules and PKCs for colorectal cancer progression. We identified that PKCs affected expression of EpCAM, claudins, tetraspanins. Treatment with low concentrations of PKC inhibitors resulted in decreased cell viability. In addition, immunoblotting and qRT-PCR analysis showed that apoptosis was inhibited while autophagy was induced by PKC inhibition in colon cancer cells. Furthermore, we observed decreased levels of intracellular Reactive Oxygen Species (ROS), lipid peroxidation and protein carbonyl, confirming the ROS-induced apoptosis. Taken together, our results reveal that PKC signalling modulates not only cell adhesion dynamics but also cell death-related mechanisms.Abbreviations: PKC: Protein Kinase C; EpCAM: Epithelial cell adhesion molecule; FBS: fetal bovine serum; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); CAM: cell adhesion molecule; ROS: reactive oxygen species	[Dukel, Muzaffer] Mehmet Akif Ersoy Univ, Fac Art & Sci, Mol Biol & Genet Dept, Burdur, Turkey; [Dukel, Muzaffer; Tavsan, Zehra; Gok, Deniz Erkan; Kayali, Hulya Ayar] Izmir Biomed & Genome Ctr, TR-35340 Izmir, Turkey; [Erdogan, Duygu] Dokuz Eylul Univ, Izmir Int Biomed & Genome Inst, Izmir, Turkey; [Kayali, Hulya Ayar] Dokuz Eylul Univ, Sci Fac, Chem Dept, Biochem Div, Izmir, Turkey		Kayali, HA (corresponding author), Izmir Biomed & Genome Ctr, TR-35340 Izmir, Turkey.	hulya.ayarkayali@gmail.com	Tavsan, Zehra/AAR-6576-2021	Erdogan, Duygu/0000-0002-4930-7017	Dokuz Eylul University, Department of Scientific Research ProjectsDokuz Eylul University [KB.FEN.001]	This work was supported by the Dokuz Eylul University, Department of Scientific Research Projects (2016.KB.FEN.001).	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Migr.		2019	13	1					83	97		10.1080/19336918.2018.1530933			15	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	IC0SK	WOS:000470670000004	30289336	gold, Green Published			2022-04-25	
J	Wang, L; Hu, T; Shen, J; Zhang, L; Chan, RLY; Lu, L; Li, MX; Cho, CH; Wu, WKK				Wang, Lin; Hu, Tao; Shen, Jing; Zhang, Lin; Chan, Ruby Lok-Yi; Lu, Lan; Li, Mingxing; Cho, Chi Hin; Wu, William. Ka Kei			Dihydrotanshinone I induced apoptosis and autophagy through caspase dependent pathway in colon cancer	PHYTOMEDICINE			English	Article						Dihydrotanshinone I; Apoptosis; Autophagy; Caspase; Mitochondria; Colon cancer	MITOCHONDRIAL RELEASE; CELL; AIF; DOWNSTREAM	Background: Dihydrotanshinone I (DHTS) was previously reported to exhibit the most potent anti-cancer activity among several tanshinones in colon cancer cells. Its cytotoxic action was reactive oxygen species (ROS) dependent but p53 independent. Purpose: To further study the anti-cancer activity of DHTS and its molecular mechanisms of action in colon cancer both in vitro and in vivo. Methods: Caspase activity was detected by fluorescence assay. Apoptosis was detected by flow cytometry and TUNEL assay. Protein levels were analyzed by western blotting. Knockdown of target gene was achieved by siRNA transfection. Formation of LOB puncta and activation of caspase-3 were detected by confocal fluorescence microscope. In vivo anti-colon cancer activity of DHTS was observed in xenograft tumors in NOD/SCID mice. Results: Anti-colon cancer activity of DHTS by inducing apoptosis and autophagy was observed both in vitro and in vivo. Mitochondria mediated caspase dependent pathway was essential in DHTS-induced cytotoxicity. The apoptosis induced by DHTS was suppressed by knockdown of apoptosis inducing factor (AIF), inhibition of caspase-3/9 but was increased after knockdown of caspase-2. Meantime, knockdown of caspase-2, pretreatment with Z-VAD-fmk or NAC (N-Acety-L-Cysteine) efficiently inhibited the autophagy induced by DHTS. A crosstalk between cytochrome c and AIF was also reported. Conclusion: DHTS-induced caspase and ROS dependent apoptosis and autophagy were mediated by mitochondria in colon cancer. DHTS could be a promising leading compound for the development of anti-tumor agent or be developed as an adjuvant drug for colon cancer therapy. (C) 2015 Elsevier GmbH. All rights reserved.	[Wang, Lin; Hu, Tao; Shen, Jing; Zhang, Lin; Chan, Ruby Lok-Yi; Lu, Lan; Li, Mingxing; Cho, Chi Hin] Chinese Univ Hong Kong, Lo Kwee Seong Integrated Biomed Sci Bldg, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China; [Wu, William. Ka Kei] Chinese Univ Hong Kong, Fac Med, Dept Anaesthesia & Intens Care, Hong Kong, Hong Kong, Peoples R China		Wang, L (corresponding author), Chinese Univ Hong Kong, Lo Kwee Seong Integrated Biomed Sci Bldg, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China.	wanglinster@gmail.com	Cho, Chi Hin/C-6543-2014; Hu, Tao/O-2570-2014; Wu, William K.K./A-3277-2009	Cho, Chi Hin/0000-0002-7658-3260; Wu, William K.K./0000-0002-5662-5240; WANG, LIN/0000-0001-7883-4900; Hu, Tao/0000-0002-0601-3078; LI, Mingxing/0000-0001-5729-3850	Innovation and Technology Support Programme; Tier 3/Seed Projects; Innovation and Technology Commission, Hong Kong [ITS/212/12]; General Research Fund, Hong Kong Research Grant Council, Hong Kong [CUHK463613]	This work was supported by Innovation and Technology Support Programme, Tier 3/Seed Projects, Innovation and Technology Commission, Hong Kong (ITS/212/12) and General Research Fund, Hong Kong Research Grant Council, Hong Kong (CUHK463613).	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J	Jeong, HS; Choi, HY; Lee, ER; Kim, JH; Jeon, K; Lee, HJ; Cho, SG				Jeong, Hyo-Soon; Choi, Hye Yeon; Lee, Eung-Ryoung; Kim, Jung-Hyun; Jeon, Kilsoo; Lee, Hyun-Joo; Cho, Ssang-Goo			Involvement of caspase-9 in autophagy-mediated cell survival pathway	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH			English	Article						NSAIDs; Caspase; Apoptosis; Autophagy; MCF-7	NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROSTATE-CANCER CELLS; BREAST-CANCER; INDUCED APOPTOSIS; COX INHIBITORS; CYTOCHROME-C; DEATH; EXPRESSION; MODEL; COLON	Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered for use in the prevention and treatment of cancer malignancy. FR122047 (FR) is known to have an anti-inflammatory effect, but the anticancer activity of the chemical has not yet been identified. In the present study, we could find that treatment of breast cancer MCF-7 cells with FR led to apoptosis accompanying with apparent activation of caspases. Treatment of caspase-specific inhibitors revealed that FR-induced apoptosis was caspase-8-dependent and inhibition of caspase-9 activity resulted in unexpected, marked enhancement of cell death. Knockdown of caspase-9 expression by specific siRNA caused increased susceptibility to FR-induced cell death, consistent with the results obtained with treatment of caspase-9 inhibitor. Inhibition of caspase-9 blocked the autophagic process by modulating lysosomal pH and acid-dependent cathepsin activities and augmented cell death due to blockage of cytoprotective autophagy. MCF-7 cells treated with sulforaphane, an autophagy-inducing drug, also showed marked accumulation of LC3-II, and co-treatment with caspase-9 inhibitor brought about increased susceptibility to sulforaphane-induced cell death. Different from the cases with FR or sulforaphane, etoposide- or doxorubicin-induced cell death was suppressed with co-treatment of caspase-9 inhibitor, and the drugs failed to induce significant autophagy in MCF-7 cells. Taken together, our data originally suggest that inhibition of caspase-9 may block the autophagic flux and enhance cell death due to blockage of cytoprotective autophagy. (c) 2010 Elsevier B.V. All rights reserved.	Konkuk Univ, Dept Anim Biotechnol BK21, Anim Resources Res Ctr, Seoul 143701, South Korea; Konkuk Univ, RCTCP, Seoul 143701, South Korea		Cho, SG (corresponding author), Konkuk Univ, Dept Anim Biotechnol, Seoul 143701, South Korea.	ssangoo@konkuk.ac.kr	Kim, Jung-Hyun/AAK-8795-2021; CHOI, HYEYEON/O-1234-2019; Jeon, Kilsoo/D-5187-2011	Kim, Jung-Hyun/0000-0001-7176-409X; 	Korean government (MEST)Ministry of Education, Science and Technology, Republic of KoreaKorean Government [2009-0083694, 2010-0001348]; Ministry for Health, Welfare, and Family Affairs [A08-4065]; Rural Development AdministrationRural Development Administration (RDA) [20070501-034-001-009-02-00]; Korea Research Council of Fundamental Science Technology; KRIBB Initiative [KGM3110912]; Korean government (MEST), Republic of KoreaMinistry of Education, Science and Technology, Republic of KoreaKorean Government	We thank Dr. T. Yoshimori (Research Institute for Microbial Diseases, Osaka University, Japan) for providing the GFP-LC3 plasmid and Dr. Seunghwa Park (Konkuk University, South Korea) for helping with the transmission electron microscopy. This work was supported in part by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (No. 2009-0083694 and No. 2010-0001348) and by a grant from Korea Health 21 R&D Project, Ministry for Health, Welfare, and Family Affairs (A08-4065), a grant from BioGreen 21 Program, Rural Development Administration (Code # 20070501-034-001-009-02-00), and Top Brand Project grant from Korea Research Council of Fundamental Science & Technology and KRIBB Initiative program (KGM3110912). We acknowledge a graduate fellowship provided by the Korean government (MEST) through the Brain Korea 21 project, Republic of Korea.	Abedin MJ, 2007, CELL DEATH DIFFER, V14, P500, DOI 10.1038/sj.cdd.4402039; Abraham MC, 2004, TRENDS CELL BIOL, V14, P184, DOI 10.1016/j.tcb.2004.03.002; Akdemir F, 2006, DEVELOPMENT, V133, P1457, DOI 10.1242/dev.02332; Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Baek SJ, 2006, PROG LIPID RES, V45, P1, DOI 10.1016/j.plipres.2005.10.001; Baron JA, 2000, ANNU REV MED, V51, P511, DOI 10.1146/annurev.med.51.1.511; Bursch W, 2001, CELL DEATH DIFFER, V8, P569, DOI 10.1038/sj.cdd.4400852; Cao C, 2006, INT J RADIAT ONCOL, V66, pS554, DOI 10.1016/j.ijrobp.2006.07.1033; Cheng I, 2007, BRIT J CANCER, V97, P557, DOI 10.1038/sj.bjc.6603874; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; Ferguson HA, 2003, J BIOL CHEM, V278, P45793, DOI 10.1074/jbc.M307979200; Fernando P, 2005, FASEB J, V19, P1671, DOI 10.1096/fj.04-2981fje; Gyrd-Hansen M, 2006, MOL CELL BIOL, V26, P7880, DOI 10.1128/MCB.00716-06; Hanif R, 1996, BIOCHEM PHARMACOL, V52, P237, DOI 10.1016/0006-2952(96)00181-5; Harris RE, 2003, CANCER RES, V63, P6096; HARRIS RE, 1995, PREV MED, V24, P119, DOI 10.1006/pmed.1995.1022; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; IVY GO, 1984, SCIENCE, V226, P985, DOI 10.1126/science.6505679; Janicke RU, 1998, J BIOL CHEM, V273, P9357, DOI 10.1074/jbc.273.16.9357; Jia L, 1997, BRIT J HAEMATOL, V98, P673, DOI 10.1046/j.1365-2141.1997.2623081.x; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kern MA, 2006, CANCER RES, V66, P7059, DOI 10.1158/0008-5472.CAN-06-0325; Kim BW, 2008, CANCER BIOL THER, V7, P1080, DOI 10.4161/cbt.7.7.6164; Kim SH, 2004, J CANCER RES CLIN, V130, P551, DOI 10.1007/s00432-004-0567-6; Kundu N, 2002, CANCER RES, V62, P2343; Lanza-Jacoby S, 2004, MOL CANCER THER, V3, P417; Lee ER, 2005, J BIOL CHEM, V280, P31498, DOI 10.1074/jbc.M505537200; Lupulescu A, 1996, PROSTAG LEUKOTR ESS, V54, P83, DOI 10.1016/S0952-3278(96)90064-2; Mazhar D, 2006, BRIT J CANCER, V94, P346, DOI 10.1038/sj.bjc.6602942; Ochi T, 2000, EUR J PHARMACOL, V391, P49, DOI 10.1016/S0014-2999(00)00051-0; Ochi T, 2002, BRIT J PHARMACOL, V135, P782, DOI 10.1038/sj.bjp.0704511; Ravikumar B, 2006, HUM MOL GENET, V15, P1209, DOI 10.1093/hmg/ddl036; Sato K, 2003, BRIT J CANCER, V89, P1366, DOI 10.1038/sj.bjc.6601253; SCHREINEMACHERS DM, 1994, EPIDEMIOLOGY, V5, P138, DOI 10.1097/00001648-199403000-00003; Shah N, 2004, BLOOD, V104, P2873, DOI 10.1182/blood-2003-10-3720; Sheng HM, 1998, CANCER RES, V58, P362; Stupack DG, 2006, NATURE, V439, P95, DOI 10.1038/nature04323; Tegeder I, 2001, FASEB J, V15, P2057, DOI 10.1096/fj.01-0390rev; Thorburn A, 2008, APOPTOSIS, V13, P1, DOI 10.1007/s10495-007-0154-9; Uchiyama R, 2007, INFECT IMMUN, V75, P2894, DOI 10.1128/IAI.01639-06; Wang WH, 2003, JNCI-J NATL CANCER I, V95, P1784, DOI 10.1093/jnci/djg106; Wu YT, 2008, AUTOPHAGY, V4, P457, DOI 10.4161/auto.5662; Yanagisawa H, 2003, CELL DEATH DIFFER, V10, P798, DOI 10.1038/sj.cdd.4401246; Yorimitsu T, 2005, CELL DEATH DIFFER, V12, P1542, DOI 10.1038/sj.cdd.4401765	44	40	40	0	11	ELSEVIER SCIENCE BV	AMSTERDAM	PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS	0167-4889	0006-3002		BBA-MOL CELL RES	Biochim. Biophys. Acta-Mol. Cell Res.	JAN	2011	1813	1					80	90		10.1016/j.bbamcr.2010.09.016			11	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	715GC	WOS:000286867800008	20888374	Bronze			2022-04-25	
J	Nam, TW; Park, SY; Lee, JH; Roh, JI; Lee, HW				Nam, Tae Wool; Park, Song Yi; Lee, Jae Hoon; Roh, Jae Il; Lee, Han-Woong			Effect of EI24 expression on the tumorigenesis of Apc(Min)/+ colorectal cancer mouse model	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Colorectal cancer; EI24; Apc(Min/+) mice	PROTEIN-KINASE-C; DOWN-REGULATION; BREAST-CANCER; ALPHA; OVEREXPRESSION; RESISTANCE; AUTOPHAGY; IGF-1R; GENES	Etoposide-induced 2.4 kb transcript (EI24, also known as PIGS) is a p53 target gene involved in cell growth suppression and apoptosis and known to be frequently altered in human cancers. Although EI24 expression is decreased in various cancers and is associated with colorectal cancer progression and metastasis, the physiological function of EI24 in colorectal cancer is yet unclear. We generated an EI24 conditional transgenic (Tg) mouse to study the therapeutic effects of EI24 in vivo and evaluated whether EI24 plays a role of a tumor suppressor using EI24 Tg mouse crossed with Apc(Min/+) mouse, which develops multiple intestinal adenomas. The overexpression of EI24 failed to cause any notable difference in the number of polyps, lengths of the intestine and spleen, and survival rate between Apc(Min/+) and Apc(Min/+) EI24 Tg mice. EI24 plays no significant role in colon cancer caused by the substitutional mutation of Apc in mice. Therefore, our result dismisses the hypothesized direct link between Apc(Min/+) mutation and EI24 expression in colorectal cancer model. (C) 2019 The Authors. Published by Elsevier Inc.	[Nam, Tae Wool; Park, Song Yi; Lee, Jae Hoon; Roh, Jae Il; Lee, Han-Woong] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biochem, Seoul 03722, South Korea		Lee, HW (corresponding author), Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biochem, Seoul 03722, South Korea.	hwl@yonsei.ac.kr			National Research Foundation of Korea (NRF)National Research Foundation of Korea [2017R1A4A1015328, 2018R1A2A1A05022746]	This work was supported by grants from the National Research Foundation of Korea (NRF; 2017R1A4A1015328 and 2018R1A2A1A05022746). Both grants were supported in managing the mouse and gave funds for studying Ei24. The National Research Foundation of Korea was not involved in study design, data collection, data analysis, or interpretation of study results.	Armaghany Tannaz, 2012, Gastrointest Cancer Res, V5, P19; Beck GR, 2001, CELL GROWTH DIFFER, V12, P61; Burns TF, 2001, ONCOGENE, V20, P4601, DOI 10.1038/sj.onc.1204484; Cho A., 2009, CURR PROTOC CELL BIO, V42; Choi JM, 2015, LUNG CANCER, V90, P175, DOI 10.1016/j.lungcan.2015.08.019; Choi JM, 2013, ONCOTARGET, V4, P2383, DOI 10.18632/oncotarget.1434; Devkota S, 2016, AUTOPHAGY, V12, P2038, DOI 10.1080/15548627.2016.1217371; Devkota S, 2012, INT J BIOCHEM CELL B, V44, P1887, DOI 10.1016/j.biocel.2012.06.034; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Gentile M, 2001, ONCOGENE, V20, P7753, DOI 10.1038/sj.onc.1204993; Griner EM, 2007, NAT REV CANCER, V7, P281, DOI 10.1038/nrc2110; Gu ZM, 2000, MOL CELL BIOL, V20, P233, DOI 10.1128/MCB.20.1.233-241.2000; Gwak J, 2009, J CELL MOL MED, V13, P2171, DOI 10.1111/j.1582-4934.2009.00683.x; Jeong DU, 2017, J CELL PHYSIOL, V232, P78, DOI 10.1002/jcp.25446; Lee J, 2011, INT J EXP PATHOL, V92, P251, DOI 10.1111/j.1365-2613.2011.00762.x; MOSER AR, 1995, EUR J CANCER, V31A, P1061, DOI 10.1016/0959-8049(95)00181-H; O'Gorman S, 1997, P NATL ACAD SCI USA, V94, P14602, DOI 10.1073/pnas.94.26.14602; Oster H, 2006, CANCER RES, V66, P6955, DOI 10.1158/0008-5472.CAN-06-0268; Rajagopalan H, 2002, NATURE, V418, P934, DOI 10.1038/418934a; Rhodes DR, 2004, NEOPLASIA, V6, P1, DOI 10.1016/S1476-5586(04)80047-2; Ritland SR, 1999, CARCINOGENESIS, V20, P51, DOI 10.1093/carcin/20.1.51; RODRIGUES NR, 1990, P NATL ACAD SCI USA, V87, P7555, DOI 10.1073/pnas.87.19.7555; RONCUCCI L, 1991, CANCER EPIDEM BIOMAR, V1, P57; SAKANOUE Y, 1991, INT J CANCER, V48, P803, DOI 10.1002/ijc.2910480602; Schell MJ, 2016, NAT COMMUN, V7, DOI 10.1038/ncomms11743; Shiratsuchi I, 2011, ANTICANCER RES, V31, P2541; Skrzypczak M, 2010, PLOS ONE, V5, DOI 10.1371/journal.pone.0013091; Suga K, 1998, BIOCHEM MOL BIOL INT, V44, P523; Sun YJ, 2009, PROSTATE, V69, P1119, DOI 10.1002/pros.20961; Weitz J, 2005, LANCET, V365, P153, DOI 10.1016/S0140-6736(05)17706-X; Zhao XS, 2005, CANCER RES, V65, P2125, DOI 10.1158/0008-5472.CAN-04-3377; Zhao YG, 2012, J BIOL CHEM, V287, P42053, DOI 10.1074/jbc.M112.415968	32	2	2	1	2	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	JUL 5	2019	514	4					1087	1092		10.1016/j.bbrc.2019.04.186			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	IC8EM	WOS:000471209100010	31097220	hybrid			2022-04-25	
J	Masui, A; Hamada, M; Kameyama, H; Wakabayashi, K; Takasu, A; Imai, T; Iwai, S; Yura, Y				Masui, Atsushi; Hamada, Masakazu; Kameyama, Hiroyasu; Wakabayashi, Ken; Takasu, Ayako; Imai, Tomoaki; Iwai, Soichi; Yura, Yoshiaki			Autophagy as a Survival Mechanism for Squamous Cell Carcinoma Cells in Endonuclease G-Mediated Apoptosis	PLOS ONE			English	Article							PROTEIN-KINASE-C; MALIGNANT GLIOMA-CELLS; COLON-CANCER CELLS; INHIBITOR SAFINGOL; HUMAN HEAD; INDUCTION; DEATH; MACROAUTOPHAGY; DEGRADATION; CISPLATIN	Safingol, L-threo-dihydrosphingosine, induces cell death in human oral squamous cell carcinoma (SCC) cells through an endonuclease G (endoG) -mediated pathway. We herein determined whether safingol induced apoptosis and autophagy in oral SCC cells. Safingol induced apoptotic cell death in oral SCC cells in a dose-dependent manner. In safingol-treated cells, microtubule-associated protein 1 light chain 3 (LC3)-I was changed to LC3-II and the cytoplasmic expression of LC3, amount of acidic vesicular organelles (AVOs) stained by acridine orange and autophagic vacuoles were increased, indicating the occurrence of autophagy. An inhibitor of autophagy, 3-methyladenine (3-MA), enhanced the suppressive effects of safingol on cell viability, and this was accompanied by an increase in the number of apoptotic cells and extent of nuclear fragmentation. The nuclear translocation of endoG was minimal at a low concentration of safingol, but markedly increased when combined with 3-MA. The suppressive effects of safingol and 3-MA on cell viability were reduced in endoG siRNA-transfected cells. The scavenging of reactive oxygen species (ROS) prevented cell death induced by the combinational treatment, whereas a pretreatment with a pan-caspase inhibitor z-VAD-fmk did not. These results indicated that safingol induced apoptosis and autophagy in SCC cells and that the suppression of autophagy by 3-MA enhanced apoptosis. Autophagy supports cell survival, but not cell death in the SCC cell system in which apoptosis occurs in an endoG-mediated manner.	[Masui, Atsushi; Hamada, Masakazu; Kameyama, Hiroyasu; Wakabayashi, Ken; Takasu, Ayako; Imai, Tomoaki; Iwai, Soichi; Yura, Yoshiaki] Osaka Univ, Grad Sch Dent, Dept Oral & Maxillofacial Surg, 1-8 Yamadaoka, Suita, Osaka 5650871, Japan		Hamada, M (corresponding author), Osaka Univ, Grad Sch Dent, Dept Oral & Maxillofacial Surg, 1-8 Yamadaoka, Suita, Osaka 5650871, Japan.	hmdmskz@dent.osaka-u.ac.jp	Imai, Tomoaki/AAY-9065-2020	Imai, Tomoaki/0000-0002-1404-8721; Yura, Yoshiaki/0000-0002-9469-5477	Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [25861929]	This work was supported by a Grant-in Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 25861929, http://www.jsps.go.jp/english/e.grants/index.html). The funder had a role in data collection and analysis, as well as in preparing the manuscript.; This work was supported by a Grant-in Aid for Scientific Research from the Japan Society for the Promotion of Science (No.25861929). The funder had a role in data collection and analysis, as well as in preparing the manuscript.	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J	Guo, Y; Shan, QQ; Gong, PY; Wang, SC				Guo, Yong; Shan, Qing Qing; Gong, Ping Yu; Wang, Sen Chun			The autophagy induced by curcumin via MEK/ERK pathway plays an early anti-leukemia role in human Philadelphia chromosome-positive acute lymphoblastic leukemia SUP-B15 cells	JOURNAL OF CANCER RESEARCH AND THERAPEUTICS			English	Article						Autophagy; curcumin; Philadelphia chromosome-positive acute lymphoblastic leukemia; RAF/MEK/ERK	CHRONIC MYELOID-LEUKEMIA; COLON-CANCER CELLS; SIGNALING PATHWAYS; TYROSINE KINASE; DEATH; APOPTOSIS; INDUCTION; THERAPY; MACROAUTOPHAGY; TRANSFORMATION	Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL tyrosine kinase which activates the downstream signaling pathways, such as Akt/mTOR, RAF/MEK/ERK, and STAT5 pathways. Curcumin has been shown to have inhibitory effects on cancers by inducing apoptosis and autophagy. We demonstrated that curcumin inhibited activation of Akt-mTOR, ABL/STAT5 pathways, inhibited cell proliferation, and induced apoptosis in Ph+ ALL cells. Experiments here, were conducted to determine whether autophagy via MEK/ERK pathway involved in anti-leukemia effect of curcumin in Ph+ ALL. Materials and Methods: Ph+ ALL cell line SUP-B15 was treated with curcumin. Cytotoxic activity of curcumin was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Signaling protein and specific maker of autophagy and conversion of LC3-I to LC3-II were determined by Western blot analysis. Cell apoptosis was determined by flow cytometry. Results: Curcumin treatment up-regulated the activation of RAF/MEK/ERK at 4 h and 8 h after curcumin exposure in SUP-B15 cells, curcumin treatment induced autophagy at exactly 4 h and 8 h after curcumin exposure. Curcumin exerted cytotoxic activity against SUP-B15 cells at 4 h and 8 h, which was independent of apoptosis. MEK specific inhibitor U0126 inhibited the occurrence of autophagy, and then blocked curcumin-induced cytotoxicity at 4 h and 8 h. Conclusions: Curcumin induce autophagic cell death in SUP-B15 cells via activating RAF/MEK/ERK pathway. These findings suggest that autophagic mechanism contribute to the curcumin-induced early SUP-B15 cell death, and autophagy is another anti-leukemia mechanism of curcumin.	[Guo, Yong; Shan, Qing Qing; Gong, Ping Yu] Sichuan Univ, West China Hosp, Dept Hematol, 37 Guo Xue Xiang, Chengdu 610041, Sichuan, Peoples R China; [Guo, Yong; Shan, Qing Qing; Gong, Ping Yu] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, 37 Guo Xue Xiang, Chengdu 610041, Sichuan, Peoples R China; [Wang, Sen Chun] Sichuan Prov Peoples Hosp, Dept Hematol, Chengdu 610041, Sichuan, Peoples R China		Gong, PY (corresponding author), Sichuan Univ, West China Hosp, Dept Hematol, 37 Guo Xue Xiang, Chengdu 610041, Sichuan, Peoples R China.; Gong, PY (corresponding author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, 37 Guo Xue Xiang, Chengdu 610041, Sichuan, Peoples R China.	gongyuping@hotmail.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81400123]; Foundation of the Science and Technology Department of Sichuan Province [2013SZ0025]	National Natural Science Foundation of China (No. 81400123), Foundation of the Science and Technology Department of Sichuan Province (No. 2013SZ0025).	Aggarwal BB, 2003, ANTICANCER RES, V23, P363; Aoki H, 2007, MOL PHARMACOL, V72, P29, DOI 10.1124/mol.106.033167; Dombret H, 2002, BLOOD, V100, P2357, DOI 10.1182/blood-2002-03-0704; Druker BJ, 2001, NEW ENGL J MED, V344, P1038, DOI 10.1056/NEJM200104053441402; Ellington AA, 2006, CARCINOGENESIS, V27, P298, DOI 10.1093/carcin/bgi214; Eskelinen EL, 2005, CELL DEATH DIFFER, V12, P1468, DOI 10.1038/sj.cdd.4401721; Faderl S, 2003, CANCER-AM CANCER SOC, V98, P1337, DOI 10.1002/cncr.11664; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Gruber F, 2009, BRIT J HAEMATOL, V145, P581, DOI 10.1111/j.1365-2141.2009.07666.x; Guillon-Munos A, 2006, AUTOPHAGY, V2, P140, DOI 10.4161/auto.2.2.2443; Hochhaus A, 2009, LEUKEMIA, V23, P1054, DOI 10.1038/leu.2009.38; Karunagaran D, 2005, CURR CANCER DRUG TAR, V5, P117, DOI 10.2174/1568009053202081; Kim JY, 2012, ARCH ORAL BIOL, V57, P1018, DOI 10.1016/j.archoralbio.2012.04.005; Kunnumakkara AB, 2008, CANCER LETT, V269, P199, DOI 10.1016/j.canlet.2008.03.009; Lee YJ, 2011, KOREAN J PHYSIOL PHA, V15, P1, DOI 10.4196/kjpp.2011.15.1.1; Li B, 2013, INT J GYNECOL CANCER, V23, P803, DOI 10.1097/IGC.0b013e31828c9581; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Mathew R, 2007, GENE DEV, V21, P1367, DOI 10.1101/gad.1545107; Moorman AV, 2007, BLOOD, V109, P3189, DOI 10.1182/blood-2006-10-051912; O'Sullivan-Coyne G, 2009, BRIT J CANCER, V101, P1585, DOI 10.1038/sj.bjc.6605308; Ogier-Denis E, 2000, J BIOL CHEM, V275, P39090, DOI 10.1074/jbc.M006198200; Ottmann OG, 2002, BLOOD, V100, P1965, DOI 10.1182/blood-2001-12-0181; Pattingre S, 2003, J BIOL CHEM, V278, P16667, DOI 10.1074/jbc.M210998200; Piccaluga PP, 2006, EXPERT OPIN BIOL TH, V6, P1011, DOI 10.1517/14712598.6.10.1011; Pui CH, 2006, NEW ENGL J MED, V354, P166, DOI 10.1056/NEJMra052603; Sawyers CL, 1997, BAILLIERE CLIN HAEM, V10, P223, DOI 10.1016/S0950-3536(97)80004-2; Schultz KR, 2009, J CLIN ONCOL, V27, P5175, DOI 10.1200/JCO.2008.21.2514; Sharma RA, 2005, EUR J CANCER, V41, P1955, DOI 10.1016/j.ejca.2005.05.009; Shintani T, 2004, SCIENCE, V306, P990, DOI 10.1126/science.1099993; Skorski T, 1997, EMBO J, V16, P6151, DOI 10.1093/emboj/16.20.6151; Wu JC, 2011, MOL NUTR FOOD RES, V55, P1646, DOI 10.1002/mnfr.201100454; Yamauchi Y, 2012, PHYTOTHER RES, V26, P1779, DOI 10.1002/ptr.4645	32	10	11	2	8	WOLTERS KLUWER MEDKNOW PUBLICATIONS	MUMBAI	WOLTERS KLUWER INDIA PVT LTD , A-202, 2ND FLR, QUBE, C T S  NO 1498A-2 VILLAGE MAROL, ANDHERI EAST, MUMBAI, 400059, INDIA	0973-1482	1998-4138		J CANCER RES THER	J. Canc. Res. Ther.		2018	14			1			S125	S131		10.4103/0973-1482.172111			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GM1NJ	WOS:000437835100021	29578162	gold			2022-04-25	
J	Xia, D; Ji, WL; Xu, CT; Lin, X; Wang, XK; Xia, Y; Lv, P; Song, QS; Ma, DL; Chen, YY				Xia, Dan; Ji, Wanli; Xu, Chentong; Lin, Xin; Wang, Xiaokun; Xia, Yan; Lv, Ping; Song, Quansheng; Ma, Dalong; Chen, Yingyu			Knockout of MARCH2 inhibits the growth of HCT116 colon cancer cells by inducing endoplasmic reticulum stress	CELL DEATH & DISEASE			English	Article							UNFOLDED PROTEIN RESPONSE; ER STRESS; SIGNALING PATHWAY; PROSTATE-CANCER; GRP78; AUTOPHAGY; INVOLVEMENT; RECURRENCE; ACTIVATION; MECHANISMS	Membrane-associated RING-CH protein 2 (MARCH2), a member of the MARCH family, functions in vesicle trafficking and autophagy regulation. In this study, we established MARCH2 knockout HCT116 cell lines using CRISPR/Cas9-mediated genome editing to evaluate the role of MARCH2 in colon cancer in vitro and in vivo. Knockout of MARCH2 suppressed cell proliferation, and promoted autophagy, apoptosis and G2/M phase cell cycle arrest. These effects were associated with activation of endoplasmic reticulum (ER) stress. In addition, loss of MARCH2 sensitized HCT116 cells to the chemotherapy drugs etoposide and cisplatin. Moreover, we analyzed the clinical significance of MARCH2 in human colon carcinoma (n=100). High MARCH2 expression was significantly associated with advanced clinicopathological features and poorer overall survival in colon carcinoma. MARCH2 expression correlated negatively with expression of the unfolded protein response molecule p-PERK in colon cancer. Collectively, these data reveal a relationship between MARCH2, ER stress and colon cancer, and indicates MARCH2 may have an important role in the development and progression of colon cancer.	[Xia, Dan; Xu, Chentong; Lin, Xin; Wang, Xiaokun; Xia, Yan; Lv, Ping; Song, Quansheng; Ma, Dalong; Chen, Yingyu] Peking Univ, Sch Basic Med Sci, Key Lab Med Immunol, Dept Immunol,Minist Hlth,Hlth Sci Ctr, 38 Xueyuan Rd, Beijing 100191, Peoples R China; [Xia, Dan] Shandong Med Coll, Dept Pathol, 6 Jucai Rd, Linyi 276000, Peoples R China; [Xia, Dan; Xu, Chentong; Lin, Xin; Wang, Xiaokun; Xia, Yan; Lv, Ping; Song, Quansheng; Ma, Dalong; Chen, Yingyu] Peking Univ, Ctr Human Dis Genom, 38 Xueyuan Rd, Beijing 100191, Peoples R China; [Ji, Wanli] Shandong Med Coll, Affiliated Hosp, Dept Pathol, 80 Jintan Rd, Linyi 276000, Peoples R China		Chen, YY (corresponding author), Peking Univ, Sch Basic Med Sci, Dept Immunol, 38 Xueyuan Rd, Beijing 100191, Peoples R China.	yingyu_chen@bjmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [3137089, 814201080028, 91430101]; Projects of medical and health technology development program in Shandong province [2016WS0569]; The science and technology plan project of Shandong higher education institutions [J17KA238]	This work was supported by grants from the National Natural Science Foundation of China (31370898, 81420108002, 91430101), Projects of medical and health technology development program in Shandong province (2016WS0569), The science and technology plan project of Shandong higher education institutions (J17KA238).	Ando T, 2001, J BIOL CHEM, V276, P42971, DOI 10.1074/jbc.M106460200; Ariyasu D, 2017, INT J MOL SCI, V18, DOI 10.3390/ijms18020382; Bartee E, 2004, J VIROL, V78, P1109, DOI 10.1128/JVI.78.3.1109-1120.2004; Boutell C, 2002, J VIROL, V76, P841, DOI 10.1128/JVI.76.2.841-850.2002; Brewer JW, 2000, P NATL ACAD SCI USA, V97, P12625, DOI 10.1073/pnas.220247197; Burdelski C, 2015, CLIN CANCER RES, V21, P3471, DOI 10.1158/1078-0432.CCR-14-0620; Cai Y, 2016, J CELL BIOL, V215, P245, DOI 10.1083/jcb.201605065; Cao ZF, 2008, CELL SIGNAL, V20, P73, DOI 10.1016/j.cellsig.2007.08.019; Carroll D, 2014, ANNU REV BIOCHEM, V83, P409, DOI 10.1146/annurev-biochem-060713-035418; Chen L, 2016, LEUKEMIA RES, V49, P7, DOI 10.1016/j.leukres.2016.07.006; Cheng J, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0068001; Cong L, 2013, SCIENCE, V339, P819, DOI 10.1126/science.1231143; Cubillos-Ruiz JR, 2017, CELL, V168, P692, DOI 10.1016/j.cell.2016.12.004; Daneshmand S, 2007, HUM PATHOL, V38, P1547, DOI 10.1016/j.humpath.2007.03.014; Ghosh R, 2014, CELL, V158, P534, DOI 10.1016/j.cell.2014.07.002; Greenman C, 2007, NATURE, V446, P153, DOI 10.1038/nature05610; Guo ML, 2015, AUTOPHAGY, V11, P995, DOI 10.1080/15548627.2015.1052205; Han SO, 2012, J CELL BIOL, V199, P817, DOI 10.1083/jcb.201208192; Hiramatsu N, 2015, AM J PATHOL, V185, P1800, DOI 10.1016/j.ajpath.2015.03.009; Kang BR, 2016, SCI REP-UK, V6, DOI 10.1038/srep34922; Kugimiya N, 2015, J CELL MOL MED, V19, P1569, DOI 10.1111/jcmm.12531; Malumbres M, 2005, TRENDS BIOCHEM SCI, V30, P630, DOI 10.1016/j.tibs.2005.09.005; Moscat J, 2016, CELL, V167, P606, DOI 10.1016/j.cell.2016.09.030; Nakamura N, 2005, MOL BIOL CELL, V16, P1696, DOI 10.1091/mbc.E04-03-0216; Nishimura T, 2017, EMBO J, V36, P1719, DOI 10.15252/embj.201695189; Oakes SA, 2017, AM J PHYSIOL-CELL PH, V312, pC93, DOI 10.1152/ajpcell.00266.2016; Pytel D, 2016, PLOS GENET, V12, DOI 10.1371/journal.pgen.1006518; Rani S, 2017, MOL CELLS, V40, P66, DOI 10.14348/molcells.2017.2259; Ron D, 2007, NAT REV MOL CELL BIO, V8, P519, DOI 10.1038/nrm2199; Rozpedek W, 2016, CURR MOL MED, V16, P533, DOI 10.2174/1566524016666160523143937; Schlafli AM, 2016, ONCOTARGET, V7, P39544, DOI 10.18632/oncotarget.9647; Senft D, 2015, TRENDS BIOCHEM SCI, V40, P141, DOI 10.1016/j.tibs.2015.01.002; Shuda M, 2003, J HEPATOL, V38, P605, DOI 10.1016/S0168-8278(03)00029-1; Tameire F, 2015, SEMIN CANCER BIOL, V33, P3, DOI 10.1016/j.semcancer.2015.04.002; Wu HM, 2014, HUM PATHOL, V45, P1936, DOI 10.1016/j.humpath.2014.04.023; Wu XB, 2014, NAT BIOTECHNOL, V32, P670, DOI 10.1038/nbt.2889; Xia D, 2016, AUTOPHAGY, V12, P1614, DOI 10.1080/15548627.2016.1192752; Xie YX, 2016, SCI REP-UK, V6, DOI 10.1038/srep38832; Xue Z, 2011, J BIOL CHEM, V286, P30859, DOI 10.1074/jbc.M111.273714; Zhang Z, 2004, J BIOL CHEM, V279, P16000, DOI 10.1074/jbc.M312264200; Zheng HC, 2008, HUM PATHOL, V39, P1042, DOI 10.1016/j.humpath.2007.11.009	41	11	12	3	12	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	2041-4889			CELL DEATH DIS	Cell Death Dis.	JUL	2017	8								e2957	10.1038/cddis.2017.347			11	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	FC5GR	WOS:000406870400046	28749466	gold, Green Published			2022-04-25	
J	Su, ZY; Yang, ZZ; Xu, YQ; Chen, YB; Yu, Q				Su, Zhenyi; Yang, Zuozhang; Xu, Yongqing; Chen, Yongbin; Yu, Qiang			MicroRNAs in apoptosis, autophagy and necroptosis	ONCOTARGET			English	Article						microRNA; apoptosis; autophagy; necroptosis; cancer progression	HEPATOCELLULAR-CARCINOMA CELLS; SUPPRESSES TUMOR-GROWTH; BREAST-CANCER CELLS; BCL-X-L; PROMOTES APOPTOSIS; COLORECTAL-CANCER; DOWN-REGULATION; PANCREATIC-CANCER; SIGNALING PATHWAYS; MEDIATED CLEAVAGE	MicroRNAs (miRNAs) are endogenous 22 nt non-coding RNAs that target mRNAs for cleavage or translational repression. Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis. We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression. We also discuss how miRNAs link different types of cell death.	[Su, Zhenyi] Southeast Univ, Sch Med, Dept Biochem & Mol Biol, Nanjing 210009, Jiangsu, Peoples R China; [Su, Zhenyi] Harvard Univ, Dept Cell Biol, Sch Med, Boston, MA 02115 USA; [Yang, Zuozhang] Kunming Med Univ, Tumor Hosp Yunnan Prov, Bone & Soft Tissue Tumors Res Ctr Yunnan Prov, Dept Orthopaed,Affiliated Hosp 3, Kunming 650118, Yunnan, Peoples R China; [Xu, Yongqing] Chengdu Mil Command, Kunming Gen Hosp, Dept Orthopaed, Kunming 650118, Yunnan, Peoples R China; [Chen, Yongbin] Chinese Acad Sci, Kunming Inst Zool, Key Lab Anim Models & Human Dis Mech, Kunming 650223, Yunnan, Peoples R China; [Yu, Qiang] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China		Yang, ZZ (corresponding author), Kunming Med Univ, Tumor Hosp Yunnan Prov, Bone & Soft Tissue Tumors Res Ctr Yunnan Prov, Dept Orthopaed,Affiliated Hosp 3, Kunming 650118, Yunnan, Peoples R China.	yangzuozhang@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81460440, 31300666, 81260322, 81372322]; Natural Science Foundation of Yunnan ProvinceNatural Science Foundation of Yunnan Province [2012FB163]; Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University [2014FB059]; Specialty Fund of High-level Talents Medical Personnel Training of Yunnan Province [D-201242]	This research was supported in part by grants from the National Natural Science Foundation of China (No. 81460440, No. 31300666, No. 81260322, and No. 81372322), the Natural Science Foundation of Yunnan Province (No. 2012FB163), the Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University (No. 2014FB059), and the Specialty Fund of High-level Talents Medical Personnel Training of Yunnan Province (No. D-201242).	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J	Grossi, V; Peserico, A; Tezil, T; Simone, C				Grossi, Valentina; Peserico, Alessia; Tezil, Tugsan; Simone, Cristiano			p38 alpha MAPK pathway: A key factor in colorectal cancer therapy and chemoresistance	WORLD JOURNAL OF GASTROENTEROLOGY			English	Article						p38 mitogen-activated protein kinase; Chemoresistance; Molecularly-targeted drugs; Colorectal cancer; Cell death	ACTIVATED PROTEIN-KINASE; JUN NH2-TERMINAL KINASE; SIGNAL-REGULATED KINASE; AUTOPHAGIC CELL-DEATH; INDUCED APOPTOSIS; OVARIAN-CANCER; IN-VITRO; MULTIKINASE INHIBITOR; MAMMARY TUMORIGENESIS; TRANSDUCTION PATHWAY	Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional therapies is frequently observed in advanced stages, where treatments become ineffective. Resistance to cisplatin, irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase (MAPK) signaling and recent studies identified p38 alpha MAPK as a mediator of resistance to various agents in CRC patients. Studies published in the last decade showed a dual role for the p38 alpha pathway in mammals. Its role as a negative regulator of proliferation has been reported in both normal (including cardiomyocytes, hepatocytes, fibroblasts, hematopoietic and lung cells) and cancer cells (colon, prostate, breast, lung tumor cells). This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli. However, despite its anti-proliferative and tumor suppressor activity in some tissues, the p38 alpha pathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism, invasion, inflammation and angiogenesis. In this review, we summarize current knowledge about the predominant role of the p38 alpha MAPK pathway in CRC development and chemoresistance. In our view, this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.	[Grossi, Valentina; Peserico, Alessia; Tezil, Tugsan; Simone, Cristiano] Univ Bari Aldo Moro, Dept Biomed Sci & Human Oncol DIMO, Div Med Genet, I-70124 Bari, Italy; [Grossi, Valentina; Peserico, Alessia; Tezil, Tugsan; Simone, Cristiano] IRCCS Oncol Giovanni Paolo II, Natl Canc Inst, I-70124 Bari, Italy; [Peserico, Alessia] Fdn Mario Negri Sud, I-66030 Santa Maria Imbaro, CH, Italy		Simone, C (corresponding author), Univ Bari Aldo Moro, Dept Biomed Sci & Human Oncol DIMO, Div Med Genet, Via Nazl 8-A, I-70124 Bari, Italy.	simone@negrisud.it	tezil, tugsan/P-4053-2019; Simone, Cristiano/K-3452-2018; Tezil, Tugsan/A-3909-2013; GROSSI, Valentina/O-6546-2019; Grossi, Valentina/K-9821-2016	Simone, Cristiano/0000-0002-2628-7658; Tezil, Tugsan/0000-0003-0796-3718; GROSSI, Valentina/0000-0003-3843-1618; Grossi, Valentina/0000-0003-3843-1618; Peserico, Alessia/0000-0003-2025-2419	Italian Association for Cancer Research (AIRC) fellowshipFondazione AIRC per la ricerca sul cancro; Italian Foundation for Cancer Research (FIRC) fellowshipsFondazione AIRC per la ricerca sul cancro; 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Gastroenterol.	AUG 21	2014	20	29					9744	9758		10.3748/wjg.v20.i29.9744			15	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	AN6TK	WOS:000340730300009	25110412	hybrid, Green Published			2022-04-25	
J	Ma, YM; Han, W; Li, J; Hu, LH; Zhou, YB				Ma, Yi-ming; Han, Wei; Li, Jia; Hu, Li-hong; Zhou, Yu-bo			Physalin B not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in human colon cancer cells in vitro	ACTA PHARMACOLOGICA SINICA			English	Article						physalin B; Physalis angulata L; HCT116 colon cancer cells; autophagy; reactive oxygen species; p38 mitogen-activated protein kinases; microtubule-associated proteins; apoptosis; ubiquitins; N-acetyl-L-cysteine	BIOLOGICAL EVALUATION; APOPTOSIS; DIFFERENTIATION; PROTEIN; STRESS; DESIGN; FUSION; ARREST; SYSTEM; ROLES	Aim: To investigate the effects of physalin B insolated from Physalis divericata on human colon cancer cells in vitro and its anticancer mechanisms. Methods: Human HCT116 colon cancer cell line was tested. Cell viability and apoptosis were detected, and relevant proteins were measured using Western blot analyses. Autophagosomes were observed in stable GFP-LC3 HCT116 cells. Localization of autophagosomes and lysosomes was evaluated in GFP-LC3/RFP-LAMP1-co-transfected cells. Microtubules and F-actin microfilaments were observed with confocal microscope. Mitochondrial ROS (mito-ROS) was detected with flow cytometry in the cells stained with MitoSox dye. Results: Physalin B inhibited the viability of HCT116 cells with an IC50 value of 1.35 mu mol/L. Treatment of the cells with physalin B (2.5-10 mu mol/L) induced apoptosis and the cleavage of PARP and caspase-3. Meanwhile, physalin B treatment induced autophagosome formation, and accumulation of LC3-II and p62, but decreased Beclin 1 protein level. Marked changes of microtubules and F-actin microfilaments were observed in physalin B-treated cells, which led to the blockage of co-localization of autophagosomes and lysosomes. Physalin B treatment dose-dependently increased the phosphorylation of p38, ERK and JNK in the cells, whereas the p38 inhibitor SB202190, ERK inhibitor U0126 or JNK inhibitor SP600125 could partially reduce physalin B-induced PARP cleavage and p62 accumulation. Moreover, physalin B treatment dose-dependently increased mito-ROS production in the cells, whereas the ROS scavenger NAC could reverse physalin B-induced effects, including incomplete autophagic response, accumulation of ubiquitinated proteins, changes of microtubules and F-actin, activation of p38, ERK and JNK, as well as cell death and apoptosis. Conclusion: Physalin B induces mito-ROS, which not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in HCT116 cells in vitro.	[Ma, Yi-ming; Han, Wei; Li, Jia; Hu, Li-hong; Zhou, Yu-bo] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China		Hu, LH (corresponding author), Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China.	lhhu@simm.ac.cn; ybzhou@simm.ac.cn	Ma, Yiming/AAG-3479-2019; Li, Jia/F-9116-2011		National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81473244, 81270942, 81125023]; National Science and Technology Major Projects for "Major New Drugs Innovation and Development" [2012ZX09301001-004, 2013ZX09508104]	This work was supported by grants from the National Natural Science Foundation of China (No 81473244, 81270942, and 81125023), and the National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2012ZX09301001-004, 2013ZX09508104).	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Sin.	APR	2015	36	4					517	527		10.1038/aps.2014.157			11	Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	CE9ZW	WOS:000352203300012	25832431	Green Published, Bronze			2022-04-25	
J	Wang, LJ; Chen, PR; Hsu, LP; Hsu, WL; Liu, DW; Chang, CH; Hsu, YC; Lee, JW				Wang, Ling-Jung; Chen, Peir-Rong; Hsu, Lee-Ping; Hsu, Wen-Lin; Liu, Dai-Wei; Chang, Chung-Hsing; Hsu, Yih-Chih; Lee, Jeng-Woei			Concomitant Induction of Apoptosis and Autophagy by Prostate Apoptosis Response-4 in Hypopharyngeal Carcinoma Cells	AMERICAN JOURNAL OF PATHOLOGY			English	Article							TUMOR-SUPPRESSOR PAR-4; COLON-CANCER CELLS; PROTEIN-KINASE; MAMMALIAN AUTOPHAGY; INHIBITS AUTOPHAGY; MEDIATED CLEAVAGE; CYCLIN D1; EXPRESSION; DEATH; PHOSPHORYLATION	The tumor-suppressive activity of prostate apoptosis response-4 (Par-4) has been demonstrated in a variety of human cancers. In this study, for the first time to our knowledge, we demonstrated that a higher intensity of Par-4 was significantly correlated with a better response in patients with hypopharyngeal carcinoma undergoing radiotherapy alone or concurrent chemoradiotherapy. Mechanistically, an elevated expression of Par-4 induced apoptosis of hypopharyngeal carcinoma cells and sensitized cells toward chemotherapeutic agents or X-ray irradiation. Along with apoptotic incitation, intriguingly, autophagic flux also increased on Par-4 stimulation and contributed to cell death. Moreover, the expressions of multiple common regulators involved in apoptosis and autophagy were regulated by Par-4. Taken together, our results suggested a prognostic role of Par-4 in hypopharyngeal carcinoma and showed novel activity of Par-4 in apoptosis and autophagy induction.	[Wang, Ling-Jung; Lee, Jeng-Woei] Tzu Chi Univ, Inst Med Sci, Hualien 97004, Taiwan; [Chen, Peir-Rong] Tzu Chi Univ, Dept Otolaryngol, Hualien 97004, Taiwan; [Lee, Jeng-Woei] Tzu Chi Univ, Dept Life Sci, Hualien 97004, Taiwan; [Hsu, Wen-Lin; Liu, Dai-Wei] Tzu Chi Univ, Sch Med, Hualien 97004, Taiwan; [Hsu, Lee-Ping] Buddhist Tzu Chi Gen Hosp, Dept Otorhinolaryngol, Taichung, Taiwan; [Hsu, Wen-Lin; Liu, Dai-Wei] Buddhist Tzu Chi Gen Hosp, Dept Radiat Oncol, Hualien, Taiwan; [Chang, Chung-Hsing] Kaohsiung Med Univ, Res Ctr Excellence Environm Med, Kaohsiung, Taiwan; [Chang, Chung-Hsing] Kaohsiung Med Univ, Dept Dermatol, Kaohsiung, Taiwan; [Hsu, Yih-Chih] Chung Yuan Christian Univ, Dept Biosci Technol, Tao Yuan, Taiwan; [Hsu, Yih-Chih] Chung Yuan Christian Univ, Ctr Nanotechnol, Tao Yuan, Taiwan		Lee, JW (corresponding author), Tzu Chi Univ, Dept Life Sci, 701 Zhongyang Rd,Sect 3, Hualien 97004, Taiwan.	jwlee@mail.tcu.edu.tw	Hsu, Yih-Chih/AAV-2616-2020	Chang, Chung Hsing/0000-0003-2197-4923	Taiwan National Science CouncilMinistry of Science and Technology, Taiwan [NSC99-2320-B-320-014-MY2]; Taiwan Department of Health [DOH97-TD-I-111-TM017]	Supported by the Taiwan National Science Council grant NSC99-2320-B-320-014-MY2 and the Taiwan Department of Health grant DOH97-TD-I-111-TM017.	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J. Pathol.	FEB	2014	184	2					418	430		10.1016/j.ajpath.2013.10.012			13	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	297LU	WOS:000330257700013	24418097	Bronze			2022-04-25	
J	Kralova, V; Benesova, S; Cervinka, M; Rudolf, E				Kralova, Vera; Benesova, Sona; Cervinka, Miroslav; Rudolf, Emil			Selenite-induced apoptosis and autophagy in colon cancer cells	TOXICOLOGY IN VITRO			English	Article						Sodium selenite; Colon cancer; Apoptosis; Autophagy	SODIUM-SELENITE; COLORECTAL-CANCER; DNA-DAMAGE; P53; ACTIVATION; EXPRESSION; DEATH; CHEMOPREVENTION; PATHWAYS; P38	Sodium selenite (Se) is known to induce diverse stress responses in malignant cells which may lead to various types of cell death including apoptosis and/or autophagy. In colon cancer cells, Se activates several signaling pathways whose interactions and ultimate endpoints may vary in individual study models. In our previous work we showed differences in Se-dependent growth inhibition, cell cycle alterations and apoptosis in colon cancer cells with functional (HCT-116) and deleted (HCT-116-p53KO) p53. Moreover, detailed morphological and biochemical analyses revealed the presence of autophagy in Se-treated cells. Thus the aim of this study was to investigate in detail mechanisms, relationship and crosstalk between apoptosis and autophagy in Se-treated HCT-116 cancer cells differing in p53 status since p53 has been shown to play a well-known role in apoptosis but dichotomous role in autophagy. We report that the absence of p53 in malignant colonocytes changes patterns of response to Se-induced stress which include differential activation of MAP kinases (p38 - HCT-116 and JNK - HCT-116 p53KO) including their respective roles in the process of apoptosis and autophagy as well as the involvement of mTOR or PI3K signaling. Our results seem to suggest that deletion of p53 inevitably leads to a higher level of instability and delays in an individual cell decision in the face of stress whether to activate apoptosis or autophagy which may consequently occur simultaneously with mutual dichotomous relationship. (C) 2011 Elsevier Ltd. All rights reserved.	[Kralova, Vera; Benesova, Sona; Cervinka, Miroslav; Rudolf, Emil] Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Hradec Kralove 50038, Czech Republic		Rudolf, E (corresponding author), Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Simkova 870, Hradec Kralove 50038, Czech Republic.	rudolf@lfhk.cuni.cz	Králová, Věra/B-6608-2017; Rudolf, Emil/B-5956-2017; Cervinka, Miroslav/R-7387-2016	Králová, Věra/0000-0001-5971-4110; Rudolf, Emil/0000-0002-9526-3174; Cervinka, Miroslav/0000-0001-8602-4756	GAUK [129609]; Ministry of Education of Czech RepublicMinistry of Education, Youth & Sports - Czech Republic [MSM 0021620820]	This research was supported by GAUK No. 129609 and Ministry of Education of Czech Republic Research Project MSM 0021620820.	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Vitro	MAR	2012	26	2					258	268		10.1016/j.tiv.2011.12.010			11	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	902DU	WOS:000301019600009	22200533				2022-04-25	
J	Baldea, I; Olteanu, D; Filip, GA; Pogacean, F; Coros, M; Suciu, M; Tripon, SC; Cenariu, M; Magerusan, L; Stefan-van Staden, RI; Pruneanu, S				Baldea, Ioana; Olteanu, Diana; Filip, Gabriela Adriana; Pogacean, Florina; Coros, Maria; Suciu, Maria; Tripon, Septimiu Cassian; Cenariu, Mihai; Magerusan, Lidia; Stefan-van Staden, Raluca-Ioana; Pruneanu, Stela			Cytotoxicity mechanisms of nitrogen-doped graphene obtained by electrochemical exfoliation of graphite rods, on human endothelial and colon cancer cells	CARBON			English	Article						Nitrogen-doped graphene; Electrochemical exfoliation of graphite; Cytotoxicity; Oxidative stress; Apoptosis; DNA lesions; Autophagy	WALLED CARBON NANOTUBES; IN-VITRO; QUANTUM DOTS; SIGNALING PATHWAYS; COLORECTAL-CANCER; PROTEIN-KINASE; OXIDE; AUTOPHAGY; TOXICITY; NANOMATERIALS	Three nitrogen-doped graphene samples were synthesized by electrochemical exfoliation of graphite rods via pulses of current. Depending on the synthesis conditions, the samples had different content of nitrogen (0.79, 2.56 and 2.33 wt%) and were denoted as NGr-1, NGr-2 and NGr-3, respectively. All samples consist in a mixture of graphene oxide, few- and multi-layer graphene. Several biological effects (cytotoxicity, oxidative stress induction, apoptosis, autophagy and DNA lesions) induced by the N-doped graphenes on human endothelial and colon cancer cells were investigated. The in vitro effects of graphenes were different and depended on the type of cell and the amount of nitrogen in the structure. On human endothelial cells, the graphenes showed antioxidant effects and were less toxic than on colon cancer cells, especially the one with low content of nitrogen (NGr-1). In contrast, on colon cancer cells the graphenes induced cell death by various mechanisms: free radicals generation, apoptosis, autophagy and DNA damage. The most severe DNA lesions and ultrastructural changes were produced by graphene with high content of nitrogen (NGr-2 and NGr-3). Our research demonstrates the cytotoxic effect of graphene with high content of nitrogen on colon cancer cells and antioxidant and protective properties on human endothelial cells. (C) 2019 Elsevier Ltd. All rights reserved.	[Baldea, Ioana; Olteanu, Diana; Filip, Gabriela Adriana] Iuliu Hatieganu Univ Med & Pharm, Physiol Dept, Cluj Napoca, Romania; [Pogacean, Florina; Coros, Maria; Suciu, Maria; Tripon, Septimiu Cassian; Magerusan, Lidia; Pruneanu, Stela] Natl Inst Res & Dev Isotop & Mol Technol, Donat St 67-103, RO-400293 Cluj Napoca, Romania; [Suciu, Maria; Tripon, Septimiu Cassian] Babes Bolyai Univ, Biol & Geol Fac, Mol Biol & Biotechnol Dept, 4-7 Clin Str, Cluj Napoca 400007, Romania; [Cenariu, Mihai] Univ Agr Sci & Vet Med, Dept Anim Reprod, Cluj Napoca, Romania; [Stefan-van Staden, Raluca-Ioana] Natl Inst Res Electrochem & Condensed Matter, Lab Electrochem, 202 Splaiul Independentei St, Bucharest 060021 6, Romania; [Stefan-van Staden, Raluca-Ioana] Natl Inst Res Electrochem & Condensed Matter, PATLAB, 202 Splaiul Independentei St, Bucharest 060021 6, Romania; [Stefan-van Staden, Raluca-Ioana] Univ Politehn Bucuresti, Fac Appl Chem & Mat Sci, Bucharest, Romania		Filip, GA (corresponding author), Iuliu Hatieganu Univ Med & Pharm, Physiol Dept, Cluj Napoca, Romania.; Pruneanu, S (corresponding author), Natl Inst Res & Dev Isotop & Mol Technol, Donat St 67-103, RO-400293 Cluj Napoca, Romania.	adrianafilip33@yahoo.com; gabriela.filip@umfcluj.ro	Suciu, Maria/N-7405-2017; Coros, Maria/S-1091-2019; Magerusan, Lidia/R-8552-2016; Ioana, Baldea/Y-6129-2019; Adriana, Filip Gabriela/AAB-7418-2019; Olteanu, Elena Diana/A-4750-2017; Pogacean, Florina/B-7876-2012; Coros, Maria/C-2635-2012; Lidia, Magerusan/X-2146-2019; Cenariu, Mihai Cosmin/C-2558-2012; Magerusan, Lidia/ABC-7589-2021	Suciu, Maria/0000-0001-5449-9108; Coros, Maria/0000-0002-7733-4725; Magerusan, Lidia/0000-0002-7998-7754; Adriana, Filip Gabriela/0000-0002-7447-4925; Olteanu, Elena Diana/0000-0002-3034-3659; Lidia, Magerusan/0000-0002-7998-7754; Cenariu, Mihai Cosmin/0000-0001-6501-0128; Baldea, Ioana/0000-0003-4046-7310	Ministry of Research and Innovation, CNCS - UEFISCDI, within PNCDI III [PN-III-P4-ID-PCCF2016-0006]; Project: Research Center and Advanced Technologies for Alternative Energies -CETATEA [POS-CCE 623/11.03.2014]	This work was supported by a grant of Ministry of Research and Innovation, CNCS - UEFISCDI, project number PN-III-P4-ID-PCCF2016-0006, within PNCDI III. TEM measurements were partially supported through the infrastructure obtained in the Project: Research Center and Advanced Technologies for Alternative Energies -CETATEA - POS-CCE 623/11.03.2014. The authors are grateful to PhD student Alexandru Turza for recording the XRD measurements, Dr. Emese Gal for Elemental Analysis, Dr. Ioan Ovidiu Pana and Dr. Cristian Leostean for recording XPS measurements, Dr. Camelia Berghian-Grosan for recording Raman measurements, Dr. Maria Perde (Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania) for assistance with the DCFDA assay and Dr. Olga Soritau (Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania) for helpful comments and suggestions.	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J	Zhao, Y; Yang, J; Liao, WJ; Liu, XY; Zhang, H; Wang, S; Wang, DL; Feng, JN; Yu, L; Zhu, WG				Zhao, Ying; Yang, Jing; Liao, Wenjuan; Liu, Xiangyu; Zhang, Hui; Wang, Shan; Wang, Donglai; Feng, Jingnan; Yu, Li; Zhu, Wei-Guo			Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity	NATURE CELL BIOLOGY			English	Article							TRANSCRIPTION FACTORS; CELL-DEATH; LIFE-SPAN; ACTIVATION; BECLIN-1; TARGET; GENE; TUMORIGENESIS; EXPRESSION; PROTEINS	Autophagy is characterized by the sequestration of bulk cytoplasm, including damaged proteins and organelles, and delivery of the cargo to lysosomes for degradation. Although the autophagic pathway is also linked to tumour suppression activity, the mechanism is not yet clear. Here we report that cytosolic FoxO1, a forkhead O family protein, is a mediator of autophagy. Endogenous FoxO1 was required for autophagy in human cancer cell lines in response to oxidative stress or serum starvation, but this process was independent of the transcriptional activity of FoxO1. In response to stress, FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2), a NAD(+)-dependent histone deacetylase, and the acetylated FoxO1 bound to Atg7, an E1-following protein, to influence the autophagic process leading to cell death. This FoxO1-modulated cell death is associated with tumour suppressor activity in human colon tumours and a xenograft mouse model. Our finding links the anti-neoplastic activity of FoxO1 and the process of autophagy.	[Zhao, Ying; Yang, Jing; Liao, Wenjuan; Liu, Xiangyu; Zhang, Hui; Wang, Donglai; Feng, Jingnan; Zhu, Wei-Guo] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100191, Peoples R China; [Zhang, Hui; Wang, Shan] Peking Univ, Hlth Sci Ctr, Dept Surg, Affiliated Hosp 2, Beijing 100044, Peoples R China; [Yu, Li] Tsinghua Univ, Dept Biol Sci, Beijing 100084, Peoples R China; Peking Univ, Beijing 00142, Peoples R China; [Zhu, Wei-Guo] Peking Univ, Hlth Sci Ctr, Sch Oncol, Beijing 00142, Peoples R China		Zhu, WG (corresponding author), Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100191, Peoples R China.	zhuweiguo@bjmu.edu.cn	liu, xiangyu/D-8213-2014; zhu, wei-guo/E-1334-2012	Zhu, Wei-Guo/0000-0001-8385-6581			Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Al-Mubarak B, 2009, CHANNELS, V3, P233; Arden KC, 2007, CELL, V128, P235, DOI 10.1016/j.cell.2007.01.009; 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Cell Biol.	JUL	2010	12	7					665	U88		10.1038/ncb2069			19	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	618RW	WOS:000279374400010	20543840				2022-04-25	
J	Zheng, Z; He, QS; Xu, LT; Cui, WH; Bai, H; Zhang, Z; Rao, J; Dou, FF				Zheng, Zhi; He, Qinsi; Xu, Liting; Cui, Wenhao; Bai, Hua; Zhang, Zhe; Rao, Jun; Dou, Fangfang			The peiminine stimulating autophagy in human colorectal carcinoma cells via AMPK pathway by SQSTM1	OPEN LIFE SCIENCES			English	Article						peiminine; autophagy; natural product; autophagic cell death; SQTEM1; AMPK/mTOC/ULK signaling pathway	APOPTOSIS; GROWTH; P62	Autophagy is a conserved catabolic process, which functions in maintenance of cellular homeostasis in eukaryotic cells. The self-eating process engulfs cellular long-lived proteins and organelles with double-membrane vesicles, and forms a so-called autophagosome. Degradation of contents via fusion with lysosome provides recycled building blocks for synthesis of new molecules during stress, e.g. starvation. Peiminine is a steroidal alkaloid extracted from Fritillaria thunbergii which is widely used in Traditional Chinese Medicine. Previously, peiminine has been identified to induce autophagy in human colorectal carcinoma cells. In this study, we further investigated whether peiminine could induce autophagic cell death via activating autophagy-related signaling pathway AMPK-mTOR-ULK by promoting SQSTM1(P62). Xenograft tumor growth in vivo suggested that both peiminine and starvation inhibit the growth of tumor size and weight, which was prominently enhanced when peiminine and starvation combined. The therapeutical effect of peiminine in cancer treatment is to be expected.	[Zheng, Zhi; He, Qinsi; Xu, Liting; Rao, Jun; Dou, Fangfang] Nanchang Univ, Grad Sch Med, Nanchang 330029, Jiangxi, Peoples R China; [Zheng, Zhi; He, Qinsi; Xu, Liting; Rao, Jun; Dou, Fangfang] Jiangxi Canc Hosp, Jiangxi Canc Ctr, Nanchang 330029, Jiangxi, Peoples R China; [Cui, Wenhao] Lavion Life Inc, Life Sci R&D Ctr, Beijing 100020, Peoples R China; [Bai, Hua] China Acad Chinese Med Sci, Guanganmen Hosp, South Area, Beijing 102618, Peoples R China; [Zhang, Zhe] China Japan Friendship Hosp, Dept TCM Gastroenterol, Beijing 100029, Peoples R China		Dou, FF (corresponding author), Nanchang Univ, Grad Sch Med, Nanchang 330029, Jiangxi, Peoples R China.	zheng_sheva@hotmail.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81260592]	This work was supported by the National Natural Science Foundation of China (No. 81260592). The funding institutes had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	Alers S, 2012, MOL CELL BIOL, V32, P2, DOI 10.1128/MCB.06159-11; Aneja R, 2007, CANCER RES, V67, P3862, DOI 10.1158/0008-5472.CAN-06-4282; Feng LF, 2014, AUTOPHAGY, V10, P1442, DOI 10.4161/auto.29486; Ferrandiz N, 2009, DNA REPAIR, V8, P390, DOI 10.1016/j.dnarep.2008.12.001; Gump JM, 2011, TRENDS CELL BIOL, V21, P387, DOI 10.1016/j.tcb.2011.03.007; Inoue D, 2012, CANCER SCI, V103, P760, DOI 10.1111/j.1349-7006.2012.02216.x; Kim J, 2011, NAT CELL BIOL, V13, P132, DOI 10.1038/ncb2152; Kim PK, 2008, P NATL ACAD SCI USA, V105, P20567, DOI 10.1073/pnas.0810611105; Komatsu M, 2011, AUTOPHAGY, V7, P1088, DOI 10.4161/auto.7.9.16474; Kuo WL, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0090171; Liang JY, 2013, CANCER RES, V73, P2929, DOI 10.1158/0008-5472.CAN-12-3876; Long Z, 2016, TALANTA, V151, P239, DOI 10.1016/j.talanta.2016.01.027; Lozy F, 2012, SEMIN CELL DEV BIOL, V23, P395, DOI 10.1016/j.semcdb.2012.01.005; Lyu Q, 2015, BIOCHEM BIOPH RES CO, V462, P38, DOI 10.1016/j.bbrc.2015.04.102; Mihaylova MM, 2011, NAT CELL BIOL, V13, P1016, DOI 10.1038/ncb2329; Moscat J, 2009, CELL, V137, P1001, DOI 10.1016/j.cell.2009.05.023; Neufeld TP, 2012, J CELL SCI, V125, P2359, DOI 10.1242/jcs.103333; Shimizu S, 2014, INT J MOL SCI, V15, P3145, DOI 10.3390/ijms15023145; Tsujimoto Y, 2005, CELL DEATH DIFFER, V12, P1528, DOI 10.1038/sj.cdd.4401777; Wang DD, 2014, NUTR CANCER, V66, P441, DOI 10.1080/01635581.2013.878737; White E, 2009, CLIN CANCER RES, V15, P5308, DOI 10.1158/1078-0432.CCR-07-5023; Zhang Y, 2013, J MATER CHEM B, V1, P132, DOI 10.1039/c2tb00071g	22	4	5	2	12	SCIENDO	WARSAW	DE GRUYTER POLAND SP Z O O, BOGUMILA ZUGA 32A STR, 01-811 WARSAW, POLAND	2391-5412			OPEN LIFE SCI	Open Life Sci.	JAN	2016	11	1					358	366		10.1515/biol-2016-0047			9	Biology	Science Citation Index Expanded (SCI-EXPANDED)	Life Sciences & Biomedicine - Other Topics	EI4YH	WOS:000392499400011		gold			2022-04-25	
J	Xie, CM; Liu, XY; Sham, KWY; Lai, JMY; Cheng, CHK				Xie, Chuan-Ming; Liu, Xiao-Yu; Sham, Kathy W. Y.; Lai, Josie M. Y.; Cheng, Christopher H. K.			Silencing of EEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1-dependent autophagy in colon cancer cells	AUTOPHAGY			English	Review						elongation factor-2 kinase; autophagy; colon cancer; AMPK; ULK1; ATG; MTOR; ROS; cancer growth; cell survival	PROTEIN-SYNTHESIS; PHOSPHORYLATION; AMPK; GLIOBLASTOMA; TRANSLATION; ASSOCIATION; ACTIVATION; RESISTANCE; INDUCTION; APOPTOSIS	EEF2K (eukaryotic elongation factor-2 kinase), also known as Ca2+/calmodulin-dependent protein kinase III, functions in downregulating peptide chain elongation through inactivation of EEF2 (eukaryotic translation elongation factor 2). Currently, there is a limited amount of information on the promotion of autophagic survival by EEF2K in breast and glioblastoma cell lines. However, the precise role of EEF2K in carcinogenesis as well as the underlying mechanism involved is still poorly understood. In this study, contrary to the reported autophagy-promoting activity of EEF2K in certain cancer cells, EEF2K is shown to negatively regulate autophagy in human colon cancer cells as indicated by the increase of LC3-II levels, the accumulation of LC3 dots per cell, and the promotion of autophagic flux in EEF2K knockdown cells. EEF2K negatively regulates cell viability, clonogenicity, cell proliferation, and cell size in colon cancer cells. Autophagy induced by EEF2K silencing promotes cell survival and does not potentiate the anticancer efficacy of the AKT inhibitor MK-2206. In addition, autophagy induced by silencing of EEF2K is attributed to induction of protein synthesis and activation of the AMPK-ULK1 pathway, independent of the suppression of MTOR activity and ROS generation. Knockdown of AMPK or ULK1 significantly abrogates EEF2K silencing-induced increase of LC3-II levels, accumulation of LC3 dots per cell as well as cell proliferation in colon cancer cells. In conclusion, silencing of EEF2K promotes autophagic survival via activation of the AMPK-ULK1 pathway in colon cancer cells. This finding suggests that upregulation of EEF2K activity may constitute a novel approach for the treatment of human colon cancer.	[Xie, Chuan-Ming; Liu, Xiao-Yu; Sham, Kathy W. Y.; Lai, Josie M. Y.; Cheng, Christopher H. K.] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China; [Cheng, Christopher H. K.] Chinese Univ Hong Kong, Ctr Novel Funct Mol, Hong Kong, Hong Kong, Peoples R China		Cheng, CHK (corresponding author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China.	chkcheng@cuhk.edu.hk	CHENG, Ki Christopher/R-9641-2018; Xie, Chuan-Ming/AAT-9557-2021	CHENG, Ki Christopher/0000-0001-8970-9048; Xie, Chuan-Ming/0000-0003-4362-6612; Sham, Kathy Wai-yan/0000-0002-8883-2551; Xiaoyu, LIU/0000-0001-5259-7038	Chinese University of Hong KongChinese University of Hong Kong	This work was supported by a Strategic Investments Scheme from the Chinese University of Hong Kong. We thank the Chinese University of Hong Kong for the provision of Direct Grants. We also thank the depositors of the Addgene plasmid pDONR223-EEF2K (# 23726), Dr William Hahn and Dr David Root of Broad Institute of Harvard and Massachusetts Institute of Technology, Massachusetts.	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J	Deng, HM; Huang, L; Liao, ZK; Liu, M; Li, Q; Xu, RH				Deng, Huiming; Huang, Ling; Liao, Zhongkai; Liu, Mi; Li, Qiang; Xu, Ronghua			Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells	CELL DEATH & DISEASE			English	Article							PROLIFERATION; CHEMOTHERAPY; ANTIFUNGAL; ACTIVATION; MECHANISMS; PROTEINS; SURVIVAL; GROWTH; GLI1	Itraconazole is as an antifungal medication used to treat systemic fungal infections. Recently, it has been reported to be effective in suppressing tumor growth by inhibiting the Hedgehog signaling pathway and angiogenesis. In the present study, we investigated whether itraconazole induces autophagy-mediated cell death of colon cancer cells through the Hedgehog signaling pathway. Cell apoptosis and cell cycle distribution of the colon cancer cell lines SW-480 and HCT-116 were detected by flow cytometry and terminal TUNEL assay. Autophagy and signal proteins were detected by western blotting and cell proliferation-associated antigen Ki-67 was measured using immunohistochemistry. The images of autophagy flux and formation of autophagosomes were observed by laser scanning confocal and/or transmission electron microscopy. Colon cancer cell xenograft mouse models were also established. Itraconazole treatment inhibited cell proliferation via G1 cell cycle arrest as well as autophagy-mediated apoptosis of SW-480 and HCT-116 colon cancer cells. In addition, the Hedgehog pathway was found to be involved in activation of itraconazole-mediated autophagy. After using the Hedgehog agonist recombinant human Sonic Hedgehog (rhshh), itraconazole could counteract the activation of rhshh. Moreover, treatment with itraconazole produced significant cancer inhibition in HCT-116-bearing mice. Thus, itraconazole may be a potential and effective therapy for the treatment of colon cancer.	[Deng, Huiming; Xu, Ronghua] Huazhong Univ Sci & Technol, Dept Gastrointestinal Surg, Union Shenzhen Hosp, 89 Taoyuan Rd, Shenzhen 518000, Peoples R China; [Deng, Huiming] Zengcheng Dist Peoples Hosp Guangzhou, Dept Gen Surg, 1 Guangming East Rd, Guangzhou 511300, Peoples R China; [Huang, Ling; Liu, Mi] Hainan Med Univ, Sch Hainan Prov Drug Safety Evaluat Res Ctr, 3 Xueyuan Rd, Haikou 571199, Hainan, Peoples R China; [Huang, Ling] Hainan Med Univ, Key Lab Emergency & Trauma, Minist Educ, 3 Xueyuan Rd, Haikou 571199, Hainan, Peoples R China; [Liao, Zhongkai; Li, Qiang] Hainan Med Univ, Dept Gastrointestinal Oncol, Affiliated Hosp 1, 31 Longhua Rd, Haikou 570102, Hainan, Peoples R China		Xu, RH (corresponding author), Huazhong Univ Sci & Technol, Dept Gastrointestinal Surg, Union Shenzhen Hosp, 89 Taoyuan Rd, Shenzhen 518000, Peoples R China.	hyfyweichang@163.com	Xu, Ronghua/AAE-8353-2021		National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81403006, 81760674]; Natural Science Foundation of Hainan Province [ZDXM2015080]; Cultivating Foundation of Hainan Medical University [HY2018-23]	This work was supported by National Natural Science Foundation of China [No: 81403006 and 81760674], Natural Science Foundation of Hainan Province [No: ZDXM2015080] and Cultivating Foundation of Hainan Medical University [No: HY2018-23]. The funder had no role in the study design, data collection or analysis, decision to publish or preparation of the manuscript.	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JUL 17	2020	11	7							539	10.1038/s41419-020-02742-0			15	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	MP7NE	WOS:000552387300001	32681018	Green Published, gold			2022-04-25	
J	Marinkovic, M; Sprung, M; Buljubasic, M; Novak, I				Marinkovic, Mija; Sprung, Matilda; Buljubasic, Maja; Novak, Ivana			Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy	OXIDATIVE MEDICINE AND CELLULAR LONGEVITY			English	Review							CELL LUNG-CANCER; INHIBITS TUMOR-GROWTH; BECLIN 1 EXPRESSION; COLON-CANCER; HEPATOCELLULAR-CARCINOMA; DIRECT PHOSPHORYLATION; MOLECULAR-MECHANISMS; FAVORABLE PROGNOSIS; IMMUNE-RESPONSES; DOWN-REGULATION	In the last two decades, accumulating evidence pointed to the importance of autophagy in various human diseases. As an essential evolutionary catabolic process of cytoplasmatic component digestion, it is generally believed that modulating autophagic activity, through targeting specific regulatory actors in the core autophagy machinery, may impact disease processes. Both autophagy upregulation and downregulation have been found in cancers, suggesting its dual oncogenic and tumor suppressor properties during malignant transformation. Identification of the key autophagy targets is essential for the development of new therapeutic agents. Despite this great potential, no therapies are currently available that specifically focus on autophagy modulation. Although drugs like rapamycin, chloroquine, hydroxychloroquine, and others act as autophagy modulators, they were not originally developed for this purpose. Thus, autophagy may represent a new and promising pharmacologic target for future drug development and therapeutic applications in human diseases. Here, we summarize our current knowledge in regard to the interplay between autophagy and malignancy in the most significant tumor types: pancreatic, breast, hepatocellular, colorectal, and lung cancer, which have been studied in respect to autophagy manipulation as a promising therapeutic strategy. Finally, we present an overview of the most recent advances in therapeutic strategies involving autophagy modulators in cancer.	[Marinkovic, Mija; Buljubasic, Maja; Novak, Ivana] Univ Split, Sch Med, Soltanska 2, Split 21000, Croatia; [Sprung, Matilda] Univ Split, Fac Sci, Rudera Boskov 33, Split 21000, Croatia		Novak, I (corresponding author), Univ Split, Sch Med, Soltanska 2, Split 21000, Croatia.	ivana.novak@mefst.hr	, Matilda/ABD-1905-2020; Buljubasic, Maja/E-1241-2017; Sprung, Matilda/D-5067-2017	, Matilda/0000-0001-5008-2700; Buljubasic, Maja/0000-0003-2466-2036; Sprung, Matilda/0000-0001-5008-2700; Novak, Ivana/0000-0003-0682-7052	Croatian Science Foundation [UIP-11-2013-5246]; Transautophagy COST Action by the EU COST [CA15138]	I.N. laboratory is supported by the Croatian Science Foundation (Grant no. UIP-11-2013-5246) and Transautophagy COST Action by the EU COST (CA15138).	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Cell. Longev.		2018	2018								8023821	10.1155/2018/8023821			18	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	FV8CV	WOS:000424813400001	29643976	Green Published, Green Submitted, gold			2022-04-25	
J	Wu, M; Lao, YZ; Xu, NH; Wang, XY; Tan, HS; Fu, WW; Lin, ZX; Xu, HX				Wu, Man; Lao, Yuanzhi; Xu, Naihan; Wang, Xiaoyu; Tan, Hongsheng; Fu, Wenwei; Lin, Zhixiu; Xu, Hongxi			Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death	PHYTOMEDICINE			English	Article						Apoptosis; Autophagy; Guttiferone K; Natural compound; Starvation	COLON-CANCER; APOPTOSIS; COMPOUND; TARGET; JNK; PROLIFERATION; INHIBITION; TOLERANCE	Background: Medicinal plants have long been an excellent source of pharmaceutical agents. Autophagy, a catabolic degradation process through lysosomes, plays an important role in tumorigenesis and cancer therapy. Purpose: Through a screen designed to identify autophagic regulators from a library of natural compounds, we found that Guttiferone K (GUTK) can activate autophagy in several cancer cell lines. The objective of this study is to investigate the mechanism by which GUTK sensitizes cancer cells to cell death in nutrient starvation condition. Methods: Cell death analysis was performed by propidium iodide staining with flow cytometry or Annexin V-FITC/PI staining assay. DCFH-DA staining was used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Cell viability was measured by MTT assay. Results: Exposure to GUTK was observed to markedly induce GFP-LC3 puncta formation and activate the accumulation of LC3-II and the degradation of p62 in HeLa cells, suggesting that GUTK is an autophagy inducer. Importantly, hydroxychloroquine, an autophagy inhibitor, was found to significantly prevent GUTK-induced cell death in nutrient starvation conditions, suggesting that the cell death observed is largely dependent on autophagy. We further provide evidence that GUTK inhibits Akt phosphorylation, thereby inhibiting the mTOR pathway in cancer cells during nutrient starvation. In addition, GUTK causes the accumulation of reactive oxygen species (ROS) and the phosphorylation of JNK in EBSS, which may mediate both autophagy and apoptosis. Conclusion: These data indicate that GUTK sensitizes cancer cells to nutrient stress-induced cell death though Akt/mTOR dependent autophagy pathway. (C) 2015 The Authors. Published by Elsevier GmbH.	[Wu, Man; Lao, Yuanzhi; Wang, Xiaoyu; Tan, Hongsheng; Fu, Wenwei; Xu, Hongxi] Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China; [Wu, Man; Lao, Yuanzhi; Wang, Xiaoyu; Tan, Hongsheng; Fu, Wenwei; Xu, Hongxi] Engn Res Ctr Shanghai Coll TCM New Drug Discovery, Shanghai 201203, Peoples R China; [Xu, Naihan] Tsinghua Univ, Grad Sch Shenzhen, Div Life Sci, Key Lab Hlth Sci & Technol, Shenzhen 518055, Peoples R China; [Lin, Zhixiu] Chinese Univ Hong Kong, Sch Chinese Med, Fac Sci, Shatin, Hong Kong, Peoples R China		Xu, HX (corresponding author), Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China.	xuhongxi88@gmail.com	Xu, Hongxi/AAC-2799-2020; tan, Hongsheng/AAD-5830-2020; wu, man/AAD-5877-2020; Xu, Naihan/C-2778-2018; Fu, Wenwei/AAD-6756-2020; Lin, Zhi-Xiu/H-2807-2016; , Yuanzhi/D-3936-2015	, Yuanzhi/0000-0002-7803-4484; Xu, Hongxi/0000-0001-6238-4511	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81303188, 21272135]; Natural Science Foundation of ShanghaiNatural Science Foundation of Shanghai [14ZR1441300]	We would like to thank Professor Kevin Ryan (Beatson Institute for Cancer Research, CRUK) for providing the MEF Bax/Bak<SUP>-/-</SUP> cell line. This work was supported by the National Natural Science Foundation of China (No. 81303188 and 21272135) and the Natural Science Foundation of Shanghai (14ZR1441300).	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J	Coker-Gurkan, A; Arisart, ED; Obakan, P; Guvenir, E; Unsal, NP				Coker-Gurkan, Ajda; Arisan, Elif Damla; Obakan, Pinar; Guvenir, Esin; Unsal, Narcin Palavan			Inhibition of autophagy by 3-MA potentiates purvalanol-induced apoptosis in Bax deficient HCT 116 colon cancer cells	EXPERIMENTAL CELL RESEARCH			English	Article						Colon cancer; Apoptosis; Autophagy; CDK inhibitors; Bax	IN-VITRO; ROSCOVITINE; DEATH; MACROAUTOPHAGY; OLOMOUCINE; PATHWAY	The purine-derived analogs, roscovitine and purvalanol are selective synthetic inhibitors of cyclin-dependent kinases (CDKs) induced cell cycle arrest and lead to apoptotic cell death in various cancer cells. Although a number of studies investigated the molecular mechanism of each CDK inhibitor on apoptotic cell death mechanism with their therapeutic potential, their regulatory role on autophagy is not clarified yet. In this paper, our aim was to investigate molecular mechanism of CDK inhibitors on autophagy and apoptosis in wild type (wt) and Bax deficient HCT 116 cells. Exposure of HCT 116 wt and Bax(-/-) cells to roscovitine or purvalanol for 24 h decreased cell viability in dose-dependent manner. However, Bax deficient HCT 116 cells were found more resistant against purvalanol treatment compared to wt cells. We also established that both CDK inhibitors induced apoptosis through activating mitochondria-mediated pathway in caspase-dependent manner regardless of Bax expression in HCT 116 colon cancer cells. Concomitantly, we determined that purvalanol was also effective on autophagy in HCT 116 colon cancer cells. Inhibition of autophagy by 3-MA treatment enhanced the purvalanol induced apoptotic cell death in HCT 116 Bax(-/-) cells. Our results revealed that mechanistic action of each CDK inhibitor on cell death mechanism differs. While purvalanol treatment activated apoptosis and autophagy in HCT 116 cells, roscovitine was only effective on caspase-dependent apoptotic pathway. Another important difference between two CDK inhibitors, although roscovitine treatment overcame Bax-mediated drug resistance in HCT 116 cells, purvalanol did not exert same effect. (C) 2014 Elsevier Inc. All rights reserved.	[Coker-Gurkan, Ajda; Arisan, Elif Damla; Obakan, Pinar; Guvenir, Esin; Unsal, Narcin Palavan] Istanbul Kultur Univ, Mol Biol & Genet Dept, Sci & Literature Fac, TR-34156 Istanbul, Turkey		Coker-Gurkan, A (corresponding author), Istanbul Kultur Univ, Mol Biol & Genet Dept, Sci & Literature Fac, Atakoy Campus, TR-34156 Istanbul, Turkey.	a.coker@iku.edu.tr	OBAKAN, PINAR/D-2836-2015; Arisan, Elif Damla/W-8682-2019	Arisan, Elif Damla/0000-0002-4844-6381; Gurkan, Ajda/0000-0003-1475-2417	Istanbul Kultur University Scientific Projects Support CenterIstanbul Kultur University	This work was supported by Istanbul Kultur University Scientific Projects Support Center.	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Cell Res.	OCT 15	2014	328	1					87	98		10.1016/j.yexcr.2014.07.022			12	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	AQ1KK	WOS:000342540100007	25088259				2022-04-25	
J	Yu, L; Hou, JG; Li, YF; Wang, Y; Hong, M; Yang, YM				Yu, Lei; Hou, Ji-Guang; LI, Yun-Feng; Wang, Yin; Hong, Ming; Yang, Yan-Ming			Inhibiting endoplasmic reticulum stress mediated-autophagy enhances the pro-apoptotic effects of resveratrol derivative in colon cancer cells	NEOPLASMA			English	Article						endoplasmic reticulum stress; trans-3; 5; 4'-trimethoxystilbene; apoptosis; autophagy; colon cancer		Previous studies have demonstrated that endoplasmic reticulum stress (ERS) might play a major role in inducing cellular autophagy and apoptosis in multiple types of cancer. Herein, we observed that trans-3,5,4'-trimethoxystilbene (TMS) exposure facilitated apoptotic cell death and ERS-mediated autophagy in colon cancer SW480 and HCT116 cells. Interestingly, our data demonstrated that ERS was not involved in TMS-induced apoptosis. However, ERS notably induced protective autophagy in SW480 and HCT116 cells. In addition, inhibiting cellular ERS significantly improved the pro-apoptotic effects of TMS. Thus, our results indicated that TMS-mediated autophagy was dependent on ERS, while apoptotic cell death might be induced in the ERS-independent pathway after TMS treatment. Generally, inhibiting ERS-mediated autophagy can enhance the pro-apoptotic effects of TMS. TMS might be a potential therapeutic agent for colon cancer treatment.	[Yu, Lei; Hou, Ji-Guang; LI, Yun-Feng; Wang, Yin; Yang, Yan-Ming] Second Hosp Jilin Univ, Dept Radiotherapy, Changchun, Peoples R China; [Hong, Ming] Guangzhou Univ, Inst Adv Diagnost & Clin Med, Zhongshan Peoples Hosp, Zhongshan, Peoples R China; [Hong, Ming] Zhongshan Peoples Hosp, Joint Biomed Inst, Zhongshan, Peoples R China; [Hong, Ming] Dongguan & Guangzhou Univ Chinese Med, Cooperat Acad Math Engn Chinese Med, Dongguan, Peoples R China		Yang, YM (corresponding author), Second Hosp Jilin Univ, Dept Radiotherapy, Changchun, Peoples R China.; Hong, M (corresponding author), Guangzhou Univ, Inst Adv Diagnost & Clin Med, Zhongshan Peoples Hosp, Zhongshan, Peoples R China.; Hong, M (corresponding author), Zhongshan Peoples Hosp, Joint Biomed Inst, Zhongshan, Peoples R China.; Hong, M (corresponding author), Dongguan & Guangzhou Univ Chinese Med, Cooperat Acad Math Engn Chinese Med, Dongguan, Peoples R China.	hongming1986@gzucm.edu.cn; richard8207@126.com			projects of science and technology development plan of Jilin province [20190201203JC, 20190201214JC]; projects of Guangdong Basic and Applied Basic Research Foundation [2019A1515110167]	This research was supported by the projects of science and technology development plan of Jilin province (20190201203JC, 20190201214JC) and the projects of Guangdong Basic and Applied Basic Research Foundation (2019A1515110167) .	Abdel-Aziz AK, 2016, EXP NEUROL, V283, P129, DOI 10.1016/j.expneurol.2016.06.004; Abdouh M, 2019, J EXP CLIN CANC RES, V38, DOI 10.1186/s13046-019-1248-2; Avila-Galvez MA, 2019, MOL NUTR FOOD RES, V63, DOI 10.1002/mnfr.201801239; Baek SH, 2016, PHYTOMEDICINE, V23, P566, DOI 10.1016/j.phymed.2016.02.011; Devis-Jauregui L, 2021, AUTOPHAGY, V17, P1077, DOI 10.1080/15548627.2020.1752548; Fan YM, 2020, INT J ONCOL, V57, P925, DOI 10.3892/ijo.2020.5107; Fuggetta MP, 2006, J EXP CLIN CANC RES, V25, P189; Gimenez-Bastida JA, 2019, MOL NUTR FOOD RES, V63, DOI 10.1002/mnfr.201900629; Hashemzaei M, 2017, ONCOL REP, V38, P819, DOI 10.3892/or.2017.5766; Hashemzaei M, 2016, ENVIRON TOXICOL PHAR, V46, P110, DOI 10.1016/j.etap.2016.07.010; Hong M, 2020, MOL NUTR FOOD RES, V64, DOI 10.1002/mnfr.201901115; Hsieh MJ, 2019, PHYTOMEDICINE, V58, DOI 10.1016/j.phymed.2018.12.028; Krasanakis T, 2019, ONCOL REP, V42, P2228, DOI 10.3892/or.2019.7351; Kumar D, 2013, MOL CANCER, V12, DOI 10.1186/1476-4598-12-171; Lee TY, 2021, AUTOPHAGY, V17, P4141, DOI [10.1080/15548627.2021.1904495, 10.6084/m9.figshare.14259880.v3]; Lin FZ, 2019, PHYTOMEDICINE, V54, P1, DOI 10.1016/j.phymed.2018.09.181; Lindeman TE, 2011, MUTAGENESIS, V26, P629, DOI 10.1093/mutage/ger024; de Faria JML, 2016, INVEST OPHTH VIS SCI, V57, P4356, DOI 10.1167/iovs.16-19197; Ming H, 2020, PHYTOMEDICINE, V68, DOI 10.1016/j.phymed.2020.153174; Moller F, 2007, PHYTOMEDICINE, V14, P716, DOI 10.1016/j.phymed.2007.09.001; Pak S, 2019, J EXP CLIN CANC RES, V38, DOI 10.1186/s13046-019-1342-5; Qomaladewi NP, 2019, INT J MOL SCI, V20, DOI 10.3390/ijms20092081; Yamamoto K, 2020, AUTOPHAGY, V16, P1524, DOI 10.1080/15548627.2020.1769973; Zhou YX, 2016, MOL CARCINOGEN, V55, P1317, DOI 10.1002/mc.22374	24	0	0	5	5	AEPRESS SRO	BRATISLAVA	BAJZOVA 7, BRATISLAVA, 821 08, SLOVAKIA	0028-2685	1338-4317		NEOPLASMA	Neoplasma		2021	68	6					1236	+		10.4149/neo_2021_210422N552			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	XN0II	WOS:000729198300001	34648300				2022-04-25	
J	Zhou, YJ; Zhou, XT; Huang, XJ; Hong, T; Zhang, K; Qi, WC; Guo, M; Nie, SP				Zhou, Yujia; Zhou, Xingtao; Huang, Xiaojun; Hong, Tao; Zhang, Ke; Qi, Wucheng; Guo, Mi; Nie, Shaoping			Lysosome-Mediated Cytotoxic Autophagy Contributes to Tea Polysaccharide-Induced Colon Cancer Cell Death via mTOR-TFEB Signaling	JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY			English	Article						tea polysaccharide; autophagy; lysosome; colon cancer cell; mTOR-TFEB signaling	RELEASE	Targeting autophagy and lysosome may serve as a promising strategy for cancer therapy. Tea polysaccharide (TP) has shown promising antitumor effects. However, its mechanism remains elusive. Here, TP was found to have a significant inhibitory effect on the proliferation of colon cancer line HCT116 cells. RNA-seq analysis showed that TP upregulated autophagy and lysosome signal pathways, which was further confirmed through experiments. Immunofluorescence experiments indicated that TP activated transcription factor EB (TFEB), a key nuclear transcription factor modulating autophagy and lysosome biogenesis. In addition, TP inhibited the activity of mTOR, while it increased the expression of Lamp1. Furthermore, TP ameliorated the lysosomal damage and autophagy flux barrier caused by Baf A1 (lysosome inhibitor). Hence, our data suggested that TP repressed the proliferation of HCT116 cells by targeting lysosome to induce cytotoxic autophagy, which might be achieved through mTOR-TFEB signaling. In summary, TP may be used as a potential drug to overcome colon cancer.	[Zhou, Yujia; Zhou, Xingtao; Huang, Xiaojun; Hong, Tao; Zhang, Ke; Qi, Wucheng; Guo, Mi; Nie, Shaoping] Nanchang Univ, State Key Lab Food Sci & Technol, China Canada Joint Lab Food Sci & Technol Nanchan, Nanchang 330047, Jiangxi, Peoples R China		Zhou, XT; Nie, SP (corresponding author), Nanchang Univ, State Key Lab Food Sci & Technol, China Canada Joint Lab Food Sci & Technol Nanchan, Nanchang 330047, Jiangxi, Peoples R China.	zhouxingtao@ncu.edu.cn; spnie@ncu.edu.cn	周, 兴涛/F-2927-2019	周, 兴涛/0000-0002-1902-9677; Nie, Shao-Ping/0000-0002-2412-4679	National Natural Science Foundation of China for Distinguished Young ScholarsNational Natural Science Foundation of China (NSFC)National Science Fund for Distinguished Young Scholars [31825020]; Natural Science Foundation of Jiangxi ProvinceNatural Science Foundation of Jiangxi Province [20192BAB204024]	Grant support is from the National Natural Science Foundation of China for Distinguished Young Scholars (31825020) and the Natural Science Foundation of Jiangxi Province (20192BAB204024).	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Agric. Food Chem.	JAN 20	2021	69	2					686	697		10.1021/acs.jafc.0c07166			12	Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Agriculture; Chemistry; Food Science & Technology	PZ2IO	WOS:000612563800007	33369397				2022-04-25	
J	Liu, YX; Yang, B; Zhang, LR; Cong, XL; Liu, Z; Hu, Y; Zhang, J; Hu, HX				Liu, Yuxia; Yang, Bin; Zhang, Lirong; Cong, Xianling; Liu, Zhen; Hu, Yu; Zhang, Jing; Hu, Haixia			Ginkgolic acid induces interplay between apoptosis and autophagy regulated by ROS generation in colon cancer	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Colon cancer; Ginkgolic acids; Cell cycle arrest; Apoptosis and autophagy; ROS	EPITHELIAL-MESENCHYMAL TRANSITION; CELL-CYCLE ARREST; PANCREATIC-CANCER; MITOCHONDRIA; GROWTH	Presently, developing effective anti-colon cancer drugs still remains to be important. Ginkgolic acids (GA), as a botanical drug extracted from the seed coat of Ginkgo biloba L, possess various bioactive properties. Our findings, for the first time, indicated that GA suppressed colon cancer cell proliferation, migration and invasion. GA led to cell death through G0/G1 phase arrest. In addition, apoptosis was significantly induced by GA treatment. The intrinsic apoptosis pathway was included, proved by the release of cytochrome c (Cyto-c) from the mitochondria into the cytosol. GA-induced autophagy was supported by the dose-dependent increase of LC3BII, autophagy-related gene-5 (ATG-5) and Beclin-1. Notably, silencing ATG-5 further reduced the cell viability and enhanced apoptosis in GA-treated colon cancer cells, indicating that GA-induced apoptosis rather than autophagy contributes to colon cancer cell death. And mammalian target of rapamycin complex 1 (mTORC1) was dose-dependently reduced by GA, evidenced by the reduction of p-mTOR, p-p70 ribosomal S6 kinase (p70s6k) and p-pras40. Moreover, GA markedly resulted in reactive oxygen species (ROS) generation, along with increased H2O2 and O-2(-). However, blocking ROS generation using its scavenger, NAC, significantly recovered GA-induced cells death, supported by the increase of cell viability, and the decrease of apoptosis. The expressions of autophagy- and cell cycle arrest-related molecules, as well as mTORC1 were also reversed by N-acetyl-L-cysteine (NAC) in GA-treated cells. In vivo, GA reduced tumor growth without toxicity to animals. In conclusion, our study illustrated that GA caused G0/G1 phase arrest and triggered intrinsic apoptosis and autophagy modulated by ROS generation in human colon cancer, elucidating that GA might be considered as a potential agent for colon cancer therapy. (C) 2018 Published by Elsevier Inc.	[Liu, Yuxia] Jilin Univ, China Japan Union Hosp, Med Records Room,126 Xiantai Rd, Changchun 130033, Jilin, Peoples R China; [Yang, Bin] Jilin Univ, China Japan Union Hosp, Dept Breast Surg, 126 Xiantai Rd, Changchun 130033, Jilin, Peoples R China; [Zhang, Lirong; Cong, Xianling; Hu, Yu] Jilin Univ, China Japan Union Hosp, Dept Pathol, 126 Xiantai Rd, Changchun 130033, Jilin, Peoples R China; [Liu, Zhen] Tradit Chinese Med Hosp Luhe Dist, Dept TCM Pediat, Nanjing 223300, Jiangsu, Peoples R China; [Zhang, Jing] Jilin Univ, Dept Nephrol, China Japan Union Hosp, 126 Xiantai Rd, Changchun 130033, Jilin, Peoples R China; [Hu, Haixia] Jilin Univ, Colorectal Surg, China Japan Union Hosp, 126 Xiantai Rd, Changchun 130033, Jilin, Peoples R China		Zhang, J (corresponding author), Jilin Univ, Dept Nephrol, China Japan Union Hosp, 126 Xiantai Rd, Changchun 130033, Jilin, Peoples R China.; Hu, HX (corresponding author), Jilin Univ, Colorectal Surg, China Japan Union Hosp, 126 Xiantai Rd, Changchun 130033, Jilin, Peoples R China.	3322399048@qq.com; huhaixiajl@foxmail.com					Brentnall M, 2013, BMC CELL BIOL, V14, DOI 10.1186/1471-2121-14-32; Chen LH, 2016, BMC CANCER, V16, DOI 10.1186/s12885-016-2468-x; Dixon SJ, 2014, NAT CHEM BIOL, V10, P9, DOI 10.1038/nchembio.1416; Eymin B, 2010, CELL ADHES MIGR, V4, P114, DOI 10.4161/cam.4.1.10977; Ghavami S, 2012, CELL DEATH DIS, V3, DOI 10.1038/cddis.2012.61; Iwatsuki M, 2010, INT J CANCER, V126, P1828, DOI 10.1002/ijc.24879; Jung CH, 2009, MOL BIOL CELL, V20, P1992, DOI 10.1091/mbc.E08-12-1249; Lamouille S, 2014, NAT REV MOL CELL BIO, V15, P178, DOI 10.1038/nrm3758; Laplante M, 2009, J CELL SCI, V122, P3589, DOI 10.1242/jcs.051011; Lu JM, 2012, MED SCI MONITOR, V18, pBR293; Ma JG, 2015, ONCOTARGET, V6, P20993, DOI 10.18632/oncotarget.3663; Malumbres M, 2009, NAT REV CANCER, V9, P153, DOI 10.1038/nrc2602; Martinou JC, 2011, DEV CELL, V21, P92, DOI 10.1016/j.devcel.2011.06.017; Moscat J, 2009, CELL, V137, P1001, DOI 10.1016/j.cell.2009.05.023; Pei Z, 2017, BIOCHEM BIOPH RES CO, V493, P455, DOI 10.1016/j.bbrc.2017.08.170; Pyo JO, 2013, NAT COMMUN, V4, DOI 10.1038/ncomms3300; Quirke P, 2015, LANCET ONCOL, V16, P121, DOI 10.1016/S1470-2045(14)71223-9; Relja B, 2010, INT J MOL MED, V26, P733, DOI 10.3892/ijmm_00000520; Richter JD, 2005, NATURE, V433, P477, DOI 10.1038/nature03205; Saha A, 2011, PLOS PATHOG, V7, DOI 10.1371/journal.ppat.1001275; Sentelle RD, 2012, NAT CHEM BIOL, V8, P831, DOI 10.1038/NCHEMBIO.1059; Siegel R, 2013, CA-CANCER J CLIN, V63, P11, DOI 10.3322/caac.21166; Su ZY, 2015, MOL CANCER, V14, DOI 10.1186/s12943-015-0321-5; Xiang TX, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0029783; Yu J, 2011, ASIAN PAC J CANCER P, V12, P1925; Zhang JW, 2013, NAT CELL BIOL, V15, P1186, DOI 10.1038/ncb2822; Zhou CC, 2010, CHEMOTHERAPY, V56, P393, DOI 10.1159/000317750	27	28	31	6	27	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	MAR 25	2018	498	1					246	253		10.1016/j.bbrc.2018.01.091			8	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	GC2SR	WOS:000429633400037	29353042				2022-04-25	
J	Kim, KY; Oh, TW; Yang, HJ; Kim, YW; Ma, JY; Park, KI				Kim, Kwang-Youn; Oh, Tae-Woo; Yang, Hye-Jin; Kim, Young-Woo; Ma, Jin-Yeul; Park, Kwang-Il			Ethanol extract of Chrysanthemum zawadskii Herbich induces autophagy and apoptosis in mouse colon cancer cells through the regulation of reactive oxygen species	BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article						Chrysanthemum zawadskii Herbich; Colon cancer; Apoptosis; Autophagy; Reactive oxygen species	INHIBITION; LINARIN; PATHWAYS; DEATH; P53	Background Recent research has suggested that autophagy can provide a better mechanism for inducing cell death than current therapeutic strategies. This study investigated the effects of using an ethanol extract of Chrysanthemum zawadskii Herbich (ECZ) to induce apoptosis and autophagy associated with reliable signal pathways in mouse colon cancer CT-26 cells. Methods Using ECZ on mouse colon cancer CT-26 cells, cell viability, annexin V/propidium iodide staining, acridine orange staining, reactive oxygen species (ROS) and western blotting were assayed. Results ECZ exhibited cytotoxicity in CT-26 cells in a dose-dependent manner. ECZ induced apoptosis was confirmed by caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and increased production of reactive oxygen species (ROS). Furthermore, it was shown that ECZ induced autophagy via the increased conversion of microtubule-associated protein 1 light chain 3II, the degradation of p62, and the formation of acidic vesicular organelles. The inhibition of ROS production by N-Acetyl-L-cysteine resulted in reduced ECZ-induced apoptosis and autophagy. Furthermore, the inhibition of autophagy by 3-methyladenine resulted in enhanced ECZ-induced apoptosis via increased ROS generation. Conclusion These findings confirmed that ECZ induced ROS-mediated autophagy and apoptosis in colon cancer cells. Therefore, ECZ may serve as a novel potential chemotherapeutic candidate for colon cancer.	[Kim, Kwang-Youn; Oh, Tae-Woo; Yang, Hye-Jin; Ma, Jin-Yeul; Park, Kwang-Il] KIOM, Korean Med KM Applicat Ctr, Daegu 41062, South Korea; [Kim, Young-Woo] Daegu Haany Univ, Coll Oriental Med, Dept Herbal Formula Med Res Ctr MRC GHF, Gyongsan 38610, South Korea		Park, KI (corresponding author), KIOM, Korean Med KM Applicat Ctr, Daegu 41062, South Korea.	kipark@kiom.re.kr			Korea Institute of Oriental Medicine - Ministry of Education, Science and Technology (MEST), Republic of KoreaMinistry of Education, Science and Technology, Republic of Korea [KSN1812102]; National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2017R1D1A1B03032284]; Ministry of Oceans and Fisheries, Republic of Korea [20190055]	This work was supported by a grant (No. KSN1812102) from the Korea Institute of Oriental Medicine funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea. This work was also supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1D1A1B03032284) and by grant (No. 20190055) funded by the Ministry of Oceans and Fisheries, Republic of Korea.	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Altern. Med.	OCT 21	2019	19	1							274	10.1186/s12906-019-2688-0			10	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	JF4DZ	WOS:000491339200003	31638961	Green Published, gold			2022-04-25	
J	Lampada, A; O'Prey, J; Szabadkai, G; Ryan, KM; Hochhauser, D; Salomoni, P				Lampada, Aikaterini; O'Prey, James; Szabadkai, Gyorgy; Ryan, Kevin M.; Hochhauser, Daniel; Salomoni, Paolo			mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism	CELL DEATH AND DIFFERENTIATION			English	Article							GROWTH-FACTOR RECEPTOR; PRIMARY COLON-CANCER; TARGETING AUTOPHAGY; TUMOR PROGRESSION; OPEN-LABEL; CETUXIMAB; TUMORIGENESIS; EGFR; RESISTANCE; INHIBITION	The intracellular autophagic degradative pathway can have a tumour suppressive or tumour-promoting role depending on the stage of tumour development. Upon starvation or targeting of oncogenic receptor tyrosine kinases (RTKs), autophagy is activated owing to the inhibition of PI3K/AKT/mTORC1 signalling pathway and promotes survival, suggesting that autophagy is a relevant therapeutic target in these settings. However, the role of autophagy in cancer cells where the PI3K/AKT/mTORC1 pathway is constitutively active remains partially understood. Here we report a role for mTORC1-independent basal autophagy in regulation of RTK activation and cell migration in colorectal cancer (CRC) cells. PI3K and RAS-mutant CRC cells display basal autophagy levels despite constitutive mTORC1 signalling, but fail to increase autophagic flux upon RTK inhibition. Inhibition of basal autophagy via knockdown of ATG7 or ATG5 leads to decreased phosphorylation of several RTKs, in particular c-MET. Internalised c-MET colocalised with LAMP1-negative, LC3-positive vesicles. Finally, autophagy regulates c-MET phosphorylation via an mTORC2-dependent mechanism. Overall, our findings reveal a previously unappreciated role of autophagy and mTORC2 in regulation of oncogenic RTK activation, with implications for understanding of cancer cell signalling.	[Lampada, Aikaterini; Salomoni, Paolo] UCL Canc Inst, Dept Canc Biol, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England; [Lampada, Aikaterini; Hochhauser, Daniel] UCL Canc Inst, Dept Oncol, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England; [O'Prey, James; Ryan, Kevin M.] Beatson Inst, Glasgow, Lanark, Scotland; [Szabadkai, Gyorgy] UCL, Dept Cell & Dev Biol, Consortium Mitochondrial Res, London, England		Salomoni, P (corresponding author), UCL Canc Inst, Dept Canc Biol, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.; Hochhauser, D (corresponding author), UCL Canc Inst, Dept Oncol, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.	d.hochhauser@ucl.ac.uk; p.salomoni@ucl.ac.uk		Szabadkai, Gyorgy/0000-0002-3006-3577; Hochhauser, Daniel/0000-0001-5522-9281	UCL Grand Challenges; Cancer Research UK Programme GrantCancer Research UK [C2259/A16569]; Samantha Dickson Brain Cancer Unit; Cancer Research UKCancer Research UK [15816, 22903, 16569, 16463] Funding Source: researchfish	We thank Dr Pablo Rodriguez-Viciana (University College London, UK), Dr Ivana Bjedov (University College London, UK), Professor Bart Vanhaesebroeck (University College London, UK), Dr Benoit Bilanges (University College London, UK), Professor Clare Futter (University College London, UK), Professor Bert Vogelstein (Johns Hopkins University, USA), Professor Alberto Bardelli (University of Torino, Italy) for reagents. Special thanks also to all members of PS and DH laboratories and the CRUK UCL Centre Core Services and the UCL Scientific Services. AL was recipient of a PhD studentship award from the UCL Grand Challenges. DH was supported by the Cancer Research UK Programme Grant (C2259/A16569). PS is head of the Brain Tumour Charity-funded Samantha Dickson Brain Cancer Unit.	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JUN	2017	24	6					1045	1062		10.1038/cdd.2017.41			18	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	EV4AY	WOS:000401701800011	28475179	Green Submitted, Green Published, Bronze			2022-04-25	
J	Vizcaino, C; Rodriguez-Sanchez, MA; Nunez, LE; Moris, F; Portugal, J				Vizcaino, Carolina; Rodriguez-Sanchez, Maria A.; Nunez, Luz-Elena; Moris, Francisco; Portugal, Jose			Cytotoxic effects of mithramycin DIG-MSK can depend on the rise of autophagy	TOXICOLOGY IN VITRO			English	Article						Autophagy; Mithramycin; Cell death; A2780 cells; HCT116 cells	CELL-DEATH; PAGETS-DISEASE; CANCER-CELLS; TRANSCRIPTION; APOPTOSIS; LUNG; INTERPLAY; BINDING; ANALOG; BASAL	DIG-MSK (demycarosil-3D-beta-D-digitoxosyl mithramycin SK; EC-8042), a novel analogue of mithramycin A, induced autophagy in HCT116 human colon carcinoma and, to a lesser extent, in A2780 human ovarian carcinoma cell lines, which was followed by apoptosis and/or necrotic cell death in a time-dependent way. The effects of DIG-MSK included changes in the expression of a set of genes involved in autophagy, the progression of cells through the different phases of cell cycle, and their halting at the checkpoints. Cells treated with the glucose analogue 2-DG (2-deoxy-D-glucose), which induces autophagy because it impairs cell metabolism, or co-treated with 2-DG plus DIG-MSK, also showed altered gene expression and autophagy. In A2780 cells, some genes involved in autophagy were down-regulated by the different treatments, yet the levels of the proteins they encode could be enough to ensure autophagic flux. In HCT116 cells, up-regulation of several pro-autophagic genes resulted in strong autophagic response. Acidic cell organelles and autophagic flux were more evident in HCT116 than in A2780 cells. DIG-MSK was still cytotoxic in cells that underwent autophagy induced by 2-DG. Therefore, we verified that autophagy resulting from a stress response did not protect cells against DIG-MSK, but, instead, autophagy promoted by either 2-DG or the novel mithralogue can enhance the antitumour activity, which depended on the cell type. (C) 2015 Elsevier Ltd. All rights reserved.	[Vizcaino, Carolina; Rodriguez-Sanchez, Maria A.; Portugal, Jose] CSIC, Inst Biol Mol Barcelona, E-08028 Barcelona, Spain; [Nunez, Luz-Elena; Moris, Francisco] EntreChem SL, Oviedo, Spain		Portugal, J (corresponding author), CSIC, Inst Biol Mol Barcelona, Parc Cient Barcelona 10, E-08028 Barcelona, Spain.	jpmbmc@ibmb.csic.es	Portugal, José/K-4504-2014	Portugal, José/0000-0002-1923-9666	Spanish Ministry of Science and InnovationSpanish Government [BFU2010-15518]; FEDER program of the European CommunityEuropean Commission; JAE-Predoc fellowship (CSIC); European Social FundEuropean Social Fund (ESF)	This work was partially supported by Grant BFU2010-15518 from the Spanish Ministry of Science and Innovation, and the FEDER program of the European Community, and it was performed within the framework of the "Xarxa de Referencia en Biotecnologia" of the Generalitat de Catalunya. Carolina Vizcaino was recipient of a JAE-Predoc2010 fellowship (CSIC), co-financed by the European Social Fund.	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Vitro	OCT	2015	29	7					1537	1544		10.1016/j.tiv.2015.06.008			8	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	CR3WJ	WOS:000361263500026	26079942	Green Submitted			2022-04-25	
J	Song, YW; Shrestha, S; Gyawali, R; Lee, DS; Cho, SK				Song, Yeon Woo; Shrestha, Sabina; Gyawali, Rajendra; Lee, Dong-Sun; Cho, Somi Kim			Citrus unshiu leaf extract containing phytol as a major compound induces autophagic cell death in human gastric adenocarcinoma AGS cells	JOURNAL OF THE KOREAN SOCIETY FOR APPLIED BIOLOGICAL CHEMISTRY			English	Article						AGS human gastric adenocarcinoma cells; Autophagy; Citrus unshiu; Phytol	COLON-CANCER CELLS; ANTIPROLIFERATIVE ACTIVITIES; RAT HEPATOCYTES; CYCLE ARREST; VITAMIN-E; APOPTOSIS; CARCINOMA; INHIBITION; FLAVONOIDS; INDUCTION	The pharmaceutical potential of the methanolic extract of Citrus unshiu leaves (MECL) was assessed through analysis of its inhibitory effect on cancer cells. The antiproliferative activities of the leaves were evaluated using several cancer cell lines and considerable cytotoxicity was observed in human gastric adenocarcinoma AGS cells. Inhibition of AGS cell viability was both time-and dose-dependent, and MECL induced non-apoptotic cell death. AGS cells treated with MECL increased the formation of acidic vesicular organelles and GFP-LC3 puncta. Pretreatment with an autophagy inhibitor, 3-methyladenine, inhibited MECL-induced cell death. These results indicated that the mechanism underlying the anticancer effects of MECL in AGS cells could be via the induction of autophagic cell death. The major compounds of MECL were identified as phytol, 4-ethenyl-2-methoxyphenol, hexadecanoic acid, 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, and vitamin E using gas chromatography-mass spectrometry. These results indicate that C. unshiu leaves can be exploited for numerous pharmaceutical applications as a source of anticancer ingredients.	[Song, Yeon Woo; Lee, Dong-Sun; Cho, Somi Kim] Jeju Natl Univ, SARI, Fac Biotechnol, Coll Appl Life Sci, Jeju 690756, South Korea; [Shrestha, Sabina; Lee, Dong-Sun; Cho, Somi Kim] Jeju Natl Univ, Subtrop Hort Res Inst, Jeju 690756, South Korea; [Gyawali, Rajendra] Kathmandu Univ, Dept Pharm, Kavre, Dhulikhel, Nepal		Cho, SK (corresponding author), Jeju Natl Univ, SARI, Fac Biotechnol, Coll Appl Life Sci, Jeju 690756, South Korea.	somikim@jejunu.ac.kr	Shrestha, Sabina/AAZ-5437-2020		Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2014047495]; Ministry of Education [2013R1A1A2A10012017]	This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014047495) and by the Ministry of Education (2013R1A1A2A10012017). This work was done while the author has research year Jeju National University in 2013.	Adams R. 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Korean Soc. Appl. Biol. Chem.	APR	2015	58	2					257	265		10.1007/s13765-015-0026-x			9	Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology	CH9LH	WOS:000354356600014					2022-04-25	
J	Lei, S; Ding, Y; Fu, Y; Wu, S; Xie, X; Wang, CC; Liang, HJ				Lei, Shun; Ding, Yao; Fu, Yun; Wu, Shuang; Xie, Xiong; Wang, Cancan; Liang, Houjie			The preclinical analysis of TW-37 as a potential anti-colorectal cancer cell agent	PLOS ONE			English	Article							SMALL-MOLECULE INHIBITOR; AUTOPHAGY; BCL-2; COMBINATIONS; APOPTOSIS; PATHWAYS; TARGET; DEATH	TW-37 is a novel, potent and non-peptide Bcl-2 small-molecule inhibitor. Its activity in colorectal cancer (CRC) cells is studied. In both HCT-116 cells and primary human colon cancer cells, treatment with TW-37 at only nM concentration efficiently inhibited cell survival and proliferation. TW-37 also induced caspase-3/9 and apoptosis activation in CRC cells. Feedback autophagy activation was observed in TW-37-treated CRC cells. Reversely pharmacological autophagy inhibition or Beclin-1 knockdown by targeted-shRNA potentiated TW-37-induced apoptosis and killing of CRC cells. In vivo, intravenous injection of TW-37 inhibited HCT-116 tumor growth in mice. TW-37's anti-tumor activity was further potentiated against Beclin-1-silenced HCT-116 tumors. Together, targeting Bcl-2 family protein by TW-37 efficiently inhibits CRC cell growth in vitro and in vivo. Inhibition of feedback autophagy activation could further sensitize TW-37.	[Lei, Shun; Ding, Yao; Wu, Shuang; Xie, Xiong; Wang, Cancan; Liang, Houjie] Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing, Peoples R China; [Lei, Shun; Ding, Yao; Wu, Shuang; Xie, Xiong; Wang, Cancan; Liang, Houjie] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing, Peoples R China; [Fu, Yun] Gao Xin Dist Peoples Hosp Chong Qing, Dept Gen Surg, Chongqing, Peoples R China		Liang, HJ (corresponding author), Third Mil Med Univ, Southwest Hosp, Dept Oncol, Chongqing, Peoples R China.; Liang, HJ (corresponding author), Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing, Peoples R China.	lianghoujie@sina.com			National Nature Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81702443, 81702929]	This study was supported by the grants from National Nature Science Foundation of China (Grant No. 81702443 and 81702929). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Xiong, W; Dong, JH; Kong, SJ				Xiong, Wei; Dong, Jianhua; Kong, Shujia			Dentatin exerts anticancer effects on human colon cancer cell lines via cell cycle arrest, autophagy, inhibition of cell migration and JAK/STAT signalling pathway	JOURNAL OF BUON			English	Article						colon cancer; dentatin; autophagy; migration; S-phase arrest	NATURAL-PRODUCTS; COUMARINS	Purpose: Colon cancer is a malignant disease with significant mortality. In the present study the anticancer effects of a carbazole alkaloid, Dentatin, were examined against colon cancer cells. Methods: The colon cancer HT-29 cell line and the normal CCD-18 CO colon cell line were used in the present study. MTT assay was used to check the proliferation rate of the cancer cells. Autophagy was detected by electron microscopy. DNA damage was checked by alkaline comet assay. Cell cycle analysis was performed by flow cytometry. Cell migration was monitored by wound healing assay. Protein expression was checked by western blot analysis. Results: The results showed that Dentatin inhibited the growth of HT-29 cancer cells in a concentration-dependent manner and with IC50 of 25 mu M. However, the IC50 of Dentatin against the normal CCD-18CO colon cells was four times higher (ie., 100 mu M). Dentatin inhibited the proliferation of the HT-29 cancer cells by triggering S-phase arrest. This was also accompanied with increase in the expression of cyclin D1 and decrease in the expression of Cyclin A and B1. Moreover, Dentatin also induced autophagy in the HT-29 cells which was associated with upregulation of LC3 II and downregulation of Beclin-1 expression. Comet assay revealed that Dentatin induced DNA damage in the HT-29 cells. Dentatin also significantly inhibited the migration of the HT-29 cells. Finally the effects of Dentatin were examined on the JAK/STAT signalling pathway and it was found that Dentatin inhibited this pathway. Conclusion: Dentatin may prove to be an essential lead molecule for the management of colon cancer.	[Xiong, Wei; Dong, Jianhua] Kunming Med Univ, Yunnan Canc Hosp, Dept Colorectal Canc Surg, Kunming 650118, Yunnan, Peoples R China; [Kong, Shujia] Kunming Med Univ, Yunnan Canc Hosp, Dept Pharm, Kunming 650118, Yunnan, Peoples R China; [Kong, Shujia] Kunming Med Univ, Affiliated Hosp 3, Kunming 650118, Yunnan, Peoples R China		Kong, SJ (corresponding author), Kunming Med Univ, Yunnan Canc Hosp, Dept Pharm, Kunming 650118, Yunnan, Peoples R China.; Kong, SJ (corresponding author), Kunming Med Univ, Affiliated Hosp 3, Kunming 650118, Yunnan, Peoples R China.	ShylaFinnecesi@yahoo.com					Arbab IA, 2012, EVID-BASED COMPL ALT, V7, P21; Harvey AL, 2015, NAT REV DRUG DISCOV, V14, P111, DOI 10.1038/nrd4510; Hua F, 2018, INT J MOL MED, V41, P3485, DOI 10.3892/ijmm.2018.3531; Karakas HE, 2014, TURK J BIOL, V38, P720, DOI 10.3906/biy-1408-16; Lawson CD, 2018, J CELL BIOL, V217, P447, DOI 10.1083/jcb.201612069; Ng RC, 2018, SAINS MALAYS, V47, P1749, DOI 10.17576/jsm-2018-4708-14; O'Shea JJ, 2015, ANNU REV MED, V66, P311, DOI 10.1146/annurev-med-051113-024537; Otto T, 2017, NAT REV CANCER, V17, P93, DOI 10.1038/nrc.2016.138; Petersen GM, 2018, GENETIC EPIDEMIOLOGY, P187; Reddy B.S., 2018, DIET COLON CANC EVID, P47, DOI DOI 10.1201/9781351071406; Ricci-Vitiani L, 2007, NATURE, V445, P111, DOI 10.1038/nature05384; Schlafli AM, 2015, EUR J HISTOCHEM, V59, P137, DOI 10.4081/ejh.2015.2481; Taha MM, 2013, J ETHNOPHARMACOL, V145, P343; Thakur A, 2015, EUR J MED CHEM, V101, P476, DOI 10.1016/j.ejmech.2015.07.010; Thomas SJ, 2015, BRIT J CANCER, V113, P365, DOI 10.1038/bjc.2015.233; Yarla NS, 2016, SEMIN CANCER BIOL, V40-41, P48, DOI 10.1016/j.semcancer.2016.02.001	16	6	6	2	5	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	JUL-AUG	2019	24	4					1488	1493					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	IR7BT	WOS:000481595900023	31646796				2022-04-25	
J	Bai, JH; Xu, J; Zhao, J; Zhang, R				Bai, Jing Hui; Xu, Jian; Zhao, Jian; Zhang, Rui			Ganoderma lucidum Polysaccharide Enzymatic Hydrolysate Suppresses the Growth of Human Colon Cancer Cells via Inducing Apoptosis	CELL TRANSPLANTATION			English	Article						colon cancer; enzymatically hydrolyzed polysaccharide; Ganoderma lucidum	COLORECTAL-CANCER; ANTIOXIDANT ACTIVITY; ANTITUMOR-ACTIVITY; IN-VITRO; AUTOPHAGY; PROMOTES	Ganoderma lucidum is a popular traditional Chinese medicine used in China to improve health. Previous researches have revealed that the polysaccharide from G. lucidum could exert diversity activities, including immunomodulation, antioxidant, and antitumor effects. However, the effect of enzymatically hydrolyzed G. lucidum polysaccharide (EGLP) in colorectal cancer (CRC) progression remains unknown. The present research aimed to investigate the antitumor mechanism of EGLP in human colon cancer cells. For this purpose, the cytotoxic effects of EGLP were measured by the (3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method. The apoptosis was evoked upon EGLP treatment, which was assayed using flow cytometry. The results indicated that EGLP may induce apoptosis in human colon cancer cell (HCT-116) cells via the upregulation of BCL-2 associated X protein (Bax), phospho-extracellular regulated protein kinases (P-ERK), and cleaved caspase-3 expression and downregulation of B-cell lymphoma-2 (Bcl-2), phospho-serine/threonine kinase 1 (p-Akt1), and cyclo-oxygen-ase (COX-2) expression. The obtained findings indicated EGLP as a new therapeutic agent in fighting CRC.	[Bai, Jing Hui] China Med Univ, Liaoning Canc Hosp & Inst, Dept Internal Med, Canc Hosp, Shenyang, Peoples R China; [Xu, Jian; Zhao, Jian; Zhang, Rui] China Med Univ, Liaoning Canc Hosp & Inst, Dept Colorectal Surg, Canc Hosp, Shenyang, Peoples R China		Zhang, R (corresponding author), China Med Univ, Liaoning Canc Hosp & Inst, Canc Hosp, 44 Xiaoheyan Rd, Shenyang 110042, Liaoning, Peoples R China.	zhangr190221@163.com					Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Fleita D, 2015, LWT-FOOD SCI TECHNOL, V63, P1236, DOI 10.1016/j.lwt.2015.04.024; Fortin O, 2018, NUTR CANCER, V70, P632, DOI 10.1080/01635581.2018.1460672; Gill CIR, 2002, BRIT J NUTR, V88, pS73, DOI 10.1079/BJN2002632; Haggar Fatima A, 2009, Clin Colon Rectal Surg, V22, P191, DOI 10.1055/s-0029-1242458; Hou Y, 2012, CARBOHYD POLYM, V87, P153, DOI 10.1016/j.carbpol.2011.07.031; Ji J., 2010, INT J BIOL, V3, P74, DOI [10.5539/ijb.v3n1p74, DOI 10.5539/IJB.V3N1P74]; Jiang YF, 2017, BIOMED PHARMACOTHER, V96, P865, DOI 10.1016/j.biopha.2017.09.060; Kim YJ, 2015, BIOORG MED CHEM LETT, V25, P2559, DOI 10.1016/j.bmcl.2015.04.054; Kong M, 2019, INT J IMMUNOPATH PH, V33, DOI 10.1177/2058738419869489; Li Q, 2013, INT J BIOL MACROMOL, V57, P245, DOI 10.1016/j.ijbiomac.2013.03.034; Li WJ, 2011, J AGR FOOD CHEM, V59, P3707, DOI 10.1021/jf1049497; Liu ZJ, 2018, BRAZ J MED BIOL RES, V51, DOI [10.1590/1414-431X20187256, 10.1590/1414-431x20187256]; Luo JM, 2018, J FUNCT FOODS, V47, P127, DOI 10.1016/j.jff.2018.05.041; Ma R, 2018, BIOMED PHARMACOTHER, V108, P119, DOI 10.1016/j.biopha.2018.08.038; Pan K, 2013, INT J BIOL MACROMOL, V55, P301, DOI 10.1016/j.ijbiomac.2013.01.022; Risso A, 2001, AM J PHYSIOL-ENDOC M, V281, pE924, DOI 10.1152/ajpendo.2001.281.5.E924; Sajadimajd S, 2019, CURR PHARM DESIGN, V25, P1210, DOI 10.2174/1381612825666190425155126; Shao P, 2015, INT J BIOL MACROMOL, V74, P420, DOI 10.1016/j.ijbiomac.2014.12.021; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Song G, 2019, BIOMED PHARMACOTHER, V112, DOI 10.1016/j.biopha.2019.01.054; Souers AJ, 2013, NAT MED, V19, P202, DOI 10.1038/nm.3048; Stevens RG, 2007, CANCER LETT, V252, P171, DOI 10.1016/j.canlet.2006.11.009; Xin MG, 2014, NAT COMMUN, V5, DOI 10.1038/ncomms5935; Yang GH, 2016, J RECEPT SIG TRANSD, V36, P6, DOI 10.3109/10799893.2014.970275; Yousef BA, 2018, PHYTOMEDICINE, V40, P140, DOI 10.1016/j.phymed.2018.01.008; Yu Y, 2018, CARBOHYD POLYM, V183, P91, DOI 10.1016/j.carbpol.2017.12.009; Zhang RJ, 2019, ONCOTARGETS THER, V12, P4109, DOI 10.2147/OTT.S195615; Zhang T, 2014, LWT-FOOD SCI TECHNOL, V56, P9, DOI 10.1016/j.lwt.2013.11.010; Zhou HY, 2018, WORLD J SURG ONCOL, V16, DOI 10.1186/s12957-018-1441-3; Zou P, 2018, CHEM-BIOL INTERACT, V279, P129, DOI 10.1016/j.cbi.2017.11.010	31	2	3	12	18	SAGE PUBLICATIONS INC	THOUSAND OAKS	2455 TELLER RD, THOUSAND OAKS, CA 91320 USA	0963-6897	1555-3892		CELL TRANSPLANT	Cell Transplant.	JAN-DEC	2020	29								0963689720931435	10.1177/0963689720931435			9	Cell & Tissue Engineering; Medicine, Research & Experimental; Transplantation	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Research & Experimental Medicine; Transplantation	NU2ER	WOS:000573455300077	32495637	Green Published, gold			2022-04-25	
J	Wang, LB; Jiang, XL; Zhang, XG; Shu, P				Wang, Liangbin; Jiang, Xinlei; Zhang, Xingguo; Shu, Peng			Prognostic implications of an autophagy-based signature in colorectal cancer	MEDICINE			English	Article						autophagy; colorectal cancer; prognosis; regulatory network inference; subtype	CONSENSUS MOLECULAR SUBTYPES; TUMOR GENE-EXPRESSION; III COLON-CANCER; STAGE-II; RECURRENCE; SURVIVAL; FLUOROURACIL; PREDICTION; SCORE	Background: The heterogeneity of colorectal cancer (CRC) poses a significant challenge to the precise treatment of patients. CRC has been divided into 4 consensus molecular subtypes (CMSs) with distinct biological and clinical characteristics, of which CMS4 has the mesenchymal identity and the highest relapse rate. Autophagy plays a vital role in CRC development and therapeutic response. Methods: The gene expression profiles collected from 6 datasets were applied to this study. Network analysis was applied to integrate the subtype-specific molecular modalities and autophagy signature to establish an autophagy-based prognostic signature for CRC (APSCRC). Results: Network analysis revealed that 6 prognostic autophagy genes (VAMP7, DLC1, FKBP1B, PEA15, PEX14, and DNAJB1) predominantly regulated the mesenchymal modalities of CRC. The APSCRC was constructed by these 6 core genes and applied for risk calculation. Patients were divided into high- and low-risk groups based on APSCRC score in all cohorts. Patients within the high-risk group showed an unfavorable prognosis. In multivariate analysis, the APSCRC remained an independent predictor of prognosis. Moreover, the APSCRC achieved higher prognostic power than commercialized multigene signatures. Conclusions: We proposed and validated an autophagy-based signature, which is a promising prognostic biomarker of CRC patients. Further prospective studies are warranted to test and validate its efficiency for clinical application.	[Wang, Liangbin] Beilun Peoples Hosp, Dept Anorectal Surg, Ningbo, Peoples R China; [Jiang, Xinlei] Tianjin Chengjian Univ, Sch Environm & Municipal Engn, Tianjin Key Lab Aquat Sci & Technol, Tianjin, Peoples R China; [Zhang, Xingguo; Shu, Peng] Beilun Peoples Hosp, Mol Lab, Ningbo, Peoples R China		Shu, P (corresponding author), Beilun Peoples Hosp, 1288 East Lushan Rd, Ningbo 315800, Peoples R China.	m17757498873@163.com					Arnold M, 2015, LANCET ONCOL, V16, P36, DOI 10.1016/S1470-2045(14)71123-4; Barrier A, 2006, J CLIN ONCOL, V24, P4685, DOI 10.1200/JCO.2005.05.0229; Chang WJ, 2014, GUT, V63, P1457, DOI 10.1136/gutjnl-2013-305475; de Sousa e Melo F, 2011, CELL STEM CELL, V9, P476, DOI 10.1016/j.stem.2011.10.008; Devenport SN, 2019, CELLS-BASEL, V8, DOI 10.3390/cells8111349; Dienstmann R, 2017, ANN ONCOL, V28, P1023, DOI 10.1093/annonc/mdx052; Ferlay J, 2010, INT J CANCER, V127, P2893, DOI 10.1002/ijc.25516; Fletcher MNC, 2013, NAT COMMUN, V4, DOI 10.1038/ncomms3464; Funke V, 2013, CANCER LETT, V335, P431, DOI 10.1016/j.canlet.2013.02.053; Guinney J, 2015, NAT MED, V21, P1350, DOI 10.1038/nm.3967; Huang Z, 2019, DOSE-RESPONSE, V17, DOI 10.1177/1559325819894179; Janku F, 2011, NAT REV CLIN ONCOL, V8, P528, DOI 10.1038/nrclinonc.2011.71; Jorissen RN, 2009, CLIN CANCER RES, V15, P7642, DOI 10.1158/1078-0432.CCR-09-1431; Kon M, 2011, SCI TRANSL MED, V3, DOI 10.1126/scitranslmed.3003182; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Koustas E, 2019, AM J CLIN ONCOL-CANC, V42, P767, DOI 10.1097/COC.0000000000000592; Koustas E, 2019, CANCERS, V11, DOI 10.3390/cancers11040533; Koustas E, 2018, WORLD J GASTRO ONCOL, V10, P367, DOI 10.4251/wjgo.v10.i11.367; Laibe S, 2012, OMICS, V16, P560, DOI 10.1089/omi.2012.0039; Margolin AA, 2006, BMC BIOINFORMATICS, V7, DOI 10.1186/1471-2105-7-S1-S7; Marisa L, 2013, PLOS MED, V10, DOI 10.1371/journal.pmed.1001453; Mejlvang J, 2018, J CELL BIOL, V217, P3640, DOI 10.1083/jcb.201711002; Miller JA, 2011, BMC BIOINFORMATICS, V12, DOI 10.1186/1471-2105-12-322; O'Connell MJ, 2010, J CLIN ONCOL, V28, P3937, DOI 10.1200/JCO.2010.28.9538; Park SY, 2015, BBA-MOL CELL RES, V1853, P2722, DOI 10.1016/j.bbamcr.2015.07.024; Parkin DM, 2005, CA-CANCER J CLIN, V55, P74, DOI 10.3322/canjclin.55.2.74; Rabinowitz JD, 2010, SCIENCE, V330, P1344, DOI 10.1126/science.1193497; Ritchie ME, 2015, NUCLEIC ACIDS RES, V43, DOI 10.1093/nar/gkv007; Roxburgh CSD, 2012, CANCER TREAT REV, V38, P451, DOI 10.1016/j.ctrv.2011.09.001; Salazar R, 2011, J CLIN ONCOL, V29, P17, DOI 10.1200/JCO.2010.30.1077; Smith JJ, 2010, GASTROENTEROLOGY, V138, P958, DOI 10.1053/j.gastro.2009.11.005; Subramanian A, 2005, P NATL ACAD SCI USA, V102, P15545, DOI 10.1073/pnas.0506580102; Sveen A, 2018, CLIN CANCER RES, V24, P794, DOI 10.1158/1078-0432.CCR-17-1234; Tripathi MK, 2014, CANCER RES, V74, P6947, DOI 10.1158/0008-5472.CAN-14-1592; Vakifahmetoglu-Norberg H, 2016, GENE DEV, V30, P870, DOI 10.1101/gad.280453.116; Van Cutsem E, 2006, EUR J CANCER, V42, P2212, DOI 10.1016/j.ejca.2006.04.012; Wang YX, 2004, J CLIN ONCOL, V22, P1564, DOI 10.1200/JCO.2004.08.186; Yothers G, 2013, J CLIN ONCOL, V31, P4512, DOI 10.1200/JCO.2012.47.3116; Zhang GJ, 2015, J EXP CLIN CANC RES, V34, DOI 10.1186/s13046-015-0189-7; Zhao M, 2015, SCI REP-UK, V5, DOI 10.1038/srep11459; Zhu FX, 2019, ONCOL LETT, V18, P5310, DOI 10.3892/ol.2019.10881	41	2	2	0	2	LIPPINCOTT WILLIAMS & WILKINS	PHILADELPHIA	TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA	0025-7974	1536-5964		MEDICINE	Medicine (Baltimore)	APR 2	2021	100	13							e25148	10.1097/MD.0000000000025148			10	Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	General & Internal Medicine	SO4RD	WOS:000658960700031	33787596	gold, Green Published			2022-04-25	
J	Wang, D; Ge, SK; Chen, Z; Song, YW				Wang, Dan; Ge, Shuke; Chen, Zhe; Song, Yongwei			Evodiamine exerts anticancer effects via induction of apoptosis and autophagy and suppresses the migration and invasion of human colon cancer cells	JOURNAL OF BUON			English	Article						evodiamine; colon cancer; apoptosis; autophagy; migration	IN-VITRO; OVARIAN-CANCER; CARCINOMA; CONSTITUENT; METASTASIS; FRUCTUS	Purpose: Colon cancer ranks as the fourth common type of cancer and is responsible for significant morbidity and mortality throughout the world. Late diagnosis and the rarity of potent and safer chemotherapeutic drugs and efficient therapeutic targets create severe obstacle in the treatment of colon cancer. This study was undertaken to examine the anticancer effects of Evodiamine against human colon cancer cells. Methods: The proliferation rate of the SW480 colon cancer cells was monitored by MTT assay. Apoptosis was detected by Annexin V/propidium iodide (PI) and acridine orange (AO)/ethidium bromide (EB) staining. Transmission electron microscopy (TEM) was used for detection of autophagy. Cell migration and invasion was detected by wound healing and transwell assays, respectively. Protein expression was determined by western blotting. Results: Evodiamine suppressed the proliferation of the SW480 colon cancer cells and exhibited an IC50 of 10 mu M. The cytotoxic effects of Evodiamine were found to be com-paratively lower against the normal CDD-18Co colon cells as evidenced from the IC50 of 100 mu M. AO/EB staining showed that Evodiamine caused apoptosis of the SW480 cells and the percentage of the apoptotic SW480 cells increased with increase in the Evodiamine concentration as indicated by annexin V/PI staining. Evodiamine-induced apoptosis was also accompanied by upregulation of caspase-3 and Bax and suppression of Bcl-2. TEM analysis showed that Evodiamine also activated autophagy in the SW480 cells by enhancing the expression of LC3 II and Beclin 1. The wound assay showed that Evodiamine suppressed the migration of the SW480 cells. Evodiamine also reduced the invasion potential of the SW480 cells as suggested by the transwell assay. Conclusion: The findings of the present study suggest that Evodiamine is a potent anticancer agent and may prove beneficial in the development of systemic therapy of colon cancer.	[Wang, Dan; Chen, Zhe; Song, Yongwei] Dalian Med Univ, Peoples Hosp Dalian 3, Dept Gen Surg, 40 QianShan Rd, Dalian 116034, Liaoning, Peoples R China; [Ge, Shuke] Dalian Municipal Cent Hosp, Dept Thyroid Surg, Dalian 116021, Liaoning, Peoples R China		Song, YW (corresponding author), Dalian Med Univ, Peoples Hosp Dalian 3, Dept Gen Surg, 40 QianShan Rd, Dalian 116034, Liaoning, Peoples R China.	WilburPottszio@yahoo.com					Arnold M, 2017, GUT, V66, P683, DOI 10.1136/gutjnl-2015-310912; Chen TC, 2016, PHYTOMEDICINE, V23, P68, DOI 10.1016/j.phymed.2015.12.003; Cordell GA, 2001, PHYTOTHER RES, V15, P183, DOI 10.1002/ptr.890; Dienstmann R, 2015, J CLIN ONCOL, V33, P1787, DOI 10.1200/JCO.2014.60.0213; Fang CS, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0115204; Fei XF, 2003, CANCER SCI, V94, P92, DOI 10.1111/j.1349-7006.2003.tb01358.x; Hong Ji-Young, 2014, J Cancer Prev, V19, P7; Hu CQ, 2016, MOL MED REP, V14, P413, DOI 10.3892/mmr.2016.5237; Jiang JL, 2009, MOLECULES, V14, P1852, DOI 10.3390/molecules14051852; Kan SF, 2004, INT J CANCER, V110, P641, DOI 10.1002/ijc.20138; Kan SF, 2007, J CELL BIOCHEM, V101, P44, DOI 10.1002/jcb.21036; Lai XJ, 2018, EUR REV MED PHARMACO, V22, P322, DOI 10.26355/eurrev_201801_14175; Lee TJ, 2006, MOL CANCER THER, V5, P2398, DOI 10.1158/1535-7163.MCT-06-0167; Liao CH, 2005, CARCINOGENESIS, V26, P968, DOI 10.1093/carcin/bgi041; Ogasawara M, 2001, BIOL PHARM BULL, V24, P917, DOI 10.1248/bpb.24.917; Peng XB, 2015, CANCER CHEMOTH PHARM, V76, P1173, DOI 10.1007/s00280-015-2902-9; Ping HC, 2003, CHINESE PHARMACOL B, V10; POTTER JD, 1993, EPIDEMIOL REV, V15, P499, DOI 10.1093/oxfordjournals.epirev.a036132; Rasul A, 2012, ONCOL REP, V27, P1481, DOI 10.3892/or.2012.1694; Shi L, 2016, TUMOR BIOL, V37, P12791, DOI 10.1007/s13277-016-5251-3; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Tu YJ, 2013, ONCOL REP, V29, P481, DOI 10.3892/or.2012.2125; Van Cutsem E, 2016, ANN ONCOL, V27, P1386, DOI 10.1093/annonc/mdw235; Wang SP, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0097512; Zhang T, 2014, INT J MOL SCI, V15, P3154, DOI 10.3390/ijms15023154; Zhong ZF, 2015, SCI REP-UK, V5, DOI 10.1038/srep16415	26	10	12	0	1	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	SEP-OCT	2019	24	5					1824	1829					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JU6CG	WOS:000501762000011	31786843				2022-04-25	
J	Guo, SJ; Liang, XX; Guo, M; Zhang, XL; Li, ZY				Guo, Songjia; Liang, Xinxin; Guo, Min; Zhang, Xiaoli; Li, Zhuoyu			Migration inhibition of water stress proteins from Nostoc commune Vauch. via activation of autophagy in DLD-1 cells	INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES			English	Article						Water stress protein 1; Colon cancer; Migration; Autophagy; EMT	EPITHELIAL-MESENCHYMAL TRANSITIONS; BETA-CATENIN; CANCER; EXPRESSION; RESISTANCE; WNT; ASSOCIATION; METASTASIS; CARCINOMA; PROMOTE	Water stress proteins (WSP1) from Nostoc commune Vauch. had been proven to selectively induce colon cancer cells apoptosis. In this study, the effect of WSP1 on migration of human colon cancer cells was investigated. It showed that WSP1 inhibited DLD-1 cell migration, but with an insignificant effect on normal human colon epithelial cells. The data further indicated that WSP1 activated autophagy through down regulation of PI3K/AKT/mTOR pathway. Meanwhile, beta catenin was degraded by autophagy, which then restrained epithelial-mesenchymal transition (EMT) of DLD-1 cell and its migration was subsequently suppressed significantly. The same changes occurred in xenografted nude mice according to the obtained immunohistochemical results. Consistently, the application of autophagy inhibitor largely reversed the inhibited migration by WSP1 treatment. Taken together, WSP1 could suppress migration of DLD-1 cells by autophagy inhibited EMT. The results suggested that WSP1 possessed the potential as a selective therapeutic agent against metastatic colon cancer. (C) 2018 Published by Elsevier B.V.	[Guo, Songjia] Shanxi Prov Peoples Hosp, Ctr Precis Med, Taiyuan 030006, Shanxi, Peoples R China; [Guo, Songjia; Liang, Xinxin; Guo, Min; Zhang, Xiaoli; Li, Zhuoyu] Shanxi Univ, Inst Biotechnol, Key Lab Chem Biol & Mol Engn, Natl Minist Educ, Taiyuan 030006, Shanxi, Peoples R China		Li, ZY (corresponding author), Shanxi Univ, Inst Biotechnol, Key Lab Chem Biol & Mol Engn, Natl Minist Educ, Taiyuan 030006, Shanxi, Peoples R China.	lzy@sxu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31770382]; National Natural Science Foundation of China for Youths [81603020]; Shanxi Province Science Foundation for Youths [201601D021108]	This study was supported by the National Natural Science Foundation of China (No. 31770382), the National Natural Science Foundation of China for Youths (No. 81603020) and Shanxi Province Science Foundation for Youths (201601D021108).	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J. Biol. Macromol.	NOV	2018	119						669	676		10.1016/j.ijbiomac.2018.07.188			8	Biochemistry & Molecular Biology; Chemistry, Applied; Polymer Science	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry; Polymer Science	GX4FD	WOS:000447682100076	30071226				2022-04-25	
J	Lim, SC; Kim, SM; Choi, JE; Kim, CH; Duong, HQ; Han, SI; Kang, HS				Lim, Sung-Chul; Kim, Sun Mi; Choi, Jeong Eun; Kim, Cho Hee; Duong, Hong-Quan; Han, Song Iy; Kang, Ho Sung			Sodium salicylate switches glucose depletion-induced necrosis to autophagy and inhibits high mobility group box protein 1 release in A549 lung adenocarcinoma cells	ONCOLOGY REPORTS			English	Article						sodium salicylate; necrosis; autophagy; ROS; CuZn superoxide dismutase	DRUG-ACTIVATED GENE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NF-KAPPA-B; OXIDATIVE STRESS; APOPTOSIS; CANCER; HMGB1; EXPRESSION; ASPIRIN; GROWTH	Sodium salicylate, the active metabolite of aspirin, has been shown to exert anti-inflammatory activities by inhibiting the expression of various pro-inflammatory factors, and has potent anti-cancer effects against a number of human cancers including colon, lung, breast and leukemia. Necrotic cell death is emerging as one of the crucial factors that trigger an inflammatory response since during necrotic death the cell membrane is ruptured and the intracellular constituents including high mobility group box 1 (HMGB1) are released into the extracellular space, thereby activating an inflammatory response. In contrast, autophagic death is regarded as a form of tumour suppressive cell death, as indicated in tumour suppressors such as beclin 1 in autophagic pathways. To better understand the anti-inflammatory properties of sodium salicylate and its effect on necrotic cell death in A549 cells induced by glucose depletion (GD), a common characteristic of the tumour micro-environment, was examined. While GD induced mostly necrotic death in A549 cells, salicylate suppresssed GD-induced necrosis and HMGB 1 release. In addition, salicylate shifted the cell death pattern to autophagy by inhibiting GD-induced Cu/Zn superoxide dismutase release and ROS production. These results indicate that the activity of salicylate to prevent necrotic death may contribute to its anti-inflammatory action and suppress tumour development possibly through switching the cell death mode from tumour-promoting necrotic cell death to tumour-suppressive autophagic cell death.	[Kim, Sun Mi; Kim, Cho Hee; Kang, Ho Sung] Pusan Natl Univ, Coll Nat Sci, Dept Mol Biol, Pusan 609735, South Korea; [Kim, Sun Mi; Kim, Cho Hee; Kang, Ho Sung] Pusan Natl Univ, Res Inst Genet Engn, Pusan 609735, South Korea; [Lim, Sung-Chul; Choi, Jeong Eun; Duong, Hong-Quan; Han, Song Iy] Chosun Univ, Coll Med, Res Ctr Resistant Cells, Kwangju 501759, South Korea; [Lim, Sung-Chul] Chosun Univ, Coll Med, Dept Pathol, Kwangju 501759, South Korea		Kang, HS (corresponding author), Pusan Natl Univ, Coll Nat Sci, Dept Mol Biol, Pusan 609735, South Korea.	sihan@chosun.ac.kr; hspkang@pusan.ac.kr	li, tao/B-2402-2008				Ahmad IM, 2005, J BIOL CHEM, V280, P4254, DOI 10.1074/jbc.M411662200; Amann R, 2002, EUR J PHARMACOL, V447, P1, DOI 10.1016/S0014-2999(02)01828-9; Backer M, 2006, DEUT MED WOCHENSCHR, V131, P1553, DOI 10.1055/s-2006-947797; Baek SJ, 2002, CARCINOGENESIS, V23, P425, DOI 10.1093/carcin/23.3.425; Baek SJ, 2001, MOL PHARMACOL, V59, P901, DOI 10.1124/mol.59.4.901; Battaglia V, 2005, J BIOL CHEM, V280, P33864, DOI 10.1074/jbc.M502391200; Bellosillo B, 1998, BLOOD, V92, P1406, DOI 10.1182/blood.V92.4.1406.416k17_1406_1414; Bernales S, 2006, PLOS BIOL, V4, P2311, DOI 10.1371/journal.pbio.0040423; Chan TA, 1998, P NATL ACAD SCI USA, V95, P681, DOI 10.1073/pnas.95.2.681; Chen XQ, 2002, INT J HEMATOL, V75, P407, DOI 10.1007/BF02982133; Chung YM, 2003, FREE RADICAL BIO MED, V34, P434, DOI 10.1016/S0891-5849(02)01301-1; Crighton D, 2006, CELL, V126, P121, DOI 10.1016/j.cell.2006.05.034; Danial NN, 2004, CELL, V116, P205, DOI 10.1016/S0092-8674(04)00046-7; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; Ding WX, 2007, J BIOL CHEM, V282, P4702, DOI 10.1074/jbc.M609267200; Elder DJE, 1996, CANCER RES, V56, P2273; Fimia GM, 2007, NATURE, V447, P1121, DOI 10.1038/nature05925; FOSSMANN E, 2007, LANCET, V369, P1603; Gatenby RA, 2004, NAT REV CANCER, V4, P891, DOI 10.1038/nrc1478; Golstein P, 2007, TRENDS BIOCHEM SCI, V32, P37, DOI 10.1016/j.tibs.2006.11.001; Hippert MM, 2006, CANCER RES, V66, P9349, DOI 10.1158/0008-5472.CAN-06-1597; Jin SK, 2007, AUTOPHAGY, V3, P28, DOI 10.4161/auto.3269; JURIVICH DA, 1992, SCIENCE, V255, P1243, DOI 10.1126/science.1546322; Kim CH, 2007, J CELL PHYSIOL, V211, P371, DOI 10.1002/jcp.20941; Klampfer L, 1999, BLOOD, V93, P2386, DOI 10.1182/blood.V93.7.2386.407k15_2386_2394; KOPP E, 1994, SCIENCE, V265, P956, DOI 10.1126/science.8052854; Law BK, 2000, J BIOL CHEM, V275, P38261, DOI 10.1074/jbc.M005545200; Lee EJ, 2003, INT J ONCOL, V23, P503; Li W, 2007, J IMMUNOL, V178, P3856, DOI 10.4049/jimmunol.178.6.3856; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Lim SC, 2007, INT J MOL MED, V20, P187; Lotze MT, 2005, NAT REV IMMUNOL, V5, P331, DOI 10.1038/nri1594; Marra DE, 2000, CIRCULATION, V102, P2124, DOI 10.1161/01.CIR.102.17.2124; Martindale JL, 2002, J CELL PHYSIOL, V192, P1, DOI 10.1002/jcp.10119; Mates J M, 1999, Front Biosci, V4, pD339; Newman D, 2003, MOL PHARMACOL, V63, P557, DOI 10.1124/mol.63.3.557; Raucci A, 2007, AUTOIMMUNITY, V40, P285, DOI 10.1080/08916930701356978; Scaffidi P, 2002, NATURE, V418, P191, DOI 10.1038/nature00858; Schlueter C, 2005, AM J PATHOL, V166, P1259, DOI 10.1016/S0002-9440(10)62344-9; Schwenger P, 1997, P NATL ACAD SCI USA, V94, P2869, DOI 10.1073/pnas.94.7.2869; Shiff SJ, 1996, EXP CELL RES, V222, P179, DOI 10.1006/excr.1996.0023; Stark LA, 2007, CARCINOGENESIS, V28, P968, DOI 10.1093/carcin/bgl220; Syntichaki P, 2003, NAT REV NEUROSCI, V4, P672, DOI 10.1038/nrn1174; Taguchi A, 2000, NATURE, V405, P354, DOI 10.1038/35012626; Tegeder I, 2001, FASEB J, V15, P2057, DOI 10.1096/fj.01-0390rev; Ulloa L, 2006, CYTOKINE GROWTH F R, V17, P189, DOI 10.1016/j.cytogfr.2006.01.003; Ulrich CM, 2006, NAT REV CANCER, V6, P130, DOI 10.1038/nrc1801; Vakkila J, 2004, NAT REV IMMUNOL, V4, P641, DOI 10.1038/nri1415; Wilson LC, 2003, INT J CANCER, V105, P747, DOI 10.1002/ijc.11173; Yang H, 2005, J LEUKOCYTE BIOL, V78, P1, DOI 10.1189/jlb.1104648; Yorimitsu T, 2006, J BIOL CHEM, V281, P30299, DOI 10.1074/jbc.M607007200; ZONG WX, 2006, GENE DEV, V20	52	7	7	0	1	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	MAY	2008	19	5					1165	1171					7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	293CI	WOS:000255312000013	18425372				2022-04-25	
J	Gurkan, AC; Arisan, ED; Yerlikaya, PO; Ilhan, H; Unsal, NP				Gurkan, Ajda Coker; Arisan, Elif Damla; Yerlikaya, Pinar Obakan; Ilhan, Halime; Unsal, Narcin Palavan			Inhibition of autophagy enhances DENSpm-induced apoptosis in human colon cancer cells in a p53 independent manner	CELLULAR ONCOLOGY			English	Article						Colon cancer; Apoptosis; Autophagy; Polyamine analogue; DENSpm	HUMAN-MELANOMA CELLS; POLYAMINE ANALOG N-1,N-11-DIETHYLNORSPERMINE; SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE; CARCINOMA-CELLS; INDUCTION; RESISTANCE; DEATH; METABOLISM; CATABOLISM; MODULATORS	One of the recently developed polyamine (PA) analogues, N (1) ,N (11)-diethylnorspermine (DENSpm), has been found to act as an apoptotic inducer in melanoma, breast, prostate and colon cancer cells. Also, its potential to induce autophagy has been established. Unfolded protein responses and starvation of amino acids are known to trigger autophagy. As yet, however, the molecular mechanism underlying PA deficiency-induced autophagy is not fully clarified. Here, we aimed to determine the apoptotic effect of DENSpm after autophagy inhibition by 3-methyladenine (3-MA) or siRNA-mediated Beclin-1 silencing in colon cancer cells. The apoptotic effects of DENSpm after 3-MA treatment or Beclin-1 silencing were determined by PI and AnnexinV/PI staining in conjunction with flow cytometry. Intracellular PA levels were measured by HPLC, whereas autophagy and the expression profiles of PA key players were determined in HCT116, SW480 and HT29 colon cancer cells by Western blotting. We found that DENSpm-induced autophagy was inhibited by 3-MA treatment and Beclin-1 silencing, and that apoptotic cell death was increased by PA depletion and spermidine/spermine N (1)-acetyltransferase (SSAT) upregulation. We also found that autophagy inhibition led to DENSpm-induced apoptosis through Atg5 down-regulation, p62 degradation and LC3 lipidation in both HCT116 and SW480 cells. p53 deficiency did not alter the response of the colon cancer cells to DENSpm-induced apoptotic cell death under autophagy suppression conditions. From our results we conclude that DENSpm-induced apoptotic cell death is increased when autophagy is inhibited by 3-MA or Beclin-1 siRNA through PA depletion and PA catabolic activation in colon cancer cells, regardless p53 mutation status.	[Gurkan, Ajda Coker; Arisan, Elif Damla; Yerlikaya, Pinar Obakan; Ilhan, Halime; Unsal, Narcin Palavan] Istanbul Kultur Univ, Sci & Letters Fac, Mol Biol & Genet Dept, Atakoy Campus, TR-34156 Istanbul, Turkey		Gurkan, AC (corresponding author), Istanbul Kultur Univ, Sci & Letters Fac, Mol Biol & Genet Dept, Atakoy Campus, TR-34156 Istanbul, Turkey.	a.coker@iku.edu.tr	Arisan, ElifDamla/AAB-1173-2021; YERLIKAYA, PINAR OBAKAN/AAG-5979-2019; Arisan, Elif Damla/W-8682-2019; GURKAN, AJDA/AAG-6669-2019	YERLIKAYA, PINAR OBAKAN/0000-0001-7058-955X; Arisan, Elif Damla/0000-0002-4844-6381; GURKAN, AJDA/0000-0003-1475-2417; Unsal Palavan, Narcin/0000-0002-2945-540X	Scientific and Technological Research Council of TURKEY [(TUBITAK)]Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [212T227]; Istanbul Kultur University Scientific Projects Support CenterIstanbul Kultur University	This work was supported by The Scientific and Technological Research Council of TURKEY [(TUBITAK), Grant Number; 212T227] and the Istanbul Kultur University Scientific Projects Support Center. We are thankful to Esin Guvenir, Merve Karatas and Derya Bulut for their technical assistance.	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Oncol.	JUN	2018	41	3					297	317		10.1007/s13402-017-0369-x			21	Oncology; Cell Biology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology; Pathology	GF8KC	WOS:000432218500005	29492901				2022-04-25	
J	Mao, MT; Liu, YM; Gao, XH				Mao, Mintao; Liu, Yumei; Gao, Xinhai			Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Colorectal cancer; Ku-0060648; Autophagy; DNA-PKcs; PI3K-AKT-mTOR	DEPENDENT PROTEIN-KINASE; ACTIVITY IN-VITRO; DNA-PKCS; THERAPEUTIC TARGET; STATISTICS; INHIBITOR; PATHWAY; PREVENTION; CHINA	The current study evaluated the potential anti-colorectal cancer (CRC) activity by Ku-0060648, a novel DNA-PKcs and PI3K duel inhibitor. In both CRC cell lines (HCT-116 and HT-29) and primary human colon cancer cells, Ku-0060648 exposure at nM concentrations efficiently inhibited cell proliferation. Meanwhile, Ku-0060648 provoked apoptosis in CRC cells. Ku-0060648 was yet ineffective to the normal colon epithelial cells. Ku-0060648 blocked PI3K-AKT-mTOR cascade and in-activated DNA-PKcs in CRC cells. Intriguingly, Ku-0060648 treatment induced feedback autophagy activation in HCT-116 cells. On the other hand, pharmacological autophagy inhibitors (3-methyladenine or chloroquine) or silencing key autophagy proteins (Beclin-1 or ATG-7) dramatically potentiated Ku-0060648-induced HCT-116 cell apoptosis. Together, these results suggest that feedback autophagy activation is a key resistance factor of Ku-0060648 in CRC cells, and autophagy inhibition sensitizes Ku-0060648-induced anti-CRC activity. (C) 2017 Elsevier Inc. All rights reserved.	[Mao, Mintao; Liu, Yumei; Gao, Xinhai] Shanghai Jiao Tong Univ, Sch Med, Tongren Hosp, Emergency Ctr, 1111 Xianxia St, Shanghai 200336, Peoples R China		Gao, XH (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Tongren Hosp, Emergency Ctr, 1111 Xianxia St, Shanghai 200336, Peoples R China.	yishenggxhsh@163.com					Amaravadi RK, 2007, CLIN CANCER RES, V13, P7271, DOI 10.1158/1078-0432.CCR-07-1595; Banerjee Hirendra Nath, 2012, J Cancer Sci Ther, V4, P12; Bouchaert P, 2012, INT J RADIAT ONCOL, V84, P1179, DOI 10.1016/j.ijrobp.2012.02.014; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Brouquet A, 2013, NAT REV GASTRO HEPAT, V10, P266, DOI 10.1038/nrgastro.2013.53; Chen MB, 2016, ONCOTARGET, V7, P17047, DOI 10.18632/oncotarget.7742; Chen MB, 2015, BIOCHEM BIOPH RES CO, V463, P954, DOI 10.1016/j.bbrc.2015.06.041; Chen WQ, 2016, CA-CANCER J CLIN, V66, P115, DOI 10.3322/caac.21338; Chen WQ, 2015, CHINESE J CANCER RES, V27, P1, DOI 10.3978/j.issn.1000-9604.2015.02.07; Dungl DA, 2015, FRONT ONCOL, V5, DOI 10.3389/fonc.2015.00240; Eriksson A, 2002, ANTICANCER RES, V22, P1787; Falck J, 2005, NATURE, V434, P605, DOI 10.1038/nature03442; Francipane MG, 2014, ONCOTARGET, V5, P49, DOI 10.18632/oncotarget.1548; Fu LL, 2013, INT J BIOCHEM CELL B, V45, P921, DOI 10.1016/j.biocel.2013.02.007; Furukawa T, 2008, J GASTROENTEROL, V43, P905, DOI 10.1007/s00535-008-2226-1; Gao YJ, 1998, IMMUNITY, V9, P367, DOI 10.1016/S1074-7613(00)80619-6; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Hennessy BT, 2005, NAT REV DRUG DISCOV, V4, P988, DOI 10.1038/nrd1902; Hosoi Y, 2004, INT J ONCOL, V25, P461; Hubbard JM, 2015, NAT REV CLIN ONCOL, V12, P73, DOI 10.1038/nrclinonc.2014.233; Janku F, 2011, NAT REV CLIN ONCOL, V8, P528, DOI 10.1038/nrclinonc.2011.71; Jung CH, 2009, MOL BIOL CELL, V20, P1992, DOI 10.1091/mbc.E08-12-1249; Kerr D, 2003, NAT REV CANCER, V3, P615, DOI 10.1038/nrc1147; Khanna KK, 2001, NAT GENET, V27, P247, DOI 10.1038/85798; Kim J, 2011, NAT CELL BIOL, V13, P132, DOI 10.1038/ncb2152; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Kuipers EJ, 2013, NAT REV CLIN ONCOL, V10, P130, DOI 10.1038/nrclinonc.2013.12; Leake Isobel, 2014, Nat Rev Gastroenterol Hepatol, V11, P270, DOI 10.1038/nrgastro.2014.60; Li JP, 2016, ONCOTARGET, V7, P77815, DOI 10.18632/oncotarget.12802; Li YM, 2012, AM J MED SCI, V343, P155, DOI 10.1097/MAJ.0b013e31821f978d; Lu PH, 2016, ONCOTARGET, V7, P45889, DOI 10.18632/oncotarget.9969; Lu XS, 2017, ONCOTARGET, V8, P988, DOI 10.18632/oncotarget.13519; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; McCoy F, 2010, CELL DEATH DIS, V1, DOI 10.1038/cddis.2010.86; Moscat J, 2011, CELL, V147, P724, DOI 10.1016/j.cell.2011.10.021; Munck JM, 2012, MOL CANCER THER, V11, P1789, DOI 10.1158/1535-7163.MCT-11-0535; Nezis IP, 2012, ANTIOXID REDOX SIGN, V17, P786, DOI 10.1089/ars.2011.4394; Palta M, 2014, NAT REV CLIN ONCOL, V11, P182, DOI 10.1038/nrclinonc.2014.43; Pandurangan AK, 2013, ASIAN PAC J CANCER P, V14, P2201, DOI 10.7314/APJCP.2013.14.4.2201; Pascale RM, 2016, DNA REPAIR, V47, P12, DOI 10.1016/j.dnarep.2016.10.004; Robert F, 2015, GENOME MED, V7, DOI 10.1186/s13073-015-0215-6; Rubinsztein DC, 2012, NAT REV DRUG DISCOV, V11, P709, DOI 10.1038/nrd3802; Schmoll HJ, 2014, NAT REV CLIN ONCOL, V11, P79, DOI 10.1038/nrclinonc.2013.254; Schonewolf CA, 2014, WORLD J GASTRO ONCOL, V6, P74, DOI 10.4251/wjgo.v6.i3.74; SEGLEN PO, 1982, P NATL ACAD SCI-BIOL, V79, P1889, DOI 10.1073/pnas.79.6.1889; Separovic D, 2010, ARCH BIOCHEM BIOPHYS, V494, P101, DOI 10.1016/j.abb.2009.11.023; Siegel RL, 2015, CA-CANCER J CLIN, V65, P5, DOI [10.3322/caac.21254, 10.3322/caac.21208, 10.1001/jamaoto.2014.2530, 10.1136/bmj.g1502]; Ullal AJ, 2014, CLIN IMMUNOL, V154, P178, DOI 10.1016/j.clim.2014.05.007; Vivanco I, 2002, NAT REV CANCER, V2, P489, DOI 10.1038/nrc839; Wrighton KH, 2013, NAT REV MOL CELL BIO, V14, P1, DOI 10.1038/nrm3499; Wu L, 2015, BIOCHEM BIOPH RES CO, V466, P547, DOI 10.1016/j.bbrc.2015.09.068; Yu R, 2014, CANCER CELL INT, V14, DOI 10.1186/1475-2867-14-49; Zhai L, 2015, BIOCHEM BIOPH RES CO, V468, P274, DOI 10.1016/j.bbrc.2015.10.113; Zhang Q, 2016, BIOCHEM BIOPH RES CO, V480, P334, DOI 10.1016/j.bbrc.2016.10.043; Zhao Z, 2017, ONCOTARGET, V8, P18312, DOI 10.18632/oncotarget.15436; Zhu YR, 2014, BIOCHEM BIOPH RES CO, V451, P112, DOI 10.1016/j.bbrc.2014.07.077	56	5	5	0	8	ACADEMIC PRESS INC ELSEVIER SCIENCE	SAN DIEGO	525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA	0006-291X	1090-2104		BIOCHEM BIOPH RES CO	Biochem. Biophys. Res. Commun.	SEP 2	2017	490	4					1244	1249		10.1016/j.bbrc.2017.07.002			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	FD4UX	WOS:000407528800018	28676397				2022-04-25	
J	Choi, JB; Kim, JH; Lee, H; Pak, JN; Shim, BS; Kim, SH				Choi, Jhin-Baek; Kim, Ju-Ha; Lee, Hyemin; Pak, Ji-Na; Shim, Bum Sang; Kim, Sung-Hoon			Reactive Oxygen Species and p53 Mediated Activation of p38 and Caspases is Critically Involved in Kaempferol Induced Apoptosis in Colorectal Cancer Cells	JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY			English	Article						Kaempferol; apoptosis; ROS; p53; p38 MAPK	HEPATOCELLULAR-CARCINOMA CELLS; COLON-CANCER; OXIDATIVE STRESS; HUMAN-DISEASES; PATHWAY; MAPK; AUTOPHAGY; DEATH; JNK; STATISTICS	Here the molecular mechanisms of Kaempferol were examined in colorectal cancers (CRCs). Kaempferol significantly exerted antiproliferative and cytotoxic effect in HCT116, HCT15, and SW480 cells. Also, Kaempferol increased sub G1 population, G2/M arrest, and the numbers of TUNEL cells in HCT116 colorectal cancer cells. Also, Kaempferol increased the PARP cleavages and activation of caspase-8, -9, and -3, phospho-p38 MAPK, p53, and p21 in HCT116 and HCT15 cells. Of note, Kaempferol generated reactive oxygen species (ROS) (43.7 +/- 0.56 vs 25.8 +/- 0.43, P < 0.01) in HCT116 cells and reversely ROS inhibitor NAC obstructed the effects of Kaempferol to cleave PARP and caspase-3 and activate phosphorylation of p38 MAPK in HCT116 colorectal cancer cells. Likewise, pancaspase inhibitor z-vad-fmk, p38 MAPK inhibitor SB203580, and p53 depletion blocked PARP and caspase-3 in Kaempferol treated HCT116 colorectal cancer cells. Therefore, these findings provide novel insight that ROS and p53 signalings mediate p38 phosphorylation and caspase activation in Kaempferol stimulated apoptosis in CRCs.	[Choi, Jhin-Baek; Kim, Ju-Ha; Lee, Hyemin; Shim, Bum Sang; Kim, Sung-Hoon] Kyung Hee Univ, Coll Korean Med, Seoul 02447, South Korea; [Pak, Ji-Na] Grad Sch East West Med Sci, Dept East West Med Sci, Yongin 17104, South Korea		Kim, SH (corresponding author), Kyung Hee Univ, Canc Mol Targeted Herbal Res Lab, 26 Kyungheedae Ro, Seoul 02447, South Korea.	sungkim7@khu.ac.kr	Shim, Bum-sang/AAH-9081-2020	kim, sunghoon/0000-0003-2423-1973	National Research Foundation of Korea (NRF)National Research Foundation of Korea [2017R1A2A1A17069297]	This study was financially supported by the National Research Foundation of Korea (NRF) (no. 2017R1A2A1A17069297).	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A, 2013, BIOL CANC; Xavier CPR, 2013, J NUTR BIOCHEM, V24, P706, DOI 10.1016/j.jnutbio.2012.04.004; Yang N, 2017, MOL MED REP, V15, P929, DOI 10.3892/mmr.2016.6081; Yoshida T, 2008, BIOCHEM BIOPH RES CO, V375, P129, DOI 10.1016/j.bbrc.2008.07.131; Youle RJ, 2008, NAT REV MOL CELL BIO, V9, P47, DOI 10.1038/nrm2308; Zhang Q, 2015, FOOD FUNCT, V6, P1518, DOI [10.1039/C5FO00142K, 10.1039/c5fo00142k]	37	28	31	2	27	AMER CHEMICAL SOC	WASHINGTON	1155 16TH ST, NW, WASHINGTON, DC 20036 USA	0021-8561	1520-5118		J AGR FOOD CHEM	J. Agric. Food Chem.	SEP 26	2018	66	38					9960	9967		10.1021/acs.jafc.8b02656			8	Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Agriculture; Chemistry; Food Science & Technology	GV5LE	WOS:000446142800011	30211553				2022-04-25	
J	Ha, TK; Kim, ME; Yoon, JH; Bae, SJ; Yeom, J; Lee, JS				Ha, Tae Kwun; Kim, Mi Eun; Yoon, Ju Hwa; Bae, Sung Jin; Yeom, Jihye; Lee, Jun Sik			Galangin induces human colon cancer cell death via the mitochondrial dysfunction and caspase-dependent pathway	EXPERIMENTAL BIOLOGY AND MEDICINE			English	Article						Human colon cancer; galangin; apoptosis; caspase activation; chromatin condensation	APOPTOSIS; AUTOPHAGY	Galangin is a member of flavonols and found in Alpinia officinarum, galangal root, and propolis. Previous studies have demonstrated that galangin has anti-cancer effects on several cancers, including melanoma, hepatoma, and leukaemia cells. However, anti-cancer activity of galangin on human colon cancer has not been established yet. In this study, we investigated the anti-cancer effects of galangin on two types of human colon cancer cells (HCT-15 and HT-29). We found that galangin induced apoptosis and DNA condensation of human colon cancer cells in a dose-dependent manner. We also determined that galangin increased the activation of caspase-3 and -9, and release of apoptosis inducing factor from the mitochondria into the cytoplasm by Western blot analysis. In addition, galangin induced human colon cancer cell death through the alteration of mitochondria membrane potential and dysfunction. These results suggest that galangin induces apoptosis of HCT-15 and HT-29 human colon cancer cells and may prove useful in the development of therapeutic agents for human colon cancer.	[Ha, Tae Kwun] Inje Univ, Coll Med, Busan Paik Hosp, Dept Surg, Pusan 633165, South Korea; [Kim, Mi Eun; Yoon, Ju Hwa; Yeom, Jihye; Lee, Jun Sik] Chosun Univ, Coll Nat Sci, Dept Biol, Kwangju 501759, South Korea; [Bae, Sung Jin] Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea		Lee, JS (corresponding author), Chosun Univ, Coll Nat Sci, Dept Biol, Kwangju 501759, South Korea.	junsiklee@chosun.ac.kr			Inje University	This work was supported by the 2013 Inje University research grant.	Chaabane W, 2013, ARCH IMMUNOL THER EX, V61, P43, DOI 10.1007/s00005-012-0205-y; Fujimoto N, 2008, DRUG METAB PHARMACOK, V23, P216, DOI 10.2133/dmpk.23.216; Gwak J, 2011, MOL PHARMACOL, V79, P1014, DOI 10.1124/mol.110.069591; Jin CH, 2012, TOXICOL LETT, V211, P45, DOI 10.1016/j.toxlet.2012.02.020; Kim DA, 2012, FOOD CHEM TOXICOL, V50, P684, DOI 10.1016/j.fct.2011.11.039; Kwon CH, 2008, TOXICOLOGY, V244, P13, DOI 10.1016/j.tox.2007.10.019; Leonard E, 2006, METAB ENG, V8, P172, DOI 10.1016/j.ymben.2005.11.001; Seelinger G, 2008, MOLECULES, V13, P2628, DOI 10.3390/molecules13102628; Sivakumar AS, 2011, CHEM-BIOL INTERACT, V193, P141, DOI 10.1016/j.cbi.2011.06.003; Tolomeo M, 2008, CANCER LETT, V265, P289, DOI 10.1016/j.canlet.2008.02.025; Wang L, 2009, AM J CLIN NUTR, V89, P905, DOI 10.3945/ajcn.2008.26913; Watson AJM, 2011, DIGEST DIS, V29, P222, DOI 10.1159/000323926; Wen M, 2012, PHARMACOLOGY, V89, P247, DOI 10.1159/000337041; Xie CH, 2012, J NUTR BIOCHEM, V23, P1184, DOI 10.1016/j.jnutbio.2011.06.013; Zhang HT, 2010, WORLD J GASTROENTERO, V16, P3377, DOI 10.3748/wjg.v16.i27.3377; Zhang WJ, 2013, J CELL BIOCHEM, V114, P152, DOI 10.1002/jcb.24312	16	42	47	0	17	SAGE PUBLICATIONS LTD	LONDON	1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND	1535-3702	1535-3699		EXP BIOL MED	Exp. Biol. Med.	SEP	2013	238	9					1047	1054		10.1177/1535370213497882			8	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	220LA	WOS:000324584000008	23925650				2022-04-25	
J	Rudolf, E; Kralova, V; Rudolf, K; John, S				Rudolf, E.; Kralova, V.; Rudolf, K.; John, S.			The role of p38 in irinotecan-induced DNA damage and apoptosis of colon cancer cells	MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS			English	Article						Colon cancer; Irinotecan; p38; Apoptosis; DNA damage	ACTIVATED PROTEIN-KINASE; COLORECTAL-CANCER; MAP KINASE; 7-ETHYL-10-HYDROXYCAMPTOTHECIN SN-38; PATHWAY; CHEMOTHERAPY; AUTOPHAGY; P38-ALPHA; PHOSPHORYLATION; CHECKPOINT	The role of p38 in irinotecan (CPT-11)-induced damage and cell death in colon cancer cell line SW620 was investigated. We demonstrate that CPT-11 treatment activates p38 in exposed cells, however with concentration dependent dynamics and differing consequences. Higher CPT-11 concentrations induce a massive early but relatively short-lasting p38 activity leading to apoptosis mediated by mitochondria and caspases. Pharmacological or siRNA inhibition of p38 then significantly prevents CPT-11-dependent cell death. Conversely, lower CPT-11 concentrations activate p38 in a delayed, however sustained manner, with apoptosis occurring only in a fraction of cells and in the absence of significant autophagy. Blocking p38 in thus treated cells increases their sensitivity toward CPT-11 and increases cell death. In summary, our results confirm the involvement of p38 in colon cancer cells response to CPT-11 while indicating a varying role of p38 in the final biological response. (C) 2013 Elsevier B.V. All rights reserved.	[Rudolf, E.; Kralova, V.; Rudolf, K.; John, S.] Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Hradec Kralove 50038, Czech Republic		Rudolf, E (corresponding author), Charles Univ Prague, Fac Med Hradec Kralove, Dept Med Biol & Genet, Simkova 870, Hradec Kralove 50038, Czech Republic.	rudolf@lfhk.cuni.cz	Rudolf, Kamil/B-8060-2017; Rudolf, Emil/B-5956-2017; Králová, Věra/B-6608-2017	Rudolf, Kamil/0000-0003-1704-132X; Rudolf, Emil/0000-0002-9526-3174; Králová, Věra/0000-0001-5971-4110	program PRVOUK [P37/01]	This work was supported by the program PRVOUK P37/01.	Ashwell JD, 2006, NAT REV IMMUNOL, V6, P532, DOI 10.1038/nri1865; Bulavin DV, 2004, ADV CANCER RES, V92, P95, DOI 10.1016/S0065-230X(04)92005-2; Bulavin DV, 1999, EMBO J, V18, P6845, DOI 10.1093/emboj/18.23.6845; Chiu SJ, 2008, TOXICOL LETT, V179, P63, DOI 10.1016/j.toxlet.2008.04.004; Comes F, 2007, CELL DEATH DIFFER, V14, P693, DOI 10.1038/sj.cdd.4402076; Cuadrado A, 2007, EMBO J, V26, P2115, DOI 10.1038/sj.emboj.7601657; Cuenda A, 2007, BBA-MOL CELL RES, V1773, P1358, DOI 10.1016/j.bbamcr.2007.03.010; Dolado I, 2007, CANCER CELL, V11, P191, DOI 10.1016/j.ccr.2006.12.013; Enslen H, 1998, J BIOL CHEM, V273, P1741, DOI 10.1074/jbc.273.3.1741; Ettlinger DE, 2006, ANTICANCER RES, V26, P1337; Fiorentini G, 2003, TUMORI J, V89, P382, DOI 10.1177/030089160308900406; Gagne JF, 2002, MOL PHARMACOL, V62, P608, DOI 10.1124/mol.62.3.608; Ghatan S, 2000, J CELL BIOL, V150, P335, DOI 10.1083/jcb.150.2.335; Han JH, 2007, TRENDS BIOCHEM SCI, V32, P364, DOI 10.1016/j.tibs.2007.06.007; Hofmann C, 2005, ANTICANCER RES, V25, P795; Hsu SC, 1999, J BIOL CHEM, V274, P25769, DOI 10.1074/jbc.274.36.25769; Kim MJ, 2008, MOL CANCER RES, V6, P1718, DOI 10.1158/1541-7786.MCR-08-0032; LAUGHTON C, 1984, ANAL BIOCHEM, V140, P417, DOI 10.1016/0003-2697(84)90187-8; Li H, 2011, CANCER RES, V71, P3625, DOI 10.1158/0008-5472.CAN-10-4475; Ling X, 2009, AM J TRANSL RES, V1, P393; Nakatomi K, 2001, BIOCHEM BIOPH RES CO, V288, P827, DOI 10.1006/bbrc.2001.5850; Paillas S, 2011, CANCER RES, V71, P1041, DOI 10.1158/0008-5472.CAN-10-2726; Phong MS, 2010, MOL CELL BIOL, V30, P3816, DOI 10.1128/MCB.00949-09; Pommier Y, 2006, NAT REV CANCER, V6, P789, DOI 10.1038/nrc1977; Sanchez-Prieto R, 2000, CANCER RES, V60, P2464; Shi Y, 2002, BIOL CHEM, V383, P1519, DOI 10.1515/BC.2002.173; Simone C, 2007, AUTOPHAGY, V3, P468, DOI 10.4161/auto.4319; Tanaka Y, 2003, J BIOL CHEM, V278, P33753, DOI 10.1074/jbc.M303313200; Tourian L, 2004, J CELL SCI, V117, P6459, DOI 10.1242/jcs.01573; Vanhoefer U, 2001, J CLIN ONCOL, V19, P1501, DOI 10.1200/JCO.2001.19.5.1501; Wen JG, 2010, LEUKEMIA RES, V34, P85, DOI 10.1016/j.leukres.2009.05.024; Wu CC, 2010, PROTEIN CELL, V1, P573, DOI 10.1007/s13238-010-0075-1; Zarubin T, 2005, CELL RES, V15, P11, DOI 10.1038/sj.cr.7290257; Zhuang SG, 2000, J BIOL CHEM, V275, P25939, DOI 10.1074/jbc.M001185200	34	20	20	5	20	ELSEVIER SCIENCE BV	AMSTERDAM	PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS	0027-5107			MUTAT RES-FUND MOL M	Mutat. Res.-Fundam. Mol. Mech. Mutagen.	JAN-FEB	2013	741						27	34		10.1016/j.mrfmmm.2013.02.002			8	Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology	137RZ	WOS:000318456400004	23422270				2022-04-25	
J	Sameri, S; Mohammadi, C; Mehrabani, M; Najafi, R				Sameri, Saba; Mohammadi, Chiman; Mehrabani, Mehrnaz; Najafi, Rezvan			Targeting the hallmarks of cancer: the effects of silibinin on proliferation, cell death, angiogenesis, and migration in colorectal cancer	BMC COMPLEMENTARY MEDICINE AND THERAPIES			English	Article						Colorectal cancer; Silibinin; Angiogenesis; Autophagy; Apoptosis; Migration	ENDOTHELIAL-CELLS; CARCINOMA-CELLS; CYCLE ARREST; HYPOXIA; EXPRESSION; GROWTH; APOPTOSIS; AUTOPHAGY; ACTIVATION; INDUCTION	Background Silibinin, as a chemopreventive agent, has shown anti-cancer efficacy against different types of cancers. In the present study, we investigated the anti-cancer activities of silibinin on CT26 mouse colon cell line. Methods CT26 cells were treated with different concentrations of silibinin. To examine the cytotoxic effect of silibinin on proliferation, apoptosis, autophagy, angiogenesis, and migration, MTT, colony-forming assay, Annexin V/PI flow cytometry, RT-qPCR, and Scratch assay were used. Results Silibinin was found to significantly reduce CT26 cells survival. Furthermore, silibinin strongly induced apoptosis and autophagy by up-regulating the expression of Bax, Caspase-3, Atg5, Atg7 and BECN1 and down-regulating Bcl-2. Silibinin considerably down-regulated the expression of COX-2, HIF-1 alpha, VEGF, Ang-2, and Ang-4 as well as the expression of MMP-2, MMP-9, CCR-2 and CXCR-4. Conclusions The present study revealed that silibinin shows anticancer activities by targeting proliferation, cell survival, angiogenesis, and migration of CT26 cells.	[Sameri, Saba; Mohammadi, Chiman; Najafi, Rezvan] Hamadan Univ Med Sci, Res Ctr Mol Med, Hamadan, Iran; [Mehrabani, Mehrnaz] Kerman Univ Med Sci, Inst Neuropharmacol, Physiol Res Ctr, Kerman, Iran		Najafi, R (corresponding author), Hamadan Univ Med Sci, Res Ctr Mol Med, Hamadan, Iran.	re.najafi@umsha.ac.ir			Hamadan University of Medical Sciences [9811158675]	This study was funded by Hamadan University of Medical Sciences under Grant numbers 9811158675.	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J	Chen, L; He, M; Zhang, M; Sun, Q; Zeng, S; Zhao, H; Yang, H; Liu, ML; Ren, S; Meng, XL; Xu, HB				Chen, Li; He, Man; Zhang, Meng; Sun, Qiang; Zeng, Sha; Zhao, Hui; Yang, Han; Liu, Maolun; Ren, Shan; Meng, Xianli; Xu, Haibo			The Role of non-coding RNAs in colorectal cancer, with a focus on its autophagy	PHARMACOLOGY & THERAPEUTICS			English	Review						Colorectal cancer; ncRNA; miRNA; lncRNA; circRNA; Autophagy	EPITHELIAL-MESENCHYMAL TRANSITION; COLON-CANCER; CELL-PROLIFERATION; SIGNALING PATHWAY; PROMOTES ANGIOGENESIS; ATTENUATES AUTOPHAGY; INDUCED APOPTOSIS; METASTASIS; EMT; SUPPRESSES	Colorectal cancer (CRC) is one of malignant afflictions burdening people worldwide, mainly caused by shortages of effective medical intervention and poorly mechanistic understanding of the pathogenesis of CRC. Non-coding RNAs (ncRNAs) are a type of heterogeneous transcripts without the capability of coding protein, but have the po-tency of regulating protein-coding gene expression. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic contents are delivered to cellular lysosomes for degradation, resulting in the turnover of cellular components and producing energy for cell functions. A growing body of evidence reveals that ncRNAs, autophagy, and the crosstalks of ncRNAs and autophagy play intricate roles in the initiation, progression, metas-tasis, recurrence and therapeutic resistance of CRC, which confer ncRNAs and autophagy to serve as clinical bio-markers and therapeutic targets for CRC. In this review, we sought to delineate the complicated roles of ncRNAs, mainly including miRNAs, lncRNAs and circRNAs, in the pathogenesis of CRC, particularly focus on the regulatory role of ncRNAs in CRC-related autophagy, attempting to shed light on the complex pathological mechanisms, in-volving ncRNAs and autophagy, responsible for CRC tumorigenesis and development, so as to underpin the ncRNAs-and autophagy-based therapeutic strategies for CRC in clinical setting. (c) 2021 Elsevier Inc. All rights reserved.	[Chen, Li; He, Man; Zhang, Meng; Sun, Qiang; Zeng, Sha; Zhao, Hui; Yang, Han; Liu, Maolun; Ren, Shan; Meng, Xianli; Xu, Haibo] Chengdu Univ Tradit Chinese Med, State Key Lab Southwestern Chinese Med Resources, Chengdu 611137, Peoples R China; [Chen, Li; He, Man; Zhang, Meng; Sun, Qiang; Zeng, Sha; Zhao, Hui; Yang, Han; Liu, Maolun; Ren, Shan; Xu, Haibo] Chengdu Univ Tradit Chinese Med, Sch Pharm, Dept Pharmacol, 1166 Liutai Ave, Chengdu 611137, Peoples R China; [Meng, Xianli] Chengdu Univ Tradit Chinese Med, Innovat Inst Chinese Med & Pharm, 1166 Liutai Ave, Chengdu 611137, Peoples R China		Xu, HB (corresponding author), Chengdu Univ Tradit Chinese Med, Sch Pharm, Dept Pharmacol, 1166 Liutai Ave, Chengdu 611137, Peoples R China.; Meng, XL (corresponding author), Chengdu Univ Tradit Chinese Med, Innovat Inst Chinese Med & Pharm, 1166 Liutai Ave, Chengdu 611137, Peoples R China.	xlm999@cdutcm.edu.cn; haibo.xu@cdutcm.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81573813, 81173598]; Excellent Talent Program of Chengdu University of Traditional Chinese Medicine of China [YXRC2019002, ZRYY1917]; Fund of Scientific Research Innovation Team Construction in Sichuan Provincial University of China [18TD0017]; Open Research Fund of State Key Laboratory of Southwestern Chinese Medicine Resources of China [2020 XSGG006]	This work was sponsored by the National Natural Science Foundation of China (Nos. 81573813 and 81173598), the Excellent Talent Program of Chengdu University of Traditional Chinese Medicine of China (Nos. YXRC2019002 and ZRYY1917), the Fund of Scientific Research Innovation Team Construction in Sichuan Provincial University of China (No. 18TD0017), and Open Research Fund of State Key Laboratory of Southwestern Chinese Medicine Resources of China (No. 2020 XSGG006).	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Ther.	OCT	2021	226								107868	10.1016/j.pharmthera.2021.107868		APR 2021	16	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	TF7GY	WOS:000670887200001	33901505				2022-04-25	
J	Cernigliaro, C; D'Anneo, A; Carlisi, D; Giuliano, M; Gammazza, AM; Barone, R; Longhitano, L; Cappello, F; Emanuele, S; Distefano, A; Campanella, C; Calvaruso, G; Lauricella, M				Cernigliaro, Cesare; D'Anneo, Antonella; Carlisi, Daniela; Giuliano, Michela; Gammazza, Antonella Marino; Barone, Rosario; Longhitano, Lucia; Cappello, Francesco; Emanuele, Sonia; Distefano, Alfio; Campanella, Claudia; Calvaruso, Giuseppe; Lauricella, Marianna			Ethanol-Mediated Stress Promotes Autophagic Survival and Aggressiveness of Colon Cancer Cells via Activation of Nrf2/HO-1 Pathway	CANCERS			English	Article						colon cancer cells; ethanol; Nrf2; HO-1; ER stress; autophagy; MMPs	ENDOPLASMIC-RETICULUM STRESS; COLORECTAL-CANCER; OXIDATIVE STRESS; POSSIBLE MECHANISMS; HUMAN OSTEOSARCOMA; ALCOHOL INTAKE; NRF2; EXPRESSION; RECEPTOR; PARTHENOLIDE	Epidemiological studies suggest that chronic alcohol consumption is a lifestyle risk factor strongly associated with colorectal cancer development and progression. The aim of the present study was to examine the effect of ethanol (EtOH) on survival and progression of three different colon cancer cell lines (HCT116, HT29, and Caco-2). Our data showed that EtOH induces oxidative and endoplasmic reticulum (ER) stress, as demonstrated by reactive oxygen species (ROS) and ER stress markers Grp78, ATF6, PERK and, CHOP increase. Moreover, EtOH triggers an autophagic response which is accompanied by the upregulation of beclin, LC3-II, ATG7, and p62 proteins. The addition of the antioxidant N-acetylcysteine significantly prevents autophagy, suggesting that autophagy is triggered by oxidative stress as a prosurvival response. EtOH treatment also upregulates the antioxidant enzymes SOD, catalase, and heme oxygenase (HO-1) and promotes the nuclear translocation of both Nrf2 and HO-1. Interestingly, EtOH also upregulates the levels of matrix metalloproteases (MMP2 and MMP9) and VEGF. Nrf2 silencing or preventing HO-1 nuclear translocation by the protease inhibitor E64d abrogates the EtOH-induced increase in the antioxidant enzyme levels as well as the migration markers. Taken together, our results suggest that EtOH mediates both the activation of Nrf2 and HO-1 to sustain colon cancer cell survival, thus leading to the acquisition of a more aggressive phenotype.	[Cernigliaro, Cesare; Carlisi, Daniela; Emanuele, Sonia; Lauricella, Marianna] Univ Palermo, Inst Biochem, Dept Biomed Neurosci & Adv Diagnost BIND, I-90127 Palermo, Italy; [D'Anneo, Antonella; Giuliano, Michela; Calvaruso, Giuseppe] Univ Palermo, Lab Biochem, Dept Biol Chem & Pharmaceut Sci & Technol STEBICE, I-90127 Palermo, Italy; [Gammazza, Antonella Marino; Barone, Rosario; Cappello, Francesco; Campanella, Claudia] Univ Palermo, Inst Human Anat, Dept Biomed Neurosci & Adv Diagnost BIND, I-90127 Palermo, Italy; [Gammazza, Antonella Marino; Barone, Rosario; Cappello, Francesco; Campanella, Claudia] Euromediterranean Inst Sci & Technol, I-90100 Palermo, Italy; [Longhitano, Lucia; Distefano, Alfio] Univ Catania, Dept Biomed & Biotechnol Sci, I-95123 Catania, Italy		Lauricella, M (corresponding author), Univ Palermo, Inst Biochem, Dept Biomed Neurosci & Adv Diagnost BIND, I-90127 Palermo, Italy.	cesare.cernigliaro@unipa.it; antonella.danneo@unipa.it; daniela.carlisi@unipa.it; michela.giuliano@unipa.it; antonella.marino@hotmail.it; rosario.barone@unipa.it; lucia.longhitano@unict.it; francapp@hotmail.com; sonia.emanuele@unipa.it; distalfio@gmail.com; claudiettacam@hotmail.com; giuseppe.calvaruso@unipa.it; marianna.lauricella@unipa.it	Lauricella, Marianna/ABD-1263-2020; Gammazza, Antonella Marino/AAV-3123-2020; D’Anneo, Antonella/P-1064-2019; Barone, Rosario/ABD-8488-2020; barone, rosario/ABA-6758-2021; Cappello, Francesco/F-9153-2012	D’Anneo, Antonella/0000-0002-1785-8236; CERNIGLIARO, Cesare/0000-0002-0264-4921; GIULIANO, Michela/0000-0002-5114-6267; LAURICELLA, Marianna/0000-0002-0157-3834; barone, rosario/0000-0002-8240-1240; Cappello, Francesco/0000-0001-9288-1148	Gruppo Azione Locale (GAL) of Golfo di Castellammare, Italy [17/2015]; Italian National Operational Programme (PON) "Imprese e Competitivita" 2014-2020 FESR - Italian Ministry of Economic Development [F/090012/01-02/X36]	This work has been carried out with the financial support from Gruppo Azione Locale (GAL) of Golfo di Castellammare, Italy (Progetto Operativo n. 17/2015, misura 313B). Part of this work was funded by the Italian National Operational Programme (PON) "Imprese e Competitivita" 2014-2020 FESR, grant awarded by the Italian Ministry of Economic Development to the project titled "Gestione di un servizio integrato multi centrico di diagnostica e terapia personalizzata in oncologia" (Project code: F/090012/01-02/X36).	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J	Yoo, HS; Won, SB; Kwon, YH				Yoo, Ho Soo; Won, Sae Bom; Kwon, Young Hye			Luteolin Induces Apoptosis and Autophagy in HCT116 Colon Cancer Cells via p53-Dependent Pathway	NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL			English	Article								Although a dietary phytochemical luteolin has been shown to regulate various anticancer mechanisms, a role of luteolin in autophagy regulation is mostly unidentified. Here, we investigated whether luteolin exhibits its anticancer effects by induction of apoptosis and autophagy in a p53-dependent manner in colon cancer cells. Cell viability was determined using trypan blue exclusion test. The expressions of proteins and mRNAs were measured by immunoblotting and reverse transcription polymerase chain reaction, respectively. Luteolin at 10 - 20 mu M induced cytotoxicity in p53 wild-type HCT116 colon cancer cells but not in p53 mutant HT-29 cells and normal colon cells. Luteolin exhibited its anticancer effect by increasing p53 phosphorylation and p53 target gene expression, leading to apoptosis and cell cycle arrest in HCT116 cells. We identified that luteolin can induce autophagy in p53 wild-type cells but not in p53 mutant cells, suggesting that luteolin-induced autophagy is p53-dependent; however, chloroquine-mediated inhibition of autophagy did not alter cytotoxicity and apoptosis of cells treated with luteolin. In conclusion, the present data showed that luteolin inhibits the growth of HCT116 colon cancer cells through p53-dependent regulation of apoptosis and cell cycle arrest regardless of the induction of autophagy.	[Yoo, Ho Soo; Kwon, Young Hye] Seoul Natl Univ, Dept Food & Nutr, Seoul, South Korea; [Won, Sae Bom] Chungwoon Univ, Dept Human Nutr & Food Sci, Hongseong, Chungnam, South Korea; [Kwon, Young Hye] Seoul Natl Univ, Res Inst Human Ecol, Seoul, South Korea		Kwon, YH (corresponding author), 1 Gwanak Ro, Seoul 08826, South Korea.	hye0414@snu.ac.kr			Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future PlanningNational Research Foundation of Korea [NRF-2017R1A2B4011432]	This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (no. NRF-2017R1A2B4011432).	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Cancer	FEB 7	2022	74	2					677	686		10.1080/01635581.2021.1903947		MAR 2021	10	Oncology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Nutrition & Dietetics	ZG0RC	WOS:000632285400001	33757400				2022-04-25	
J	Bijnsdorp, IV; Peters, GJ; Temmink, OH; Fukushima, M; Kruyt, FA				Bijnsdorp, Irene V.; Peters, Godefridus J.; Temmink, Olaf H.; Fukushima, Masakazu; Kruyt, Frank A.			Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells	INTERNATIONAL JOURNAL OF CANCER			English	Article						cell death; caspase; trifluorothymidine; 5-fluorouracil; cathepsin B; autophagy	THYMIDYLATE SYNTHASE INHIBITION; CYSTEINE CATHEPSINS; APOPTOSIS; TAS-102; PATHWAYS; ANTIMETABOLITE; SENSITIVITY; METABOLISM; MECHANISMS; RESISTANCE	Trifluorothymidine (TFT) is part of the oral drug formulation TAS-102. Both 5-fluorouracil (5-FU) and TFT can inhibit thymidylate synthase and be incorporated into DNA. TFT shows only moderate cross-resistance to 5-FU. Therefore, we examined whether mechanistic differences in cell death could underlie their different modes of action in colorectal cancer cell lines (WiDR, Lovo92 and Colo320). Drug cytotoxicity was determined by SRB- and clonogenic assays, cell death by flow cytometry (PI and annexin V), caspase cleavage by Western blotting and activity assays and in vivo activity in the hollow fiber assay. The IC50 values of TFT were 1-6 fold lower than for 5-FU, and clonogenic survival was less than 0.9% at 3 mu M TFT, while 2-20% of the cells still survived after 20 mu M 5-FU. In general, TFT was a more potent inducer of apoptosis than 5-FU, although the contribution of caspases varied between the used cell lines and necrosis-like cell death was detected. Accordingly, both drugs induced caspase (Z-VAD) independent cell death and lysosomal cathepsin B was involved. Activation of autophagy recovery mechanisms was only triggered by 5-FU, but not by TFT as determined by LC3B expression and cleavage. Inhibition of autophagy by 3-MA in 5-FU exposed cells reduced cell survival. Also, in vivo TFT (as TAS-102) caused more cell death than a 5-FU formulation. We conclude that TFT and 5-FU induce cell death via both caspase-dependent and independent mechanisms. The TFT was more potent than 5-FU, because it induces higher levels of cell death and does not elicit an autophagic survival response in the cancer cell lines. This provides a strong molecular basis for further application of TFT in cancer therapy.	[Bijnsdorp, Irene V.; Peters, Godefridus J.; Temmink, Olaf H.; Kruyt, Frank A.] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, NL-1007 MB Amsterdam, Netherlands; [Fukushima, Masakazu] Taiho Pharmaceut Co Ltd, Tokushima Res Ctr, Tokushima, Japan; [Kruyt, Frank A.] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, NL-9713 AV Groningen, Netherlands		Peters, GJ (corresponding author), Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, POB 7057, NL-1007 MB Amsterdam, Netherlands.	gj.peters@vumc.nl	Peters, Godefridus J/C-7562-2013	Peters, Godefridus J/0000-0002-5447-2877; Kruyt, Frank/0000-0002-2445-9380	Taiho Pharmaceuticals, Co., Ltd	Grant sponsor: This study was financially supported by Taiho Pharmaceuticals, Co., Ltd	Ackland SP, 2006, UPDATE CANC THERAPEU, V1, P403; Backus HHJ, 2003, EUR J CANCER, V39, P1310, DOI 10.1016/S0959-8049(03)00204-1; Bijnsdorp IV, 2008, CANCER SCI, V99, P2302, DOI 10.1111/j.1349-7006.2008.00963.x; Bijnsdorp IV, 2008, NUCLEOS NUCLEOT NUCL, V27, P699, DOI 10.1080/15257770802145017; Bijnsdorp IV, 2007, J NEURO-ONCOL, V85, P25, DOI 10.1007/s11060-007-9385-4; Broker LE, 2004, CANCER RES, V64, P27, DOI 10.1158/0008-5472.CAN-03-3060; Broker LE, 2002, CANCER RES, V62, P4081; Broker LE, 2005, CLIN CANCER RES, V11, P3155, DOI 10.1158/1078-0432.CCR-04-2223; Bruin M De, 2006, CANC THER, V4, P99; Carew JS, 2008, CANCER LETT, V269, P7, DOI 10.1016/j.canlet.2008.03.037; Carew JS, 2007, AUTOPHAGY, V3, P464, DOI 10.4161/auto.4311; Droga-Mazovec G, 2008, J BIOL CHEM, V283, P19140, DOI 10.1074/jbc.M802513200; ECKSTEIN JW, 1994, BIOCHEMISTRY-US, V33, P15086, DOI 10.1021/bi00254a018; Emura T, 2004, INT J MOL MED, V13, P545; Emura T, 2004, INT J MOL MED, V13, P249; Fazi B, 2008, AUTOPHAGY, V4, P435, DOI 10.4161/auto.5669; Festjens N, 2007, CELL DEATH DIFFER, V14, P400, DOI 10.1038/sj.cdd.4402085; Foghsgaard L, 2001, J CELL BIOL, V153, P999, DOI 10.1083/jcb.153.5.999; Fulda S, 2006, ONCOGENE, V25, P4798, DOI 10.1038/sj.onc.1209608; Giovannetti E, 2007, BRIT J CANCER, V96, P769, DOI 10.1038/sj.bjc.6603639; KEEPERS YP, 1991, EUR J CANCER, V27, P897, DOI 10.1016/0277-5379(91)90142-Z; Kruyt FAE, 2008, CANCER LETT, V263, P14, DOI 10.1016/j.canlet.2008.02.003; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; LOWE SW, 1993, CELL, V74, P957, DOI 10.1016/0092-8674(93)90719-7; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Matsuhashi N, 2004, ONCOL REP, V12, P357; Morishima N, 2002, J BIOL CHEM, V277, P34287, DOI 10.1074/jbc.M204973200; Murakami Y, 2000, INT J ONCOL, V17, P277; OConnor PM, 1997, CANCER RES, V57, P4285; Overman MJ, 2008, INVEST NEW DRUG, V26, P445, DOI 10.1007/s10637-008-9142-3; Peters GJ, 2002, BBA-MOL BASIS DIS, V1587, P194, DOI 10.1016/S0925-4439(02)00082-0; Peters GJ, 1999, CANC DRUG DISC DEV, P101; PIEDBOIS P, 1992, J CLIN ONCOL, V10, P896; PINEDO HM, 1988, J CLIN ONCOL, V6, P1653, DOI 10.1200/JCO.1988.6.10.1653; Rossi D, 2003, HAEMATOLOGICA, V88, P212; SANTI DV, 1971, BIOCHEMISTRY-US, V10, P3598, DOI 10.1021/bi00795a018; Shao YF, 2004, P NATL ACAD SCI USA, V101, P18030, DOI 10.1073/pnas.0408345102; Stoka V, 2007, BIOL CHEM, V388, P555, DOI 10.1515/BC.2007.064; Temmink OH, 2007, BRIT J CANCER, V96, P61, DOI 10.1038/sj.bjc.6603507; Temmink OH, 2007, BRIT J CANCER, V96, P231, DOI 10.1038/sj.bjc.6603549; Temmink OH, 2005, ANTI-CANCER DRUG, V16, P285, DOI 10.1097/00001813-200503000-00007; Temmink OH, 2004, NUCLEOS NUCLEOT NUCL, V23, P1491, DOI 10.1081/NCN-200027707; Temmink OH, 2007, CANCER SCI, V98, P779, DOI 10.1111/j.1349-7006.2007.00477.x; Tillman DM, 1999, CLIN CANCER RES, V5, P425; Turk B, 2007, FEBS LETT, V581, P2761, DOI 10.1016/j.febslet.2007.05.038; Voortman J, 2007, MOL CANCER THER, V6, P1046, DOI 10.1158/1535-7163.MCT-06-0577; Wilson TR, 2007, CANCER RES, V67, P5754, DOI 10.1158/0008-5472.CAN-06-3585	48	64	68	1	8	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0020-7136	1097-0215		INT J CANCER	Int. J. Cancer	MAY 15	2010	126	10					2457	2468		10.1002/ijc.24943			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	586RF	WOS:000276928700019	19816940	Bronze			2022-04-25	
J	Mariani, F; Sena, P; Roncucci, L				Mariani, Francesco; Sena, Paola; Roncucci, Luca			Inflammatory pathways in the early steps of colorectal cancer development	WORLD JOURNAL OF GASTROENTEROLOGY			English	Article						Myeloperoxidase; Colorectal carcinogenesis; Inflammation; Aberrant crypt foci; Autophagy; Hypoxia; Apoptosis	HYPOXIA-INDUCIBLE FACTOR; NF-KAPPA-B; COLON-CANCER; TRANSCRIPTION FACTOR; NITRIC-OXIDE; DNA-DAMAGE; OXIDATIVE STRESS; MYOFIBROBLAST DIFFERENTIATION; INTESTINAL TUMORIGENESIS; GASTROINTESTINAL-TRACT	Colorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.	[Mariani, Francesco; Roncucci, Luca] Univ Modena & Reggio Emilia, Dept Diagnost Clin & Publ Hlth Med, I-41124 Modena, Italy; [Sena, Paola] Univ Modena & Reggio Emilia, Dept Biomed Metab & Neural Sci, Sect Human Morphol, I-41124 Modena, Italy		Roncucci, L (corresponding author), Univ Modena & Reggio Emilia, Dept Diagnost Clin & Publ Hlth Med, Via Univ 4, I-41124 Modena, Italy.	luca.roncucci@unimore.it	Roncucci, Luca/L-1392-2016; Sena, Paola/G-9394-2016	Roncucci, Luca/0000-0002-0410-1760; Sena, Paola/0000-0003-4724-8786	Fondazione Umberto Veronesi (FUV)Fondazione Umberto Veronesi; Associazione Ricerca Tumori Intestinali (ARTI) of Modena	Supported by The Fondazione Umberto Veronesi (FUV) and the Associazione Ricerca Tumori Intestinali (ARTI) of Modena	Asano T, 2008, J SURG RES, V146, P32, DOI 10.1016/j.jss.2007.02.011; Beachy PA, 2004, NATURE, V432, P324, DOI 10.1038/nature03100; Berdowska I, 2004, CLIN CHIM ACTA, V342, P41, DOI 10.1016/j.cccn.2003.12.016; Berman DM, 2003, NATURE, V425, P846, DOI 10.1038/nature01972; 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Gastroenterol.	AUG 21	2014	20	29					9716	9731		10.3748/wjg.v20.i29.9716			16	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	AN6TK	WOS:000340730300007	25110410	hybrid, Green Published			2022-04-25	
J	Thongchot, S; Singsuksawat, E; Sumransub, N; Pongpaibul, A; Trakarnsanga, A; Thuwajit, P; Thuwajit, C				Thongchot, Suyanee; Singsuksawat, Ekapot; Sumransub, Nuttavut; Pongpaibul, Ananya; Trakarnsanga, Attaporn; Thuwajit, Peti; Thuwajit, Chanitra			Periostin regulates autophagy through integrin alpha 5 beta 1 or alpha 6 beta 4 and an AKT-dependent pathway in colorectal cancer cell migration	JOURNAL OF CELLULAR AND MOLECULAR MEDICINE			English	Article						autophagy; cancer-associated fibroblast; colorectal cancer; integrin; periostin	EPITHELIAL-MESENCHYMAL TRANSITION; COLON-CANCER; FIBROBLASTS; EXPRESSION; CARCINOMA; INVASION	Colorectal cancer (CRC) is one of the most fatal cancers with highly invasive properties. The progression of CRC is determined by the driving force of periostin (PN) from cancer-associated fibroblasts (CAFs) in the tumour microenvironment. This present work aims to investigate autophagy-mediated CRC invasion via the receptor integrin (ITG) by PN. The level of PN in 410 clinical CRC tissues was found increased and was an independent poor prognosis marker (HR = 2.578, 95% CI = 1.218-5.457,P-value = .013) with a significant correlation with overall survival time (P-value < .001). PN activated proliferation, migration and invasion of CRC cells, but with reduced autophagy. Interestingly, the reduction of LC3 autophagic protein corresponded to the increased ability of CRC cell migration. The siITG alpha 5-treated HT-29 and siITG beta 4-treated HCT-116 CRC cells attenuated epithelial-to-mesenchymal transitions (EMT)-related genes and pAKT compared with those in siITG-untreated cells. The reduction of pAKT by a PI3K inhibitor significantly restored autophagy in CRC cells. These evidences confirmed the effect of PN through either ITG alpha 5 beta 1 or ITG alpha 6 beta 4 and the AKT-dependent pathway to control autophagy-regulated cell migration. In conclusion, these results exhibited the impact of PN activation of ITG alpha 5 beta 1 or ITG alpha 6 beta 4 through pAKT in autophagy-mediated EMT and migration in CRC cells.	[Thongchot, Suyanee; Singsuksawat, Ekapot; Sumransub, Nuttavut; Thuwajit, Peti; Thuwajit, Chanitra] Mahidol Univ, Siriraj Hosp, Dept Immunol, Fac Med, 2 Wang Lang Rd, Bangkok 10700, Thailand; [Thongchot, Suyanee] Mahidol Univ, Siriraj Hosp, Siriraj Ctr Res Excellence Canc Immunotherapy, Fac Med, Bangkok, Thailand; [Pongpaibul, Ananya] Mahidol Univ, Siriraj Hosp, Dept Pathol, Fac Med, Bangkok, Thailand; [Trakarnsanga, Attaporn] Mahidol Univ, Siriraj Hosp, Dept Surg, Fac Med, Bangkok, Thailand		Thuwajit, C (corresponding author), Mahidol Univ, Siriraj Hosp, Dept Immunol, Fac Med, 2 Wang Lang Rd, Bangkok 10700, Thailand.	cthuwajit@yahoo.com	Thuwajit, Peti/AAD-1014-2021; Thuwajit, Chanitra/AAT-7933-2021	Sumransub, Nuttavut/0000-0001-7456-0623; Thuwajit, Chanitra/0000-0001-9506-6405	National Science and Technology Development Agency of Thailand [P-15-50267]; Faculty of Medicine Siriraj Hospital, Mahidol University [R016033015]	This work was financially supported by National Science and Technology Development Agency of Thailand, Grant no. P-15-50267 and the Research Grant, Faculty of Medicine Siriraj Hospital, Mahidol University, Grant no. R016033015 to CT.	Bao SD, 2004, CANCER CELL, V5, P329, DOI 10.1016/S1535-6108(04)00081-9; Barczyk M, 2010, CELL TISSUE RES, V339, P269, DOI 10.1007/s00441-009-0834-6; Baril P, 2007, ONCOGENE, V26, P2082, DOI 10.1038/sj.onc.1210009; Ben QW, 2009, INT J ONCOL, V34, P821, DOI 10.3892/ijo_00000208; Boudjadi S, 2017, CANCERS, V9, DOI 10.3390/cancers9080096; Choi KS, 2012, EXP MOL MED, V44, P109, DOI 10.3858/emm.2012.44.2.033; Devenport SN, 2019, CELLS-BASEL, V8, DOI 10.3390/cells8111349; Ferlay J, 2018, EUR J CANCER, V103, P356, DOI 10.1016/j.ejca.2018.07.005; Ferraresi A, 2017, MOL CARCINOGEN, V56, P1164, DOI 10.1002/mc.22582; Goertzen C, 2019, BIOL PROCED ONLINE, V21, DOI 10.1186/s12575-019-0100-6; Gong YZ, 2019, ONCOL REP, V42, P923, DOI 10.3892/or.2019.7216; Kikuchi Y, 2008, J HISTOCHEM CYTOCHEM, V56, P753, DOI 10.1369/jhc.2008.951061; Kudo Y, 2007, HISTOL HISTOPATHOL, V22, P1167, DOI 10.14670/HH-22.1167; Li ZW, 2015, INT J MOL SCI, V16, P12108, DOI 10.3390/ijms160612108; Lv YJ, 2017, ONCOL LETT, V14, P376, DOI 10.3892/ol.2017.6124; Moniuszko T, 2016, ONCOL LETT, V12, P783, DOI 10.3892/ol.2016.4692; Morra L, 2011, VIRCHOWS ARCH, V459, P465, DOI 10.1007/s00428-011-1151-5; Oh HJ, 2017, J PATHOL TRANSL MED, V51, P306, DOI 10.4132/jptm.2017.01.19; Puppa G, 2010, ARCH PATHOL LAB MED, V134, P837, DOI 10.1043/1543-2165-134.6.837; Qin H, 2019, CELL REPROGRAM, V21, P122, DOI 10.1089/cell.2018.0051; Ratajczak-Wielgomas K, 2015, FOLIA HISTOCHEM CYTO, V53, P120, DOI 10.5603/FHC.a2015.0014; Ruan K, 2009, CELL MOL LIFE SCI, V66, P2219, DOI 10.1007/s00018-009-0013-7; Siegel RL, 2016, CA-CANCER J CLIN, V66, P7, DOI 10.3322/caac.21332; Thongchot S, 2018, CANCER LETT, V430, P160, DOI 10.1016/j.canlet.2018.05.031; Thuwajit C, 2017, ONCOL LETT, V14, P623, DOI 10.3892/ol.2017.6250; Underwood TJ, 2015, J PATHOL, V235, P466, DOI 10.1002/path.4467; Utispan K, 2012, INT J ONCOL, V41, P1110, DOI 10.3892/ijo.2012.1530; Utispan K, 2010, MOL CANCER, V9, DOI 10.1186/1476-4598-9-13; Xiao ZM, 2015, BIOTECHNOL APPL BIOC, V62, P401, DOI 10.1002/bab.1193; Xu XW, 2016, ONCOTARGET, V7, P798, DOI 10.18632/oncotarget.5985; Zhang H, 2014, CELL PHYSIOL BIOCHEM, V33, P991, DOI 10.1159/000358670	31	5	5	2	4	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	1582-1838	1582-4934		J CELL MOL MED	J. Cell. Mol. Med.	NOV	2020	24	21					12421	12432		10.1111/jcmm.15756		SEP 2020	12	Cell Biology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Research & Experimental Medicine	OV1EP	WOS:000573376700001	32990415	Green Published, gold			2022-04-25	
J	Yin, KL; Lee, J; Liu, ZL; Kim, H; Martin, DR; Wu, DD; Liu, ML; Xue, X				Yin, Kunlun; Lee, Jordan; Liu, Zhaoli; Kim, Hyeoncheol; Martin, David R.; Wu, Dandan; Liu, Meilian; Xue, Xiang			Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production	CELL DEATH AND DIFFERENTIATION			English	Article								Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US. Understanding the mechanisms of CRC progression is essential to improve treatment. Mitochondria is the powerhouse for healthy cells. However, in tumor cells, less energy is produced by the mitochondria and metabolic reprogramming is an early hallmark of cancer. The metabolic differences between normal and cancer cells are being interrogated to uncover new therapeutic approaches. Mitochondria targeting PTEN-induced kinase 1 (PINK1) is a key regulator of mitophagy, the selective elimination of damaged mitochondria by autophagy. Defective mitophagy is increasingly associated with various diseases including CRC. However, a significant gap exists in our understanding of how PINK1-dependent mitophagy participates in the metabolic regulation of CRC. By mining Oncomine, we found that PINK1 expression was downregulated in human CRC tissues compared to normal colons. Moreover, disruption of PINK1 increased colon tumorigenesis in two colitis-associated CRC mouse models, suggesting that PINK1 functions as a tumor suppressor in CRC. PINK1 overexpression in murine colon tumor cells promoted mitophagy, decreased glycolysis and increased mitochondrial respiration potentially via activation of p53 signaling pathways. In contrast, PINK1 deletion decreased apoptosis, increased glycolysis, and reduced mitochondrial respiration and p53 signaling. Interestingly, PINK1 overexpression in vivo increased apoptotic cell death and suppressed colon tumor xenograft growth. Metabolomic analysis revealed that acetyl-CoA was significantly reduced in tumors with PINK1 overexpression, which was partly due to activation of the HIF-1 alpha-pyruvate dehydrogenase (PDH) kinase 1 (PDHK1)-PDHE1 alpha axis. Strikingly, treating mice with acetate increased acetyl-CoA levels and rescued PINK1-suppressed tumor growth. Importantly, PINK1 disruption simultaneously increased xenografted tumor growth and acetyl-CoA production. In conclusion, mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming and reducing acetyl-CoA production.	[Yin, Kunlun; Lee, Jordan; Liu, Zhaoli; Kim, Hyeoncheol; Wu, Dandan; Liu, Meilian; Xue, Xiang] Univ New Mexico, Dept Biochem & Mol Biol, Albuquerque, NM 87131 USA; [Martin, David R.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA		Xue, X (corresponding author), Univ New Mexico, Dept Biochem & Mol Biol, Albuquerque, NM 87131 USA.	xxue@salud.unm.edu	; Xue, Xiang/P-9071-2014	Wu, Dandan/0000-0003-2073-5998; Xue, Xiang/0000-0003-4704-1814; Martin, David/0000-0002-2196-5851; Liu, ZHAOLI/0000-0001-6609-0203; Liu, Meilian/0000-0003-1639-262X	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P20 GM130422, K01DK114390]; American Cancer SocietyAmerican Cancer Society [RSG-18-050-01-NEC]; University of New Mexico [P42 ES025589]; Shared Resources Pilot Project Award from UNM comprehensive cancer center; Research Program Support Pilot Project Award from UNM comprehensive cancer center [P30CA118100]; Dedicated Health Research Funds at the University of New Mexico School of Medicine; Core Utilization Voucher Program award; Metabolomic Studies Voucher Award from the Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence [P20GM121176]; Core Utilization Voucher Program award from the Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence	This research was supported in part by the National Institutes of Health (P20 GM130422, K01DK114390), a Research Scholar Grant from the American Cancer Society (RSG-18-050-01-NEC), a Research Pilot Project Grant from University of New Mexico Environmental Health Signature Program and Superfund (P42 ES025589), a Shared Resources Pilot Project Award and a Research Program Support Pilot Project Award from UNM comprehensive cancer center (P30CA118100), a new investigator award from the Dedicated Health Research Funds at the University of New Mexico School of Medicine, and a Core Utilization Voucher Program award and a Metabolomic Studies Voucher Award from the Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence (P20GM121176). We thank Dr. Jim Liu for providing us access to the SpectraMax M2 Microplate Reader, Dr. Laurie Hudson for providing us access to the microtome, Dr. Michael Paffett from the UNMCC Fluorescence Microscopy Core facility for helping with confocal imaging, Dr. Sharina P Desai from Scientific Cores off AIM center for helping with ImageStream analysis, and Dr. Jesse L Denson for proofreading the manuscript.	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AUG	2021	28	8					2421	2435		10.1038/s41418-021-00760-9		MAR 2021	15	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	TT8JU	WOS:000629091500003	33723373				2022-04-25	
J	Zhou, J; Zhang, W; Liang, B; Casimiro, MC; Whitaker-Menezes, D; Wang, M; Lisanti, MP; Lanza-Jacoby, S; Pestell, RG; Wang, CG				Zhou, Jie; Zhang, Wei; Liang, Bing; Casimiro, Mathew C.; Whitaker-Menezes, Diana; Wang, Min; Lisanti, Michael P.; Lanza-Jacoby, Susan; Pestell, Richard G.; Wang, Chenguang			PPAR gamma activation induces autophagy in breast cancer cells	INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY			English	Article						PPAR gamma; Autophagy; Breast cancer; HIF1 alpha; BNIP3	DMBA-INDUCED MAMMARY; RECEPTOR-GAMMA; CYCLIN D1; GENE-EXPRESSION; COLON-CANCER; APOPTOSIS; LIGAND; GROWTH; DEATH; DIFFERENTIATION	It has been previously shown that PPAR gamma ligands induce apoptotic cell death in a variety of cancer cells Given the evidence that these ligands have a receptor-independent function, we further examined the specific role of PPAR gamma activation in this biological process. Surprisingly, we failed to demonstrate that MDA-MB-231 breast cancer cells undergo apoptosis when treated with sub-saturation doses of troglitazone and rosightazone, which are synthetic PPAR gamma ligands. Acridine orange (AO) staining showed acidic vesicular formation within ligand-treated cells, indicative of autophagic activity. This was confirmed by autophagosome formation as indicated by redistribution of LC3, an autophagy-specific protein, and the appearance of double-membrane autophagic vacuoles by electron microscopy following exposure to ligand. To determine the mechanism by which PPAR gamma, induces autophagy, we transduced primary mammary epithelial cells with a constitutively active mutant of PPAR gamma and screened gene expression associated with PPAR gamma activation by genome-wide array analysis. HIF1 alpha and BNIP3 were among 42 genes up-regulated by active PPAR gamma. Activation of PPAR gamma induced HIF1 alpha and BNIP3 protein and mRNA abundance. HIF1 alpha knockdown by shRNA abolished the autophagosome formation induced by PPAR gamma activation. In summary, our data shows a specific induction of autophagy by PPAR gamma activation in breast cancer cells providing an understanding of distinct roles of PPAR gamma in tumorigenesis. (C) 2009 Elsevier Ltd. All rights reserved.	[Zhou, Jie; Zhang, Wei; Liang, Bing; Casimiro, Mathew C.; Whitaker-Menezes, Diana; Wang, Min; Lisanti, Michael P.; Pestell, Richard G.; Wang, Chenguang] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA; [Lisanti, Michael P.; Pestell, Richard G.; Wang, Chenguang] Thomas Jefferson Univ, Ctr Stem Cell Biol, Philadelphia, PA 19107 USA; [Lisanti, Michael P.; Pestell, Richard G.; Wang, Chenguang] Thomas Jefferson Univ, Regenerat Med Ctr, Philadelphia, PA 19107 USA; [Lanza-Jacoby, Susan] Thomas Jefferson Univ, Dept Surg, Philadelphia, PA 19107 USA; [Zhang, Wei] Beijing Normal Univ, Coll Life Sci, Key Lab Cell Proliferat & Regulat Biol, Minist Educ, Beijing 100875, Peoples R China; [Liang, Bing] Natl Ctr Biomed Anal, Inst Basic Med Sci, Beijing, Peoples R China		Wang, CG (corresponding author), Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Bluemle Life Sci Bldg,Room 1032,233 S 10th St, Philadelphia, PA 19107 USA.		Lisanti, Michael P/C-6866-2013; Lisanti, Michael P/B-6131-2018		Susan Komen Breast Cancer FoundationSusan G. Komen Breast Cancer Foundation [BCTR0504227, R01CA70896, R01CA75503, R01CA86072, R01CA86071]; DOD Synergistic Idea Award; National Natural Science FundsNational Natural Science Foundation of China (NSFC) [30300173]; National High Technology Research and Development Program of ChinaNational High Technology Research and Development Program of China [2006AA02Z4A6]; NIH Cancer Center CoreUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P30CA56036]; Pennsylvania Department of Health; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA056036, R01CA070896, R01CA075503, R01CA086072] Funding Source: NIH RePORTER	This work was supported in part by awards from the Susan Komen Breast Cancer Foundation BCTR0504227 (C.W ) R01CA70896, R01CA75503, R01CA86072, R01CA86071 (R.G.P.), DOD Synergistic Idea Award (M.P.L.), National Natural Science Funds (grant no.: 30300173 (WZ)), National High Technology Research and Development Program of China (863, grant no. 2006AA02Z4A6 (WZ)). Work conducted at the Kimmel Cancer Center was supported by the NIH Cancer Center Core grant (P30CA56036 (R.G.P.)). This project is funded in part by the Pennsylvania Department of Health grant (to C W.. R.G.P.).	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J. Biochem. Cell Biol.	NOV	2009	41	11					2334	2342		10.1016/j.biocel.2009.06.007			9	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	510WR	WOS:000271124700030	19563910	Green Accepted			2022-04-25	
J	Han, CZ; Xing, GZ; Zhang, MY; Zhong, M; Han, Z; He, CY; Liu, XP				Han, Chengzheng; Xing, Guozheng; Zhang, Mengying; Zhong, Min; Han, Zhen; He, Chiyi; Liu, Xiaoping			Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway	ONCOLOGY LETTERS			English	Article						wogonoside; human colon cancer cells; phosphatidylinositol 3 kinase; RAC-alpha serine/threonine-protein kinase; mechanistic target of rapamycin; p70 S6 kinase	ACTIVATION; EXPRESSION; ANGIOGENESIS; BAICALIN; EXTRACT; TARGETS; DEATH	Wogonoside, the main effective constituent of traditional Chinese medicine Scutellaria, belongs to the glucuronide family, with various functions, including detoxification, anti-inflammation and nourishing gallbladder, lowering blood pressure, diuresis and anti-allergic reactions. However, the effects of wogonoside on human colon cancer cells remain unclear. The present study aimed to investigate the anticancer effect of wogonoside on human colon cancer cells in vitro and its anticancer mechanisms. The results demonstrated that wogonoside significantly inhibited cell growth, induced apoptosis and mitochondrial-mediated autophagy of colon cancer cells. Furthermore, the results revealed that wogonoside significantly increased caspase-3 and caspase-9 expression levels, induced apoptosis regulator Bax/Bcl-2 and microtubule-associated protein 1A/1B-light chain 3 protein expression, suppressed the phosphatidylinositol 3 kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (Akt)/mechanistic target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) signaling pathway and induced p62 protein expression in colon cancer cells. In conclusion, these results demonstrated that wogonoside inhibits cell growth and induces mitochondrial mediated autophagy-related apoptosis in human colon cancer cells through modulation of the PI3K/Akt/mTOR/p70S6K signaling pathway.	[Han, Chengzheng] Wannan Med Coll, Affiliated Hosp 1, Clin Integrated Tradit Chinese & Western Med, Wuhu 241001, Anhui, Peoples R China; [Xing, Guozheng] Anhui Univ Technol, Sch Management Sci & Engn, 59 Hudong Rd, Maanshan 243032, Anhui, Peoples R China; [Zhang, Mengying; Zhong, Min] Wannan Med Coll, Affiliated Hosp 1, Dept Cent Lab, Wuhu 241001, Anhui, Peoples R China; [Han, Zhen; He, Chiyi] Wannan Med Coll, Affiliated Hosp 1, Dept Gastroenterol, Wuhu 241001, Anhui, Peoples R China; [Liu, Xiaoping] Wannan Med Coll, Coll Pharm, Wuhu 241001, Anhui, Peoples R China		Xing, GZ (corresponding author), Anhui Univ Technol, Sch Management Sci & Engn, 59 Hudong Rd, Maanshan 243032, Anhui, Peoples R China.	hlhugzaea8711@126.com			Natural Science Foundation of the Institutions of Higher Education from the Education Department of Anhui Province [KJ2017A261]; Natural Science Foundation of Wannan Medical College [WK2016F08]	The present study was supported by the Natural Science Foundation of the Institutions of Higher Education from the Education Department of Anhui Province (grant no. KJ2017A261) and Natural Science Foundation of Wannan Medical College (grant no. WK2016F08).	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Lett.	APR	2018	15	4					4463	4470		10.3892/ol.2018.7852			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GD9HA	WOS:000430822500057	29541215	Green Published, gold			2022-04-25	
J	Sharma, S; Evans, A; Hemers, E				Sharma, Sikander; Evans, Andrew; Hemers, Elaine			Mesenchymal-epithelial signalling in tumour microenvironment: role of high-mobility group Box 1	CELL AND TISSUE RESEARCH			English	Article						HMGB1; Myofibroblasts; Invasion; Glucose deprivation; Tumour microenvironment	INFLAMMATORY MYOFIBROBLASTIC TUMOR; GLYCATION END-PRODUCTS; DENDRITIC CELLS; COLORECTAL-CANCER; HMGB1 RELEASE; ACTIVATION; PROLIFERATION; MIGRATION; AUTOPHAGY; GROWTH	Glucose deprivation, hypoxia and acidosis are characteristic features of the central core of most solid tumours. Myofibroblasts are stromal cells present in many such solid tumours, including those of the colon, and are known to be involved in all stages of tumour progression. HMGB1 is a nuclear protein with an important role in nucleosome stabilisation and gene transcription; it is also released from immune cells and is involved in the inflammatory process. We report that the microenvironmental condition of glucose deprivation is responsible for the active release of HMGB1 from various types of cancer cell lines (HT-29, MCF-7 and A549) under normoxic conditions. Recombinant HMGB1 (10 ng/ml) triggered proliferation in myofibroblast cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose-deprived HT-29 colon cancer cells stimulated the migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGB1, RAGE and TLR4, together with specific inhibitors of PI3K and MEK1/2. Our data suggest that HMGB1 released from cancer cells under glucose deprivation is involved in stimulating colonic myofibroblast migration and invasion and that this occurs through the activation of RAGE and TLR4, resulting in the activation of the MAPK and PI3K signalling pathways. Thus, HMGB1 might be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts and is a potential therapeutic target to inhibit solid tumour growth.	[Sharma, Sikander; Evans, Andrew; Hemers, Elaine] Liverpool John Moores Univ, Sch Pharm & Bimol Sci, Biomol Sci, Liverpool L3 3AF, Merseyside, England		Hemers, E (corresponding author), Liverpool John Moores Univ, Sch Pharm & Bimol Sci, Biomol Sci, Liverpool L3 3AF, Merseyside, England.	a.r.evans@ljmu.ac.uk					BUSTIN M, 1990, BIOCHIM BIOPHYS ACTA, V1049, P231, DOI 10.1016/0167-4781(90)90092-G; Chen PN, 2005, CHEM-BIOL INTERACT, V156, P141, DOI 10.1016/j.cbi.2005.08.005; Chien MH, 2013, EXPERT OPIN THER TAR, V17, P203, DOI 10.1517/14728222.2013.740012; Chitanuwat A, 2013, J ORAL SCI, V55, P45, DOI 10.2334/josnusd.55.45; Curtin JF, 2009, PLOS MED, V6, P83, DOI 10.1371/journal.pmed.1000010; Dabiri S, 2013, ARCH IRAN MED, V16, P93, DOI 013162/AIM.008; De Wever O, 2008, INT J CANCER, V123, P2229, DOI 10.1002/ijc.23925; Downs-Kelly E, 2013, M DAWSONS GASTROINT, V5, P223; Duckworth CA, 2013, GASTROENTEROLOGY, V145, P197, DOI 10.1053/j.gastro.2013.03.012; Dumitriu IE, 2005, J IMMUNOL, V174, P7506, DOI 10.4049/jimmunol.174.12.7506; Dumitriu IE, 2007, J LEUKOCYTE BIOL, V81, P84, DOI 10.1189/jlb.0306171; Evans A, 2008, CANCER CHEMOTH PHARM, V61, P377, DOI 10.1007/s00280-007-0480-1; Gardella S, 2002, EMBO REP, V3, P995, DOI 10.1093/embo-reports/kvf198; Guan HJ, 2015, HISTOPATHOLOGY, V66, P781, DOI 10.1111/his.12519; Hamada N, 2008, AM J RESP CELL MOL, V39, P440, DOI 10.1165/rcmb.2007-0330OC; Hemers E, 2005, CANCER RES, V65, P7363, DOI 10.1158/0008-5472.CAN-05-0157; Hinz B, 2007, AM J PATHOL, V170, P1807, DOI 10.2353/ajpath.2007.070112; Holmberg C, 2013, J PROTEOME RES, V12, P3413, DOI 10.1021/pr400270q; Hu M, 2008, CANCER CELL, V13, P394, DOI 10.1016/j.ccr.2008.03.007; Jang A, 1997, CLIN EXP METASTAS, V15, P469, DOI 10.1023/A:1018470709523; Kang R, 2014, ONCOGENE, V33, P567, DOI 10.1038/onc.2012.631; Kim S, 2013, MOL MED, V19, P88, DOI 10.2119/molmed.2012.00306; Kokkola R, 2005, SCAND J IMMUNOL, V61, P1, DOI 10.1111/j.0300-9475.2005.01534.x; Lange SS, 2008, P NATL ACAD SCI USA, V105, P10320, DOI 10.1073/pnas.0803181105; Lee C-C, 2015, EVID-BASED COMPL ALT, V2015, P1, DOI DOI 10.1371/J0URNAL.P0NE.0116393; Li G, 2013, FRONT IMMUNOL, V4, P1; Li L, 2013, CELL SIGNAL, V25, P50, DOI 10.1016/j.cellsig.2012.09.020; Li W, 2015, LAB INVEST, V95, P635, DOI 10.1038/labinvest.2015.44; Liu YY, 2010, ATHEROSCLEROSIS, V208, P34, DOI 10.1016/j.atherosclerosis.2009.06.007; Luca M, 1997, AM J PATHOL, V151, P1105; Mahajan N, 2013, INT J CARDIOL, V168, P1788, DOI 10.1016/j.ijcard.2013.05.013; Mareel M, 2003, PHYSIOL REV, V83, P337, DOI 10.1152/physrev.00024.2002; Mareel M, 2009, VIRCHOWS ARCH, V454, P599, DOI 10.1007/s00428-009-0784-0; Nagarajan S, 2013, J PEDIATR GASTR NUTR, V57, P277, DOI 10.1097/MPG.0b013e31829e0b3b; Pena C, 2013, CANCER RES, V73, P1287, DOI 10.1158/0008-5472.CAN-12-1875; Ranzato E, 2010, CELL BIOCHEM BIOPHYS, V57, P9, DOI 10.1007/s12013-010-9077-0; Ranzato E, 2009, MOL CELL BIOCHEM, V332, P199, DOI 10.1007/s11010-009-0192-4; Riuzzi F, 2006, J BIOL CHEM, V281, P8242, DOI 10.1074/jbc.M509436200; Rojas A, 2010, CARCINOGENESIS, V31, P334, DOI 10.1093/carcin/bgp322; Tang DL, 2007, J LEUKOCYTE BIOL, V81, P741, DOI 10.1189/jlb.0806540; Tang D, 2013, INT J CANCER, V132, P993, DOI 10.1002/ijc.27715; Thorburn J, 2009, CELL DEATH DIFFER, V16, P175, DOI 10.1038/cdd.2008.143; Thorburn J, 2009, AUTOPHAGY, V5, P247, DOI 10.4161/auto.5.2.7552; Tripathi M, 2012, CELL ADHES MIGR, V6, P231, DOI 10.4161/cam.20419; Vaughan MB, 2000, EXP CELL RES, V257, P180, DOI 10.1006/excr.2000.4869; Wang FP, 2013, PLOS ONE, V8, DOI [10.1371/journal.pone.0061792, 10.1371/journal.pone.0069284, 10.1371/journal.pone.0062988, 10.1371/journal.pone.0064373, 10.1371/journal.pone.0080480, 10.1371/journal.pone.0078025]; Werner S, 2007, J INVEST DERMATOL, V127, P998, DOI 10.1038/sj.jid.5700786; Yang D, 2007, J LEUKOCYTE BIOL, V81, P59, DOI 10.1189/jlb.0306180; Yang X, 2015, CELL BIOSCI, V5, DOI 10.1186/s13578-015-0005-2; Yeung TM, 2013, BRIT J CANCER, V108, P2106, DOI 10.1038/bjc.2013.209; Yoshida A, 2013, HISTOPATHOLOGY, V63, P881, DOI 10.1111/his.12218	51	11	11	0	13	SPRINGER	NEW YORK	233 SPRING ST, NEW YORK, NY 10013 USA	0302-766X	1432-0878		CELL TISSUE RES	Cell Tissue Res.	AUG	2016	365	2					357	366		10.1007/s00441-016-2389-7			10	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	DR6WN	WOS:000380042100012	26979829	Green Published, hybrid			2022-04-25	
J	Chen, ST; Lee, TY; Tsai, TH; Huang, YC; Lin, YC; Lin, CP; Shieh, HR; Hsu, ML; Chi, CW; Lee, MC; Chang, HH; Chen, YJ				Chen, Shun-Ting; Lee, Tzung-Yan; Tsai, Tung-Hu; Huang, Yu-Chuen; Lin, Yin-Cheng; Lin, Chin-Ping; Shieh, Hui-Ru; Hsu, Ming-Ling; Chi, Chih-Wen; Lee, Ming-Cheng; Chang, Hen-Hong; Chen, Yu-Jen			Traditional Chinese medicine Danggui Buxue Tang inhibits colorectal cancer growth through induction of autophagic cell death	ONCOTARGET			English	Article						Danggui Buxue Tang; colorectal cancer; autophagy; traditional Chinese medicine; mammalian target of rapamycin (mTOR)	HERBAL DECOCTION; RADIX-ASTRAGALI; MTOR INHIBITORS; MAMMALIAN TARGET; STATISTICS; CARCINOMA; MODEL; MCF-7	Purpose: The induction of autophagic cell death is an important process in the development of anticancer therapeutics. We aimed to evaluate the activity of the ancient Chinese decoction Danggui Buxue Tang (DBT) against colorectal cancer (CRC) and the associated autophagy-related mechanism. Materials and methods: CT26 CRC cells were implanted into syngeneic BALB/c mice for the tumor growth assay. DBT extracts and DBT-PD (polysaccharide-depleted) fractions were orally administered. The toxicity profiles of the extracts were analyzed using measurements of body weight, hemogram, and biochemical parameters. The morphology of tissue sections was observed using light and transmission electron microscopy. Western blotting and small interference RNA assays were used to determine the mechanism. Results: DBT-PD and DBT, which contained an equal amount of DBT-PD, inhibited CT26 syngeneic tumor growth. In the tumor specimen, the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3B) was upregulated by DBT-PD and DBT. The development of autophagosomes was observed via transmission electron microscopy in tumors treated with DBT-PD and DBT. In vitro experiments for mechanism clarification demonstrated that DBT-PD could induce autophagic death in CT26 cells accompanied by LC3B lipidation, downregulation of phospho-p70(s6k), and upregulation of Atg7. RNA interference of Atg7, but not Atg5, partially reversed the effect of DBT-PD on LC3B lipidation and expression of phospho-p70(s6k) and Atg7. The changes in ultrastructural morphology and LC3B expression induced by DBT-PD were also partially blocked by the knockdown of Atg7 mRNA. Conclusion: DBT induced autophagic death of colorectal cancer cells through the upregulation of Atg7 and modulation of the mTOR/p70(s6k) signaling pathway.	[Chen, Shun-Ting] Buddhist Tzu Chi Med Fdn, Taipei Buddhist Tzu Chi Hosp, Dept Chinese Med, New Taipei 23142, Taiwan; [Chen, Shun-Ting; Lee, Tzung-Yan] Chang Gung Univ, Coll Med, Sch Chinese Med, Grad Inst Tradit Chinese Med, Taoyuan 33302, Taiwan; [Chen, Shun-Ting] Chang Gung Univ, Coll Med, Grad Inst Clin Med Sci, Taoyuan 33302, Taiwan; [Tsai, Tung-Hu] Natl Yang Ming Univ, Sch Med, Inst Tradit Med, Taipei 11221, Taiwan; [Huang, Yu-Chuen] China Med Univ, Sch Chinese Med, Taichung 40402, Taiwan; [Huang, Yu-Chuen; Chen, Yu-Jen] China Med Univ Hosp, Dept Med Res, Taichung 40402, Taiwan; [Lin, Yin-Cheng; Lin, Chin-Ping; Shieh, Hui-Ru; Hsu, Ming-Ling; Chi, Chih-Wen; Chen, Yu-Jen] Mackay Mem Hosp, Dept Med Res, New Taipei 25160, Taiwan; [Lee, Ming-Cheng] Buddhist Tzu Chi Med Fdn, Taipei Buddhist Tzu Chi Hosp, Dept Res, New Taipei 23141, Taiwan; [Chang, Hen-Hong] China Med Univ, Sch Postbaccalaureate Chinese Med, Coll Chinese Med, Taichung 40402, Taiwan; [Chang, Hen-Hong] China Med Univ, Res Ctr Chinese Med & Acupuncture, Taichung 40402, Taiwan; [Chang, Hen-Hong] China Med Univ Hosp, Dept Chinese Med, Taichung 40402, Taiwan; [Chen, Yu-Jen] Mackay Mem Hosp, Dept Radiat Oncol, Taipei 10449, Taiwan; [Tsai, Tung-Hu] Natl United Univ, Dept Chem Engn, Miaoli 36003, Taiwan		Chen, YJ (corresponding author), China Med Univ Hosp, Dept Med Res, Taichung 40402, Taiwan.; Chen, YJ (corresponding author), Mackay Mem Hosp, Dept Med Res, New Taipei 25160, Taiwan.; Chang, HH (corresponding author), China Med Univ, Sch Postbaccalaureate Chinese Med, Coll Chinese Med, Taichung 40402, Taiwan.; Chang, HH (corresponding author), China Med Univ, Res Ctr Chinese Med & Acupuncture, Taichung 40402, Taiwan.; Chang, HH (corresponding author), China Med Univ Hosp, Dept Chinese Med, Taichung 40402, Taiwan.; Chen, YJ (corresponding author), Mackay Mem Hosp, Dept Radiat Oncol, Taipei 10449, Taiwan.	tcmchh55@mail.cmu.edu.tw; chenmdphd@gmail.com	Tsai, Tung-Hu/AAG-4558-2021	Tsai, Tung-Hu/0000-0002-9007-2547	Ministry of Science Technology [MOST 103-2314-B-195-013-MY3]; Mackay Memorial Hospital of Taiwan [MMH-E-105-13, MMH-E-106-13]	This study was supported by Ministry of Science Technology (grant number MOST 103-2314-B-195-013-MY3) and Mackay Memorial Hospital (grant numbers MMH-E-105-13 and MMH-E-106-13) of Taiwan.	Bellmunt J, 2008, ANN ONCOL, V19, P1387, DOI 10.1093/annonc/mdn066; Bellot G, 2009, MOL CELL BIOL, V29, P2570, DOI 10.1128/MCB.00166-09; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; Center MM, 2009, CA-CANCER J CLIN, V59, P366, DOI 10.3322/caac.20038; Chen ST, 2016, MOLECULES, V21, DOI 10.3390/molecules21121677; Chen Y, 2009, CHIN J INTEGR MED, V15, P435, DOI 10.1007/s11655-009-0435-y; Choi RCY, 2011, EVID-BASED COMPL ALT, V2011, P1, DOI 10.1093/ecam/nen085; Choueiri TK, 2013, ANN ONCOL, V24, P2092, DOI 10.1093/annonc/mdt155; Easton JB, 2006, ONCOGENE, V25, P6436, DOI 10.1038/sj.onc.1209886; EDDY DM, 1990, ANN INTERN MED, V113, P373, DOI 10.7326/0003-4819-113-5-373; Efeyan A, 2015, NATURE, V517, P302, DOI 10.1038/nature14190; Gao J, 2011, J ETHNOPHARMACOL, V136, P21, DOI 10.1016/j.jep.2011.03.013; Gao QT, 2008, PLANTA MED, V74, P392, DOI 10.1055/s-2008-1034322; Gao QT, 2007, FEBS LETT, V581, P233, DOI 10.1016/j.febslet.2006.12.018; Gao QT, 2006, PLANTA MED, V72, P1227, DOI 10.1055/s-2006-947186; Hammond WA, 2016, THER ADV MED ONCOL, V8, P57, DOI 10.1177/1758834015614530; Huang ZB, 2015, FUTURE ONCOL, V11, P1687, DOI 10.2217/fon.15.70; Kanzawa T, 2004, CELL DEATH DIFFER, V11, P448, DOI 10.1038/sj.cdd.4401359; Kim KW, 2008, AUTOPHAGY, V4, P659, DOI 10.4161/auto.6058; Klionsky DJ, 2008, AUTOPHAGY, V4, P151, DOI 10.4161/auto.5338; Lee SY, 2016, BIOMED RES INT, V2016, DOI 10.1155/2016/7590245; Lv J, 2012, EVID-BASED COMPL ALT, V2012, DOI 10.1155/2012/284963; Moscat J, 2009, CELL, V137, P1001, DOI 10.1016/j.cell.2009.05.023; Nair Anroop B, 2016, J Basic Clin Pharm, V7, P27, DOI 10.4103/0976-0105.177703; O'Connell JB, 2004, JNCI-J NATL CANCER I, V96, P1420, DOI 10.1093/jnci/djh275; Pyo JO, 2012, EXP MOL MED, V44, P73, DOI 10.3858/emm.2012.44.2.029; Qiao LW, 2014, INT J CLIN EXP MED, V7, P3333; Rikiishi Hidemi, 2012, Int J Cell Biol, V2012, P317645, DOI 10.1155/2012/317645; Siegel RL, 2016, CA-CANCER J CLIN, V66, P7, DOI 10.3322/caac.21332; Sou Y, 2008, MOL BIOL CELL, V19, P4762, DOI 10.1091/mbc.E08-03-0309; Steelman LS, 2016, BRIT J CLIN PHARMACO, V82, P1189, DOI 10.1111/bcp.12958; Su MF, 2013, J ONCOL, V2013, DOI 10.1155/2013/102735; Su YC, 2014, INT J MOL MED, V34, P1417, DOI 10.3892/ijmm.2014.1927; Torre LA, 2015, CA-CANCER J CLIN, V65, P87, DOI 10.3322/caac.21262; Wang CC, 2013, MENOPAUSE, V20, P223, DOI 10.1097/gme.0b013e318267f64e; Wang W, 2014, BIOMED RES INT, V2014, DOI 10.1155/2014/518609; Xiong JH, 2015, PROTEIN CELL, V6, P722, DOI 10.1007/s13238-015-0195-8; Yang M, 2009, J ETHNOPHARMACOL, V124, P87, DOI 10.1016/j.jep.2009.04.007; Zhang WL, 2013, EVID-BASED COMPL ALT, V2013, DOI 10.1155/2013/483286	39	10	12	1	27	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	OCT 24	2017	8	51					88563	88574		10.18632/oncotarget.19902			12	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	FK6AP	WOS:000413585600029	29179457	Green Submitted, gold, Green Published			2022-04-25	
J	Zhang, WL; Zhang, SY; Guan, W; Huang, ZC; Kong, JQ; Huang, CL; Wang, HH; Yang, SL				Zhang, Wenliang; Zhang, Shaoyang; Guan, Wen; Huang, Zhicong; Kong, Jianqiu; Huang, Chunlong; Wang, Haihe; Yang, Shulan			Poly C Binding Protein 1 Regulates p62/SQSTM1 mRNA Stability and Autophagic Degradation to Repress Tumor Progression	FRONTIERS IN GENETICS			English	Article						PCBP1; p62; SQSTM1; autophagy; apoptosis; ovary cancer; colon cancer; caspase-8	APOPTOSIS; CASPASE-8; EXPRESSION; PCBP1; TRANSLATION; CROSSTALK; COMPLEX; P62	Accumulating evidence show that Poly C Binding Protein 1 (PCBP1) is deleted in distinct types of tumors as a novel tumor suppressor, but its tumor suppression mechanism remains elusive. Here, we firstly describe that downregulation of PCBP1 is significantly associated with clinical ovarian tumor progression. Mechanistically, PCBP1 overexpression affects various autophagy-related genes expression at various expression levels to attenuate the intrinsic cell autophagy, including the autophagy-initiating ULK, ATG12, ATG7 as well as the bona fide marker of autophagosome, LC3B. Accordingly, knockdown of the endogenous PCBP1 in turn enhances autophagy and less cell death. Meanwhile, PCBP1 upregulates p62/SQSTM1 via inhibition p62/SQSTM1 autophagolysome and proteasome degradation as well as its mRNA stability, consequently accompanying with the caspase 3 or 8 activation for tumor cell apoptosis. Importantly, clinical ovary cancer sample analysis consistently validates the relevance of PCBP1 expression to both p62/SQSTM1 and caspase-8 to overall survival, and indicates PCBP1 may be a master player to repress tumor initiation. Taken together, our results uncover the tumorigenic mechanism of PCBP1 depletion and suggest that inhibition of tumor cell autophagy with autophagic inhibitors could be an effective therapeutical strategy for PCBP1-deficient tumor.	[Zhang, Wenliang; Yang, Shulan] Sun Yat Sen Univ, Affiliated Hosp 1, Translat Med Ctr, Guangzhou, Peoples R China; [Zhang, Wenliang; Zhang, Shaoyang; Guan, Wen; Huang, Zhicong; Kong, Jianqiu; Wang, Haihe] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem, Guangzhou, Peoples R China; [Huang, Chunlong] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Guangzhou, Peoples R China; [Wang, Haihe] Sun Yat Sen Univ, Ctr Stem Cell Biol & Tissue Engn, Guangzhou, Peoples R China; [Yang, Shulan] Sun Yat Sen Univ, Guangdong Engn & Technol Res Ctr Dis Model Anim, Guangzhou, Peoples R China		Yang, SL (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 1, Translat Med Ctr, Guangzhou, Peoples R China.; Wang, HH (corresponding author), Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem, Guangzhou, Peoples R China.; Wang, HH (corresponding author), Sun Yat Sen Univ, Ctr Stem Cell Biol & Tissue Engn, Guangzhou, Peoples R China.; Yang, SL (corresponding author), Sun Yat Sen Univ, Guangdong Engn & Technol Res Ctr Dis Model Anim, Guangzhou, Peoples R China.	wanghaih@mail.sysu.edu.cn; yangshl3@mail.sysu.edu.cn	Haihe, Wang/AAD-4036-2021; 张, 文亮/AAM-6021-2020	, Haihe/0000-0002-9302-2334; zhang, wenliang/0000-0003-0454-6935	National Key R&D Program of China [2018YFA0801005]; National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31271481, 81472730]	This work was supported by the National Key R&D Program of China (No. 2018YFA0801005 to SY) and National Science Foundation of China (Nos. 31271481 and 81472730 to HW).	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Genet.	AUG 14	2020	11								930	10.3389/fgene.2020.00930			16	Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Genetics & Heredity	NJ7KI	WOS:000566221700001	32922440	Green Published, gold			2022-04-25	
J	Bonfili, L; Cuccioloni, M; Cecarini, V; Mozzicafreddo, M; Palermo, FA; Cocci, P; Angeletti, M; Eleuteri, AM				Bonfili, Laura; Cuccioloni, Massimiliano; Cecarini, Valentina; Mozzicafreddo, Matteo; Palermo, Francesco Alessandro; Cocci, Paolo; Angeletti, Mauro; Eleuteri, Anna Maria			Ghrelin induces apoptosis in colon adenocarcinoma cells via proteasome inhibition and autophagy induction	APOPTOSIS			English	Article						Ghrelin; Apoptosis; Proteasome; Autophagy; Colon adenocarcinoma cells	MULTICATALYTIC PROTEINASE COMPLEX; DES-ACYL GHRELIN; HORMONE SECRETAGOGUE RECEPTOR; CANCER-CELLS; IN-VIVO; BIOLOGICAL-ACTIVITY; OCTANOYL GHRELIN; GH SECRETAGOGUES; SKELETAL-MUSCLE; NATURAL GHRELIN	Ghrelin is a metabolism-regulating hormone recently investigated for its role in cancer survival and progression. Controversially, ghrelin may act as either anti-apoptotic or pro-apoptotic factor in different cancer cells, suggesting that the effects are cell type dependent. Limited data are currently available on the effects exerted by ghrelin on intracellular proteolytic pathways in cancer. Both the lysosomal and the proteasomal systems are fundamental in cellular proliferation and apoptosis regulation. With the aim of exploring if the proteasome and autophagy may be possible targets of ghrelin in cancer, we exposed human colorectal adenocarcinoma cells to ghrelin. Preliminary in vitro fluorimetric assays evidenced for the first time a direct inhibition of 20S proteasomes by ghrelin, particularly evident for the trypsin-like activity. Moreover, 1 mu M ghrelin induced apoptosis in colorectal adenocarcinoma cells by inhibiting the ubiquitin-proteasome system and by activating autophagy, with p53 having an "interactive" role.	[Bonfili, Laura; Cuccioloni, Massimiliano; Cecarini, Valentina; Mozzicafreddo, Matteo; Palermo, Francesco Alessandro; Cocci, Paolo; Angeletti, Mauro; Eleuteri, Anna Maria] Univ Camerino, Sch Biosci & Biotechnol, I-62032 Camerino, Macerata, Italy		Bonfili, L (corresponding author), Univ Camerino, Sch Biosci & Biotechnol, Via Gentile 3 Varano, I-62032 Camerino, Macerata, Italy.	laura.bonfili@unicam.it	Palermo, Francesco A/D-7732-2018; Angeletti, Mauro/C-2960-2014; Mozzicafreddo, Matteo/AAW-2816-2021; Cuccioloni, Massimiliano/X-7188-2019; Angeletti, Mauro/AAC-5597-2019; Cecarini, Valentina/AAU-9749-2021; Cocci, Paolo/AAL-2599-2021	Palermo, Francesco A/0000-0001-7804-7149; Angeletti, Mauro/0000-0001-6719-5517; Mozzicafreddo, Matteo/0000-0001-9835-8446; Angeletti, Mauro/0000-0001-6719-5517; Cocci, Paolo/0000-0001-6890-9796; Cuccioloni, Massimiliano/0000-0002-6025-1990; Eleuteri, Anna Maria/0000-0003-0461-1346; Cecarini, Valentina/0000-0001-9315-9747; Bonfili, Laura/0000-0002-9542-4310			Affar EB, 2001, J BIOL CHEM, V276, P2935, DOI 10.1074/jbc.M007269200; Amici M, 2008, BIOCHIMIE, V90, P790, DOI 10.1016/j.biochi.2007.12.001; Amici M, 2003, FREE RADICAL BIO MED, V34, P987, DOI 10.1016/S0891-5849(02)01369-2; Ammori JB, 2008, SURGERY, V144, P159, DOI 10.1016/j.surg.2008.03.008; Andreis PG, 2003, FEBS LETT, V536, P173, DOI 10.1016/S0014-5793(03)00051-6; Balasubramaniam A, 2009, AM J PHYSIOL-REG I, V296, pR893, DOI 10.1152/ajpregu.00015.2008; Baldanzi G, 2002, J CELL BIOL, V159, P1029, DOI 10.1083/jcb.200207165; Bedendi I, 2003, EUR J PHARMACOL, V476, P87, DOI 10.1016/S0014-2999(03)02083-1; BIEDERBICK A, 1995, EUR J CELL BIOL, V66, P3; Bonfili L, 2009, BIOCHIMIE, V91, P1131, DOI 10.1016/j.biochi.2009.06.001; BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3; Buonanno F, 2008, CHEM-BIOL INTERACT, V176, P151, DOI 10.1016/j.cbi.2008.07.007; Cassoni P, 2004, EUR J ENDOCRINOL, V150, P173, DOI 10.1530/eje.0.1500173; Cassoni P, 2001, J CLIN ENDOCR METAB, V86, P1738, DOI 10.1210/jc.86.4.1738; Cecarini V, 2011, CURR CANCER DRUG TAR, V11, P307, DOI 10.2174/156800911794519815; Cecarini V, 2012, BBA-MOL BASIS DIS, V1822, P1741, DOI 10.1016/j.bbadis.2012.07.015; Chopin L, 2011, MOL CELL ENDOCRINOL, V340, P65, DOI 10.1016/j.mce.2011.04.013; Ciechanover A, 2005, CELL DEATH DIFFER, V12, P1178, DOI 10.1038/sj.cdd.4401692; Ciechanover A, 2000, J CELL BIOCHEM, P40; Du YL, 2009, AUTOPHAGY, V5, P663, DOI 10.4161/auto.5.5.8377; Duxbury MS, 2003, BIOCHEM BIOPH RES CO, V309, P464, DOI 10.1016/j.bbrc.2003.08.024; Ekeblad S, 2007, CLIN ENDOCRINOL, V66, P115, DOI 10.1111/j.1365-2265.2006.02695.x; Eleuteri AM, 1997, J BIOL CHEM, V272, P11824, DOI 10.1074/jbc.272.18.11824; Eleuteri AM, 2000, PROTEIN EXPRES PURIF, V18, P160, DOI 10.1006/prep.1999.1187; Fujishima Y, 2011, ARCH BIOCHEM BIOPHYS, V506, P223, DOI 10.1016/j.abb.2010.12.009; Fung Jenny N. 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J	Perez-Hernandez, M; Arias, A; Martinez-Garcia, D; Perez-Tomas, R; Quesada, R; Soto-Cerrato, V				Perez-Hernandez, Marta; Arias, Alain; Martinez-Garcia, David; Perez-Tomas, Ricardo; Quesada, Roberto; Soto-Cerrato, Vanessa			Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization	CANCERS			English	Review						autophagy; anticancer therapy; autophagy inhibitors; autophagic cell death; chemoresistance; chemosensitization	ADVANCED SOLID TUMORS; LYSOSOMAL PROTEIN-DEGRADATION; RADIATION-INDUCED AUTOPHAGY; RENAL-CELL CARCINOMA; PHASE-II TRIAL; COLON-CANCER; IN-VITRO; SELECTIVE INHIBITOR; MAMMALIAN TARGET; BINDING-PROTEIN	Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic.	[Perez-Hernandez, Marta; Arias, Alain; Martinez-Garcia, David; Perez-Tomas, Ricardo; Soto-Cerrato, Vanessa] Univ Barcelona, Fac Med & Hlth Sci, Dept Pathol & Expt Therapeut, Barcelona 08905, Spain; [Perez-Hernandez, Marta; Martinez-Garcia, David; Perez-Tomas, Ricardo; Soto-Cerrato, Vanessa] Hosp Llobregat, Oncobell Program, Inst Invest Biomed Bellvitge IDIBELL, Barcelona 08908, Spain; [Arias, Alain] Univ La Frontera, Res Ctr Dent Sci CICO, Dept Integral Adult Dent, Temuco 4811230, Chile; [Arias, Alain] Univ Adventista Chile, Fac Hlth Sci, Res Grp Hlth Sci, Chillan 3780000, Chile; [Quesada, Roberto] Univ Burgos, Dept Chem, Burgos 09001, Spain		Soto-Cerrato, V (corresponding author), Univ Barcelona, Fac Med & Hlth Sci, Dept Pathol & Expt Therapeut, Barcelona 08905, Spain.; Soto-Cerrato, V (corresponding author), Hosp Llobregat, Oncobell Program, Inst Invest Biomed Bellvitge IDIBELL, Barcelona 08908, Spain.	martaperezh@ub.edu; alain.arias@ufrontera.cl; david.martinez@ub.edu; rperez@ub.edu; rquesada@ubu.es; vsoto@ub.edu	Quesada, Roberto/C-6965-2008; quesada, roberto/AAX-8833-2021; Pérez-Hernández, Marta/K-8778-2014; Soto-Cerrato, Vanessa/AAB-4392-2020; Garcia, David Martinez/P-2461-2016	Quesada, Roberto/0000-0003-2764-7157; quesada, roberto/0000-0003-2764-7157; Pérez-Hernández, Marta/0000-0003-1331-5493; Soto-Cerrato, Vanessa/0000-0001-5835-3595; Garcia, David Martinez/0000-0001-7731-2107; ARIAS, ALAIN/0000-0002-1107-9426; Perez-Tomas, Ricardo/0000-0003-3226-1240	Instituto de Salud Carlos III (European Regional Development Fund. ERDF, a way to build Europe) [PI18/00441]	This research has been partially supported by Instituto de Salud Carlos III (Grant PI18/00441) (Co-funded by European Regional Development Fund. ERDF, a way to build Europe).	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J	Talero, E; Alcaide, A; Avila-Roman, J; Garcia-Maurino, S; Vendramini-Costa, D; Motilva, V				Talero, Elena; Alcaide, Antonio; Avila-Roman, Javier; Garcia-Maurino, Sofia; Vendramini-Costa, Debora; Motilva, Virginia			Expression patterns of sirtuin 1-AMPK-autophagy pathway in chronic colitis and inflammation-associated colon neoplasia in IL-10-deficient mice	INTERNATIONAL IMMUNOPHARMACOLOGY			English	Article						Chronic inflammation; Colon carcinogenesis; IL-10-deficient mice; SIRT1; Autophagy	SODIUM-INDUCED COLITIS; ULCERATIVE-COLITIS; BOWEL-DISEASE; COLORECTAL-CANCER; KAPPA-B; AUTOPHAGY; CARCINOGENESIS; ADENOCARCINOMA; ACTIVATION; PROLIFERATION	Background: Interleukin-10-deficient (IL-10 (-/-)) mice spontaneously develop chronic colitis and adenocarcinoma through the dysplasia sequence. Autophagy malfunction is associated to inflammatory bowel disease (IBD) and colorectal cancer (CRC) pathogenesis. Autophagy is regulated by silent information regulator-1 (SIRT1), a NAD+-dependent histone deacetylase. Our aim was to investigate the expression changes of SIRT1-AMPK-autophagy pathway in the progression from chronic colitis to CRC. Methods: We studied C57BL/6-IL-10-deficient mice between 6 and 18 weeks of age. Macroscopic and histological analysis, and characterization of inflammatory and tumor biomarkers were performed. Results: IL-10-deficient mice developed colitis from the age of 6 weeks onward. The severity of inflammation and dysplasia, and the proliferative activity increased gradually with age. IL-10 (-/-) mice were characterized by improved levels of TNF-alpha and decreased expression of SIRT1. Moreover, our findings show an increase in p-AMPK expression and an activation of the autophagy in IL-10 (-/-) mice from all stages, evidenced by the accumulation of LC3-II protein, the increase in Beclin 1 expression and the reduction in Bcl-2 levels. Conclusions: SIRT1-AMPK-autophagy pathway may be involved in the maintenance of chronic inflammation and dysplasia development in the IL-10-deficient mice model. Modulation of this pathway could be a novel strategy for IBD and CRC treatment. (C) 2016 Elsevier B.V. All rights reserved.	[Talero, Elena; Alcaide, Antonio; Avila-Roman, Javier; Motilva, Virginia] Univ Seville, Sch Pharm, Dept Pharmacol, Seville, Spain; [Garcia-Maurino, Sofia] Univ Seville, Fac Biol, Dept Plant Biol & Ecol, Seville, Spain; [Vendramini-Costa, Debora] Univ Estadual Campinas, Inst Chem, Dept Organ Chem, Campinas, SP, Brazil		Talero, E (corresponding author), Univ Seville, Dept Pharmacol, Sch Pharm, Profesor Garcia Gonzalez 2, Seville 41012, Spain.	etalero@us.es	Vendramini-Costa, Debora Barbosa/G-1287-2012; García-Mauriño, Sofía/E-6707-2010; Avila-Roman, Javier/B-5337-2017; Talero, Elena/I-2613-2015	Vendramini-Costa, Debora Barbosa/0000-0001-7617-4945; García-Mauriño, Sofía/0000-0002-7698-5112; Avila-Roman, Francisco Javier/0000-0001-9766-8178	Consejeria de Innovacion, Ciencia y Empresa-Junta de Andalucia (Polfanat) [P09-AGR-5185]	This work was supported by Consejeria de Innovacion, Ciencia y Empresa-Junta de Andalucia (P09-AGR-5185, Polfanat). We thank "Centro de Investigacion, Tecnologia e Innovation (CITIUS)" of the University of Seville for providing technical assistance.	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Immunopharmacol.	JUN	2016	35						248	256		10.1016/j.intimp.2016.03.046			9	Immunology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Pharmacology & Pharmacy	DM2XX	WOS:000376212500030	27085036				2022-04-25	
J	Ju, BL; Liu, ZL; Nai, C; Zhu, XY				Ju, Banglv; Liu, Zhilan; Nai, Chao; Zhu, Xinyong			Long non-coding RNA CASC2 induces apoptosis and autophagy in human colon cancer cells via modulation of TRIM16 expression	AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH			English	Article						Colon cancer; CASC2; apoptosis; autophagy	POOR-PROGNOSIS; LNCRNA CASC2; PROLIFERATION; SUPPRESSES; MIGRATION	Long non-coding RNAs (LncRNAs) have been shown to be involved in diverse cellular and physiological processes. Recent studies have proved their potential as the prospective therapeutic targets for cancer treatment. Herein, we examined the role of LncRNA CASC2 in human colon cancer. The gene expression analysis showed that LncRNA CASC2 is significantly suppressed in colon cancer tissues and cell lines. The immunohistochemistry also showed considerable increase of the Ki67 in colon cancer tissues suggestive of their aggressiveness. Overexpression of CASC2 inhibited the growth of HT-29 cells. The inhibition of HT-29 growth was due to the induction of apoptosis which was accompanied by upsurge of Bax, depletion of Bcl-2 and activation of caspase-3 cleavage. Electron microscopic analysis showed CASC2 overexpression also induced autophagy in the HT-29 cells which was associated with increase in LC3B II and Beclin 1 expression. Bioinformatic approaches and dual luciferase assay showed that CASC2 controls the TRIM16 via microRNA-214 axis. TRIM16 was found to be overexpressed in all the colon cancer tissues and cell lines. Overexpression of CASC2 caused significant inhibition of TRIM16. Additionally, silencing of TRIM16 resulted in the inhibition of HT-29 cell growth similar to that of CASC2 overexpression. Taken together, CASC2 may prove to be an important therapeutic target for colon cancer treatment.	[Ju, Banglv; Nai, Chao] Chinese Peoples Liberat Army Gen Hosp, Dept Hepatobiliary Surg, Med Ctr 7, Beijing 100700, Peoples R China; [Liu, Zhilan] Qinghai Prov Peoples Hosp, Dept Gastroenterol, Xining 810007, Qinghai, Peoples R China; [Zhu, Xinyong] Peoples Liberat Army Gen Hosp, Med Ctr 4, Dept Gen Surg, Beijing 100048, Peoples R China		Zhu, XY (corresponding author), Peoples Liberat Army Gen Hosp, Med Ctr 4, Dept Gen Surg, Beijing 100048, Peoples R China.	zxy304@126.com					Arnold M, 2017, GUT, V66, P683, DOI 10.1136/gutjnl-2015-310912; Ba ZW, 2018, CELL PROLIFERAT, V51, DOI 10.1111/cpr.12409; Cao YJ, 2016, MOL MED REP, V14, P1019, DOI 10.3892/mmr.2016.5337; Evans JR, 2016, J CLIN INVEST, V126, P2775, DOI 10.1172/JCI84421; Fan JC, 2018, J CELL BIOCHEM, V119, P6391, DOI 10.1002/jcb.26479; Feng YQ, 2017, ARCH BIOCHEM BIOPHYS, V623, P20, DOI 10.1016/j.abb.2017.05.001; Guinney J, 2015, NAT MED, V21, P1350, DOI 10.1038/nm.3967; He XZ, 2016, TUMOR BIOL, V37, P9503, DOI 10.1007/s13277-016-4787-6; Huarte M, 2015, NAT MED, V21, P1253, DOI 10.1038/nm.3981; Li P, 2016, AM J TRANSL RES, V8, P3522; Li Q, 2018, RSC ADV, V8, P40846, DOI 10.1039/c8ra09573f; Pei Z, 2017, ONCOTARGET, V8, P18145, DOI 10.18632/oncotarget.15210; POTTER JD, 1993, EPIDEMIOL REV, V15, P499, DOI 10.1093/oxfordjournals.epirev.a036132; Prensner JR, 2011, CANCER DISCOV, V1, P391, DOI 10.1158/2159-8290.CD-11-0209; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Sutton SK, 2014, ONCOTARGET, V5, P10127, DOI 10.18632/oncotarget.2466; Tan HW, 2017, ONCOL RES, V25, P551, DOI 10.3727/096504016X14758370595285; Tauriello DVF, 2018, NATURE, V554, P538, DOI 10.1038/nature25492; Wang P, 2015, CELL SIGNAL, V27, P275, DOI 10.1016/j.cellsig.2014.11.011; Xiong XQ, 2017, BIOMED PHARMACOTHER, V93, P391, DOI 10.1016/j.biopha.2017.06.063; Yao JT, 2016, ONCOL REP, V35, P1204, DOI 10.3892/or.2015.4437; Zhang H, 2013, J HEMATOL ONCOL, V6, DOI 10.1186/1756-8722-6-37; Zhang R, 2016, ONCOL LETT, V12, P1233, DOI 10.3892/ol.2016.4770; Zhang Y, 2019, ONCOL RES, V27, P379, DOI 10.3727/096504018X15199531937158	24	4	4	0	1	E-CENTURY PUBLISHING CORP	MADISON	40 WHITE OAKS LN, MADISON, WI 53711 USA	1943-8141			AM J TRANSL RES	Am. J. Transl. Res.		2020	12	6					2695	2702					8	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	MJ7DE	WOS:000548246400008	32655801				2022-04-25	
J	Comes, F; Matrone, A; Lastella, P; Nico, B; Susca, FC; Bagnulo, R; Ingravallo, G; Modica, S; Lo Sasso, G; Moschetta, A; Guanti, G; Simone, C				Comes, F.; Matrone, A.; Lastella, P.; Nico, B.; Susca, F. C.; Bagnulo, R.; Ingravallo, G.; Modica, S.; Lo Sasso, G.; Moschetta, A.; Guanti, G.; Simone, C.			A novel cell type-specific role of p38 alpha in the control of autophagy and cell death in colorectal cancer cells	CELL DEATH AND DIFFERENTIATION			English	Article						colorectal cancer; p38 alpha; autophagic cell death; apoptosis; SB202190	ACTIVATED PROTEIN-KINASE; MALIGNANT GLIOMA-CELLS; SIGNALING PATHWAYS; P38; DIFFERENTIATION; SURVIVAL; MAPK; INHIBITION; ISOFORMS; COMPLEX	Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38 alpha/beta kinases. We report that p38 alpha is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type- specific manner. Deficiency of p38 alpha activity induces a tissue- restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38 alpha as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38 alpha pathway in the treatment of colorectal cancer.	Univ Bari, Div Med Genet, Dept Biomed Childhood, Bari, Italy; Univ Bari, Dept Human Anat & Histol, Bari, Italy; Univ Bari, Dept Pathol Anat, Bari, Italy; Univ Bari, Consorzio Mario Negri Sud, Santa Maria Imbaro Ch, Bari, Italy; Univ Bari, Clin Med Mum, Dept Internal Med, Bari, Italy; Temple Univ, Sbarro Inst Canc Res & Mol Med, Ctr Biotechnol, Coll Sci & Technol, Philadelphia, PA 19122 USA		Guanti, G (corresponding author), Univ Bari, Div Med Genet, Dept Biomed Childhood, Bari, Italy.	guanti@medgene.uniba.it; csimone@temple.edu	Ingravallo, Giuseppe/Q-1477-2016; Moschetta, Antonio/AAC-5295-2022; Moschetta, Antonio/K-6211-2016; INGRAVALLO, Giuseppe/N-2466-2019; Simone, Cristiano/K-3452-2018	Ingravallo, Giuseppe/0000-0002-4792-3545; INGRAVALLO, Giuseppe/0000-0002-4792-3545; Simone, Cristiano/0000-0002-2628-7658; Susca, Francesco Claudio/0000-0002-9899-8301; Moschetta, Antonio/0000-0003-2123-6074			ABEDIN MJ, 2006, CELL DEATH DIFFER; Abeliovich H, 2000, J CELL BIOL, V151, P1025, DOI 10.1083/jcb.151.5.1025; Archer SY, 2005, AM J PHYSIOL-GASTR L, V289, pG696, DOI 10.1152/ajpgi.00575.2004; Bakin AV, 2002, J CELL SCI, V115, P3193; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; Corin I, 2006, CANCER BIOL THER, V5, P198, DOI 10.4161/cbt.5.2.2356; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; DEMIDOV ON, 2006, ONCOGENE; Faust D, 2005, ONCOGENE, V24, P7941, DOI 10.1038/sj.onc.1208948; Gout S, 2006, CANCER RES, V66, P9117, DOI 10.1158/0008-5472.CAN-05-4605; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Halawani D, 2004, ONCOGENE, V23, P3726, DOI 10.1038/sj.onc.1207422; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; Hiramoto T, 1999, ONCOGENE, V18, P3422, DOI 10.1038/sj.onc.1202691; Houde M, 2001, J BIOL CHEM, V276, P21885, DOI 10.1074/jbc.M100236200; Kabeya Y, 2004, J CELL SCI, V117, P2805, DOI 10.1242/jcs.01131; Kanzawa T, 2003, CANCER RES, V63, P2103; Kanzawa T, 2004, CELL DEATH DIFFER, V11, P448, DOI 10.1038/sj.cdd.4401359; KATAYAMA M, 2006, CELL DEATH DIFF 0901; Laprise P, 2002, J BIOL CHEM, V277, P8226, DOI 10.1074/jbc.M110235200; Luongo D, 2002, MOL CELL BIOCHEM, V231, P43, DOI 10.1023/A:1014476706382; Marx J, 2006, SCIENCE, V312, P1160, DOI 10.1126/science.312.5777.1160; McGartland Laura P, 2004, Clin Adv Hematol Oncol, V2, P806; Medina V, 1998, JPEN-PARENTER ENTER, V22, P14, DOI 10.1177/014860719802200114; Orchel A, 2005, DIGEST DIS SCI, V50, P490, DOI 10.1007/s10620-005-2463-6; Petiot A, 2000, J BIOL CHEM, V275, P992, DOI 10.1074/jbc.275.2.992; Prakash J, 2006, J PHARMACOL EXP THER, V319, P8, DOI 10.1124/jpet.106.106054; Prick T, 2006, BIOCHEM J, V394, P153, DOI 10.1042/BJ20051243; Samoha S, 2005, ONCOLOGY-BASEL, V69, P33, DOI 10.1159/000086630; Schwab M, 2006, APOPTOSIS, V11, P1801, DOI 10.1007/s10495-006-9788-2; Simone C, 2006, J CELL PHYSIOL, V207, P309, DOI 10.1002/jcp.20514; Simone C, 2004, NAT GENET, V36, P738, DOI 10.1038/ng1378; Suarez-Cuervo C, 2004, CLIN EXP METASTAS, V21, P525, DOI 10.1007/s10585-004-3503-x; Takeuchi H, 2005, CANCER RES, V65, P3336, DOI 10.1158/0008-5472.CAN-04-3640; Tassa A, 2003, BIOCHEM J, V376, P577, DOI 10.1042/BJ20030826; ten Hove T, 2002, GUT, V50, P507, DOI 10.1136/gut.50.4.507; Tsujimoto Y, 2005, CELL DEATH DIFFER, V12, P1528, DOI 10.1038/sj.cdd.4401777; Vachon PH, 2002, GASTROENTEROLOGY, V123, P1980, DOI 10.1053/gast.2002.37072; van den Brink GR, 2004, NAT GENET, V36, P277, DOI 10.1038/ng1304; vom Dahl S, 2001, BIOCHEM J, V354, P31, DOI 10.1042/0264-6021:3540031	40	99	103	1	11	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	1350-9047	1476-5403		CELL DEATH DIFFER	Cell Death Differ.	APR	2007	14	4					693	702		10.1038/sj.cdd.4402076			10	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	148UV	WOS:000245102900006	17159917	Bronze			2022-04-25	
J	Park, GB; Jin, DH; Kim, D				Park, Ga-Bin; Jin, Dong-Hoon; Kim, Daejin			Sequential treatment with celecoxib and bortezomib enhances the ER stress-mediated autophagy-associated cell death of colon cancer cells	ONCOLOGY LETTERS			English	Article						celecoxib; bortezomib; endoplasmic reticulum stress; autophagy; colon cancer; p53	ENDOPLASMIC-RETICULUM STRESS; INDUCED APOPTOSIS; INHIBITION; SURVIVAL; RECEPTOR; BAX; P53	Treatment with celecoxib and bortezomib as single chemotherapeutic agents reduces the viability and proliferation of colorectal cancer cells. The use of these agents in combination with other chemotherapeutic agents is usually associated with adverse effects. In the present study, a combination of celecoxib and bortezomib was investigated for potential synergistic effects in colon cancer cells. The sequential exposure to celecoxib with bortezomib synergistically induced apoptotic death in human colon cancer cells compared with groups treated with a single drug or other drug combinations. c-Jun N-terminal kinase/p38-mitogen-activated protein kinase-induced endoplasmic reticulum (ER) stress through serial exposure to celecoxib and bortezomib may have induced the intracellular Ca2+ release, leading to the generation of autophagosomes in p53-expressing HCT-116 cells. Targeted inhibition of p53 activity or ER stress or treatment with the Ca2+-chelating agent BAPTA-AM suppressed the ER stress-mediated Ca2+ release and apoptosis. Although p53(-/-) HCT-116 cells were less sensitive to sequential treatment with celecoxib and bortezomib, co-localization of autophagosomes was detected in the absence of CCAAT-enhancer-binding protein homologous protein expression. Treatment of p53(-/-) HCT-116 cells with BAPTA-AM did not inhibit apoptosis following serial treatment with celecoxib and bortezomib. These results suggest that the order of drug administration is important in treating cancer and that the sequential treatment with celecoxib and bortezomib enhances the ER stress-mediated autophagy-associated cell death of colon cancer cells, regardless of p53 expression.	[Park, Ga-Bin] Kosin Univ, Coll Med, Dept Biochem, Busan 49267, South Korea; [Jin, Dong-Hoon] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Convergence, Seoul 05505, South Korea; [Jin, Dong-Hoon] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul 05505, South Korea; [Kim, Daejin] Inje Univ, Coll Med, Dept Anat, 75 Bokji St, Busan 47392, South Korea		Kim, D (corresponding author), Inje Univ, Coll Med, Dept Anat, 75 Bokji St, Busan 47392, South Korea.	kimdj@inje.ac.kr			2016 Inje University research grant [20170021]	The present study was supported by a 2016 Inje University research grant (grant no. 20170021).	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Lett.	OCT	2018	16	4					4526	4536		10.3892/ol.2018.9233			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GU1BU	WOS:000444990700057	30214587	gold, Green Published, Green Submitted			2022-04-25	
J	Zhan, Y; Kong, SX; Fan, L; Jiang, J				Zhan, Yan; Kong, Shuangxi; Fan, Liang; Jiang, Jun			Irigenin exhibits anticancer activity against human colon cancer cells via autophagy, inhibition of cell migration and invasion, and targeting of ERK/MAPK signal pathway	TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH			English	Article						Colon cancer; Isoflavonoids; Irigenin; Autophagy; Cell migration; Cell invasion		Purpose: To study the anticancer effect of naturally-occurring irigenin isoflavonoid on colon cancer, and to determine the mechanism involved. Methods: The effect of irigenin on viability of normal and cancerous colon cells was assessed by MTT assay, while clonogenic assay was used to measure colony generation. Autophagy was examined by transmission electron microscopy (TEM) and western blotting. Transwell chamber assay was used to determine the influence of irigenin isoflavonoid on cell migration and invasion. The expression levels of ERK/MAPK signal pathway-associated proteins were assayed using Western blotting. Results: Irigenin significantly decreased the viability of Caco-2 colon cancer cells, in contrast to normal CCD841 colon cells, and produced concentration-dependent anti-proliferative effects (p < 0.05). The number of cell colonies in control group decreased significantly (p < 0.05) upon exposure to irigenin. Results from TEM revealed that irigenin caused dose-dependent formation of autophagosomes, and dose-based up-regulation of the expressions of Beclin-1, LC3-I and LC3-II (p < 0.05). Moreover, irigenin markedly suppressed the migration and invasion of Coca-2 cells. Furthermore, irigenin exposure dose-dependently blocked the expressions of proteins associated with ERK/MAPK signal pathway in Coca-2 cells. Conclusion: These results indicate that irigenin exerts potent inhibitory effect on the growth and migration of colon cancer cells. Furthermore, irigenin induces autophagy, inhibits cell migration and invasion, and targets ERK/MAPK survival signal pathway. Therefore, irigenin may be a lead candidate drug for colon cancer treatment. However, there is need for further in vivo and clinical studies to validate these findings.	[Zhan, Yan; Kong, Shuangxi; Fan, Liang; Jiang, Jun] Huazhong Univ Sci & Technol, Dept Oncol, Cent Hosp Wuhan, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China		Jiang, J (corresponding author), Huazhong Univ Sci & Technol, Dept Oncol, Cent Hosp Wuhan, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China.	hardyjiangjun77730@yahoo.com					Afshari K, 2019, J CELL PHYSIOL, V234, P21519, DOI 10.1002/jcp.28777; Birt DF, 2001, PHARMACOL THERAPEUT, V90, P157, DOI 10.1016/S0163-7258(01)00137-1; Caraballo Alejandro, 2004, Rev. Soc. Bras. Med. Trop., V37, P186, DOI 10.1590/S0037-86822004000200016; Dahanukar S. A., 2000, Indian Journal of Pharmacology, V32, pS81; EMIM JAD, 1994, J PHARM PHARMACOL, V46, P118, DOI 10.1111/j.2042-7158.1994.tb03753.x; Engstrom PF, 2009, J NATL COMPR CANC NE, V7, P778, DOI 10.6004/jnccn.2009.0056; Garcia A, 2012, EUR J MED CHEM, V49, P1, DOI 10.1016/j.ejmech.2011.12.029; Gonzalez MN, 2017, SKELET MUSCLE, V7, DOI 10.1186/s13395-017-0138-6; Hampel H, 2018, SURG ONCOL CLIN N AM, V27, P319, DOI 10.1016/j.soc.2017.11.006; Heo DN, 2020, INT J BIOL MACROMOL, V146, P922, DOI 10.1016/j.ijbiomac.2019.09.215; Hutton SR, 2017, J NEUROSCI, V37, P8102, DOI 10.1523/JNEUROSCI.0473-17.2017; Leow CC, 2004, CANCER RES, V64, P6050, DOI 10.1158/0008-5472.CAN-04-0290; Li WY, 2018, J FUNCT FOODS, V45, P75, DOI 10.1016/j.jff.2018.03.024; Patwardhan B, 2005, EVID-BASED COMPL ALT, V2, P465, DOI 10.1093/ecam/neh140; Qin MJ, 2005, J INTEGR PLANT BIOL, V47, P1404, DOI 10.1111/j.1744-7909.2005.00142.x; Tahtamouni L, 2019, ANAL CELL PATHOL, V2019, DOI 10.1155/2019/1356508; Tan HD, 2018, FRONT IMMUNOL, V9, DOI 10.3389/fimmu.2018.01504; Van Blarigan E, 2017, J CLIN ONCOL, V35, DOI 10.1200/JCO.2017.35.15_suppl.10006; WON SW, 1993, PHYTOCHEMISTRY, V33, P939; Xu Y, 2018, BIOCHEM BIOPH RES CO, V496, P998, DOI 10.1016/j.bbrc.2018.01.003; Zhang L, 2016, J ETHNOPHARMACOL, V186, P1, DOI 10.1016/j.jep.2016.03.046	21	0	0	6	7	PHARMACOTHERAPY GROUP	BENIN CITY	UNIV BENIN, FACULTY PHARMACY, BENIN CITY, 00000, NIGERIA	1596-5996			TROP J PHARM RES	Trop. J. Pharm. Res.	JUL	2021	20	7					1357	1363		10.4314/tjpr.v20i7.6			7	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	TS0VN	WOS:000679375500006		gold			2022-04-25	
J	Sundarraj, K; Raghunath, A; Perumal, E				Sundarraj, Kiruthika; Raghunath, Azhwar; Perumal, Ekambaram			A review on the chemotherapeutic potential of fisetin: In vitro evidences	BIOMEDICINE & PHARMACOTHERAPY			English	Review						Apoptosis; Autophagic cell death; Cancer; Chemotherapeutic agent; Combination therapy; Fisetin	DIETARY FLAVONOID FISETIN; CELL-CYCLE ARREST; COLON-CANCER CELLS; PROSTATE-CANCER; INDUCED APOPTOSIS; BREAST-CANCER; LUNG-CANCER; MESENCHYMAL TRANSITION; PI3K/AKT/MTOR PATHWAY; INDUCED CYTOTOXICITY	During the past five decades, cancer cell lines are being successfully used as an in vitro model to discover the anticancer potential of plant secondary metabolites. Fisetin-the most popular polyphenol from fruits and vegetables, exhibits a repertoire of promising pharmacological features. Such versatile properties make fisetin an excellent anticancer agent and its efficacy as a chemotherapeutic agent against tumor heterogeneity from in vitro studies are encouraging. Fisetin is like a Pandora's box, as more research studies are being carried out, it reveals its new molecules within the cancer cells as therapeutic targets. These molecular targets orchestrate processes such as apoptosis, autophagic cell death, cell cycle, invasion, metastasis and angiogenesis in cancer cells. Besides apoptotic elicitation, fisetin's ability to induce autophagic cell death in cancer cells has been reported. This review examines the various molecular mechanisms of action elicited by fisetin leading to apoptosis and autophagic cell death as evidenced from cancer cell lines. In addition, the increased bioavailability and sustained release of fisetin improved through conjugation and enhanced effect of fisetin through synergism on various cancers are also highlighted.	[Sundarraj, Kiruthika; Raghunath, Azhwar; Perumal, Ekambaram] Bharathiar Univ, Dept Biotechnol, Mol Toxicol Lab, Coimbatore 641046, Tamil Nadu, India		Perumal, E (corresponding author), Bharathiar Univ, Dept Biotechnol, Mol Toxicol Lab, Coimbatore 641046, Tamil Nadu, India.	ekas2009@buc.edu.in	Perumal, Ekambaram/R-9319-2018; Raghunath, Azhwar/E-2720-2012; Sundarraj, Kiruthika/AAL-5777-2020	Raghunath, Azhwar/0000-0001-5217-0341; Sundarraj, Kiruthika/0000-0003-4068-4534; Perumal, Ekambaram/0000-0003-2159-8198	Department of Science and Technology, Science and Engineering Research Board, New Delhi, under the scheme Empowerment and Equity Opportunities for Excellence in ScienceDepartment of Science & Technology (India)Department of Science & Technology (DOST), Philippines [SB/EMEQ-246/2014]; University Grants Commission - Basic Scientific Research Senior Research Fellowship (UGC-BSR-SRF) - UGC-BSR, New Delhi, India [F.7-25/2007]; UGC-SAP DRS, New Delhi, India [II:F-3-30/2013]; UGC-SAP DST, New Delhi, India [FIST:SR/FST/LSI-618/2014]	This work was supported by the Department of Science and Technology, Science and Engineering Research Board, New Delhi, under the scheme Empowerment and Equity Opportunities for Excellence in Science (SB/EMEQ-246/2014). Azhwar Raghunath is the recipient of a University Grants Commission - Basic Scientific Research Senior Research Fellowship (UGC-BSR-SRF - No. F.7-25/2007) funded by UGC-BSR, New Delhi, India. The authors also thank the UGC-SAP DRS II:F-3-30/2013 and DST FIST:SR/FST/LSI-618/2014, New Delhi, India for their partial financial assistance.	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Pharmacother.	JAN	2018	97						928	940		10.1016/j.biopha.2017.10.164			13	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	FR4NC	WOS:000419041300112	29136771				2022-04-25	
J	Choi, JH; Yoon, JS; Won, YW; Park, BB; Lee, YY				Choi, Jung-Hye; Yoon, Jin Sun; Won, Young-Woong; Park, Byeong-Bae; Lee, Young Yiul			Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration	APMIS			English	Article						Chloroquine; colon cancer; autophagy; 5-fluorouracil; cell cycle	AUTOPHAGY; P53; EXPRESSION; THERAPY; BIOLOGY; ASSAY	Autophagy is a conserved catabolic process that degrades cytoplasmic proteins and organelles for recycling. The role of autophagy in tumorigenesis is controversial because autophagy can be either protective or damaging to tumor cells, and its effects may change during tumor progression. A number of cancer cell lines have been exposed to chloroquine, an anti-malarial drug, with the aim of inhibiting cell growth and inducing cell death. In addition, chloroquine inhibits a late phase of autophagy. This study was conducted to investigate the anti-cancer effect of autophagy inhibition, using chloroquine together with 5-fluorouracil (5-FU) in a colon cancer cell line. Human colon cancer DLD-1 cells were treated with 5-FU (10 mu) or chloroquine (100 mu), or a combination of both. Autophagy was evaluated by western blot analysis of microtubule-associated protein light chain3 (LC3). Proliferative activity, alterations of the cell cycle, and apoptosis were measured by MTT assays, flow cytometry, and western blotting. LC3-II protein increased after treatment with 5-FU, and chloroquine potentiated the cytotoxicity of 5-FU. MTT assays showed that 5-FU inhibited proliferation of the DLD-1 cells and that chloroquine enhanced this inhibitory effect of 5-FU. The combination of 5-FU and chloroquine induced G1 arrest, up-regulation of p27 and p53, and down-regulation of CDK2 and cyclin D1. These results suggest that chloroquine may potentiate the anti-cancer effect of 5-FU via cell cycle inhibition. Chloroquine potentiates the anti-cancer effect of 5-FU in colon cancer cells. Supplementation of conventional chemotherapy with chloroquine may provide a new cancer therapy modality.	[Choi, Jung-Hye; Won, Young-Woong; Park, Byeong-Bae; Lee, Young Yiul] Hanyang Univ, Coll Med, Dept Internal Med, Seoul 133792, South Korea; [Yoon, Jin Sun; Lee, Young Yiul] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea		Lee, YY (corresponding author), Hanyang Univ, Coll Med, Dept Internal Med, 222 Wangsimni Ro Seongdong Gu, Seoul 133792, South Korea.	leeyy@hanyang.ac.kr	Park, Byeong-Bae/D-2137-2015; Park, Byeong Bae/P-4827-2015; Won, Young-Woong/C-9794-2015	Won, Young-Woong/0000-0001-6209-8339	research fund of Hanyang University [HY-2009-MC]	This work was supported by the research fund of Hanyang University (HY-2009-MC).	Aizu W, 2006, BIOCHEM PHARMACOL, V72, P981, DOI 10.1016/j.bcp.2006.07.009; CAMPLING BG, 1988, LEUKEMIA RES, V12, P823, DOI 10.1016/0145-2126(88)90036-7; Endo S, 2011, CANCER SCI, V102, P605, DOI 10.1111/j.1349-7006.2010.01821.x; Feng ZH, 2005, P NATL ACAD SCI USA, V102, P8204, DOI 10.1073/pnas.0502857102; Ju J, 2007, CLIN CANCER RES, V13, P4245, DOI 10.1158/1078-0432.CCR-06-2890; Klionsky DJ, 2008, AUTOPHAGY, V4, P151, DOI 10.4161/auto.5338; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Levine B, 2007, NATURE, V446, P745, DOI 10.1038/446745a; Li J, 2010, EUR J CANCER, V46, P1900, DOI 10.1016/j.ejca.2010.02.021; Loehberg CR, 2007, CANCER RES, V67, P12026, DOI 10.1158/0008-5472.CAN-07-3058; Meric-Bernstam F, 2009, J CLIN ONCOL, V27, P2278, DOI 10.1200/JCO.2008.20.0766; Pistollato F, 2010, BIOCHEM PHARMACOL, V80, P1517, DOI 10.1016/j.bcp.2010.08.003; Sasaki K, 2010, BMC CANCER, V10, DOI 10.1186/1471-2407-10-370; Sato K, 2007, CANCER RES, V67, P9677, DOI 10.1158/0008-5472.CAN-07-1462; Shintani T, 2004, SCIENCE, V306, P990, DOI 10.1126/science.1099993; Solomon VR, 2009, EUR J PHARMACOL, V625, P220, DOI 10.1016/j.ejphar.2009.06.063; Tanida Isei, 2008, V445, P77, DOI 10.1007/978-1-59745-157-4_4; VERMES I, 1995, J IMMUNOL METHODS, V184, P39, DOI 10.1016/0022-1759(95)00072-I; Yang ZF, 2010, NAT CELL BIOL, V12, P814, DOI 10.1038/ncb0910-814	20	34	39	1	9	WILEY-BLACKWELL	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0903-4641			APMIS	APMIS	JUL	2012	120	7					597	604		10.1111/j.1600-0463.2012.02876.x			8	Immunology; Microbiology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Microbiology; Pathology	961ZA	WOS:000305507000009	22716215	Bronze			2022-04-25	
J	Trivedi, PP; Jena, GB; Tikoo, KB; Kumar, V				Trivedi, P. P.; Jena, G. B.; Tikoo, K. B.; Kumar, V.			Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis	MOLECULAR CARCINOGENESIS			English	Article						colitis-associated colon carcinogenesis; autophagy; Nrf2; inflammation; oxidative stress; melatonin	NF-KAPPA-B; ERYTHROID 2-RELATED FACTOR-2; INDUCED ULCERATIVE-COLITIS; UNPHOSPHORYLATED STAT3; OXIDATIVE STRESS; COLORECTAL-CANCER; RAT; INHIBITION; 1,2-DIMETHYLHYDRAZINE; TRANSCRIPTION	Colon carcinogenesis is long known to be associated with ulcerative colitis (UC), a chronic gastrointestinal disorder. Various pre-clinical and clinical studies have shown that melatonin (MEL) has beneficial effects in cancer. However, elucidation of the detailed molecular mechanisms involved in MEL-mediated protection against the colon carcinogenesis deserves further investigation. The present study was aimed at deciphering the effect of MEL on autophagy and Nrf2 signaling pathways in a mouse model of colitis-associated colon carcinogenesis (CACC). For the induction of CACC, male Swiss Albino mice were administered a single ip injection of 20mg 1, 2-dimethylhydrazine dihydrochloride (DMH)/kg bw, followed by 3 cycles of 3% w/v dextran sulfate sodium (DSS) in drinking water treatment initiated 1wk after DMH injection. One week after the initiation of DSS treatment, MEL was administered at the dose of 1mg/kg, bw, po for 8 and 18 wk. Mice were sacrificed at 10 and 20wk after DMH injection. MEL treatment decreased the progression of CACC by down regulating the process of autophagy as revealed by the expression pattern of various autophagy markers such as Beclin-1, LC3B-II/LC3B-I ratio and p62. These findings were accompanied with the increased expression of Nrf2 and the associated antioxidant enzymes, NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase-1 (HO-1) in the colon of mice with CACC. MEL intervention reduced autophagy by ameliorating inflammation and oxidative stress in the colon of mice with CACC. We conclude that MEL treatment attenuates the progression of CACC in mice by modulating autophagy and Nrf2 signaling pathways. (c) 2015 Wiley Periodicals, Inc.	[Trivedi, P. P.; Jena, G. B.] Natl Inst Pharmaceut Educ & Res, Dept Pharmacol & Toxicol, Facil Risk Assessment & Intervent Studies, Mohali, Punjab, India; [Tikoo, K. B.] Natl Inst Pharmaceut Educ & Res, Dept Pharmacol & Toxicol, Lab Chromatin Biol, Mohali, Punjab, India; [Kumar, V.] Icon Analyt Equipment Pvt Ltd, Delhi, India		Jena, GB (corresponding author), Natl Inst Pharmaceut Educ & Res, Dept Pharmacol & Toxicol, Sect 67, Sas Nagar 160062, Punjab, India.			Tikoo, Kulbhushan/0000-0003-3061-9739	National Institute of Pharmaceutical Education and Research (NIPER), Mohali	We wish to acknowledge the financial assistance received from the National Institute of Pharmaceutical Education and Research (NIPER), Mohali to undertake the present study.	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Carcinog.	MAR	2016	55	3					255	267		10.1002/mc.22274			13	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	DD2BN	WOS:000369727500003	25598500				2022-04-25	
J	Motilva, V; Garcia-Maurino, S; Talero, E; Illanes, M				Motilva, Virginia; Garcia-Maurino, Sofia; Talero, Elena; Illanes, Matilde			New paradigms in chronic intestinal inflammation and colon cancer: role of melatonin	JOURNAL OF PINEAL RESEARCH			English	Review						autophagy; chronic inflammation; colitis; colon cancer; inflammatory bowel disease; melatonin; sirtuins	NF-KAPPA-B; ACID-INDUCED COLITIS; RESVERATROL SUPPRESSES COLITIS; CERULEIN-INDUCED PANCREATITIS; ENDOPLASMIC-RETICULUM STRESS; MURINE SENESCENCE MODEL; GENOME-WIDE ASSOCIATION; CLOCK GENE-EXPRESSION; TNBS-INDUCED COLITIS; BOWEL-DISEASE	In intestinal bowel disease (IBD), immune-mediated conditions exert their effects through various cells and proinflammatory mediators. Recent data support a participation of the endoplasmic reticulum stress and mitochondrial dysfunctions in IBD. Moreover, it is evident that chronic degenerative pathologies, including IBD, share comparable disease mechanisms with alteration in the autophagy mechanisms. Chronic inflammation in IBD exposes these patients to a number of signals known to have tumorigenic effects. This circuitry of inflammation and cancer modifies apoptosis and autophagy, and promotes cellular cycle progression, invasion, and angiogenesis. Melatonin has been shown as a specific antioxidant reducing oxidative damage in both lipid and aqueous cell environments. However, several studies provide further insight into the molecular mechanisms of melatonin action in the colon. In this line, recent data suggest that melatonin modulates autophagy and sirtuin activity. An anti-autophagic property of melatonin has been demonstrated, and it could contribute to its anti-oncogenic activity. Nevertheless, there is no information about whether antitumoral effects of melatonin on colon cancer are dependent on autophagy. Sirtuins have pleiotropic effects on cancer development, being reported both as facilitator and as suppressor of colon cancer development. Sirtuins and melatonin are connected through the circadian clock machinery, and melatonin seems able to correct the alterations in sirtuin activity associated with several pathological conditions. Autophagy and sirtuin activities are linked through 5'AMP-activated protein kinase (AMPK) activation, which switches on autophagy and increases sirtuin. The effect of melatonin on AMPK and the impact of this effect on IBD and colon cancer remain an open question.	[Motilva, Virginia] Univ Seville, Dept Pharmacol, Sch Pharm, E-41012 Seville, Spain; [Garcia-Maurino, Sofia] Univ Seville, Dept Vegetal Physiol & Ecol, E-41012 Seville, Spain; [Illanes, Matilde] Univ Seville, Dept Pathol Anat, E-41012 Seville, Spain		Motilva, V (corresponding author), Univ Seville, Dept Pharmacol, Sch Pharm, C Prof Garcia Gonzalez 2, E-41012 Seville, Spain.	motilva@us.es	García-Mauriño, Sofía/E-6707-2010; Talero, Elena/I-2613-2015	García-Mauriño, Sofía/0000-0002-7698-5112; Motilva Sanchez, Virginia/0000-0001-5674-6969; Talero Barrientos/0000-0001-9955-801X			Abreu Maria T, 2002, Curr Gastroenterol Rep, V4, P481, DOI 10.1007/s11894-002-0024-0; Aggarwal BB, 2006, BIOCHEM PHARMACOL, V72, P1605, DOI 10.1016/j.bcp.2006.06.029; Anisimov VN, 1997, CARCINOGENESIS, V18, P1549, DOI 10.1093/carcin/18.8.1549; Anisimov VN, 2000, EXP TOXICOL PATHOL, V52, P71, DOI 10.1016/S0940-2993(00)80022-6; Azad MB, 2009, ANTIOXID REDOX SIGN, V11, P777, DOI 10.1089/ARS.2008.2270; Back SH, 2006, J BIOL CHEM, V281, P18691, DOI 10.1074/jbc.M602030200; 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Pineal Res.	AUG	2011	51	1					44	60		10.1111/j.1600-079X.2011.00915.x			17	Endocrinology & Metabolism; Neurosciences; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Endocrinology & Metabolism; Neurosciences & Neurology; Physiology	791VA	WOS:000292693700003	21752096	Bronze			2022-04-25	
J	Shi, YS; Wang, JQ; Liu, JY; Lin, G; Xie, FF; Pang, X; Pei, YH; Cheng, Y; Zhang, Y; Lin, ZN; Yin, ZY; Wang, XM; Niu, G; Chen, XY; Liu, G				Shi, Yesi; Wang, Junqing; Liu, Jingyi; Lin, Gan; Xie, Fengfei; Pang, Xin; Pei, Yihua; Cheng, Yi; Zhang, Yang; Lin, Zhongning; Yin, Zhengyu; Wang, Xiaomin; Niu, Gang; Chen, Xiaoyuan; Liu, Gang			Oxidative stress-driven DR5 upregulation restores TRAIL/Apo2L sensitivity induced by iron oxide nanoparticles in colorectal cancer	BIOMATERIALS			English	Article						TRAIL/Apo2L; Iron oxide nanoparticle; ROS; Autophagy; DR5; Colorectal cancer	TRAIL-INDUCED APOPTOSIS; DEATH RECEPTOR 5; COLON-CANCER; MONOCLONAL-ANTIBODY; MEDIATED APOPTOSIS; PHASE-II; COMBINATION; LIGAND; RESISTANCE; CELLS	There exists an emergency clinical demand to overcome TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) resistance, which is a major obstacle attributed to insufficient level or mutation of TRAIL receptors. Here, we developed an iron oxide cluster-based nanoplatform for both sensitization and MR image-guided evaluation to improve TRAIL/Apo2L efficacy in colorectal cancer, which has an inadequate response to TRAIL/Apo2L or chemotherapy. Specifically, NanoTRAIL (TRAIL/Apo2L-iron oxide nanoparticles) generated ROS (reactive oxygen species)-triggered JNK (c-Jun N-terminal kinase) activation and induced subsequent autophagy-assisted DR5 upregulation, resulting in a significant enhanced antitumor efficacy of TRAIL/Apo2L, which confirmed in both TRAIL-resistant HT-29, intermediately resistant SW-480 and sensitive HCT-116 cells. Furthermore, in a subcutaneous colorectal cancer mouse model, the in vivo tumor retention of NanoTRAIL can be demonstrated by MR T-2 weighted contrast imaging, and NanoTRAIL significantly suppressed tumor growth and prolonged the survival time without observable adverse effects compared with control and TRAIL/Apo2L monotherapy. Importantly, in the study of colorectal cancer patient-derived xenograft models, we found that the NanoTRAIL treatment could significantly improve the survival outcome with consistent ROS-dependent autophagy-assisted DR5 upregulation and tumor apoptosis. Our results describe a transformative design that can be applied clinically to sensitize Apo2L/TRAIL-resistant patients using FDA-approved iron oxide nanoparticles.	[Shi, Yesi; Wang, Junqing; Liu, Jingyi; Lin, Gan; Xie, Fengfei; Pang, Xin; Cheng, Yi; Zhang, Yang; Lin, Zhongning; Liu, Gang] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China; [Shi, Yesi; Wang, Junqing; Liu, Jingyi; Lin, Gan; Xie, Fengfei; Pang, Xin; Cheng, Yi; Zhang, Yang; Lin, Zhongning; Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China; [Liu, Jingyi; Pei, Yihua; Yin, Zhengyu; Wang, Xiaomin] Xiamen Univ, Sch Med, Xiamen 361105, Peoples R China; [Pei, Yihua; Yin, Zhengyu; Wang, Xiaomin] Xiamen Univ, Zhongshan Hosp, Dept Gastroenterol, Xiamen 361004, Peoples R China; [Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA; [Liu, Gang] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Biol, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China; [Wang, Junqing] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510275, Peoples R China		Liu, G (corresponding author), Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China.; Liu, G (corresponding author), Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China.	gangliu.cmitm@xmu.edu.cn	Liu, Gang/AAC-4177-2020	Liu, Gang/0000-0003-2613-7286	Major State Basic Research Development Program of ChinaNational Basic Research Program of China [2017YFA0205201]; National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [81422023, 81925019, 81371596, 51273165, U1705281, U1505221]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [20720190088]; Natural Science Foundation of Fujian Province of ChinaNatural Science Foundation of Fujian Province [2018J05144]; Program for New Century Excellent Talents in University, ChinaProgram for New Century Excellent Talents in University (NCET) [NCET-13-0502]	Y.S., J.W., and J. L. contributed equally to this work. This work was supported by the Major State Basic Research Development Program of China (Grant No. 2017YFA0205201), the National Natural Science Foundation of China (NSFC) (Grant Nos. 81422023, 81925019, 81371596, 51273165, U1705281, and U1505221), the Fundamental Research Funds for the Central Universities (Grant No. 20720190088), Natural Science Foundation of Fujian Province of China (Grant No. 2018J05144), the Program for New Century Excellent Talents in University, China (NCET-13-0502).	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J	Coppola, D; Khalil, F; Eschrich, SA; Boulware, D; Yeatman, T; Wang, HG				Coppola, Domenico; Khalil, Farah; Eschrich, Steven A.; Boulware, David; Yeatman, Timothy; Wang, Hong-Gang			Down-regulation of Bax-interacting Factor-1 in Colorectal Adenocarcinoma	CANCER			English	Article						Bif-1; colon adenocarcinoma; microarray; immunohistochemistry	CONFORMATIONAL-CHANGE; COLON-CANCER; CELL-DEATH; AUTOPHAGY; PROTEIN; BIF-1; REGION; HETEROZYGOSITY; NEUROBLASTOMA; DYSFUNCTION	BACKGROUND. Bax-interacting factor-1 (Bif-1) protein is a member of the endophilin B family that plays a critical role in apoptosis, autophagy, and mitochondrial morphology. Loss of Bif-1 suppresses programmed cell death and promotes tumorigenesis. The connection of Bif-1 to colorectal cancer remains to be evaluated. METHODS. To determine Bif-1 expression in human colorectal adenocarcinoma (CRC), the authors performed immunohistochemistry using stage-oriented cancer tissue microarrays containing 102 CRC samples of different stages and 38 samples of normal colorectal mucosa (NR). Formalin-fixed, paraffin-embedded core sections on the tissue array were immunostained using the avidin-biotin-peroxidase method and the anti-Bif-1 murine monoclonal antibody Bif-1 staining was scored by 2 independent observers. To examine Bif-1 mRNA levels, the authors performed DNA microarray analysis of 205 CRC and 10 NR samples. RESULTS. Bif-1 expression was negative in 22.5% (23 of 102) of CRCs. Moderateto strong Bif-1 staining was identified in 36.3% (37 of 102) of the tumors, and weak staining was noted in 41.2% (42 of 102). Twenty-six of 38 (68.4%) NR samples exhibited moderate to strong Bif-1 immunoreactivity, and none of them was negative. In 12 (31.6%) cases NR demonstrated weak Bif-1 stain. The mean (median) scores for CRCs and NR differed significantly: 3.2 (3.0) and 5.2 (6.0), respectively (P = .0003). The percentage of cases with negative expression also differed significantly between NR and CRC (P = .002). Decreased Bif-1 expression in CRCs was confirmed at the mRNA level by microarray analysis. CONCLUSIONS. The authors report the down-regulation of Bif-1 during the transition from NR to CRC, a novel finding in agreement with the tumor suppressor function of Bif-1. Cancer 2008;113:2665-70. (C) 2008American Cancer Society.	[Coppola, Domenico; Khalil, Farah] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Anat Pathol, Tampa, FL 33612 USA; [Coppola, Domenico; Yeatman, Timothy] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Expt Therapeut, Tampa, FL 33612 USA; [Coppola, Domenico; Yeatman, Timothy] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Gastrointestinal Programs, Tampa, FL 33612 USA; [Eschrich, Steven A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Biostat, Tampa, FL 33612 USA; [Wang, Hong-Gang] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Drug Discovery Programs, Tampa, FL 33612 USA		Coppola, D (corresponding author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Anat Pathol, 12902 Magnolia Dr, Tampa, FL 33612 USA.	Domenico.Coppola@moffitt.org	Eschrich, Steven/K-6848-2013; Wang, Hong-Gang/A-3018-2015	Eschrich, Steven/0000-0002-9833-2788; Wang, Hong-Gang/0000-0003-0551-0571	American Cancer SocietyAmerican Cancer Society [RSG-05-244-01-CCG]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA82197]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA082197] Funding Source: NIH RePORTER	Supported in part by grants from American Cancer Society (RSG-05-244-01-CCG) and National Institutes of Health (CA82197) to H.-G.W.	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J	Du, C; Wang, X; Zhang, JL; Liu, XZ; Zhu, J; Liu, YC				Du, Chuang; Wang, Xin; Zhang, Junling; Liu, Xiangzheng; Zhu, Jing; Liu, Yucun			Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells	ONCOLOGY REPORTS			English	Article						paxillin; colorectal cancer; p-Erk; apoptosis; cetuximab resistance; clinicopathological factors	COLON-CANCER; EPITHELIAL MORPHOGENESIS; MOLECULAR-MECHANISMS; MONOCLONAL-ANTIBODY; ACQUIRED-RESISTANCE; 1ST-LINE TREATMENT; GROWTH; AUTOPHAGY; KRAS; PHOSPHORYLATION	Paxillin (PXN) encodes a 68-kDa focal adhesion-associated protein and plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the relationship between PXN and clinicopathological factors in colorectal cancer, the role of PXN in cetuximab resistance, and whether knockdown of PXN expression could improve the sensitivity to cetuximab in colorectal cancer cells. In the present study, immunohistochemical staining in 148 colorectal carcinoma and 126 normal adjacent tissues was performed, which showed that the positive rate of PXN was significantly higher in the colorectal adenocarcinoma samples than that in the normal colorectal mucosa samples (P<0.001). Moreover, PXN presence was also positively correlated with TNM stage (P=0.023), distant metastasis (P=0.014), recurrence (P=0.032) and reduced survival (P=0.004). In vitro, PXN expression was positively correlated with the proliferation rate in colorectal cells insensitive to cetuximab. Inhibition of PXN expression by PXN-siRNA clearly increased apoptosis by downregulating the phosphorylation of extracellular signal regulated kinase (p-Erk) level, and overexpression of PXN by PXN-cDNA decreased apoptosis by upregulating the p-Erk level. This suggests that overexpression of PXN could be one of the reasons for cetuximab resistance, and downregulation of PXN plays an important role in improving sensitivity to cetuximab by suppressing the activitation of p-Erk in colorectal cancer cells. Above all, knockdown of PXN could represent a rational therapeutic strategy for increasing the sensitivity or overcoming cetuximab-resistance in patients with colorectal cancer.	[Du, Chuang; Wang, Xin; Zhang, Junling; Zhu, Jing; Liu, Yucun] Peking Univ, Hosp 1, Dept Gen Surg, Beijing 100034, Peoples R China; [Liu, Xiangzheng] Peking Univ, Hosp 1, Dept Thorac Surg, Beijing 100034, Peoples R China		Wang, X (corresponding author), Peking Univ, Hosp 1, Dept Gen Surg, 8 Xishiku St, Beijing 100034, Peoples R China.	wangxin_guo@126.com	liu, xiangzheng/AAC-4183-2019				Bardelli A, 2010, J CLIN ONCOL, V28, P1254, DOI 10.1200/JCO.2009.24.6116; Brand TM, 2011, CANCER BIOL THER, V11, P777, DOI 10.4161/cbt.11.9.15050; Chen DL, 2013, CARCINOGENESIS, V34, P803, DOI 10.1093/carcin/bgs400; Chen MC, 2013, NEOPLASMA, V60, P561, DOI 10.4149/neo_2013_073; Coker-Gurkan A, 2015, AMINO ACIDS, V47, P87, DOI 10.1007/s00726-014-1851-7; De Roock W, 2010, LANCET ONCOL, V11, P753, DOI 10.1016/S1470-2045(10)70130-3; Galizia G, 2007, ONCOGENE, V26, P3654, DOI 10.1038/sj.onc.1210381; Guller MC, 2009, MOL CARCINOGEN, V48, P532, DOI 10.1002/mc.20492; Ishibe S, 2004, MOL CELL, V16, P257, DOI 10.1016/j.molcel.2004.10.006; Ishibe S, 2003, MOL CELL, V12, P1275, DOI 10.1016/S1097-2765(03)00406-4; Kumar Shalini Sree, 2014, Gastrointest Cancer Res, V7, P23; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Misale S, 2012, NATURE, V486, P532, DOI 10.1038/nature11156; Munshi N, 2000, J IMMUNOL, V164, P1169, DOI 10.4049/jimmunol.164.3.1169; Nishikawa T, 2010, ANN SURG ONCOL, V17, P592, DOI 10.1245/s10434-009-0696-x; Qin J, 2011, HEPATO-GASTROENTEROL, V58, P1951, DOI 10.5754/hge11352; Sen A, 2010, J BIOL CHEM, V285, P28787, DOI 10.1074/jbc.M110.134064; Shigeta K, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0066302; Sui XB, 2014, SCI REP-UK, V4, DOI 10.1038/srep04694; Teranishi S, 2009, INVEST OPHTH VIS SCI, V50, P5646, DOI 10.1167/iovs.08-2534; Therkildsen C, 2014, ACTA ONCOL, V53, P852, DOI 10.3109/0284186X.2014.895036; Troiani T, 2013, CLIN CANCER RES, V19, P6751, DOI 10.1158/1078-0432.CCR-13-0423; Turner CE, 2000, J CELL SCI, V113, P4139; Van Cutsem E, 2011, J CLIN ONCOL, V29, P2011, DOI 10.1200/JCO.2010.33.5091; Wu DW, 2014, ONCOGENE, V33, P4385, DOI 10.1038/onc.2013.389; Xiao LJ, 2014, ONCOL LETT, V7, P189; Yin HF, 2014, CHINESE MED J-PEKING, V127, P423, DOI 10.3760/cma.j.issn.0366-6999.20121360; Zhai H, 2013, ONCOGENE, V32, P1570, DOI 10.1038/onc.2012.167	28	10	10	0	2	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	JAN	2016	35	1					409	417		10.3892/or.2015.4352			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CY0BZ	WOS:000366072500049	26530439	Bronze			2022-04-25	
J	Zhu, SJ; Wu, Q; Zhang, B; Wei, HG; Li, B; Shi, W; Fang, M; Zhu, SZ; Wang, L; Zhou, YL; Dong, YL				Zhu, Shajun; Wu, Qiong; Zhang, Bo; Wei, Huagen; Li, Ben; Shi, Wei; Fang, Miao; Zhu, Shengze; Wang, Lei; Zhou, You Lang; Dong, Yulin			Autophagy-related gene expression classification defines three molecular subtypes with distinct clinical and microenvironment cell infiltration characteristics in colon cancer	INTERNATIONAL IMMUNOPHARMACOLOGY			English	Article						Autophagy; Molecular subtypes; Tumor microenvironment; Immunotherapy; Colon cancer	EXCLUSION; SURVIVAL; IMMUNITY; THERAPY	Background: Multiple molecular subtypes with distinct clinical outcomes in colon cancer have been identified in recent years. Nonetheless, the autophagy-related molecular subtypes as well as its mediated tumor microenvironment (TME) cell infiltration characteristics have not been fully understood. Methods: Based on the seven colon cancer cohorts with 1580 samples, we performed a comprehensive genomic analysis to explore the molecular subtypes mediated by autophagy-related genes. The single-sample gene-set enrichment analysis (ssGSEA) was used to quantify the relative abundance of each cell infiltration in the TME. Unsupervised methods were used to perform autophagy subtype clustering. Least absolute shrinkage and selection operator regression (LASSO) was used to construct autophagy characterization score (APCS) signature. Results: We determined three distinct autophagy-related molecular subtypes in colon cancer. The three autophagy subtypes presented significant survival differences. Microenvironment analyses revealed the heterogeneous TME immune cell infiltration characterization between three subtypes. Cluster 1 autophagy subtype was characterized by abundant innate and adaptive immune cell infiltration. This subtype exhibited an enhanced stromal activity including activated pathways of epithelial-mesenchymal transition, TGF-beta and angiogenesis, and an increased infiltration of fibroblasts and endothelial cells. The expression of immune checkpoint molecules was also significantly up-regulated, which may mediate immune escape in Cluster 1 subtype. Cluster 2 subtype was characterized by relatively lower TME immune cell infiltration and enhanced DNA damage repair pathways. Cluster 3 subtype was characterized by the suppression of immunity. Patients with high APCS, with poorer survival, presented a significantly positive correlation with TME stromal activity. Low APCS, relevant to activated damage repair pathways, showed enhanced responses to anti-PD-1/PD-L1 immunotherapy. Two immunotherapy cohorts confirmed patients with low APCS exhibited prominently enhanced clinical response and treatment advantages. Conclusions: This study may help understand the molecular characterization of autophagy-related subtypes. We demonstrated the autophagy genes in colon cancer could drive the heterogeneity of TME immune cell infiltration. Our study represented a step toward personalized immunotherapy in colon cancer.	[Zhu, Shajun; Wei, Huagen; Fang, Miao; Zhu, Shengze; Dong, Yulin] Nantong Univ, Med Sch, Nantong 226001, Jiangsu, Peoples R China; [Zhu, Shajun] Nantong Univ, Affiliated Hosp, Dept Hepatobiliary & Pancreat Surg, Nantong 226001, Peoples R China; [Wu, Qiong; Zhang, Bo; Shi, Wei; Zhou, You Lang] Nantong Univ, Affiliated Hosp, Res Ctr Clin Med, Nantong 226001, Jiangsu, Peoples R China; [Li, Ben] Nantong Univ, Affiliated Hosp, Dept Cardiothorac Surg, Nantong 226001, Jiangsu, Peoples R China; [Wang, Lei] Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200025, Peoples R China		Dong, YL (corresponding author), Nantong Univ, Med Sch, Nantong 226001, Jiangsu, Peoples R China.; Zhou, YL (corresponding author), Nantong Univ, Affiliated Hosp, Res Ctr Clin Med, Nantong 226001, Jiangsu, Peoples R China.; Wang, L (corresponding author), Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200025, Peoples R China.	dyldyl@ntu.edu.cn					Amaravadi R, 2016, GENE DEV, V30, P1913, DOI 10.1101/gad.287524.116; Barbie DA, 2009, NATURE, V462, P108, DOI 10.1038/nature08460; Casey SC, 2016, SCIENCE, V352, P227, DOI 10.1126/science.aac9935; Chen DS, 2017, NATURE, V541, P321, DOI 10.1038/nature21349; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; Fitzwalter BE, 2018, DEV CELL, V44, P555, DOI 10.1016/j.devcel.2018.02.014; Gafar AA, 2016, PEERJ, V4, DOI 10.7717/peerj.2445; Gao JB, 2010, NEURAL NETWORKS, V23, P257, DOI 10.1016/j.neunet.2009.07.001; Gautier L, 2004, BIOINFORMATICS, V20, P307, DOI 10.1093/bioinformatics/btg405; Gurkan AC, 2018, CELL ONCOL, V41, P297, DOI 10.1007/s13402-017-0369-x; Hanzelmann S, 2013, BMC BIOINFORMATICS, V14, DOI 10.1186/1471-2105-14-7; Hartigan J. 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Immunopharmacol.	OCT	2020	87								106757	10.1016/j.intimp.2020.106757			12	Immunology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Pharmacology & Pharmacy	NU3QG	WOS:000573556600004	32769067				2022-04-25	
J	Tan, SS; Peng, XC; Peng, W; Zhao, YL; Wei, YQ				Tan, Shisheng; Peng, Xingchen; Peng, Wen; Zhao, Yinglan; Wei, Yuquan			Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer	ONCOLOGY LETTERS			English	Article						colon cancer; autophagy; apoptosis; chemotherapy; mouse; combination	STAGE-II; AUTOPHAGY; FLUOROURACIL; LEUCOVORIN; INHIBITION; 5-FLUOROURACIL; PATTERNS; MODEL	Oxaliplatin (OX) has been widely used in adjuvant and palliative treatments of advanced colon cancer; however, cancer cells ultimately become resistant in the majority of cases. Therefore, the development of a novel strategy to overcome this resistance is important for the effective treatment of colon cancer; Cell autophagy reduces the sensitivity of cancer cells to therapeutic reagents in various types of human cancer; therefore, the present study used murine CT26 colon carcinoma cells to explore whether inhibition of autophagy by 3-methyladenine (3-MA) is able to enhance OX-induced apoptosis in vitro and OX-suppressed tumor growth in vivo. CT26 cells were treated with 3-MA, OX, or 3-MA plus OX, and the autophagy, apoptosis and proliferation of the CT26 cells was investigated. Additionally, the therapeutic efficiency of the combination of 3-MA and OX treatment was evaluated in vivo by determining the survival time of the tumor-bearing mice and, thus, tumor growth rate. The treatment of CT26 cells in vitro with OX alone increased autophagy as well as apoptosis, whereas treatment with 3-MA plus OX markedly inhibited OX-induced autophagy, but increased OX-induced cell apoptosis. Furthermore, the combination of OX and 3-MA treatment significantly suppressed tumor growth in vivo and prolonged mouse survival time when compared with OX treatment alone. Similarly, 3-MA increased OX-induced cell apoptosis and decreased autophagy in xenograft tumor tissues. Thus, the administration of 3-MA may increase tumor cell sensitivity to OX by reducing its autophagic effects and enhancing its apoptotic effects. Data obtained in the present study indicates that the clinical combination of an autophagy inhibitor with OX may increase the therapeutic effect of OX and improve the clinical outcome of patients with colon cancer.	[Tan, Shisheng; Peng, Xingchen; Zhao, Yinglan; Wei, Yuquan] Sichuan Univ, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China; [Tan, Shisheng; Peng, Xingchen; Zhao, Yinglan; Wei, Yuquan] Sichuan Univ, West China Hosp, West China Med Sch, Ctr Canc, Chengdu 610041, Sichuan, Peoples R China; [Tan, Shisheng; Peng, Wen] Guizhou Prov Peoples Hosp, Dept Oncol, Guiyang 550002, Guizhou, Peoples R China		Zhao, YL (corresponding author), Sichuan Univ, State Key Lab Biotherapy, 17 Renmin Rd, Chengdu 610041, Sichuan, Peoples R China.	yinglanzhao1@sina.com; yuquanwei1@sina.com		Peng, Xingchen/0000-0001-7042-718X			Alcindor T, 2011, CURR ONCOL, V18, P18; Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Andre T, 2009, J CLIN ONCOL, V27, P3109, DOI 10.1200/JCO.2008.20.6771; Bijnsdorp IV, 2010, INT J CANCER, V126, P2457, DOI 10.1002/ijc.24943; Bleiberg H, 1998, BRIT J CANCER, V77, P1, DOI 10.1038/bjc.1998.427; Chen SN, 2010, BBA-REV CANCER, V1806, P220, DOI 10.1016/j.bbcan.2010.07.003; Dahan L, 2009, BRIT J PHARMACOL, V158, P610, DOI 10.1111/j.1476-5381.2009.00341.x; de Gramont A, 2000, J CLIN ONCOL, V18, P2938, DOI 10.1200/JCO.2000.18.16.2938; Giatromanolaki A, 2013, COLORECTAL DIS, V15, pE223, DOI 10.1111/codi.12147; Giatromanolaki A, 2010, J CLIN PATHOL, V63, P867, DOI 10.1136/jcp.2010.079525; He G, 2014, TUMOR BIOL, V35, P1003, DOI 10.1007/s13277-013-1134-z; Holohan C, 2013, NAT REV CANCER, V13, P714, DOI 10.1038/nrc3599; Howells LM, 2011, INT J CANCER, V129, P476, DOI 10.1002/ijc.25670; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Koukourakis MI, 2010, BRIT J CANCER, V103, P1209, DOI 10.1038/sj.bjc.6605904; Kuebler JP, 2007, J CLIN ONCOL, V25, P2198, DOI 10.1200/JCO.2006.08.2974; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Romano S, 2010, CELL DEATH DIFFER, V17, P145, DOI 10.1038/cdd.2009.115; Sasaki K, 2010, BMC CANCER, V10, DOI 10.1186/1471-2407-10-370; Shi W, 2009, J MOL MED, V87, P493, DOI 10.1007/s00109-009-0444-5; Shi Y, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0051076; Siegel RL, 2015, CA-CANCER J CLIN, V65, P5, DOI [10.3322/caac.21254, 10.3322/caac.21208, 10.1001/jamaoto.2014.2530, 10.1136/bmj.g1502]; Torre LA, 2015, CA CANC J CLIN; White E, 2012, NAT REV CANCER, V12, P401, DOI 10.1038/nrc3262; Xu Y, 2012, CANCER LETT, V314, P232, DOI 10.1016/j.canlet.2011.09.034	25	27	30	0	10	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-1074	1792-1082		ONCOL LETT	Oncol. Lett.	MAY	2015	9	5					2056	2062		10.3892/ol.2015.2996			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CH2IW	WOS:000353849900014	26137012	Green Submitted, gold, Green Published			2022-04-25	
J	Bhardwaj, M; Paul, S; Jakhar, R; Khan, I; Kang, JI; Kim, HM; Yun, JW; Lee, SJ; Cho, HJ; Lee, HG; Kang, SC				Bhardwaj, Monika; Paul, Souren; Jakhar, Rekha; Khan, Imran; Kang, Ji In; Kim, Ho Min; Yun, Jong Won; Lee, Seon-Jin; Cho, Hee Jun; Lee, Hee Gu; Kang, Sun Chul			Vitexin confers HSF-1 mediated autophagic cell death by activating JNK and ApoL1 in colorectal carcinoma cells	ONCOTARGET			English	Article						vitexin; HSF-1; ApoL1; autophagic cell death; colorectal carcinoma	HEAT-SHOCK FACTOR-1; TRANSCRIPTION FACTOR-1; SIGNALING PATHWAY; DNA-BINDING; ANTIOXIDANT ACTIVITIES; POTENTIAL ROLE; TUMOR-GROWTH; APOPTOSIS; PHOSPHORYLATION; PROTEIN	Heat shock transcription factor-1 (HSF-1) guards the cancerous cells proteome against the alterations in protein homeostasis generated by their hostile tumor microenvironment. Contrasting with the classical induction of heat shock proteins, the pro-oncogenic activities of HSF-1 remains to be explored. Therefore, cancer's fragile proteostatic pathway governed by HSF-1 could be a potential therapeutic target and novel biomarker by natural compounds. Vitexin, a natural flavonoid has been documented as a potent anti-tumor agent on various cell lines. However, in the present study, when human colorectal carcinoma HCT-116 cells were exposed to vitexin, the induction of HSF-1 downstream target proteins, such as heat shock proteins were suppressed. We identified HSF-1 as a potential molecular target of vitexin that interact with DNA-binding domain of HSF-1, which inhibited HSF-1 oligomerization and activation (in silico). Consequently, HSF-1 hyperphosphorylation mediated by JNK operation causes transcriptional inactivation of HSF-1, and supported ROS-mediated autophagy induction. Interestingly, in HSF-1 immunoprecipitated and silenced HCT-116 cells, co-expression of apolipoprotein 1 (ApoL1) and JNK was observed which promoted the caspase independent autophagic cell death accompanied by p62 downregulation and increased LC3-I to LC3-II conversion. Finally, in vivo findings confirmed that vitexin suppressed tumor growth through activation of autophagic cascade in HCT-116 xenograft model. Taken together, our study insights a probable novel association between HSF-1 and ApoL-1 was established in this study, which supports HSF-1 as a potential target of vitexin to improve treatment outcome in colorectal cancer.	[Bhardwaj, Monika; Paul, Souren; Jakhar, Rekha; Khan, Imran; Yun, Jong Won; Kang, Sun Chul] Daegu Univ, Dept Biotechnol, Kyongsan, Kyoungbook, South Korea; [Kang, Ji In; Kim, Ho Min] Korea Adv Inst Sci & Technol, GSMSE, Dis Mol Biochem Lab, Daejeon, South Korea; [Lee, Seon-Jin; Cho, Hee Jun; Lee, Hee Gu] Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, Daejeon, South Korea; [Lee, Seon-Jin; Lee, Hee Gu] UST, Dept Biomol Sci, Daejeon, South Korea		Kang, SC (corresponding author), Daegu Univ, Dept Biotechnol, Kyongsan, Kyoungbook, South Korea.; Lee, HG (corresponding author), Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, Daejeon, South Korea.; Lee, HG (corresponding author), UST, Dept Biomol Sci, Daejeon, South Korea.	hglee@kribb.re.kr; sckang@daegu.ac.kr	Kim, Ho Min/G-2712-2011; Lee, Seon-Jin/AAJ-8258-2020	Lee, Seon-Jin/0000-0001-7214-7536	NRF (National Research Foundation of South Korea) [2016R1A2B4009227, 2017R1A2B2005629]	This research was funded by NRF (National Research Foundation of South Korea)-2016R1A2B4009227 and 2017R1A2B2005629.	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J	Talero, E; Avila-Roman, J; Motilva, V				Talero, Elena; Avila-Roman, Javier; Motilva, Virginia			Chemoprevention with Phytonutrients and Microalgae Products in Chronic Inflammation and Colon Cancer	CURRENT PHARMACEUTICAL DESIGN			English	Review						Gut; immunology; chronic inflammation; colon cancer; inflammatory bowel disease; chemoprevention; phytonutrients; microalgae	NF-KAPPA-B; ABERRANT CRYPT FOCI; DEXTRAN SULFATE SODIUM; POLYUNSATURATED FATTY-ACIDS; ACTIVATED RECEPTOR-GAMMA; INDUCED COLORECTAL CARCINOGENESIS; RESVERATROL SUPPRESSES COLITIS; EPITHELIAL-CELL PROLIFERATION; ENDOPLASMIC-RETICULUM STRESS; CURCUMIN-INDUCED APOPTOSIS	Inflammatory bowel disease (IBD) is a chronic inflammatory disorder caused by deregulated immune responses in a genetically predisposed individual. This is a complex process mediated by cytokines, chemokines, adhesion molecules, cytoplasm nuclear receptors, among others. Recent data support a participation of the endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in IBD. Moreover, now it is evident that chronic degenerative pathologies, including IBD, share comparable disease mechanisms at the cellular level with alteration of the autophagy mechanisms. Mounting evidence suggests that the risk of developing colorectal cancer (CRC) is dramatically increased in patients with chronic inflammatory disease. Chronic inflammation in IBD exposes these patients to a number of signals known to have tumorigenic effects including nuclear factor kappa B (NF-kappa B) activation, proinflammatory cytokines and prostaglandins release and reactive oxygen species (ROS) production. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing, or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon cancer chemopreventive properties of phytochemicals derived from both plants (curcumin, resveratrol, epigallocatechin gallate, quercetin or genistein) and substances from marine environment, including microalgae species and their products. This review summarizes the mechanisms by which these naturally occurring compounds may mediate chemopreventive effects on cancer. These actions include induction of cell cycle arrest and apoptosis, inhibition of cell proliferation, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.	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Pharm. Design	SEP	2012	18	26					3939	3965		10.2174/138161212802083725			27	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	993OV	WOS:000307870100008	22632755				2022-04-25	
J	Yang, HL; Liu, HW; Shrestha, S; Thiyagarajan, V; Huang, HC; Hseu, YC				Yang, Hsin-Ling; Liu, Hui-Wen; Shrestha, Sirjana; Thiyagarajan, Varadharajan; Huang, Hui-Chi; Hseu, You-Cheng			Antrodia salmonea induces apoptosis and enhances cytoprotective autophagy in colon cancer cells	AGING-US			English	Article						Antrodia salmonea; colon cancer; apoptosis; autophagy; ROS	OXYGEN SPECIES ROS; CYCLE ARREST; IN-VITRO; MECHANISMS; INHIBITION; ACTIVATION; 5-FLUOROURACIL; AZOXYMETHANE; PROGRESSION; INDUCTION	A traditional Chinese medicinal fungus, Antrodia salmonea (AS), with antioxidant properties is familiar in Taiwan but anti-cancer activity of AS in human colon cancer is ambiguous. Hence, we explored the anti-cancer activity of AS in colon cancer cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that AS showed a remarkable effect on cell viability in colon cancer cells; SW620, HCT116, and HT29. Annexin V/propidium iodide (PI) stained cells indicated that AS induced both early/late apoptosis in SW620 cells. Additionally, cells treated with AS induced caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, mitochondrial dysfunction, and Bcl-2 associated X (Bax)/B-cell lymphoma (Bcl-2) dysregulation. Microtubule- associated protein 1A/1B-light chain 3B (LC3-II) accumulation, sequestosome 1 (p62/SQSTM1) activation, autophagy related 4B cysteine peptidase (ATG4B) inactivation, acidic vesicular organelles (AVOs) formation, and Beclin-1/Bcl-2 dysregulation revealed that AS-induced autophagy. Interestingly, cells pretreated with 3-methyladenine (3-MA) strengthened AS-induced caspase-3/apoptosis. Suppression of apoptosis by z-Val-Ala-Asp fluoromethyl ketone (Z-VAD-FMK) did not however block AS-induced autophagy, suggesting that autophagy was not attenuated by the AS-induced apoptosis. Application of N-acetylcysteine (NAC) prevented AS-induced cell death, caspase-3 activation, LC3-II accumulation, and AVOs formation, indicating that AS-induced apoptosis and autophagy was mediated by reactive oxygen species (ROS). Furthermore, AS-induced cytoprotective autophagy and apoptosis through extracellular signal-regulated kinase (ERK) signaling cascades. Moreover, in vivo data disclosed that AS inhibited colitis-associated tumorigenesis in azoxymethane (AOM)-dextran sodium sulphate (DSS)-treated mice. For the first time, we report the anti-cancer properties of this potentially advantageous mushroom for the treatment of human colon cancer.	[Yang, Hsin-Ling; Liu, Hui-Wen; Shrestha, Sirjana] China Med Univ, Coll Hlth Care, Inst Nutr, Taichung 40402, Taiwan; [Huang, Hui-Chi] China Med Univ, Coll Chinese Med, Dept Chinese Pharmaceut Sci & Chinese Med Resourc, Taichung 40402, Taiwan; [Thiyagarajan, Varadharajan; Hseu, You-Cheng] China Med Univ, Coll Pharm, Dept Cosmeceut, Taichung 40402, Taiwan; [Hseu, You-Cheng] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 41354, Taiwan; [Hseu, You-Cheng] China Med Univ, Chinese Med Res Ctr, Taichung 40402, Taiwan		Hseu, YC (corresponding author), China Med Univ, Coll Pharm, Dept Cosmeceut, Taichung 40402, Taiwan.; Hseu, YC (corresponding author), Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 41354, Taiwan.; Hseu, YC (corresponding author), China Med Univ, Chinese Med Res Ctr, Taichung 40402, Taiwan.	ychseu@mail.qmu.edu.tw	K.J., Senthil Kumar/F-5309-2011		Ministry of Science and Technology [MOST-109-2320-B-039-057-MY3, MOST-107-2320-B-039-013-MY3]; China Medical University, TaiwanChina Medical University [CMU107-TU-12, CMU108MF-19, CMU108-MF-80]; Taiwan and Chinese Medicine Research Center, China Medical University from the "Featured Areas Research Center Program" within the Ministry of Education (MOE) [CMRC-CHM-1]; Asia University	This research is funded by Ministry of Science and Technology (MOST-109-2320-B-039-057-MY3 and MOST-107-2320-B-039-013-MY3), Asia University, China Medical University (CMU107-TU-12, CMU108MF-19 and CMU108-MF-80), Taiwan and Chinese Medicine Research Center, China Medical University from the "Featured Areas Research Center Program" within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) funded this study (CMRC-CHM-1).	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J	Lian, GH; Li, FJ; Yin, YN; Chen, LL; Yang, JW				Lian, Guanghui; Li, Fujun; Yin, Yani; Chen, Linlin; Yang, Junwen			Herbal extract of Artemisia vulgaris (mugwort) induces antitumor effects in HCT-15 human colon cancer cells via autophagy induction, cell migration suppression and loss of mitochondrial membrane potential	JOURNAL OF BUON			English	Article						Artemisia vulgaris; autophagy; colon cancer; ROS	APOPTOSIS	Purpose: Artemisia vulgaris (A. vulgaris) belonging to family Compositae, commonly known as mugwort, has been used as a medicinal herb in Chinese traditional medicine for treatment of diseases. Studies have reported a diversity of activities for this plant which include antiseptic, antispasmodic, antigastric, anticancer and nervous system diseases. However, the anticancer activity of A. vulgaris in HCT-15 human colon cancer cells has not been scientifically validated. Therefore the present study aimed at evaluating the anticancer activity of methanolic extract of A. vulgaris against HCT-15 human colon cancer cell line. Methods: Cell cytotoxicity effects of the extract were evaluated by MTT cell viability assay, while clonogenic assay assessed the effects on cancer cell colony formation. Effects on reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) were evaluated by flow cytometry. In vitro wound healing assay was used to evaluate the effects on cell migration. To confirm autophagy, we evaluated the expression of several autophagy-associated proteins using Western blot assay. Results: Results indicated that the methanolic extract of A. vulgaris exhibited an IC50 value of 50 mu g/ml and exerted its cytotoxic effects in a dose-dependent manner. Moreover, it was observed that the extract inhibits colony formation and induces autophagy dose-dependently. The underlying mechanism for the induction of autophagy was found to be ROS-mediated MMP and significant inhibition of cell migration potential of colon cancer cells at the IC50 was observed. Conclusion: These results strongly stress that the methanolic extract may prove a source for the isolation of novel anticancer lead molecules for the management of colon cancer.	[Lian, Guanghui; Li, Fujun; Yin, Yani; Chen, Linlin; Yang, Junwen] Cent S Univ, Xiangya Hosp, Dept Gastroenterol, Changsha 410008, Hunan, Peoples R China		Yang, JW (corresponding author), Cent S Univ, Xiangya Hosp, Dept Gastroenterol, Changsha 410008, Hunan, Peoples R China.	junwenyang999@yahoo.com		Chen, Linlin/0000-0001-6560-126X			Azuma M, 2003, ORAL ONCOL, V39, P282, DOI 10.1016/S1368-8375(02)00116-1; Baba SA, 2015, S AFR J BOT, V99, P80, DOI 10.1016/j.sajb.2015.03.194; Bora KS, 2011, PHARM BIOL, V49, P101, DOI 10.3109/13880209.2010.497815; Chopra RN, 1956, GLOSSARY INDIAN MED, V26, P2; Ding HM, 2009, NUTR CANCER, V61, P348, DOI 10.1080/01635580802567158; FEARON ER, 1990, CELL, V61, P759, DOI 10.1016/0092-8674(90)90186-I; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; HISSIN PJ, 1976, ANAL BIOCHEM, V74, P214, DOI 10.1016/0003-2697(76)90326-2; Husain A., 2016, ADV BIOMED PHARM, V3, P227, DOI DOI 10.19046/ABP.V03I04.07; Khursheed A, 2016, ADV BIOMED PHARM, V3, P245, DOI [10.19046/abp.v03i04.08, DOI 10.19046/abp.v03i04.08, 10.19046/ abp.v03i04.08, DOI 10.19046/ABP.V03I04.08]; Kowaltowski AJ, 2009, FREE RADICAL BIO MED, V47, P333, DOI 10.1016/j.freeradbiomed.2009.05.004; Narwaria A, 1994, EXPT STUDIES ARTEMIS, V14, P10; Rejiya CS, 2009, TOXICOL IN VITRO, V23, P1034, DOI 10.1016/j.tiv.2009.06.010; Shoemaker RH, 2006, NAT REV CANCER, V6, P813, DOI 10.1038/nrc1951; Sreelatha S, 2011, FOOD CHEM TOXICOL, V49, P1270, DOI 10.1016/j.fct.2011.03.006; Yadav J. P., 2010, International Journal of Green Pharmacy, V4, P140	16	14	14	0	2	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	JAN-FEB	2018	23	1					73	78					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GB0TZ	WOS:000428762100013	29552763				2022-04-25	
J	Qased, A; Yi, HQ; Liang, N; Ma, SM; Qiao, SX; Liu, XD				Qased, Abu Baker; Yi, Heqing; Liang, Nan; Ma, Shumei; Qiao, Shixing; Liu, Xiaodong			MicroRNA-18a upregulates autophagy and ataxia telangiectasia mutated gene expression in HCT116 colon cancer cells	MOLECULAR MEDICINE REPORTS			English	Article						ataxia telangiectasia mutated; miR-18a; autophagy; ionizing radiation; colon cancer	MIR-17-92 CLUSTER; ATM; TARGET; DAMAGE; MIR-21	Autophagy is an evolutionarily conserved, multi-step lysosomal degradation process in which a cell degrades its own long-lived proteins and damaged organelles. Ataxia telangiectasia mutated (ATM) has recently been shown to upregulate the process of autophagy. Previous studies showed that certain microRNAs, including miR-18a, potentially regulate ATM in cancer cells. However, the mechanisms behind the modulation of ATM by miR-18a remain to be elucidated in colon cancer cells. In the present study, we explored the impact of miR-18a on the autophagy process and ATM expression in HCT116 colon cancer cells. To determine whether a preliminary link exists between autophagy and miR-18a, HCT116 cells were irradiated and quantitative (q) PCR was performed to measure miR-18a expression. HCT116 cells were transfected with an miR-18a mimic to study its impact on indicators of autophagy. Western blotting and luciferase assays were implemented to explore the impact of miR-18a on ATM gene expression in HCT116 cells. The results showed that miR-18a expression was strongly stimulated by radiation. Ectopic overexpression of miR-18a in HCT116 cell lines potently enhanced autophagy and ionizing radiation-induced autophagy. Moreover, miR-18a overexpression led to the upregulation of ATM expression and suppression of mTORC1 activity. Results of the present study pertaining to the role of miR-18a in regulating autophagy and ATM gene expression in colon cancer cells revealed a novel function for miR-18a in a critical cellular event and on a crucial gene with significant impacts in cancer development, progression, treatment and in other diseases.	[Qased, Abu Baker; Qiao, Shixing] Jilin Univ, Dept Surg, Hosp 2, Changchun 130041, Jilin, Peoples R China; [Yi, Heqing; Liang, Nan; Ma, Shumei; Liu, Xiaodong] Jilin Univ, Key Lab Radiobiol, Minist Hlth, Sch Publ Hlth, Changchun 130021, Jilin, Peoples R China; [Qased, Abu Baker] Univ Mosul, Dept Surg, Coll Med, Mosul, Iraq		Qiao, SX (corresponding author), Jilin Univ, Dept Surg, Hosp 2, 218 Ziqiang St, Changchun 130041, Jilin, Peoples R China.	shixingqiaojdey@yahoo.com; liuxiaod@jlu.edu.cn	Liu, Xiaodong/R-5861-2019		NSFCNational Natural Science Foundation of China (NSFC) [30770649, 30970682]; Research Fund for the Doctoral Program of Higher Education of ChinaResearch Fund for the Doctoral Program of Higher Education of China (RFDP)Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) [20100061110070]	The authors would like to thank Dr Yin-Yuan Mo (Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA) for providing them with a (pCDHCMV-MCS-EF1-copGFP) lenti-vector. They are also grateful to Mr. Song Zhiheng for his technical assistance. This study was sponsored by an NSFC grant (30770649, 30970682) and the Research Fund for the Doctoral Program of Higher Education of China (20100061110070).	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Med. Rep.	FEB	2013	7	2					559	564		10.3892/mmr.2012.1214			6	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	073TB	WOS:000313764300037	23229340	Bronze			2022-04-25	
J	Li, SY; Yang, G; Zhu, XS; Cheng, L; Sun, YY; Zhao, ZX				Li, Siying; Yang, Guang; Zhu, Xiaosong; Cheng, Lin; Sun, Yueyue; Zhao, Zhongxi			Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway	ONCOLOGY REPORTS			English	Article						rapamycin; S-allylmercaptocysteine; autophagy; Nrf2; colorectal cancer; p62	SIGNALING PATHWAY; MAMMALIAN TARGET; DUAL ROLES; L-CYSTEINE; MTOR; NRF2; RESISTANCE	The natural plant-derived product S-allylmercaptocysteine (SAMC) has been studied in cancer therapy as a single and combination chemotherapeutic agent. The present study was employed to verify the combination use of SAMC and rapamycin that is the mTOR inhibitor with anticancer ability but has limited efficacy due to drug resistance, and to explore the underlying mechanisms. We combined rapamycin and SAMC for colorectal cancer treatment in the HCT-116 cancer cells and a xenograft murine model. The in vivo study was established by xenografting HCT-116 cells in BALB/c nude mice. It was found that the combination therapy had enhanced tumor-suppressing ability with the upregulation of the Bax/Bcl-2 ratio as a consequence of activated apoptosis, inhibition of autophagic activity and prevention of Akt phosphorylation. The rapamycin and SAMC combination activated antioxidant transcription expressions of Nrf2 and downstream gene NQO1. Concomitantly, autophagosome cargo p62 was downregulated, indicating that the p62 played a negative-regulatory role between Nrf2 and autophagy. Our results show that the combination of SAMC and rapamycin enhanced the anticancer ability, which could be used for the treatment of colorectal cancer. The underling mechanism of autophagy/p62/Nrf2 pathway discovered may provide a new direction for drug development, especially for traditional Chinese medicines.	[Li, Siying; Zhu, Xiaosong; Sun, Yueyue; Zhao, Zhongxi] Shandong Univ, Sch Pharmaceut Sci, 44 West Wenhua Rd, Jinan 250012, Shandong, Peoples R China; [Yang, Guang] Shandong Univ, Dept Joint Surg, Shandong Prov Hosp, Jinan 250021, Shandong, Peoples R China; [Cheng, Lin] Heze Municipal Hosp, Dept Endocrinol, Heze 274000, Shandong, Peoples R China		Zhao, ZX (corresponding author), Shandong Univ, Sch Pharmaceut Sci, 44 West Wenhua Rd, Jinan 250012, Shandong, Peoples R China.	zxzhao@sdu.edu.cn			National 'Major Science and Technology Project-Prevention and Treatment of AIDS, Viral Hepatitis, and Other Major Infectious Diseases' [2013ZX10005004]; Major Project of Science and Technology of Shandong Province [2015ZDJS04001]; Science and Technology Enterprise Technology Innovation Fund of Jiangsu Province [BC2014172]; Small and Medium Enterprise Technology Innovation Project of Lianyungang City [CK1333]	This study was supported by the funds from National 'Major Science and Technology Project-Prevention and Treatment of AIDS, Viral Hepatitis, and Other Major Infectious Diseases' (grant no. 2013ZX10005004), Major Project of Science and Technology of Shandong Province (grant no. 2015ZDJS04001), Science and Technology Enterprise Technology Innovation Fund of Jiangsu Province (grant no. BC2014172), Small and Medium Enterprise Technology Innovation Project of Lianyungang City (grant no. CK1333).	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Rep.	SEP	2017	38	3					1637	1644		10.3892/or.2017.5849			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FB7CM	WOS:000406298700034	28737825	Bronze			2022-04-25	
J	Fujiya, M; Konishi, H; Kamel, MKM; Ueno, N; Inaba, Y; Moriichi, K; Tanabe, H; Ikuta, K; Ohtake, T; Kohgo, Y				Fujiya, M.; Konishi, H.; Kamel, M. K. Mohamed; Ueno, N.; Inaba, Y.; Moriichi, K.; Tanabe, H.; Ikuta, K.; Ohtake, T.; Kohgo, Y.			microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1	ONCOGENE			English	Article						microRNAs; heterogeneous nuclear ribonucleoproteins; colon cancer; apoptosis; autophagy; ubiquitin	POSTTRANSCRIPTIONAL REGULATION; COLORECTAL-CANCER; NONCODING RNAS; C-ELEGANS; GENE; MUTATIONS; RAS; EXPRESSION; PROLIFERATION; TUMORIGENESIS	It is well known that microRNAs (miRs) are abnormally expressed in various cancers and target the messenger RNAs (mRNAs) of cancer-associated genes. While (miRs) are abnormally expressed in various cancers, whether miRs directly target oncogenic proteins is unknown. The present study investigated the inhibitory effects of miR-18a on colon cancer progression, which was considered to be mediated through its direct binding and degradation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). An MTT assay and xenograft model demonstrated that the transfection of miR-18a induced apoptosis in SW620 cells. A binding assay revealed direct binding between miR-18a and hnRNP A1 in the cytoplasm of SW620 cells, which inhibited the oncogenic functions of hnRNP A1. A competitor RNA, which included the complementary sequence of the region of the miR-18a-hnRNP A1 binding site, repressed the effects of miR-18a on the induction of cancer cell apoptosis. In vitro single and in vivo double isotope assays demonstrated that miR-18a induced the degradation of hnRNP A1. An immunocytochemical study of hnRNP A1 and LC3-II and the inhibition of autophagy by 3-methyladenine and ATG7, p62 and BAG3 siRNA showed that miR-18a and hnRNP A1 formed a complex that was degraded through the autophagolysosomal pathway. This is the first report showing a novel function of a miR in the autophagolysosomal degradation of an oncogenic protein resulting from the creation of a complex consisting of the miR and a RNA-binding protein, which suppressed cancer progression.	[Fujiya, M.; Konishi, H.; Kamel, M. K. Mohamed; Ueno, N.; Inaba, Y.; Moriichi, K.; Tanabe, H.; Ikuta, K.; Ohtake, T.; Kohgo, Y.] Asahikawa Med Coll, Dept Med, Div Gastroenterol & Hematol Oncol, Asahikawa, Hokkaido 0788510, Japan		Fujiya, M (corresponding author), Asahikawa Med Coll, Dept Med, Div Gastroenterol & Hematol Oncol, 2-1 Midorigaoka Higashi, Asahikawa, Hokkaido 0788510, Japan.	fjym@asahikawa-med.ac.jp	Kohgo, Yutaka/AAN-4863-2020	Tanabe, Hiroki/0000-0001-9029-5081	Grants-in-Aid for Scientific ResearchMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) [24790671] Funding Source: KAKEN		Bartel DP, 2004, CELL, V116, P281, DOI 10.1016/S0092-8674(04)00045-5; Calin GA, 2002, P NATL ACAD SCI USA, V99, P15524, DOI 10.1073/pnas.242606799; CAPON DJ, 1983, NATURE, V304, P507, DOI 10.1038/304507a0; Eiring AM, 2010, CELL, V140, P652, DOI 10.1016/j.cell.2010.01.007; Eulalio A, 2008, CELL, V132, P9, DOI 10.1016/j.cell.2007.12.024; Filipowicz W, 2008, NAT REV GENET, V9, P102, DOI 10.1038/nrg2290; FORRESTER K, 1987, NATURE, V327, P298, DOI 10.1038/327298a0; Guan RJ, 1999, GASTROENTEROLOGY, V116, P1063, DOI 10.1016/S0016-5085(99)70009-0; Guil S, 2007, NAT STRUCT MOL BIOL, V14, P591, DOI 10.1038/nsmb1250; He L, 2005, NATURE, V435, P828, DOI 10.1038/nature03552; Hope NR, 2011, HUM PATHOL, V42, P393, DOI 10.1016/j.humpath.2010.08.006; Jo OD, 2008, J BIOL CHEM, V283, P23274, DOI 10.1074/jbc.M801185200; Johnson SM, 2005, CELL, V120, P635, DOI 10.1016/j.cell.2005.01.014; Kettern N, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0016398; Kirkin V, 2009, MOL CELL, V34, P259, DOI 10.1016/j.molcel.2009.04.026; LEE RC, 1993, CELL, V75, P843, DOI 10.1016/0092-8674(93)90529-Y; Liu WH, 2009, GASTROENTEROLOGY, V136, P683, DOI 10.1053/j.gastro.2008.10.029; Mattick JS, 2001, MOL BIOL EVOL, V18, P1611, DOI 10.1093/oxfordjournals.molbev.a003951; Michlewski G, 2008, MOL CELL, V32, P383, DOI 10.1016/j.molcel.2008.10.013; Motoyama K, 2009, INT J ONCOL, V34, P1069, DOI 10.3892/ijo_00000233; NIGRO JM, 1989, NATURE, V342, P705, DOI 10.1038/342705a0; POWELL SM, 1992, NATURE, V359, P235, DOI 10.1038/359235a0; Qased A, 2013, MOL MED REP, V7, P559, DOI 10.3892/mmr.2012.1214; Sampson VB, 2007, CANCER RES, V67, P9762, DOI 10.1158/0008-5472.CAN-07-2462; Taft RJ, 2010, J PATHOL, V220, P126, DOI 10.1002/path.2638; Tao J, 2012, MOL MED REP, V5, P167, DOI 10.3892/mmr.2011.591; Thiele BJ, 2004, CIRC RES, V95, P1058, DOI 10.1161/01.RES.0000149166.33833.08; Tsuchiya N, 2011, CANCER RES, V71, P4628, DOI 10.1158/0008-5472.CAN-10-2475; Ushigome M, 2005, INT J ONCOL, V26, P635; Ventura A, 2008, CELL, V132, P875, DOI 10.1016/j.cell.2008.02.019; Wienholds E, 2005, SCIENCE, V309, P310, DOI 10.1126/science.1114519; WIGHTMAN B, 1993, CELL, V75, P855, DOI 10.1016/0092-8674(93)90530-4; Winter J, 2009, NAT CELL BIOL, V11, P228, DOI 10.1038/ncb0309-228; Wu JM, 2012, CARCINOGENESIS, V33, P519, DOI 10.1093/carcin/bgr304; Yamakuchi M, 2010, P NATL ACAD SCI USA, V107, P6334, DOI 10.1073/pnas.0911082107; Yu YJ, 2012, CARCINOGENESIS, V33, P68, DOI 10.1093/carcin/bgr246; Zhang Y, 2012, MOL CANCER, V11, DOI 10.1186/1476-4598-11-23; Zhao YC, 2011, BREAST CANCER RES TR, V127, P69, DOI 10.1007/s10549-010-0972-2	38	43	43	0	13	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	0950-9232	1476-5594		ONCOGENE	Oncogene	OCT 2	2014	33	40					4847	4856		10.1038/onc.2013.429			10	Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity	AR0EH	WOS:000343240100006	24166503				2022-04-25	
J	Won, SJ; Yen, CH; Liu, HS; Wu, SY; Lan, SH; Jiang-Shieh, YF; Lin, CN; Su, CL				Won, Shen-Jeu; Yen, Cheng-Hsin; Liu, Hsiao-Sheng; Wu, Shan-Ying; Lan, Sheng-Hui; Jiang-Shieh, Ya-Fen; Lin, Chun-Nan; Su, Chun-Li			Justicidin A-Induced Autophagy Flux Enhances Apoptosis of Human Colorectal Cancer Cells via Class III PI3K and Atg5 Pathway	JOURNAL OF CELLULAR PHYSIOLOGY			English	Article							HUMAN HEPATOMA-CELLS; MONITORING AUTOPHAGY; KAPPA-B; DEATH; THERAPY; EXPRESSION; PROTEIN; INHIBITION; PROCUMBENS; LIGNANS	Our previous reports showed that justicidin A (JA), a novel and pure arylnaphthalide lignan isolated from Justicia procumbens, induces apoptosis of human colorectal cancer cells and hepatocellular carcinoma cells, leading to the suppression of both tumor cell growth in NOD-SCID mice. Here, we reveal that JA induces autophagy in human colorectal cancer HT-29 cells by conversion of autophagic marker LC3-I to LC3-II. Furthermore, LC3 puncta and autophagic vesicle formation, and SQSTM1/p62 suppression were observed. Administration of autophagy inhibitor (bafilomycin A1 and chloroquine) and transfection of a tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) demonstrated that JA induces autophagy flux in HT-29 cells. Expression of LC3, SQSTM1, Beclin 1, and nuclear DNA double-strand breaks (representing apoptosis) were also detected in the tumor tissue of HT-29 cells transplanted into NOD-SCID mice orally administrated with JA. In addition, the expression of autophagy signaling pathway-related molecules p-PDK1, p-mTOR, p-p70S6k/p-RPS6KB2 was decreased, whereas that of class III PI3K, Beclin 1, Atg5-Atg12, and mitochondrial BNIP3 was increased in response to JA. Pre-treatment of the cells with class III PI3K inhibitor 3-methyladenine or Atg5 shRNA attenuated JA-induced LC3-II expression and LC3 puncta formation, indicating the involvement of class III PI3K and Atg5. A novel mechanism was demonstrated in the anticancer compound JA; pre-treatment with 3-methyladenine or Atg5 shRNA blocked JA-induced suppression in cell growth and colony formation, respectively, via inhibition of apoptosis. In contrast, administration of apoptosis inhibitor Z-VAD did not affect JA-induced autophagy. Our data suggest the chemotherapeutic potential of JA for treatment of human colorectal cancer. (C) 2014 Wiley Periodicals, Inc.	[Won, Shen-Jeu; Liu, Hsiao-Sheng; Wu, Shan-Ying; Lan, Sheng-Hui] Natl Cheng Kung Univ, Coll Med, Dept Microbiol & Immunol, Tainan 70101, Taiwan; [Yen, Cheng-Hsin] Chang Jung Christian Univ, Dept Nursing, Tainan, Taiwan; [Yen, Cheng-Hsin; Su, Chun-Li] Natl Taiwan Normal Univ, Dept Human Dev & Family Studies, Taipei 10610, Taiwan; [Liu, Hsiao-Sheng] Natl Cheng Kung Univ, Coll Med, Ctr Infect Dis, Tainan 70101, Taiwan; [Liu, Hsiao-Sheng] Natl Cheng Kung Univ, Coll Med, Signaling Res Ctr, Tainan 70101, Taiwan; [Jiang-Shieh, Ya-Fen] Natl Cheng Kung Univ, Coll Med, Dept Anat, Tainan 70101, Taiwan; [Lin, Chun-Nan] Kaohsiung Med Univ, Sch Pharm, Kaohsiung, Taiwan		Su, CL (corresponding author), Natl Taiwan Normal Univ, Dept Human Dev & Family Studies, 162,Sec 1,He Ping East Rd, Taipei 10610, Taiwan.	chunlisu@ntnu.edu.tw	Lan, Sheng-Hui/AAV-1662-2021	Wu, Shan-Ying/0000-0003-2380-5760; Liu, Hsiao-Sheng/0000-0003-0576-7203	National Science CouncilMinistry of Science and Technology, Taiwan [NSC 96-2313-B-309-001-MY2, 98-2313-B-003-002-MY3, 101-2313-B-003-002-MY3]; Ministry of Economic Affairs [100-EC-17-A-17-S1-152]; National Taiwan Normal University [99-D, 100NTNU-D-06]	Contract grant sponsor: National Science Council;; Contract grant numbers: NSC 96-2313-B-309-001-MY2, 98-2313-B-003-002-MY3, 101-2313-B-003-002-MY3.; Contract grant sponsor: The Ministry of Economic Affairs;; Contract grant number: 100-EC-17-A-17-S1-152.; Contract grant sponsor: National Taiwan Normal University;; Contract grant number: 99-D, 100NTNU-D-06.	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Cell. Physiol.	APR	2015	230	4					930	946		10.1002/jcp.24825			17	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	AX4QP	WOS:000346916900022	25216025				2022-04-25	
J	Mo, SB; Dai, WX; Xiang, WQ; Li, YQ; Feng, Y; Zhang, L; Li, QG; Cai, GX				Mo, Shaobo; Dai, Weixing; Xiang, Wenqiang; Li, Yaqi; Feng, Yang; Zhang, Long; Li, Qingguo; Cai, Guoxiang			Prognostic and predictive value of an autophagy-related signature for early relapse in stages I-III colon cancer	CARCINOGENESIS			English	Article							COLORECTAL-CANCER; CURATIVE RESECTION; RECURRENCE; SURVIVAL; PROTEIN; EXPRESSION; BREAST; P53; DISEASE; LEVEL	We postulated that expression differences of autophagy-related genes are instrumental in stratifying the risk of early relapse after surgery and evaluating the prognosis of patients with stages I-III colon cancer. Therefore, propensity score matching analysis was performed between patients in early relapse group and long-term survival group from GSE39582 test series and internal validation series. Using Cox regression model, a nine-autophagy-related signature (CAPN2, ATG16L2, TP63, SIRT1, RPS6KB1, PEX3, ATG5, UVRAG, NAF1) was established to classify patients into those at high risk of early relapse (high-risk group), and those at low risk of early relapse (low-risk group). Relapse-free survival (RFS) was significantly different between the two groups in test [hazard ratio (HR): 2.019, 95% confidence interval (CI): 1.362-2.992, P < 0.001], internal validation (HR: 2.464, 95% CI: 1.196-5.079, P < 0.001) and another two external validation series (GSE14333-HR: 2.250, 95% CI: 1.227-4.126, P = 0.007; GSE33113-HR: 5.552, 95% CI: 2.098-14.693, P < 0.001). Then, based on RFS, we developed a nomogram, integrating the nine-autophagy-related classifier and four clinicopathological risk factors to evaluate prognosis of stages I-III colon cancer patients. Time-dependent receiver operating curve at 2 years showed that the integrated signature (area under curve = 0.758) had better prognostic accuracy than American Joint Committee on Cancer TNM stage (area under curve = 0.620). In conclusion, we identified and built a nine-autophagy-related signature, a credible approach to early relapse prediction in stages I-III colon cancer patients, which can assist physicians in devising more efficient therapeutic strategies.	[Mo, Shaobo; Dai, Weixing; Xiang, Wenqiang; Li, Yaqi; Feng, Yang; Zhang, Long; Li, Qingguo; Cai, Guoxiang] Fudan Univ, Dept Colorectal Surg, Shanghai Canc Ctr, Shanghai 200032, Peoples R China; [Mo, Shaobo; Dai, Weixing; Xiang, Wenqiang; Li, Yaqi; Feng, Yang; Li, Qingguo; Cai, Guoxiang] Fudan Univ, Dept Oncol, Shanghai Med Coll, Shanghai 200032, Peoples R China; [Zhang, Long] Fudan Univ, Shanghai Canc Ctr, Canc Inst, Shanghai 200032, Peoples R China		Li, QG; Cai, GX (corresponding author), Fudan Univ, Dept Colorectal Surg, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.; Li, QG; Cai, GX (corresponding author), Fudan Univ, Dept Oncol, Shanghai Med Coll, Shanghai 200032, Peoples R China.	oncosurgeonli@sohu.com; gxcaifuscc@163.com			National Key R&D Program of China [2016YFC0905300, 2016YFC0905301]; Grant of Science and Technology Commission of Shanghai MunicipalityScience & Technology Commission of Shanghai Municipality (STCSM) [16401970502]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81572351]; Shanghai Shenkang Program [SHDC12014206]	the National Key R&D Program of China (No. 2016YFC0905300 and 2016YFC0905301); the Grant of Science and Technology Commission of Shanghai Municipality (No. 16401970502); the Grant of National Natural Science Foundation of China (No. 81572351) and Shanghai Shenkang Program (No. SHDC12014206).	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J	Sui, XB; Kong, N; Ye, L; Han, WD; Zhou, JC; Zhang, Q; He, C; Pan, HM				Sui, Xinbing; Kong, Na; Ye, Li; Han, Weidong; Zhou, Jichun; Zhang, Qin; He, Chao; Pan, Hongming			p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents	CANCER LETTERS			English	Review						P38; JNK; Autophagy; Apoptosis; Chemoresistance	ACTIVATED PROTEIN-KINASE; N-TERMINAL KINASE; SIGNAL-TRANSDUCTION PATHWAYS; COLORECTAL-CANCER GROWTH; CELL-DEATH; C-JUN; OXIDATIVE STRESS; UP-REGULATION; COLON-CANCER; REGULATES AUTOPHAGY	The Mitogen Activated Protein Kinase (MAPK) signaling plays a critical role in the outcome and the sensitivity to anticancer therapies. Activated MAPK can transmit extracellular signals to regulate cell growth, proliferation, differentiation, migration, apoptosis and so on. Apoptosis as well as macroautophagy (hereafter referred to as autophagy) can be induced by extracellular stimuli such the treatment of chemotherapeutic agents, resulting in different cell response to these drugs. However, the molecular mechanisms mediating these two cellular processes remain largely unknown. Recently, several studies provide new insights into p38 and JNK MAPK pathways function in the control of the balance of autophagy and apoptosis in response to genotoxic stress. Our increased understanding of the role of p38 and JNK MAPK pathways in regulating the balance of autophagy and apoptosis will hopefully provide prospective strategies for cancer therapy. (C) 2013 Elsevier Ireland Ltd. All rights reserved.	[Sui, Xinbing; Kong, Na; Han, Weidong; Pan, Hongming] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Med Oncol, Hangzhou 310003, Zhejiang, Peoples R China; [Sui, Xinbing; Kong, Na; Han, Weidong; He, Chao; Pan, Hongming] Biomed Res Ctr, Hangzhou, Zhejiang, Peoples R China; [Sui, Xinbing; Kong, Na; Han, Weidong; He, Chao; Pan, Hongming] Key Lab Biotherapy Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China; [Ye, Li] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Gen Med, Hangzhou 310003, Zhejiang, Peoples R China; [He, Chao] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Colorectal Surg, Hangzhou 310003, Zhejiang, Peoples R China; [Zhou, Jichun] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Surg Oncol, Hangzhou 310003, Zhejiang, Peoples R China; [Zhang, Qin] Zhejiang Prov Peoples Hosp, Dept Gastrointestinal Surg, Hangzhou 310016, Zhejiang, Peoples R China		Zhang, Q (corresponding author), Zhejiang Prov Peoples Hosp, Dept Gastrointestinal Surg, Hangzhou 310016, Zhejiang, Peoples R China.	hz166cn@163.com; drhechao@yahoo.com.cn; hzzju@zju.edu.cn	Zhou, Jichun/Q-8646-2019	Zhou, Jichun/0000-0002-0727-4034	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81301891, 81272593]; Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LQ13H160008]	This study is supported by grants from National Natural Science Foundation of China (Grant Nos. 81301891 and 81272593) and Zhejiang Provincial Natural Science Foundation of China (Grant No. LQ13H160008).	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MAR 28	2014	344	2					174	179		10.1016/j.canlet.2013.11.019			6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AB3EC	WOS:000331673100004	24333738		Y	N	2022-04-25	
J	Ortiz, LMG; Croce, AL; Aredia, F; Sapienza, S; Fiorillo, G; Syeda, TM; Buzzetti, F; Lombardi, P; Scovassi, AI				Ortiz, Luis Miguel Guaman; Croce, Anna Leta; Aredia, Francesca; Sapienza, Simone; Fiorillo, Gaetano; Syeda, Tanjia Monir; Buzzetti, Franco; Lombardi, Paolo; Scovassi, Anna Ivana			Effect of new berberine derivatives on colon cancer cells	ACTA BIOCHIMICA ET BIOPHYSICA SINICA			English	Article						apoptosis; autophagy; berberine; colon cancer; fluorescence	AUTOPHAGY; AMPLIFICATION; MECHANISMS; APOPTOSIS; DEATH	The natural alkaloid berberine has been recently described as a promising anticancer drug. In order to improve its efficacy and bioavailability, several derivatives have been designed and synthesized and found to be even more potent than the lead compound. Among the series of berberine derivatives we have produced, five compounds were identified to be able to heavily affect the proliferation of human HCT116 and SW613-B3 colon carcinoma cell lines. Remarkably, these active compounds exhibit high fluorescence emission property and ability to induce autophagy.	[Ortiz, Luis Miguel Guaman; Croce, Anna Leta; Aredia, Francesca; Sapienza, Simone; Scovassi, Anna Ivana] CNR, Ist Genet Mol, I-27100 Pavia, Italy; [Ortiz, Luis Miguel Guaman] Univ Tecn Particular Loja, Dept Ciencias Salud, Loja, Ecuador; [Aredia, Francesca] Univ Pavia, Dipartimento Biol & Biotecnol L Spallanzani, I-27100 Pavia, Italy; [Fiorillo, Gaetano; Syeda, Tanjia Monir; Buzzetti, Franco; Lombardi, Paolo] Naxospharma Srl, Novate Milanese, Italy		Scovassi, AI (corresponding author), CNR, Ist Genet Mol, I-27100 Pavia, Italy.	scovassi@igm.cnr.it	Ortiz, Luis Miguel Guaman/X-9496-2019	Ortiz, Luis Miguel Guaman/0000-0003-2919-4905; Lombardi, Paolo/0000-0002-7971-7404; Scovassi, Anna Ivana/0000-0003-3484-9881	Regione Lombardia, Italy (Project Plant Cell)Regione Lombardia [13810040]; Regione Lombardia, Italy (Naxospharma)	The work was supported by a grant from Regione Lombardia, Italy (Project Plant Cell, grant No. 13810040 to A.I.S. and Naxospharma).	Aredia F, 2013, APOPTOSIS, V18, P1586, DOI 10.1007/s10495-013-0898-3; Aredia Francesca, 2012, Cells, V1, P520, DOI 10.3390/cells1030520; Aredia F, 2013, FUTURE MED CHEM, V5, P1009, DOI 10.4155/fmc.13.85; Bhowmik D, 2012, J PHYS CHEM B, V116, P2314, DOI 10.1021/jp210072a; Bottone MG, 2003, EXP CELL RES, V290, P49, DOI 10.1016/S0014-4827(03)00312-4; Donzelli M, 1999, ONCOGENE, V18, P439, DOI 10.1038/sj.onc.1202309; Fan XD, 2015, J TRANSL MED, V13, DOI 10.1186/s12967-015-0450-z; Fatokun AA, 2014, BRIT J PHARMACOL, V171, P2000, DOI 10.1111/bph.12416; Galluzzi L, 2015, EMBO J, V34, P856, DOI 10.15252/embj.201490784; Giansanti V, 2013, J CELL MOL MED, V17, P103, DOI 10.1111/j.1582-4934.2012.01652.x; Gorrini C, 2003, INT J MOL MED, V11, P737; Guaman-Ortiz L.M., 2014, BIOMED RES INT, V2014; Hou Q, 2011, CANCER SCI, V102, P1287, DOI 10.1111/j.1349-7006.2011.01933.x; Hu XJ, 2014, MOL MED REP, V9, P1883, DOI 10.3892/mmr.2014.1999; Iwasa K, 1997, PLANTA MED, V63, P196, DOI 10.1055/s-2006-957651; Lee KH, 2014, SCI REP-UK, V4, DOI 10.1038/srep06394; Liu ZJ, 2009, MUTAT RES-FUND MOL M, V662, P75, DOI 10.1016/j.mrfmmm.2008.12.009; Ortiz LMG, 2014, MOLECULES, V19, P12349, DOI 10.3390/molecules190812349; Peng PL, 2008, INT J RADIAT ONCOL, V70, P529, DOI 10.1016/j.ijrobp.2007.08.034; Pierpaoli E, 2013, BIOFACTORS, V39, P672, DOI 10.1002/biof.1131; Rubinsztein DC, 2012, NAT REV DRUG DISCOV, V11, P709, DOI 10.1038/nrd3802; Singh IP, 2013, EXPERT OPIN THER PAT, V23, P215, DOI 10.1517/13543776.2013.746314; Sui X, 2013, CELL DEATH DIS, V4, DOI 10.1038/cddis.2013.350; Tillhon M, 2012, BIOCHEM PHARMACOL, V84, P1260, DOI 10.1016/j.bcp.2012.07.018; Uzasci S, 2014, J CHROMATOGR A, V1338, P184, DOI 10.1016/j.chroma.2014.02.068; Wang N, 2010, J CELL BIOCHEM, V111, P1426, DOI 10.1002/jcb.22869; Wang Y, 2012, MUTAT RES-FUND MOL M, V734, P20, DOI 10.1016/j.mrfmmm.2012.04.005; Waters ML, 2002, CURR OPIN CHEM BIOL, V6, P736, DOI 10.1016/S1367-5931(02)00359-9; Zhu Y, 2014, MOL MED REP, V10, P1734, DOI 10.3892/mmr.2014.2405	29	33	35	1	20	OXFORD UNIV PRESS	OXFORD	GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND	1672-9145	1745-7270		ACTA BIOCH BIOPH SIN	Acta Biochim. Biophys. Sin.	OCT	2015	47	10					824	833		10.1093/abbs/gmv077			10	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	CS3VQ	WOS:000362003700008	26341980	Bronze			2022-04-25	
J	Wu, QX; Yuan, SX; Ren, CM; Yu, Y; Sun, WJ; He, BC; Wu, K				Wu, Qiu-Xiang; Yuan, Shuang-Xue; Ren, Chun-Mei; Yu, Yu; Sun, Wen-Juan; He, Bai-Cheng; Wu, Ke			Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells	ONCOLOGY REPORTS			English	Article						oridonin; colon cancer; proliferation inhibition; PTEN; p38 MAPK	COLORECTAL-CANCER; PANCREATIC-CANCER; GROWTH-INHIBITION; IN-VITRO; APOPTOSIS; EXPRESSION; AUTOPHAGY; PATHWAY; TETRANDRINE; SENESCENCE	Oridonin (ORI) has been reported as an antiproliferation and apoptosis-inducing natural product in various cancer cells. However, the exact molecular mechanism underlying these effects remains unclear. In the present study, we demonstrated the antiproliferation effect of ORI in HCT116 cells, and analyzed the possible molecular mechanism which mediates this effect. We found that ORI inhibits proliferation, induces cell cycle arrest and apoptosis in HCT116 cells, thus also tumor growth. Mechanically, we found that ORI has no substantial effect on mRNA expression of phosphatase and tensin homologue (PTEN), but increases the total protein level of PTEN and markedly reduces the phosphorylation of PTEN; Exogenous expression of PTEN potentiates the anticancer effect of ORI, while knockdown of PTEN attenuates it. ORI also increases the phosphorylation of p38 MAPK, and p38 MAPK-specific inhibitor reduces the antiproliferation effect ORI in HCT116 cells. Moreover, inhibition of p38 MAPK increases the phosphorylation of PTEN, and reverses ORI-induced decrease of PTEN phosphorylation. Our findings suggested that ORI may be a potential anticancer drug for colon cancer, this effect may be mediated by enhancing the function of PTEN through reducing its phosphorylation, which may be resulted from the ORI-induced activation of p38 MAPK.	[Wu, Qiu-Xiang; Yuan, Shuang-Xue; Ren, Chun-Mei; Yu, Yu; Sun, Wen-Juan; He, Bai-Cheng; Wu, Ke] Chongqing Med Univ, Sch Pharm, Chongqing Municipal Key Lab Higher Educ Inst Bioc, Chongqing 400016, Peoples R China; [Wu, Qiu-Xiang; Yuan, Shuang-Xue; Ren, Chun-Mei; Sun, Wen-Juan; He, Bai-Cheng; Wu, Ke] Chongqing Med Univ, Sch Pharm, Dept Pharmacol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Yu, Yu] Chongqing Med Univ, Sch Pharm, Dept Chem, Chongqing 400016, Peoples R China		He, BC; Wu, K (corresponding author), Chongqing Med Univ, Sch Pharm, Dept Pharmacol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China.	hebaicheng99@yahoo.com; wukecqmu@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [NSFC 81372120, 81572226]	We thank Professor Tong-Chuan He of the University of Chicago Medical Center (Chicago, IL, USA) for his kind provision of the recombinant adenoviruses. The present study was supported by the Research Grant from the National Natural Science Foundation of China (grant nos. NSFC 81372120 and 81572226 to Bai-Cheng He).	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Rep.	JUN	2016	35	6					3341	3348		10.3892/or.2016.4735			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	DM7OT	WOS:000376550600024	27108927	Bronze			2022-04-25	
J	Yoshimoto, T; Morine, Y; Takasu, C; Feng, R; Ikemoto, T; Yoshikawa, K; Iwahashi, S; Saito, Y; Kashihara, H; Akutagawa, M; Emoto, T; Kinouchi, Y; Shimada, M				Yoshimoto, Toshiaki; Morine, Yuji; Takasu, Chie; Feng, Rui; Ikemoto, Tetsuya; Yoshikawa, Kozo; Iwahashi, Syuichi; Saito, Yu; Kashihara, Hideya; Akutagawa, Masatake; Emoto, Takahiro; Kinouchi, Yosuke; Shimada, Mitsuo			Blue light-emitting diodes induce autophagy in colon cancer cells by Opsin 3	ANNALS OF GASTROENTEROLOGICAL SURGERY			English	Article						autophagy; blue light-emitting diode; colorectal cancer; Opsin 3; photoreceptor	APOPTOSIS; MITOCHONDRIA; IRRADIATION; MELANOMA; NECROSIS; SYSTEM	Background: Light emitting-diodes (LED) have various effects on living organisms and recent studies have shown the efficacy of visible light irradiation from LED for anticancer therapies. However, the mechanism of LED's effects on cancer cells remains unclear. The aim of the present study was to investigate the effects of LED on colon cancer cell lines and the role of photoreceptor Opsin 3 (Opn3) on LED irradiation in vitro. Methods: Human colon cancer cells (HT-29 or HCT-116) were seeded onto laboratory dishes and irradiated with 465-nm LED at 30 mW/cm(2) for 30 minutes. Cell Counting Kit-8 was used to measure cell viability, and apoptosis and caspase 3/8 expression were evaluated by AnnexinV/PI and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Autophagy and expression of LC-3 and beclin-1 were also evaluated by autophagy assays, RT-PCR and Western blotting. We further tested Opn3 knockdown by Opn3 siRNA and the G(i/o) G-protein inhibitor NF023 in these assays. Results: Viability of HT-29 and HCT-116 cells was lower in 465-nm LED-irradiated cultures than in control cultures. LC-3 and beclin-1 expressions were significantly higher in LED-irradiated cultures, and autophagosomes were detected in irradiated cells. The reductive effect of cancer cell viability following blue LED irradiation was reversed by Opn3 knockdown or NF023 treatment. Furthermore, increased LC-3 and beclin-1 expression that resulted from blue LED irradiation was suppressed by Opn3 knockdown or NF023 treatment. Conclusion: Blue LED irradiation suppressed the growth of colon cancer cells and Opn3 may play an important role as a photoreceptor.	[Yoshimoto, Toshiaki; Morine, Yuji; Takasu, Chie; Feng, Rui; Ikemoto, Tetsuya; Yoshikawa, Kozo; Iwahashi, Syuichi; Saito, Yu; Kashihara, Hideya; Shimada, Mitsuo] Tokushima Univ, Dept Surg, Grad Sch, Tokushima, Japan; [Akutagawa, Masatake; Emoto, Takahiro] Tokushima Univ, Grad Sch Technol Ind & Social Sci, Tokushima, Japan; [Kinouchi, Yosuke] Tokushima Univ, Ctr Res Adm & Collaborat, Tokushima, Japan		Morine, Y (corresponding author), Tokushima Univ, Dept Surg, Grad Sch, Tokushima, Japan.	ymorine@tokushima-u.ac.jp					Barolet D, 2008, SEMIN CUTAN MED SURG, V27, P227, DOI 10.1016/j.sder.2008.08.003; Canu N, 2005, J NEUROCHEM, V92, P1228, DOI 10.1111/j.1471-4159.2004.02956.x; de Assis LVM, 2016, BBA-MOL CELL RES, V1863, P1119, DOI 10.1016/j.bbamcr.2016.03.001; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; del Olmo-Aguado S, 2016, NEUROCHEM RES, V41, P2324, DOI 10.1007/s11064-016-1946-5; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Kim S, 2013, PHOTOMED LASER SURG, V31, P554, DOI 10.1089/pho.2012.3343; Koyanagi M, 2014, BBA-BIOENERGETICS, V1837, P710, DOI 10.1016/j.bbabio.2013.09.003; Koyanagi M, 2013, P NATL ACAD SCI USA, V110, P4998, DOI 10.1073/pnas.1219416110; Kuse Y, 2014, SCI REP-UK, V4, DOI 10.1038/srep05223; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Mathew R, 2009, CELL, V137, P1062, DOI 10.1016/j.cell.2009.03.048; Matsumoto N, 2014, ANTICANCER RES, V34, P4709; Nikoletopoulou V, 2013, BBA-MOL CELL RES, V1833, P3448, DOI 10.1016/j.bbamcr.2013.06.001; Oh PS, 2016, INT J BIOCHEM CELL B, V70, P13, DOI 10.1016/j.biocel.2015.11.004; Oh PS, 2015, J PHOTOCH PHOTOBIO B, V142, P197, DOI 10.1016/j.jphotobiol.2014.12.006; Park JY, 2016, BIOCHEM BIOPH RES CO, V470, P336, DOI 10.1016/j.bbrc.2016.01.049; Sakai K, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0141238; Sparsa A, 2010, ANTICANCER RES, V30, P143; Terakita A, 2014, ZOOL SCI, V31, P653, DOI 10.2108/zs140094; Vinck E, 2006, LASER MED SCI, V21, P11, DOI 10.1007/s10103-005-0366-6; Yamashita T, 2010, P NATL ACAD SCI USA, V107, P22084, DOI 10.1073/pnas.1012498107; Yang F, 2013, CELL DEATH DIS, V4, DOI 10.1038/cddis.2013.425; Yoshida A, 2013, J PHOTOCH PHOTOBIO B, V129, P1, DOI 10.1016/j.jphotobiol.2013.09.003; Zhou HY, 2016, CANCER BIOMARK, V17, P1, DOI 10.3233/CBM-160613	25	18	19	2	7	WILEY-V C H VERLAG GMBH	WEINHEIM	POSTFACH 101161, 69451 WEINHEIM, GERMANY	2475-0328			ANN GASTROENT SURG	Ann. Gastroent. Surg.	MAR	2018	2	2					154	161		10.1002/ags3.12055			8	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	GX0HT	WOS:000447391700009	29863164	Green Published, gold			2022-04-25	
J	Zhang, ZH; Xu, M; Sun, X; Guo, X				Zhang, Zhihang; Xu, Meng; Sun, Xu; Guo, Xu			Naturally occurring glycyrrhizin triterpene exerts anticancer effects on colorectal cancer cells via induction of apoptosis and autophagy and suppression of cell migration and invasion by targeting MMP-9 and MMP-2 expression	JOURNAL OF BUON			English	Article						glycyrrhizin; colorectal cancer; apoptosis; autophagy; cell invasion	ACID; HEREDITARY; CYCLE	Purpose: The main aim of the current study was to investi-gate the anticancer properties of naturally occurring triter-pene - glycyrrhizin - against human colorectal carcinoma cells along with evaluation of its effects on cells apoptosis, autophagy and cell migration and invasion. Methods: Cell viability was evaluated by CellTiter95 (R) Aqueous One Solution cell viability assay, while the effects on cell apoptosis were observed by fluorescence microscopy using DAPI staining. Effects on autophagy were detected by transmission electron microscopy (TEM) along with western blot method. Transwell assay was performed to monitor the effects on cell migration and invasion. Results: Glycyrrhizin induced selective and dose-dependent inhibition of cell growth in SW48 human colorectal carcinoma cells with lesser cytotoxicity in normal colon cells (CCD-18Co). Glycyrrhizin also led to cell apoptotic effects manifested by chromatin condensation and nuclear fragmentation as evidenced by brighter fluorescence. Apoptosis was confirmed by western blot which showed increase in Bax expression and decrease in Bcl-2 expression. TEM analysis showed that glycyrrhizin-treated cells at 12 mu M showed autophagosomes indicating onset of autophagy. Western blot assay confirmed the autophagy results which showed glycyrrhizin-treated cells indicated increased expression of Beclin-1, LC3B-I and LC3B-II in a dose-dependent manner. Glycyrrhizin treatment also led to inhibition of both cell migration and invasion. Conclusion: The results of this study reveal that glycyrrhi-zin can be developed as a potent anticancer agent against colorectal cancer provided further studied are performed, especially on its toxicity to humans.	[Zhang, Zhihang; Xu, Meng; Sun, Xu; Guo, Xu] Dalian Cent Hosp, Dept Anorectal Surg, Southwest Rd 826, Dalian 116000, Peoples R China		Zhang, ZH (corresponding author), Dalian Cent Hosp, Dept Anorectal Surg, Southwest Rd 826, Dalian 116000, Peoples R China.	zhangzhihang7279@126.com					Asl MN, 2008, PHYTOTHER RES, V22, P709, DOI 10.1002/ptr.2362; Brenner H, 2011, ANN INTERN MED, V154, P22, DOI 10.7326/0003-4819-154-1-201101040-00004; Burt RW, 2000, GASTROENTEROLOGY, V119, P837, DOI 10.1053/gast.2000.16508; Canada CCSNCIo, 2008, CAN CANC STAT 2008; Cappell M S, 2007, Minerva Gastroenterol Dietol, V53, P351; Center MM, 2009, CA-CANCER J CLIN, V59, P366, DOI 10.3322/caac.20038; Farooqui A, 2018, BIOMED PHARMACOTHER, V97, P752, DOI 10.1016/j.biopha.2017.10.147; Haghshenas V, 2014, ADV PHARM BULL, V4, P437, DOI 10.5681/apb.2014.064; Humphries A, 2008, NAT REV CANCER, V8, P415, DOI 10.1038/nrc2392; Jasperson KW, 2010, GASTROENTEROLOGY, V138, P2044, DOI 10.1053/j.gastro.2010.01.054; Jemal A, 2011, CA-CANCER J CLIN, V61, P69, DOI [10.3322/caac.20107, 10.3322/caac.20115]; Jeong HG, 2002, PHARMACOL RES, V46, P221, DOI 10.1016/S1043-6618(02)00121-4; Khan R, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0056020; Lin SC, 2018, ONCOL REP, V39, P703, DOI 10.3892/or.2017.6123; Meng YQ, 2012, CHEM RES CHINESE U, V28, P214; Moh Saudi, 2013, HLTH AWARENESS CTR C; Rahmani M, 2018, CANCER RES, V78, P3075, DOI 10.1158/0008-5472.CAN-17-3024; Rhodes JM, 2002, TRENDS MOL MED, V8, P10, DOI 10.1016/S1471-4914(01)02194-3; Rossi T, 2005, IN VIVO, V19, P319; Rustgi AK, 2007, GENE DEV, V21, P2525, DOI 10.1101/gad.1593107; Lopez PJT, 2014, CLIN MED INSIGHTS-GA, V7, P33, DOI 10.4137/CGast.S14039; Thirugnanam S, 2008, ONCOL REP, V20, P1387, DOI 10.3892/or_00000157; Tsoi KKF, 2009, CLIN GASTROENTEROL H, V7, P682, DOI 10.1016/j.cgh.2009.02.016; Vasen HFA, 2008, GUT, V57, DOI 10.1136/gut.2007.136127; Wan XY, 2009, CHEM-BIOL INTERACT, V181, P15, DOI 10.1016/j.cbi.2009.04.013; Whitlock EP, 2008, 080505124EF1 AG HEAL; Wu X, 2018, BIOMED RES INT, V7, P5; Zhang Z, 2019, ARCH MED SCI, V15, P174, DOI 10.5114/aoms.2018.79429	28	1	1	1	2	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	JAN-FEB	2020	25	1					188	193					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	KQ7HD	WOS:000517089300024	32277631				2022-04-25	
J	Dent, P; Booth, L; Roberts, JL; Poklepovic, A; Cridebring, D; Reiman, EM				Dent, Paul; Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew; Cridebring, Derek; Reiman, Eric M.			Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43	AGING-US			English	Article						Alzheimer's; chaperone; GRP78; autophagy; neratinib	ENDOPLASMIC-RETICULUM STRESS; OSU-03012; ACTIVATION; CHAPERONES; CARCINOMA; TOXICITY; BINDING; KINASE; TARGET; MUTANT	Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer's Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.	[Dent, Paul; Booth, Laurence] Dept Biochem & Mol Biol, Richmond, VA 23298 USA; [Roberts, Jane L.] Dept Pharmacol & Toxicol, Richmond, VA 23298 USA; [Poklepovic, Andrew] Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA; [Cridebring, Derek; Reiman, Eric M.] Translat Genom Res Inst TGEN, Phoenix, AZ 85004 USA; [Reiman, Eric M.] Banner Alzheimers Inst, Phoenix, AZ 85006 USA		Dent, P (corresponding author), Dept Biochem & Mol Biol, Richmond, VA 23298 USA.	paul.dent@vcuhealth.org			Puma Biotechnology; Commonwealth Health Research Board of Virginia; Massey Cancer Center; Universal Chair in Signal Transduction; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [P30 AG019610]	The Dent laboratory received financial support from Puma Biotechnology for these studies. The Dent laboratory received financial support from the Commonwealth Health Research Board of Virginia. Studies were also in part funded by Massey Cancer Center and the Universal Chair in Signal Transduction. Dr. Reiman received financial support from National Institute on Aging grant P30 AG019610, for which he is the PI.	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J	Li, XX; Huang, LY; Peng, JJ; Liang, L; Shi, DB; Zheng, HT; Cai, SJ				Li, Xin-Xiang; Huang, Li-Yong; Peng, Jun-Jie; Liang, Lei; Shi, De-Bing; Zheng, Hong-Tu; Cai, San-Jun			Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						klotho; colon cancer; growth; invasion	EXPRESSION INDUCES APOPTOSIS; LUNG-CANCER; TUMOR PROGRESSION; PROLIFERATION; RESTORATION; AUTOPHAGY	Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers including colon cancer. However, the potential role and molecular events for KL in colon cancer remain unclear. The present study aimed to investigate the expression of KL in human colon cancer by immunohistochemistry, and to analyze the correlation between KL expression and clinicopathological characteristics of patients with colon cancer. Functional analysis after lentivirus-mediated gain of KL expression was used to assess the tumor growth and invasion in colon cancer cells in vitro and in vivo. The rate of KL expression was significantly decreased in cancer tissues compared with that in adjacent non-cancer tissues (ANCT) (60.3 vs.77.9%, P=0.022), and KL expression was negatively associated with Dukes staging (P=0.034) and depth of tumor invasion (P=0.008). Overexpression of KL in vitro inhibited cell proliferative activities and invasive potential in colon cancer cells, companied with decreased expression of p-IGF1R, p-PI3K, p-AKT, PCNA and MMP-2. In addition, the tumor volumes in the HT-29 subcutaneous tumor model treated with lentivirus-mediated KL vector (Lv-KL) was significantly smaller than those of the negative control (NC) group (P<0.01). Taken together, our findings indicate that the expression of KL is downregulated in human colon caner and correlates with tumor invasion and Dukes staging, while overexpression of KL suppresses growth and invasion through inhibition of IGF1R-mediated PI3K/AKT pathway in colon cancer cells, suggesting that KL may serve as a potential therapeutic target for the treatment of colon cancer.	[Li, Xin-Xiang] Fudan Univ, Shanghai Canc Ctr, Dept Colorectal Surg, Shanghai 200032, Peoples R China; [Li, Xin-Xiang] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China		Li, XX (corresponding author), Fudan Univ, Shanghai Canc Ctr, Dept Colorectal Surg, 270 Dongan Rd, Shanghai 200032, Peoples R China.	lixinxiang2014@163.com					Abramovitz L, 2011, CLIN CANCER RES, V17, P4254, DOI 10.1158/1078-0432.CCR-10-2749; Antonic V, 2013, J CANCER, V4, P227, DOI 10.7150/jca.5835; Camilli TC, 2011, PIGM CELL MELANOMA R, V24, P175, DOI 10.1111/j.1755-148X.2010.00792.x; Chang B, 2012, ONCOL REP, V28, P1022, DOI 10.3892/or.2012.1865; Chen B, 2012, CANCER BIOL THER, V13, P1221, DOI 10.4161/cbt.21420; Chen B, 2010, J EXP CLIN CANC RES, V29, DOI 10.1186/1756-9966-29-99; Chen L, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0053949; Dermaku-Sopjani M, 2013, MOL MEMBR BIOL, V30, P369, DOI 10.3109/09687688.2013.837518; Doi S, 2011, J BIOL CHEM, V286, P8655, DOI 10.1074/jbc.M110.174037; Fu YC, 2009, CANCER BIOL THER, V8, P1002, DOI 10.4161/cbt.8.11.8285; Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013; Kuro-O M, 2008, BIOL CHEM, V389, P233, DOI 10.1515/BC.2008.028; Kuro-O M, 2012, CURR OPIN NEPHROL HY, V21, P362, DOI 10.1097/MNH.0b013e32835422ad; Liabakk NB, 1996, CANCER RES, V56, P190; Lim DY, 2012, BMC GASTROENTEROL, V12, DOI 10.1186/1471-230X-12-9; Lu L, 2008, CANCER INVEST, V26, P185, DOI 10.1080/07357900701638343; Pan J, 2011, TUMOR BIOL, V32, P729, DOI 10.1007/s13277-011-0174-5; Poh WJ, 2012, MOL CANCER, V11, DOI 10.1186/1476-4598-11-14; RISIO M, 1992, J CELL BIOCHEM, P79; Rubinek T, 2012, BREAST CANCER RES TR, V133, P649, DOI 10.1007/s10549-011-1824-4; Shu GS, 2013, CELL ONCOL, V36, P121, DOI 10.1007/s13402-012-0118-0; Usuda J, 2011, LUNG CANCER, V74, P332, DOI 10.1016/j.lungcan.2011.03.004; Usuda J, 2011, LUNG CANCER, V72, P355, DOI 10.1016/j.lungcan.2010.10.008; Wang LJ, 2011, AM J CANCER RES, V1, P111; Wang Y, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0057391; Xie B, 2013, PATHOL ONCOL RES, V19, P611, DOI 10.1007/s12253-013-9663-8; Xie BA, 2013, HUM PATHOL, V44, P795, DOI 10.1016/j.humpath.2012.07.023; Xie B, 2013, CANCER CELL INT, V13, DOI 10.1186/1475-2867-13-18; Yahata K, 2000, J MOL MED, V78, P389, DOI 10.1007/s001090000131; Ye XM, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0055615; Young PE, 2013, J CANCER, V4, P217, DOI 10.7150/jca.5829; Zhu Y, 2013, CANCER SCI, V104, P663, DOI 10.1111/cas.12134	32	38	40	1	6	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1019-6439	1791-2423		INT J ONCOL	Int. J. Oncol.	AUG	2014	45	2					611	618		10.3892/ijo.2014.2430			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AK5RR	WOS:000338484600017	24818842	Bronze			2022-04-25	
J	Tsai, CH; Hung, AC; Chen, YY; Chiu, YW; Hsieh, PW; Lee, YC; Su, YH; Chang, PC; Hu, SCS; Yuan, SSF				Tsai, Chun-Hao; Hung, Amos C.; Chen, Yuan-Yin; Chiu, Ya-Wen; Hsieh, Pei-Wen; Lee, Yi-Chen; Su, Yu-Han; Chang, Po-Chih; Hu, Stephen Chu-Sung; Yuan, Shyng-Shiou F.			3 '-hydroxy-4 '-methoxy-beta-methyl-beta-nitrostyrene inhibits tumorigenesis in colorectal cancer cells through ROS-mediated DNA damage and mitochondrial dysfunction	ONCOTARGET			English	Article						beta-nitrostyrene; cell cycle; ROS; colorectal cancer; DNA damage	BETA-NITROSTYRENE DERIVATIVES; COLON-CANCER; OXIDATIVE STRESS; APOPTOSIS; ACTIVATION; AUTOPHAGY; MECHANISMS; GENERATION; INDUCTION; GROWTH	The beta-nitrostyrene family has been shown to suppress cell proliferation and induce apoptosis in types of various cancers. However, the mechanisms underlying the anticancer effects of beta-nitrostyrenes in colorectal cancer remain poorly understood. In this study, we synthesized a beta-nitrostyrene derivative, CYT-Rx20 (3'-hydroxy-4'-methoxy- beta-methyl-beta-nitrostyrene), and investigated its anticancer activities in human colorectal cancer cells both in vitro and in vivo. Our findings showed that treatment with CYT-Rx20 reduced cell viability and induced DNA damage in colorectal cancer cells. In addition, CYT-Rx20 induced cell cycle arrest of colorectal cancer cells at the G2/M phase and upregulated the protein expression of phospho-ERK, cyclin B1, phospho-cdc2 (Tyr15), aurora A, and aurora B, while it downregulated the expression of cdc25A and cdc25C. Furthermore, we found that CYT-Rx20 caused accumulation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential. The effects of CYT-Rx20 on cell viability, DNA damage, and mitochondrial membrane potential were reversed by pretreatment with the thiol antioxidant N-acetyl-L-cysteine (NAC), suggesting that ROS-mediated DNA damage and mitochondrial dysregulation play a critical role in these events. Finally, the nude mice xenograft study showed that CYT-Rx20 significantly reduced tumor growth of implanted colorectal cancer cells accompanied by elevated protein expression of aurora A, aurora B, gamma H2AX, phosphor-ERK, and MDA in the tumor tissues. Taken together, these results suggest that CYT-Rx20 may potentially be developed as a novel beta-nitrostyrene-based anticancer agent for colorectal cancer.	[Tsai, Chun-Hao; Hung, Amos C.; Chen, Yuan-Yin; Chiu, Ya-Wen; Lee, Yi-Chen; Su, Yu-Han; Yuan, Shyng-Shiou F.] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Translat Res Ctr, Kaohsiung, Taiwan; [Tsai, Chun-Hao; Yuan, Shyng-Shiou F.] Kaohsiung Med Univ, Coll Med, Grad Inst Med, Kaohsiung, Taiwan; [Hsieh, Pei-Wen] Chang Gung Univ, Coll Med, Sch Tradit Chinese Med, Grad Inst Nat Prod, Taoyuan, Taiwan; [Hsieh, Pei-Wen] Chang Gung Univ, Coll Med, Grad Inst Biomed Sci, Taoyuan, Taiwan; [Lee, Yi-Chen] Kaohsiung Med Univ, Coll Med, Sch Med, Dept Anat, Kaohsiung, Taiwan; [Chang, Po-Chih] I Shou Univ, E Da Hospital, Dept Surg, Divis Gen Surg, Kaohsiung, Taiwan; [Hu, Stephen Chu-Sung] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Dermatol, Kaohsiung, Taiwan; [Hu, Stephen Chu-Sung] Kaohsiung Med Univ, Coll Med, Dept Dermatol, Kaohsiung, Taiwan; [Yuan, Shyng-Shiou F.] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Obstet & Gynecol, Kaohsiung, Taiwan		Yuan, SSF (corresponding author), Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Translat Res Ctr, Kaohsiung, Taiwan.; Yuan, SSF (corresponding author), Kaohsiung Med Univ, Coll Med, Grad Inst Med, Kaohsiung, Taiwan.; Yuan, SSF (corresponding author), Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Obstet & Gynecol, Kaohsiung, Taiwan.	yuanssf@ms33.hinet.net		Hung, Amos/0000-0001-7572-8897; Hu, Stephen Chu-Sung/0000-0002-1832-4471; yuan, shyng-shiou/0000-0002-4753-788X	Kaohsiung Medical University Hospital [KMUH103-3R28, KMUH102-2T07, KMUH102-2R25]; Kaohsiung Medical University [KMU-DT103010, KMU-TP103D18]; National Health Research InstitutesNational Health Research Institutes, Japan [NHRI-EX104-10212BI]; E-Da Hospital/I-Shou University [EDAHP102024]; Ministry of Health and Welfare of Taiwan [MOHW104-TDU-B-212-124-003]	The work was supported by grants from Kaohsiung Medical University Hospital (KMUH103-3R28, KMUH102-2T07, KMUH102-2R25), Kaohsiung Medical University (Aim for the Top Journals Grant, KMU-DT103010, KMU-TP103D18), National Health Research Institutes (NHRI-EX104-10212BI), E-Da Hospital/I-Shou University (EDAHP102024), and Ministry of Health and Welfare (MOHW104-TDU-B-212-124-003, Health and welfare surcharge of tobacco products) of Taiwan.	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J	Guaman-Ortiz, LM; Bailon-Moscoso, N; Morocho, V; Vega-Ojeda, D; Gordillo, F; Suarez, AI				Guaman-Ortiz, Luis Miguel; Bailon-Moscoso, Natalia; Morocho, Vladimir; Vega-Ojeda, Daisy; Gordillo, Fernando; Suarez, Alirica I.			Onoseriolide, from Hedyosmum racemosum, induces cytotoxicity and apoptosis in human colon cancer cells	NATURAL PRODUCT RESEARCH			English	Article						Hedyosmum racemosum; onoseriolide; colon cancer; cytotoxicity; apoptosis; autophagy	CHEMICAL-CONSTITUENTS; SESQUITERPENES; AUTOPHAGY; PLANTS	The number of colon cancer patients is increasing, and new alternatives for treatment are important. We focused on the sesquiterpene lactone onoseriolide from Hedyosmum racemosum, which is widely used in traditional medicine. This compound was evaluated to determine its cytotoxic effect and the mechanism of cell death that is induced in the human colon cancer cell line RKO. A dose-dependent decrease in cell viability was observed. p53 expression increased followed by an increase in p21 expression, which is involved in cell cycle arrest in the G(2)/M phase. Caspase-3 activation and PARP-1 cleavage, which are apoptotic markers, were also monitored. Autophagy markers were also studied, and Beclin 1 was downregulated, while LC-3II increased in a dose-dependent manner. There were no changes in SQSTM1/p62 regulation. Onoseriolide exerts cytotoxic and cytostatic effects, activating the autophagy pathway as a protective mechanism and apoptosis as the cell death pathway.	[Guaman-Ortiz, Luis Miguel; Bailon-Moscoso, Natalia; Vega-Ojeda, Daisy] Univ Tecn Particular Loja, Dept Ciencias Salud, Loja, Ecuador; [Morocho, Vladimir; Gordillo, Fernando; Suarez, Alirica I.] Univ Tecn Particular Loja, Dept Quim & Ciencias Exactas, Loja, Ecuador; [Suarez, Alirica I.] Cent Univ Venezuela, Fac Farm, Caracas, Venezuela		Guaman-Ortiz, LM (corresponding author), Univ Tecn Particular Loja, Dept Ciencias Salud, Loja, Ecuador.	lmguaman@utpl.edu.ec	Bailon-Moscoso, Natalia/Z-1548-2019; Morocho, Vladimir/Z-2544-2019	Morocho, Vladimir/0000-0001-5156-0700	Universidad Tecnica Particular de Loja (UTPL), Loja, Ecuador [PROY_QUI_1144]	This work was supported by Universidad Tecnica Particular de Loja (UTPL), Loja, Ecuador. PROY_QUI_1144.	Acebey L, 2010, PLANTA MED, V76, P365, DOI 10.1055/s-0029-1186192; Babaei G, 2018, BIOMED PHARMACOTHER, V106, P239, DOI 10.1016/j.biopha.2018.06.131; Cao CM, 2008, CHEM BIODIVERS, V5, P219, DOI 10.1002/cbdv.200890020; Chino H, 2019, MOL CELL, V74, P909, DOI 10.1016/j.molcel.2019.03.033; Chiu WJ, 2018, J CLIN MED, V7, DOI 10.3390/jcm7100321; Diaz-Villasenor A, 2008, TOXICOL APPL PHARM, V231, P291, DOI 10.1016/j.taap.2008.05.018; Fernandez AF, 2018, NATURE, V558, P136, DOI 10.1038/s41586-018-0162-7; Galluzzi L, 2018, CELL DEATH DIFFER, V25, P486, DOI 10.1038/s41418-017-0012-4; Geng YD, 2020, NAT PROD RES, V34, P2616, DOI 10.1080/14786419.2018.1544976; Gordy C, 2012, PROTEIN CELL, V3, P17, DOI 10.1007/s13238-011-1127-x; Hu M, 2018, GENE, V678, P261, DOI 10.1016/j.gene.2018.08.048; KAWABATA J, 1981, AGR BIOL CHEM TOKYO, V45, P1447, DOI 10.1080/00021369.1981.10864706; Li JN, 2001, CANCER RES, V61, P1493; Liu R, 2019, MOLECULES, V24, DOI 10.3390/molecules24101908; Radice M, 2019, J ETHNOPHARMACOL, V244, DOI 10.1016/j.jep.2019.111932; Shoaib M, 2017, BMC COMPLEM ALTERN M, V17, DOI 10.1186/s12906-016-1517-y; Su KM, 2014, BOT STUD, V55, DOI 10.1186/1999-3110-55-21; Teng A, 2019, CANCER-AM CANCER SOC, V125, P3749, DOI 10.1002/cncr.32325; Todzia Carol A., 1993, Novon, V3, P81, DOI 10.2307/3391430; Wang YS, 2017, CASE REP INFECT DIS, V2017, P1, DOI 10.1155/2017/7052908	20	2	2	0	1	TAYLOR & FRANCIS LTD	ABINGDON	2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND	1478-6419	1478-6427		NAT PROD RES	Nat. Prod. Res.	SEP 17	2021	35	18					3151	3155		10.1080/14786419.2019.1690485		NOV 2019	5	Chemistry, Applied; Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	UP6GB	WOS:000497019400001	31736362				2022-04-25	
J	Guo, WJ; Sun, Y; Liu, W; Wu, XX; Guo, LL; Cai, PF; Wu, XF; Wu, XD; Shen, Y; Shu, YQ; Gu, YH; Xu, Q				Guo, Wenjie; Sun, Yang; Liu, Wen; Wu, Xingxin; Guo, Lele; Cai, Peifen; Wu, Xuefeng; Wu, Xudong; Shen, Yan; Shu, Yongqian; Gu, Yanhong; Xu, Qiang			Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer	AUTOPHAGY			English	Article						mitophagy; inflammasome; inflammation-associated cancer; colitis; andrographolide	DEXTRAN SULFATE SODIUM; AUTOPHAGIC CELL-DEATH; BOWEL-DISEASE; ULCERATIVE-COLITIS; COLORECTAL-CANCER; MITOCHONDRIAL-DNA; MURINE COLITIS; T-CELLS; INTERLEUKIN-1; ANDROGRAPHOLIDE	Nonresolving inflammation in the intestine predisposes individuals to the development of colitis-associated cancer (CAC). Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and CAC. However, few agents have been reported to reduce CAC by targeting inflammasomes. Here we show that the small molecule andrographolide (Andro) protects mice against azoxymethane/dextran sulfate sodium-induced colon carcinogenesis through inhibiting the NLRP3 inflammasome. Administration of Andro significantly attenuated colitis progression and tumor burden. Andro also inhibited NLRP3 inflammasome activation in macrophages both in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3-PYCARD-CASP1 complex assembly, and lower IL1B secretion. Importantly, Andro was found to trigger mitophagy in macrophages, leading to a reversed mitochondrial membrane potential collapse, which in turn inactivated the NLRP3 inflammasome. Moreover, downregulation of the PIK3CA-AKT1-MTOR-RPS6KB1 pathway accounted for Andro-induced autophagy. Finally, Andro-driven inhibition of the NLRP3 inflammasome and amelioration of murine models for colitis and CAC were significantly blocked by BECN1 knockdown, or by various autophagy inhibitors. Taken together, our findings demonstrate that mitophagy-mediated NLRP3 inflammasome inhibition by Andro is responsible for the prevention of CAC. Our data may help guide decisions regarding the use of Andro in patients with inflammatory bowel diseases, which ultimately reduces the risk of CAC.	[Guo, Wenjie; Sun, Yang; Liu, Wen; Wu, Xingxin; Guo, Lele; Wu, Xuefeng; Wu, Xudong; Shen, Yan; Xu, Qiang] Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Sch Life Sci, Nanjing 210008, Jiangsu, Peoples R China; [Guo, Wenjie] Jiangsu Univ, Sch Pharm, Zhenjiang, Peoples R China; [Cai, Peifen; Shu, Yongqian; Gu, Yanhong] Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, Nanjing, Peoples R China		Sun, Y (corresponding author), Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Sch Life Sci, Nanjing 210008, Jiangsu, Peoples R China.	yangsun@nju.edu.cn; guyhphd@163.com; molpharm@163.com	Wu, xingxin/A-3595-2009; Guo, Wenjie/AAQ-7553-2020; Shu, Yongqian/ABD-5698-2021		Science Fund for Creative Research Groups of NSFCScience Fund for Creative Research Groups [81121062]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [91229109, 81330079, 90913023, 91129728]; National Science and Technology Major Project [2012ZX09304-001]; Jiangsu Province Clinical Science and Technology Project (Clinical Research Center) [BL2012008]	This work was supported by Science Fund for Creative Research Groups of NSFC (No. 81121062), National Natural Science Foundation of China (Nos. 91229109, 81330079, 90913023, 91129728), National Science and Technology Major Project (No. 2012ZX09304-001), and Jiangsu Province Clinical Science and Technology Project (Clinical Research Center, BL2012008).	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J	Hirayama, A; Kami, K; Sugimoto, M; Sugawara, M; Toki, N; Onozuka, H; Kinoshita, T; Saito, N; Ochiai, A; Tomita, M; Esumi, H; Soga, T				Hirayama, Akiyoshi; Kami, Kenjiro; Sugimoto, Masahiro; Sugawara, Maki; Toki, Naoko; Onozuka, Hiroko; Kinoshita, Taira; Saito, Norio; Ochiai, Atsushi; Tomita, Masaru; Esumi, Hiroyasu; Soga, Tomoyoshi			Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry	CANCER RESEARCH			English	Article							ADENYLATE ENERGY-CHARGE; COLORECTAL-CANCER; AUTOPHAGY; HYPOXIA; CELLS; ACID; PATHWAYS; GROWTH; MITOCHONDRIA; NUCLEOTIDES	Most cancer cells predominantly produce energy by glycolysis rather than oxidative phosphorylation via the tricarboxylic acid (TCA) cycle, even in the presence of an adequate oxygen supply (Warburg effect). However, little has been reported regarding the direct measurements of global metabolites in clinical tumor tissues. Here, we applied capillary electrophoresis time-of-flight mass spectrometry, which enables comprehensive and quantitative analysis of charged metabolites, to simultaneously measure their levels in tumor and grossly normal tissues obtained from 16 colon and 12 stomach cancer patients. Quantification of 94 metabolites in colon and 95 metabolites in stomach involved in glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acid and nucleotide metabolisms resulted in the identification of several cancer-specific metabolic traits. Extremely low glucose and high lactate and glycolytic intermediate concentrations were found in both colon and stomach tumor tissues, which indicated enhanced glycolysis and thus confirmed the Warburg effect. Significant accumulation of all amino acids except glutamine in the tumors implied autophagic degradation of proteins and active glutamine breakdown for energy production, i.e., glutaminolysis. In addition, significant organ-specific differences were found in the levels of TCA cycle intermediates, which reflected the dependency of each tissue on aerobic respiration according to oxygen availability. The results uncovered unexpectedly poor nutritional conditions in the actual tumor microenvironment and showed that capillary electrophoresis coupled to mass spectrometry-based metabolomics, which is capable of quantifying the levels of energy metabolites in tissues, could be a powerful tool for the development of novel anticancer agents that target cancer-specific metabolism. [Cancer Res 2009;69(11):4918-25]	[Hirayama, Akiyoshi; Kami, Kenjiro; Sugimoto, Masahiro; Sugawara, Maki; Toki, Naoko; Tomita, Masaru; Soga, Tomoyoshi] Keio Univ, Inst Adv Biosci, Yamagata 9970052, Japan; [Onozuka, Hiroko; Kinoshita, Taira; Saito, Norio; Ochiai, Atsushi; Esumi, Hiroyasu] Natl Canc Ctr Hosp E, Chiba, Japan		Soga, T (corresponding author), Keio Univ, Inst Adv Biosci, Yamagata 9970052, Japan.	soga@sfc.keio.ac.jp	Sugimoto, Masahiro/B-7391-2014; Soga, Tomoyoshi/B-8105-2014	Soga, Tomoyoshi/0000-0001-9502-2509; Sugimoto, Masahiro/0000-0003-3316-2543	Ministry of Health, Labour and WelfareMinistry of Health, Labour and Welfare, Japan; Global COE ProgramMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Ministry of Education, Culture, Sports, Science and Technology of JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); City of Tsuruoka	Grant support: Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare and a grant from the Global COE Program entitled, "Human Metabolomic Systems Biology." This work was also supported by KAKENHI (Grant-in-Aid for Scientific Research) on Priority Areas "Systems Genomes" and on "Lifesurveyor" from the Ministry of Education, Culture, Sports, Science and Technology of Japan as well as research foods from the Yamagata prefectural government and the City of Tsuruoka.	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JUN 1	2009	69	11					4918	4925		10.1158/0008-5472.CAN-08-4806			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	455JL	WOS:000266755000047	19458066				2022-04-25	
J	Zhang, HB; Ramakrishnan, SK; Triner, D; Centofanti, B; Maitra, D; Gyorffy, B; Sebolt-Leopold, JS; Dame, MK; Varani, J; Brenner, DE; Fearon, ER; Omary, MB; Shah, YM				Zhang, Huabing; Ramakrishnan, Sadeesh K.; Triner, Daniel; Centofanti, Brook; Maitra, Dhiman; Gyorffy, Balazs; Sebolt-Leopold, Judith S.; Dame, Michael K.; Varani, James; Brenner, Dean E.; Fearon, Eric R.; Omary, M. Bishr; Shah, Yatrik M.			Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1	SCIENCE SIGNALING			English	Article							PHOTODYNAMIC THERAPY; CHOROIDAL NEOVASCULARIZATION; MACULAR DEGENERATION; CELL-PROLIFERATION; TEAD/TEF FAMILY; HIPPO; SURVIVAL; PATHWAY; GROWTH; ACTIVATION	Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1 activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. We found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetically or chemically induced mouse models of CRC, in patient-derived xenografts, and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high-molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (signal transducer and activator of transcription 3; a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viability of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells under hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death, whereas culturing cells under normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers.	[Zhang, Huabing; Ramakrishnan, Sadeesh K.; Triner, Daniel; Centofanti, Brook; Maitra, Dhiman; Omary, M. Bishr; Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA; [Gyorffy, Balazs] Semmelweis Univ, Dept Pediat 2, MTA SE Pediat & Nephrol Res Grp, MTA TTK Lendulet Canc Biomarker Res Grp, H-1117 Budapest, Hungary; [Sebolt-Leopold, Judith S.] Univ Michigan, Sch Med, Dept Radiol, Ann Arbor, MI 48109 USA; [Dame, Michael K.; Varani, James; Brenner, Dean E.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA; [Fearon, Eric R.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA; [Fearon, Eric R.; Omary, M. Bishr; Shah, Yatrik M.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA; [Omary, M. Bishr] Dept Vet Affairs Ann Arbor Hlth Care Syst, Ann Arbor, MI 48105 USA		Shah, YM (corresponding author), Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA.	shahy@umich.edu	Gyorffy, Balazs/AAA-9135-2021	Omary, Bishr/0000-0002-8624-2347; zhang, huabing/0000-0001-8402-7830; , dhiman/0000-0002-8775-2963; Gyorffy, Balazs/0000-0002-5772-3766; Dame, Michael K/0000-0003-3760-1654	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA148828, DK095201, CA181855-01, CA046592-26S3, DK52951]; University of Michigan Gastrointestinal Peptide Research Center grant [DK034933]; GI SPORE [CA130810]; OTKA (Hungarian Scientific Research Fund) grantOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [K108655]; American Heart AssociationAmerican Heart Association [15POST22650034]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA046592, R21CA181855, R01CA148828, P50CA130810] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK052951, P30DK034933, R56DK052951, K01DK091415, R01DK095201, P30DK020572] Funding Source: NIH RePORTER	This work was supported by NIH grants CA148828 and DK095201 to Y.M.S; CA181855-01 and CA046592-26S3 to J.V.; and DK52951 to M.B.O.; University of Michigan Gastrointestinal Peptide Research Center grant DK034933; GI SPORE CA130810. B.G. was supported by OTKA (Hungarian Scientific Research Fund) grant K108655. S.K.R was supported by a postdoctoral fellowship from the American Heart Association (15POST22650034).	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Signal.	OCT 6	2015	8	397							ra98	10.1126/scisignal.aac5418			12	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	CU1YU	WOS:000363319100001	26443705	Green Accepted			2022-04-25	
J	Wang, Z; Yang, X; Liu, C; Li, X; Zhang, BY; Wang, B; Zhang, Y; Song, C; Zhang, TZ; Liu, MH; Liu, BY; Ren, MM; Jiang, HP; Zou, JH; Liu, XY; Zhang, HQ; Zhu, WG; Yin, YX; Zhang, Z; Gu, W; Luo, JY				Wang, Zhe; Yang, Xin; Liu, Cheng; Li, Xin; Zhang, Buyu; Wang, Bo; Zhang, Yu; Song, Chen; Zhang, Tianzhuo; Liu, Minghui; Liu, Boya; Ren, Mengmeng; Jiang, Hongpeng; Zou, Junhua; Liu, Xiaoyun; Zhang, Hongquan; Zhu, Wei-Guo; Yin, Yuxin; Zhang, Zhang; Gu, Wei; Luo, Jianyuan			Acetylation of PHF5A Modulates Stress Responses and Colorectal Carcinogenesis through Alternative Splicing-Mediated Upregulation of KDM3A	MOLECULAR CELL			English	Article							GENE-EXPRESSION; CANCER; AUTOPHAGY; JMJD1A; REQUIREMENT; METABOLISM; MECHANISMS; GROWTH; JHDM2A	Alternative pre-mRNA-splicing-induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. Here, we uncover a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHF5A, a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses, which is dependent on p300. PHF5A acetylation strengthens the interaction among U2 snRNPs and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation-induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer. Our findings uncover a mechanism of an anti-stress pathway through which acetylation on PHF5A promotes the cancer cells' capacity for stress resistance and consequently contributes to colon carcinogenesis.	[Wang, Zhe; Yang, Xin; Zhang, Yu; Song, Chen; Zhang, Tianzhuo; Liu, Minghui; Liu, Boya; Ren, Mengmeng; Zou, Junhua; Luo, Jianyuan] Peking Univ, Hlth Sci Ctr, Ctr Med Genet, Dept Med Genet, Beijing 100191, Peoples R China; [Liu, Cheng; Zhang, Hongquan] Peking Univ, Hlth Sci Ctr, Dept Anat Histol & Embryol, Beijing 100191, Peoples R China; [Li, Xin] Peking Union Med Coll Hosp, Dept Allergy, Beijing 100730, Peoples R China; [Zhang, Buyu; Liu, Xiaoyun] Peking Univ, Hlth Sci Ctr, Dept Microbiol, Beijing 100191, Peoples R China; [Wang, Bo; Jiang, Hongpeng] Peking Univ, Peoples Hosp, Dept Gastroenterol Surg, Beijing 100044, Peoples R China; [Zhu, Wei-Guo] Shenzhen Univ, Sch Med, Dept Biochem & Mol Biol, Shenzhen 518060, Peoples R China; [Yin, Yuxin] Peking Univ, Hlth Sci Ctr, Inst Syst Biomed, Beijing 100191, Peoples R China; [Zhang, Zhang] Jingjie PTM Biolab Hangzhou Co Ltd, Hangzhou 310018, Zhejiang, Peoples R China; [Gu, Wei] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA; [Luo, Jianyuan] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing Key Lab Prot Posttranslat Modificat & Cel, Beijing 100191, Peoples R China		Luo, JY (corresponding author), Peking Univ, Hlth Sci Ctr, Ctr Med Genet, Dept Med Genet, Beijing 100191, Peoples R China.; Luo, JY (corresponding author), Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing Key Lab Prot Posttranslat Modificat & Cel, Beijing 100191, Peoples R China.	luojianyuan@bjmu.edu.cn	Luo, Jianyuan/ABI-7585-2020	Luo, Jianyuan/0000-0001-6057-2914; Yang, Xin/0000-0003-0222-5839; Zhu, Wei-Guo/0000-0001-8385-6581	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81874147, 81671389, 81471405, 81621063, 81720108027]; Innovative Fund for Doctoral Students of Peking University Health Science Center (2018)	We thank John Luo and Ruizhi Li (Cornell University) for editorial assistance. We thank Peng Zhang (Northwest A&F University) for RNA sequencing analysis assistance. This work was supported by National Natural Science Foundation of China (81874147, 81671389, 81471405, 81621063, and 81720108027), and Innovative Fund for Doctoral Students of Peking University Health Science Center (2018).	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Cell	JUN 20	2019	74	6					1250	+		10.1016/j.molcel.2019.04.009			20	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	IE2RL	WOS:000472231600015	31054974	Bronze			2022-04-25	
J	Lin, KC; Lin, MW; Hsu, MN; Guan, YC; Chao, YC; Tuan, HY; Chiang, CS; Hu, YC				Lin, Kuan-Chen; Lin, Mei-Wei; Hsu, Mu-Nung; Guan Yu-Chen; Chao, Yu-Chan; Tuan, Hsing-Yu; Chiang, Chi-Shiun; Hu, Yu-Chen			Graphene oxide sensitizes cancer cells to chemotherapeutics by inducing early autophagy events, promoting nuclear trafficking and necrosis	THERANOSTICS			English	Article						graphene oxide; autophagy; cisplatin; chemoresistance; nuclear import; LC3	CISPLATIN RESISTANCE; PHOTOTHERMAL THERAPY; SIGNALING PATHWAYS; EPIGENETIC CONTROL; IN-SITU; COMPLEXES; MEMBRANE; AGENTS; ACETYLATION; MACROPHAGES	Rationale: Cisplatin (CDDP) is a broad-spectrum anticancer drug but chemoresistance to CDDP impedes its wide use for cancer therapy. Autophagy is an event occurring in the cytoplasm and cytoplasmic LC3 puncta formation is a hallmark of autophagy. Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we aimed to evaluate whether combined use of GO with CDDP (GO/CDDP) overcomes chemoresistance in different cancer cells and uncover the underlying mechanism. Methods: We treated different cancer cells with GO/CDDP and evaluated the cytotoxicity, death mechanism, autophagy induction and nuclear entry of CDDP. We further knocked down genes essential for autophagic flux and deciphered which step is critical to nuclear import and cell death. Finally, we performed immunoprecipitation, mass spectrometry and immunofluorescence labeling to evaluate the association of LC3 and CDDP. Results: We uncovered that combination of GO and CDDP (GO/CDDP) promoted the killing of not only CT26 cells, but also ovarian, cervical and prostate cancer cells. In the highly chemosensitized Skov-3 cells, GO/CDDP significantly enhanced concurrent nuclear import of CDDP and autophagy marker LC3 and elevated cell necrosis, which required autophagy initiation and progression but did not necessitate late autophagy events (e.g., autophagosome completion and autolysosome formation). The GO/CDDP-elicited nuclear trafficking and cell death also required importin alpha/beta, and LC3 also co-migrated with CDDP and histone H1/H4 into the nucleus. In particular, GO/CDDP triggered histone H4 acetylation in the nucleus, which could decondense the chromosome and enable CDDP to more effectively access chromosomal DNA to trigger cell death. Conclusion: These findings shed light on the mechanisms of GO/CDDP-induced chemosensitization and implicate the potential applications of GO/CDDP to treat multiple cancers.	[Lin, Kuan-Chen; Lin, Mei-Wei; Hsu, Mu-Nung; Tuan, Hsing-Yu; Hu, Yu-Chen] Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu 30013, Taiwan; [Lin, Mei-Wei] Ind Technol Res Inst, Biomed Technol & Device Res Labs, Hsinchu 31057, Taiwan; [Guan Yu-Chen] Natl Chiao Tung Univ, Inst Biomed Engn, Hsinchu 30010, Taiwan; [Guan Yu-Chen] Natl Chiao Tung Univ, Dept Biol Sci & Technol, Hsinchu 30010, Taiwan; [Chao, Yu-Chan] Acad Sinica, Inst Mol Biol, Taipei 11529, Taiwan; [Chiang, Chi-Shiun] Natl Tsing Hua Univ, Dept Biomed Engn & Environm Sci, Hsinchu 30013, Taiwan; [Hu, Yu-Chen] Natl Tsing Hua Univ, Frontier Res Ctr Fundamental & Appl Sci Matters, Hsinchu 30013, Taiwan		Hu, YC (corresponding author), Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu 30013, Taiwan.; Hu, YC (corresponding author), Natl Tsing Hua Univ, Frontier Res Ctr Fundamental & Appl Sci Matters, Hsinchu 30013, Taiwan.	yuchen@che.nthu.edu.tw	Chao, Yu-Chan/ABF-6571-2021; Chiang, Chi-Shiun/A-9562-2008	Chao, Yu-Chan/0000-0002-9528-8806; Chiang, Chi-Shiun/0000-0002-2581-4129; Tuan, Hsing-Yu/0000-0003-2819-2270	National Tsing Hua University (Toward World-Class University Project) [106N526CE1, 105N526CE1, 104N2050E1]; Ministry of Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [MOST 103-2221-E-007-093-MY3]	The authors acknowledge the support from the National Tsing Hua University (Toward World-Class University Project 106N526CE1, 105N526CE1, 104N2050E1) and Ministry of Science and Technology (MOST 103-2221-E-007-093-MY3).	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J	Nagappan, A; Lee, WS; Yun, JW; Lu, JN; Chang, SH; Jeong, JH; Kim, GS; Jung, JM; Hong, SC				Nagappan, Arulkumar; Lee, Won Sup; Yun, Jeong Won; Lu, Jing Nan; Chang, Seong-Hwan; Jeong, Jae-Hoon; Kim, Gon Sup; Jung, Jin-Myung; Hong, Soon Chan			Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells	PLOS ONE			English	Article							ARSENIC TRIOXIDE; POLY(ADP-RIBOSE) POLYMERASE; CYCLE PROGRESSION; DOWN-REGULATION; UP-REGULATION; DEATH; PATHWAY; BCL-2; MODULATION; INDUCTION	Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate-ribose) polymerase (PARP) activation were also observed in As(4)O(6)treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, Delta psi m) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B-cell lymphoma-2 (Bcl-2) and Xlinked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubuleassociated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose-and time-dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.	[Nagappan, Arulkumar; Lee, Won Sup; Yun, Jeong Won; Lu, Jing Nan] Gyeongsang Natl Univ, Sch Med, Dept Internal Med, Inst Hlth Sci, 90 Chilam Dong, Jinju, South Korea; [Chang, Seong-Hwan] Konkuk Univ, Sch Med, Dept Surg, Seoul, South Korea; [Jeong, Jae-Hoon] Korea Inst Radiol & Med Sci, Res Ctr Radiotherapy, Seoul, South Korea; [Kim, Gon Sup] Gyeongsang Natl Univ, Res Inst Life Sci, 900 Gajwadong, Jinju, South Korea; [Kim, Gon Sup] Gyeongsang Natl Univ, Coll Vet Med, 900 Gajwadong, Jinju, South Korea; [Jung, Jin-Myung] Gyeongsang Natl Univ, Sch Med, Dept Neurosurg, Inst Hlth Sci, 90 Chilam Dong, Jinju, South Korea; [Hong, Soon Chan] Gyeongsang Natl Univ, Sch Med, Inst Hlth Sci, Dept Surg, 90 Chilam Dong, Jinju, South Korea; [Lu, Jing Nan] Fifth Hosp Shijiazhuang, Shijiazhuang, Peoples R China		Lee, WS (corresponding author), Gyeongsang Natl Univ, Sch Med, Dept Internal Med, Inst Hlth Sci, 90 Chilam Dong, Jinju, South Korea.	lwshmo@hanmail.net		Chang, Seong-Hwan/0000-0002-0419-4418; Hong, Soon-Chan/0000-0003-4499-8741	National Research Foundation of Korea (NRF) - Korea government (MEST)Ministry of Education, Science and Technology, Republic of KoreaNational Research Foundation of KoreaKorean Government [20120002631]; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of KoreaMinistry of Health & Welfare, Republic of Korea [0820050]	The present study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government (MEST) (no. 20120002631), in part by a grant of the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (0820050).	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J	Torricelli, C; Daveri, E; Salvadori, S; Valacchi, G; Ietta, F; Muscettola, M; Carlucci, F; Maioli, E				Torricelli, C.; Daveri, E.; Salvadori, S.; Valacchi, G.; Ietta, F.; Muscettola, M.; Carlucci, F.; Maioli, E.			Phosphorylation-independent mTORC1 inhibition by the autophagy inducer Rottlerin	CANCER LETTERS			English	Article						Rottlerin; AMPK; mTOR; Raptor; Autophagy	KINASE-C-DELTA; COLON-CARCINOMA CELLS; MAMMALIAN TARGET; HUMAN PROSTATE; S6 KINASE; PROTEIN; CANCER; AMPK; ULK1; MIGRATION	We recently found that Rottlerin not only inhibits proliferation but also causes Bcl-2- and Beclin 1-independent autophagic death in apoptosis-resistant breast adenocarcinoma MCF-7 cells. Having excluded a role for canonical signaling pathways, the current study was aimed to investigate the contribution of the AMPK/mTOR axis in autophagy induction and to search for the upstream signaling molecules potentially targeted by Rottlerin. Using several enzyme inhibitors, Western blotting analysis, mTOR siRNA and pull down assay, we demonstrate that the Rottlerin-triggered autophagy is mediated by inhibition of mTORC1 activity through a novel AMPK and mTORC1 phosphorylation-independent mechanism, likely mediated by the direct interaction between Rottlerin and mTOR. (C) 2015 Elsevier Ireland Ltd. All rights reserved.	[Torricelli, C.; Daveri, E.; Salvadori, S.; Ietta, F.; Maioli, E.] Univ Siena, Dept Life Sci, I-53100 Siena 7, Italy; [Valacchi, G.] Univ Ferrara, Dept Biol & Evolut, I-44100 Ferrara, Italy; [Valacchi, G.] Kyung Hee Univ, Dept Food & Nutr, Seoul 130701, South Korea; [Muscettola, M.] Univ Siena, Dept Med Surg & Neurosci, I-53100 Siena 4, Italy; [Carlucci, F.] Univ Siena, Dept Med Biotechnol, I-53100 Siena 4, Italy		Maioli, E (corresponding author), Univ Siena, Dept Life Sci, Via Aldo Moro, I-53100 Siena 7, Italy.	emanuela.maioli@unisi.it	Daveri, Elena/C-6910-2019	Daveri, Elena/0000-0001-8351-2762; MAIOLI, Emanuela/0000-0002-0701-1445; Ietta, Francesca/0000-0002-2160-8790	Istituto Toscano Tumori	This work has received financial support from the Istituto Toscano Tumori (grant 2010).	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APR 28	2015	360	1					17	27		10.1016/j.canlet.2015.01.040			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CE6UO	WOS:000351973900003	25661734				2022-04-25	
J	Pourhanifeh, MH; Mehrzadi, S; Kamali, M; Hosseinzadeh, A				Pourhanifeh, Mohammad Hossein; Mehrzadi, Saeed; Kamali, Mahboobeh; Hosseinzadeh, Azam			Melatonin and gastrointestinal cancers: Current evidence based on underlying signaling pathways	EUROPEAN JOURNAL OF PHARMACOLOGY			English	Review						Melatonin; Oral cancer; Esophageal cancer; Gastric cancer; Liver cancer; Hepatocellular carcinoma; Cholangiocarcinoma; Colon cancer; Colorectal cancer; Pancreatic cancer; Angiogenesis; Apoptosis; Autophagy; Inflammation; Oxidative stress; Proliferation; Metastasis; Invasion; Signaling pathway; Gastrointestinal cancers; Resistance	HUMAN HEPATOCELLULAR-CARCINOMA; ENDOPLASMIC-RETICULUM STRESS; APOPTOTIC CELL-DEATH; INFLAMMATORY-BOWEL-DISEASE; ENDOTHELIAL GROWTH-FACTOR; PINEAL HORMONE MELATONIN; FACTOR-KAPPA-B; COLORECTAL-CANCER; INTRAHEPATIC CHOLANGIOCARCINOMA; IN-VITRO	Gastrointestinal (GI) cancers, leading causes of cancer-related deaths, have been serious challenging human diseases up to now. Because of high rates of mortality, late-stage diagnosis, metastasis to distant locations, and low effectiveness and adverse events of routine standard therapies, the quality of life and survival time are low in patients with GI cancers. Hence, many efforts need to be done to explore and find novel efficient treatments. Beneficial effects of melatonin have been reported in a wide variety of human diseases. Melatonin has antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. Various studies have showed the regulatory effects of melatonin on apoptotsis, autophagy and angiogenesis; these properties result in the inhibition of invasion, migration, and proliferation of GI cancer cells in vivo and in vitro. Together, this review suggests that melatonin in combination with anticancer agents may improve the efficacy of routine medicine and survival rate of patients with cancer.	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J. Pharmacol.	NOV 5	2020	886								173471	10.1016/j.ejphar.2020.173471			15	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	OE6JJ	WOS:000580634600022	32877658				2022-04-25	
J	Moura, AF; Lima, KSB; Sousa, TS; Marinho, JDB; Pessoa, C; Silveira, ER; Pessoa, ODL; Costa-Lotufo, LV; Moraes, MO; Araujo, AJ				Moura, A. F.; Lima, K. S. B.; Sousa, T. S.; Marinho-Filho, J. D. B.; Pessoa, C.; Silveira, E. R.; Pessoa, O. D. L.; Costa-Lotufo, L. V.; Moraes, M. O.; Araujo, A. J.			In vitro antitumor effect of a lignan isolated from Combretum fruticosum, trachelogenin, in HCT-116 human colon cancer cells	TOXICOLOGY IN VITRO			English	Article						Lignans; Combretum fruticosum; Autophagy; Anticancer	COLORIMETRIC ASSAY; SIGNALING PATHWAY; GLIOMA-CELLS; AUTOPHAGY; DEATH; ACCUMULATION; HYDROLYSIS; INDUCTION; FRUIT	The use of natural products in therapeutics has been growing over the years. Lignans are compounds with large pharmaceutical use, which has aroused interest in the search for new drugs to treat diseases. The present study evaluated the cytotoxicity of (-)-trachelogenin, a dibenzylbutyrolactone type lignan isolated from Combretum fruticosum, against several tumor and non-tumor cell lines using the MTT assay and its possible mechanism of action. (-)-Trachelogenin showed IC50 values ranging of 0.8-32.4 mu M in SF-295 and HL-60 cell lines, respectively and IC50 values > 64 mu M in non-tumor cell lines. (-)-trachelogenin persistently induced autophagic cell death, with cytoplasmic vacuolization and formation of autophagosomes mediated by increasing LC3 activation and altering the expression levels of Beclin-1.	[Moura, A. F.; Marinho-Filho, J. D. B.; Pessoa, C.; Costa-Lotufo, L. V.; Moraes, M. O.; Araujo, A. J.] Univ Fed Ceara, Dept Fisiol & Farmacol, BR-60430270 Fortaleza, Ceara, Brazil; [Lima, K. S. B.; Silveira, E. R.; Pessoa, O. D. L.] Univ Fed Ceara, Dept Quim Organ & Inorgan, BR-60451970 Fortaleza, Ceara, Brazil; [Lima, K. S. B.; Sousa, T. S.; Silveira, E. R.; Pessoa, O. D. L.] Univ Fed Ceara, Dept Quim Organ & Inorgan, BR-60021940 Fortaleza, Ceara, Brazil; [Lima, K. S. B.] Univ Estadual Ceara, Dept Quim, BR-60714903 Fortaleza, Ceara, Brazil; [Sousa, T. S.] Inst Fed Educ Ciencia & Tecnol Piaui, BR-6460000 Picos, PI, Brazil; [Marinho-Filho, J. D. B.; Araujo, A. J.] Univ Fed Piaui, Curso Med, BR-64200500 Parnaiba, PI, Brazil; [Costa-Lotufo, L. V.] Univ Sao Paulo, Dept Farmacol, BR-05508900 Sao Paulo, SP, Brazil		Moura, AF (corresponding author), NPDM, Coronel Nunes Melo 1000, BR-60430270 Fortaleza, Ceara, Brazil.	andreafmoura@gmail.com; edil@ufc.br; odorico@ufc.br	Pessoa, Otilia DL/L-8863-2016; Araújo, Ana Jersia/D-1049-2019; Marinho-Filho, José Delano Barreto/D-1232-2019; Costa-Lotufo, Leticia V/D-4998-2014; Costa-Lotufo, Leticia/ABC-5742-2021	Pessoa, Otilia DL/0000-0002-1617-7586; Araújo, Ana Jersia/0000-0001-7182-7097; Marinho-Filho, José Delano Barreto/0000-0002-2493-6159; Costa-Lotufo, Leticia V/0000-0003-1861-5153; Costa-Lotufo, Leticia/0000-0003-1861-5153			American Cancer Society, 2016, KEY STAT COL CANC; Bardhan Kankana, 2013, Cancers (Basel), V5, P676, DOI 10.3390/cancers5020676; BIEDERBICK A, 1995, EUR J CELL BIOL, V66, P3; Braga FC, 2007, FITOTERAPIA, V78, P353, DOI [10.1016/j.fitote.2007.02.007, 10.1016/J.fitote.2007.02.007]; Chifenti Barbara, 2013, Clin Exp Reprod Med, V40, P33, DOI 10.5653/cerm.2013.40.1.33; DARZYNKIEWICZ Z, 1992, CYTOMETRY, V13, P795, DOI 10.1002/cyto.990130802; Lima GRD, 2012, MOLECULES, V17, P9142, DOI 10.3390/molecules17089142; Eloff JN, 2008, J ETHNOPHARMACOL, V119, P686, DOI 10.1016/j.jep.2008.07.051; Geng Y, 2010, NEURO-ONCOLOGY, V12, P473, DOI 10.1093/neuonc/nop048; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Haeri Mohammad, 2012, J Ophthalmic Vis Res, V7, P45; ICHIKAWA K, 1986, CHEM PHARM BULL, V34, P3514; Institute Nacional do Cancer (INCA), 2016, EST CANC BRAS; Isoda H, 2014, CHEM-BIOL INTERACT, V220, P269, DOI 10.1016/j.cbi.2014.07.006; IWAKAMI S, 1992, CHEM PHARM BULL, V40, P1196, DOI 10.1248/cpb.40.1196; JOHN LMD, 1992, J NAT PROD, V55, P1313, DOI 10.1021/np50087a022; Kang K, 2007, BIOL PHARM BULL, V30, P2352, DOI 10.1248/bpb.30.2352; Kanzawa T, 2003, CANCER RES, V63, P2103; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Lee Kuo-Hsiung, 2003, Phytochemistry Reviews, V2, P341, DOI 10.1023/B:PHYT.0000045495.59732.58; Lee W, 2015, SCI REP-UK, V5, DOI 10.1038/srep09701; LOWRY OH, 1951, J BIOL CHEM, V193, P265; MACRAE WD, 1984, PHYTOCHEMISTRY, V23, P1207, DOI 10.1016/S0031-9422(00)80428-8; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; MELO JG, 2007, ACTA BOT BRAS, V21, P27; Mervai Z, 2015, FITOTERAPIA, V100, P19, DOI 10.1016/j.fitote.2014.10.017; MOSMANN T, 1983, J IMMUNOL METHODS, V65, P55, DOI 10.1016/0022-1759(83)90303-4; Nascimento S.C., 1985, REV I ANTIBIOT U FED, V22, P19; Paglin S, 2001, CANCER RES, V61, P439; Paska C., 1996, TOXICOL LETT, V88, P104; Qian XJ, 2016, J GEN VIROL, V97, P1134, DOI 10.1099/jgv.0.000432; Sano R, 2013, BBA-MOL CELL RES, V1833, P3460, DOI 10.1016/j.bbamcr.2013.06.028; SCHRODER HC, 1990, Z NATURFORSCH C, V45, P1215; Serra CP, 2005, PHYTOMEDICINE, V12, P424, DOI 10.1016/j.phymed.2004.07.002; Shin HS, 2015, BIOL PHARM BULL, V38, P1707, DOI 10.1248/bpb.b15-00332; Solyomvary A, 2017, MINI-REV MED CHEM, V17, P1053, DOI 10.2174/1389557516666160614005828; Solyomvary A, 2015, PROCESS BIOCHEM, V50, P2281, DOI 10.1016/j.procbio.2015.09.011; Solyomvary A, 2014, NAT PROD RES, V28, P732, DOI 10.1080/14786419.2013.879473; TRUMM S, 1989, Planta Medica, V55, P658, DOI 10.1055/s-2006-962248; Umezawa Toshiaki, 2003, Wood Research, P27; VERMES I, 1995, J IMMUNOL METHODS, V184, P39, DOI 10.1016/0022-1759(95)00072-I; Vijayakurup V, 2014, MOL BIOL REP, V41, P85, DOI 10.1007/s11033-013-2840-8; Xia PY, 2013, EMBO J, V32, P2685, DOI 10.1038/emboj.2013.189; Zhu CC, 2013, ACTA PHARM SIN B, V3, P109, DOI 10.1016/j.apsb.2013.02.004	44	11	11	0	6	PERGAMON-ELSEVIER SCIENCE LTD	OXFORD	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND	0887-2333			TOXICOL IN VITRO	Toxicol. Vitro	MAR	2018	47						129	136		10.1016/j.tiv.2017.11.014			8	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	FX9HO	WOS:000426409400014	29174024				2022-04-25	
J	Hsuan, SW; Chyau, CC; Hung, HY; Chen, JH; Chou, FP				Hsuan, Shu-Wen; Chyau, Charng-Cherng; Hung, Hsiao-Yu; Chen, Jing-Hsien; Chou, Fen-Pi			The induction of apoptosis and autophagy by Wasabia japonica extract in colon cancer	EUROPEAN JOURNAL OF NUTRITION			English	Article						Apoptosis; Autophagy; Colon cancer; RAD001; Wasabia japonica	CELL-DEATH; IN-VITRO; PATHWAY; ISOTHIOCYANATE; EVEROLIMUS; IDENTIFICATION; COMBINATION; INHIBITION; EXPRESSION; TARGET	Wasabia japonica (wasabi) has been shown to exhibit properties of detoxification, anti-inflammation and the induction of apoptosis in cancer cells. This study aimed to investigate the molecular mechanism of the cytotoxicity of wasabi extract (WE) in colon cancer cells to evaluate the potential of wasabi as a functional food for chemoprevention. Colo 205 cells were treated with different doses of WE, and the cytotoxicity was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Apoptosis and autophagy were detected by 4',6-diamidino-2-phenylindole, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbo-yanine iodide and staining for acidic vascular organelles (AVOs), along with Western blotting. The results demonstrated that WE induced the extrinsic pathway and mitochondrial death machinery through the activation of TNF-alpha, Fas-L, caspases, truncated Bid and cytochrome C. WE also induced autophagy by decreasing the phosphorylation of Akt and mTOR and promoting the expression of microtubule-associated protein 1 light chain 3-II and AVO formation. An in vivo xenograft model verified that tumor growth was delayed by WE treatment. Our studies revealed that WE exhibits anti-colon cancer properties through the induction of apoptosis and autophagy. These results provide support for the application of WE as a chemopreventive functional food and as a prospective treatment of colon cancer.	[Hsuan, Shu-Wen; Hung, Hsiao-Yu; Chou, Fen-Pi] Chung Shan Med Univ, Coll Med, Inst Biochem & Biotechnol, Taichung 402, Taiwan; [Chyau, Charng-Cherng] Hung Kuang Univ, Biotechnol Res Inst, Taichung, Taiwan; [Chen, Jing-Hsien] Chung Shan Med Univ, Sch Nutr, Taichung 402, Taiwan; [Chen, Jing-Hsien; Chou, Fen-Pi] Chung Shan Med Univ, 110,Sec 1,Jiangou N Rd, Taichung 402, Taiwan; [Chou, Fen-Pi] Chung Shan Med Univ Hosp, Clin Lab, Taichung 40201, Taiwan		Chen, JH; Chou, FP (corresponding author), Chung Shan Med Univ, 110,Sec 1,Jiangou N Rd, Taichung 402, Taiwan.	cjh0828@csmu.edu.tw; fpchou@csmu.edu.tw			National Science Council of TaiwanMinistry of Science and Technology, Taiwan [NSC 99-2632-B-040-001-MY3, NSC100-2313-B-040-002-MY3]	This study was supported by the Grants from the National Science Council of Taiwan (NSC 99-2632-B-040-001-MY3 and NSC100-2313-B-040-002-MY3).	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J. Nutr.	MAR	2016	55	2					491	503		10.1007/s00394-015-0866-5			13	Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Nutrition & Dietetics	DF3RD	WOS:000371262400006	25720497				2022-04-25	
J	Lee, HY; Chung, KJ; Hwang, IH; Gwak, J; Park, S; Ju, BG; Yun, E; Kim, DE; Chung, YH; Na, M; Song, GY; Oh, S				Lee, Hyun-Young; Chung, Kyu Jin; Hwang, In Hyun; Gwak, Jungsuk; Park, Seoyoung; Ju, Bong Gun; Yun, Eunju; Kim, Dong-Eun; Chung, Young-Hwa; Na, MinKyun; Song, Gyu-Yong; Oh, Sangtaek			Activation of p53 with Ilimaquinone and Ethylsmenoquinone, Marine Sponge Metabolites, Induces Apoptosis and Autophagy in Colon Cancer Cells	MARINE DRUGS			English	Article						ilimaquinone; ethylsmenoquinone; p53; colon cancer; apoptosis; autophagy	BETA-CATENIN DEGRADATION; IN-VITRO; PATHWAY; PHOSPHORYLATION; PROLIFERATION; INDUCTION; COMPLEX; SUPPRESS; BINDING; ARREST	The tumor suppressor, p53, plays an essential role in the cellular response to stress through regulating the expression of genes involved in cell cycle arrest, apoptosis and autophagy. Here, we used a cell-based reporter system for the detection of p53 response transcription to identify the marine sponge metabolites, ilimaquinone and ethylsmenoquinone, as activators of the p53 pathway. We demonstrated that ilimaquinone and ethylsmenoquinone efficiently stabilize the p53 protein through promotion of p53 phosphorylation at Ser15 in both HCT116 and RKO colon cancer cells. Moreover, both compounds upregulate the expression of p21(WAF1/CIP1), a p53-dependent gene, and suppress proliferation of colon cancer cells. In addition, ilimaquinone and ethylsmenoquinone induced G(2)/M cell cycle arrest and increased caspase-3 cleavage and the population of cells that positively stained with Annexin V-FITC, both of which are typical biochemical markers of apoptosis. Furthermore, autophagy was elicited by both compounds, as indicated by microtubule-associated protein 1 light chain 3 (LC3) puncta formations and LC3-II turnover in HCT116 cells. Our findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by activation of the p53 pathway and may have significant potential as chemo-preventive and therapeutic agents for human colon cancer.	[Lee, Hyun-Young; Park, Seoyoung; Oh, Sangtaek] Kookmin Univ, Dept Bio & Fermentat Convergence Technol, Seoul 136702, South Korea; [Chung, Kyu Jin; Yun, Eunju; Na, MinKyun; Song, Gyu-Yong] Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea; [Hwang, In Hyun] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA; [Gwak, Jungsuk; Ju, Bong Gun] Sogang Univ, Dept Life Sci, Seoul 121742, South Korea; [Kim, Dong-Eun] Konkuk Univ, Dept Biosci & Biotechnol, Seoul 143701, South Korea; [Chung, Young-Hwa] Pusan Natl Univ, Dept Cognomechatron Engn, BK21, Pusan 609735, South Korea		Na, M (corresponding author), Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea.	IHyunYoungg@gmail.com; doccap@naver.com; inhyun-hwang@uiowa.edu; dmulder@dreamwiz.com; qkr092@nate.com; bgju@sogang.ac.kr; yunej@cnu.ac.kr; kimde@konkuk.ac.kr; younghc@pusan.ac.kr; mkna@cnu.ac.kr; gysong@cnu.ac.kr; ohsa@kookmin.ac.kr		Na, MinKyun/0000-0002-4865-6506; Song, Gyu Yong/0000-0001-6058-5790; Kim, Dong-Eun/0000-0001-6545-8387	Basic Science Research Program [2013062764, 2014R1A2A2A01006793]; Fundamental Technology Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2012M3A9B2028335]	This work was supported by the Basic Science Research Program (2013062764; 2014R1A2A2A01006793) and the Fundamental Technology Program (2012M3A9B2028335) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology.	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Drugs	JAN	2015	13	1					543	557		10.3390/md13010543			15	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	AZ7MO	WOS:000348403200030	25603347	gold, Green Published, Green Submitted			2022-04-25	
J	Francipane, MG; Lagasse, E				Francipane, Maria Giovanna; Lagasse, Eric			Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor Torin-1	ONCOTARGET			English	Article						colorectal cancer; cancer stem cells; mTOR; apoptosis	EXTENDS LIFE-SPAN; MAMMALIAN TARGET; RAPAMYCIN MTOR; LYMPH-NODE; PHOSPHORYLATION; ACTIVATION; EXPRESSION; PATHWAY; KINASE; RICTOR	Metastatic colorectal cancer (CRC) is incurable for most patients. Since mammalian target of rapamycin (mTOR) has been suggested as a crucial modulator of tumor biology, we aimed at evaluating the effectiveness of mTOR targeting for CRC therapy. To this purpose, we analyzed mTOR expression and the effect of mTOR inhibition in cancer stem-like cells isolated from three human metastatic CRCs (CoCSCs). CoCSCs exhibited a strong mTOR complex 2 (mTORC2) expression, and a rare expression of mTOR complex 1 (mTORC1). This latter correlated with differentiation, being expressed in CoCSC-derived xenografts. We indicate Serum/glucocorticoid-regulated kinase 1 (SGK1) as the possible main mTORC2 effector in CoCSCs, as highlighted by the negative effect on cancer properties following its knockdown. mTOR inhibitors affected CoCSCs differently, resulting in proliferation, autophagy as well as apoptosis induction. The apoptosis-inducing mTOR inhibitor Torin-1 hindered growth, motility, invasion, and survival of CoCSCs in vitro, and suppressed tumor growth in vivo with a concomitant reduction in vessel formation. Torin-1 also affected the expression of markers for cell proliferation, angio-/lympho-genesis, and stemness in vivo, including Ki67, DLL1, DLL4, Notch, Lgr5, and CD44. Importantly, Torin-1 did not affect the survival of normal colon stem cells in vivo, suggesting its selectivity towards cancer cells. Thus, we propose Torin-1 as a powerful drug candidate for metastatic CRC therapy.	[Francipane, Maria Giovanna; Lagasse, Eric] Univ Pittsburgh, Sch Med, McGowan Inst Regenerat Med, Pittsburgh, PA 15260 USA; [Francipane, Maria Giovanna; Lagasse, Eric] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA; [Francipane, Maria Giovanna] RiMed Fdn, Palermo, Italy		Lagasse, E (corresponding author), Univ Pittsburgh, Sch Med, McGowan Inst Regenerat Med, Pittsburgh, PA 15260 USA.	Lagasse@pitt.edu	Francipane, Maria Giovanna/D-6537-2014	Francipane, Maria Giovanna/0000-0002-7194-7918	Ri.MED foundation	This work was supported by Ri.MED foundation (MGF). The authors thank Lynda Guzik for help with cell cycle analysis and cell sorting, and for English editing, and Julie Chandler for providing qRT-PCR primers and human fetal intestinal epithelial cells.	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J	Yang, WL; Perillo, W; Liou, D; Marambaud, P; Wang, P				Yang, Weng-Lang; Perillo, William; Liou, Deanna; Marambaud, Philippe; Wang, Ping			AMPK inhibitor compound C suppresses cell proliferation by induction of apoptosis and autophagy in human colorectal cancer cells	JOURNAL OF SURGICAL ONCOLOGY			English	Article						AMPK; compound C; apoptosis; autophagy; colorectal cancer	ACTIVATED PROTEIN-KINASE; DOWN-REGULATION; IN-VITRO; FLUOROURACIL-LEUCOVORIN; SURVIVIN; GROWTH; METFORMIN; P53; CARCINOMA; MECHANISM	Background and Objectives AMP-activated protein kinase (AMPK) is a main regulator of energy metabolism through the inhibition of biosynthetic pathways and enhancement of ATP-generating pathways. However, targeting AMPK as anti-tumor therapy remains controversial. In this study, we examined the effect of compound C, a small molecule inhibitor of AMPK, on the proliferation of several human colorectal cancer cell lines with diverse characteristics. Methods Four human colorectal cancer cell lines (HCT116, DLD-1, SW480, and KM12C) were treated with compound C. Cell viability was determined by MTS assay. Cell cycle prolife was analyzed by flow cytometry. Acidic vesicular organelles were detected by acridine orange staining. Protein levels were measured by western blotting. Results Compound C inhibited the growth of four cell lines in a dose-dependent manner and caused G2/M arrest. Compound C increased sub-G1 cell population and induced chromatin condensation and cleavage of PARP in HCT116 and KM12C cells, while it induced acidic vesicular formation and conversion of LC3-I to autophagosome-associated LC3-II in DLD-1 and SW480 cells. Survivin, an anti-apoptotic protein, was down-regulated in all cell lines treated with compound C. Conclusions Compound C induces apoptotic or autophagic death in colorectal cancer cells and the preferred death mode is cell type-dependent. J. Surg. Oncol. 2012; 106:680688. (c) 2012 Wiley Periodicals, Inc.	[Yang, Weng-Lang] Feinstein Inst Med Res, Dept Surg, Surg Res Lab, Manhasset, NY 11030 USA; [Yang, Weng-Lang; Perillo, William; Liou, Deanna; Wang, Ping] N Shore Univ Hosp, Dept Surg, Manhasset, NY USA; [Yang, Weng-Lang; Perillo, William; Liou, Deanna; Wang, Ping] Long Isl Jewish Med Ctr, Manhasset, NY USA; [Marambaud, Philippe] Feinstein Inst Med Res, Litwin Zuker Res Ctr Study Alzheimers Dis, Manhasset, NY 11030 USA		Yang, WL (corresponding author), Feinstein Inst Med Res, Dept Surg, Surg Res Lab, 350 Community Dr, Manhasset, NY 11030 USA.	wlyang@nshs.edu		Marambaud, Philippe/0000-0002-8983-1497; Wang, Ping/0000-0002-1557-0394	Faculty Practice Plan Research Fund of North Shore-Long Island Jewish Health System; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [GM057468]; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM057468] Funding Source: NIH RePORTER	Grant sponsor: Faculty Practice Plan Research Fund of North Shore-Long Island Jewish Health System; Grant sponsor: National Institutes of Health grant; Grant number: GM057468.	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Surg. Oncol.	NOV	2012	106	6					680	688		10.1002/jso.23184			9	Oncology; Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Surgery	026CJ	WOS:000310249900006	22674626				2022-04-25	
J	Chiacchiera, F; Grossi, V; Cappellari, M; Peserico, A; Simonatto, M; Germani, A; Russo, S; Moyer, MP; Resta, N; Murzilli, S; Simone, C				Chiacchiera, Fulvio; Grossi, Valentina; Cappellari, Marianna; Peserico, Alessia; Simonatto, Marta; Germani, Aldo; Russo, Silvana; Moyer, Mary P.; Resta, Nicoletta; Murzilli, Stefania; Simone, Cristiano			Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models	CANCER LETTERS			English	Article						Colorectal cancer; Cell death; p38; ERK; Animal models	ACTIVATED PROTEIN-KINASE; MAPK SIGNALING PATHWAYS; DEPENDENT REGULATION; CELL PROLIFERATION; AMPK-FOXO3A AXIS; HUMAN BREAST; P38-ALPHA; COLON; INHIBITORS; MUTATIONS	We recently demonstrated that p38 alpha is required to maintain colorectal cancer (CRC) metabolism, as its inhibition leads to FoxO3A activation, autophagy, cell death, and tumor growth reduction both in vitro and in vivo. Here we show that inhibition of p38 alpha is followed by TRAIL-mediated activation of caspase-8 and FoxO3A-dependent HER3 upregulation with consequent overactivation of the MEK-ERK1/2 survival pathway. p38 alpha and MEK combined inhibition specifically induces apoptosis by enabling TRAIL signaling propagation through t-Bid and caspase-3, and fosters cell death in CRC cells and preclinical mouse models. Current MEK1-directed pharmacological strategies could thus be exploited, in combination with p38 alpha inhibition, to develop new approaches for CRC treatment. (C) 2012 Elsevier Ireland Ltd. All rights reserved.	[Chiacchiera, Fulvio; Grossi, Valentina; Cappellari, Marianna; Peserico, Alessia; Germani, Aldo; Simone, Cristiano] Consorzio Mario Negri Sud, Dept Translat Pharmacol, Lab Signal Dependent Transcript, I-66030 Santa Maria Imbaro, CH, Italy; [Simonatto, Marta] IRCCS Fdn Santa Lucia, Dulbecco Telethon Inst, I-00143 Rome, Italy; [Simonatto, Marta] European Brain Res Inst, I-00143 Rome, Italy; [Russo, Silvana] Univ Bari, Dept Pathol Anat, I-70124 Bari, Italy; [Moyer, Mary P.] INCELL Corp, San Antonio, TX 78249 USA; [Resta, Nicoletta; Simone, Cristiano] Univ Bari, DIM, Div Med Genet, I-70124 Bari, Italy; [Murzilli, Stefania] Consorzio Mario Negri Sud, Dept Translat Pharmacol, Lab Lipid Metab & Canc, I-66030 Santa Maria Imbaro, CH, Italy; [Murzilli, Stefania] Consorzio Mario Negri Sud, Dept Translat Pharmacol, Anim Care Facil, I-66030 Santa Maria Imbaro, CH, Italy		Chiacchiera, F (corresponding author), Consorzio Mario Negri Sud, Dept Translat Pharmacol, Lab Signal Dependent Transcript, Via Nazl 8-A, I-66030 Santa Maria Imbaro, CH, Italy.	fulvio.chiacchiera@ieo.eu; simone@negrisud.it	GROSSI, Valentina/O-6546-2019; Chiacchiera, Fulvio/ABD-6137-2020; Simone, Cristiano/K-3452-2018; Simonatto, Marta/AAW-3042-2020; Chiacchiera, Fulvio/K-6740-2016; Grossi, Valentina/K-9821-2016; Resta, Nicoletta/I-8424-2018	GROSSI, Valentina/0000-0003-3843-1618; Simone, Cristiano/0000-0002-2628-7658; Chiacchiera, Fulvio/0000-0003-3830-2090; Grossi, Valentina/0000-0003-3843-1618; Resta, Nicoletta/0000-0001-8640-5532; Simonatto, Marta/0000-0002-3617-4278; Peserico, Alessia/0000-0003-2025-2419	FIRC fellowshipFondazione AIRC per la ricerca sul cancro; 'Fondazione Negri Sud' fellowship; Italian Association for Cancer Research AIRCFondazione AIRC per la ricerca sul cancro [IG10177]	We thank Dr. Francesco Paolo Jori for his helpful discussion and editorial assistance, Prof. Bert Vogelstein for kindly providing Hct-116 wt and Bax null cells, Dr. Francesca De Marchi for the anti-LC3 antibody, MT Ciencioni and Dr. Giovanna Forte for technical assistance. Dr. Chiacchiera is supported by a FIRC fellowship, Dr. Grossi by a 'Fondazione Negri Sud' fellowship. This work was partially supported by a 'My First Grant 2007' and an 'Investigator Grant 2010' (IG10177) (to Dr. Simone) from the Italian Association for Cancer Research AIRC.	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NOV 1	2012	324	1					98	108		10.1016/j.canlet.2012.05.006			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	987MC	WOS:000307420200011	22579651				2022-04-25	
J	Deng, MZ; Zhang, WZ; Yuan, LL; Tan, JQ; Chen, ZH				Deng, Minzi; Zhang, Weizhi; Yuan, Lingling; Tan, Jieqiong; Chen, Zhihong			HIF-1a regulates hypoxia-induced autophagy via translocation of ANKRD37 in colon cancer	EXPERIMENTAL CELL RESEARCH			English	Article						Colon cancer; Autophagy; ANKRD37; HIF-1a; Hypoxia	CELL-SURVIVAL; GENE; PROTEINS; UBIQUITINATION; BECLIN-1; REPEATS; ZNF76	Autophagy is a basic catabolic response that eukaryotic cells use to degrade unnecessary or dysfunctional cellular components in an orderly and regulated manner. It plays important roles in maintaining cellular homeostasis, energy homeostasis, response to environmental stimuli, and the development of cancer. In solid tumors, hypoxia induces an increased HIF-1a that activates autophagy. However, the exact mechanism by which induced HIF-1a stimulates autophagy in cancer cells remains elusive. In the present study, we confirmed that ANKRD37 is upregulated in colon cancer tissue. Moreover, the higher expression level of ANKRD37 is related to a poorer survival rate. Using RNA interference, immunoblot, and immunofluorescence, we discovered that in cancer cell line RKO, hypoxia-induced HIF-1a regulates autophagy activity by increasing ANKRD37 level. In addition, intranuclear ANKRD37 played an important role in the regulation of hypoxia-induced autophagy. The translocation of ANKRD37 into cell nuclear is required for promoting cell growth and HIF-1a induced autophagy. These findings provide new insights to understand the hypoxia regulation mechanisms and the role of autophagy in cancer development.	[Deng, Minzi] Cent South Univ, Xiangya Hosp 3, Dept Gastroenterol, Changsha, Hunan, Peoples R China; [Deng, Minzi] Hunan Key Lab Nonresolving Inflammat & Canc, Changsha, Hunan, Peoples R China; [Zhang, Weizhi] CentralSouth Univ, Xiangya Hosp 2, Dept Cardiovasc Surg, Changsha, Hunan, Peoples R China; [Yuan, Lingling] Hubei Univ Med, Taihe Hosp, Shiyan 442000, Hubei, Peoples R China; [Tan, Jieqiong] Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha, Hunan, Peoples R China; [Chen, Zhihong] Hunan Normal Univ, Hunan Prov Peoples Hosp, Affiliated Hosp 1, Dept Pathol, Changsha, Hunan, Peoples R China		Chen, ZH (corresponding author), Peoples Hosp Hunan Prov, Dept Pathol, 61 Jiefangxi Rd, Changsha, Hunan, Peoples R China.	zhchen1997@hunnu.edu.cn			Medical Scientific Research Foundation of Hunan Province [B2015-93]; Science and Technology Planning Project of Hunan Province [2015JC3116, 2018JJ2225]; Chinese National Natural Science Foundation Youth Fund [81502111]; Third Xiangya Hospital of Central South University [JY201604]	This work was supported by grants from the Medical Scientific Research Foundation of Hunan Province (B2015-93); the Science and Technology Planning Project of Hunan Province (2015JC3116, 2018JJ2225); Chinese National Natural Science Foundation Youth Fund (81502111); the Third Xiangya Hospital of Central South University (JY201604).	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Cell Res.	OCT 1	2020	395	1							112175	10.1016/j.yexcr.2020.112175			8	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	NN5TN	WOS:000568850900006	32679233				2022-04-25	
J	Liu, XY; Zhang, P; Xie, CM; Sham, KWY; Ng, SSM; Chen, YC; Cheng, CHK				Liu, Xiaoyu; Zhang, Peng; Xie, Chuanming; Sham, Kathy W. Y.; Ng, Simon S. M.; Chen, Yangchao; Cheng, Christopher H. K.			Activation of PTEN by inhibition of TRPV4 suppresses colon cancer development	CELL DEATH & DISEASE			English	Article							CELL-CYCLE PROGRESSION; HEPATOCELLULAR-CARCINOMA; NUCLEAR PTEN; ION-CHANNEL; RECEPTOR; MTOR; AUTOPHAGY; GROWTH; PROLIFERATION; TRANSITION	Transient receptor potential vanilloid type 4 (TRPV4) is a Ca2+-permeable cation channel that is known to be an osmosensor and thermosensor. Currently, limited evidence shows that TRPV4 plays opposite roles in either promoting or inhibiting cancer development in different cancer types. Furthermore, the precise biological functions and the underlying mechanisms of TRPV4 in carcinogenesis are still poorly understood. In this study, we demonstrated that TRPV4 is upregulated in colon cancer and associated with poor prognosis. Contrary to the reported cell death-promoting activity of TRPV4 in certain cancer cells, TRPV4 positively regulates cell survival in human colon cancer in vitro and in vivo. Inhibition of TRPV4 affects the cell cycle progression from the G1 to S phase through modulating the protein expression of D-type cyclins. Apoptosis and autophagy induced by TRPV4 silencing attenuate cell survival and potentiate the anticancer efficacy of chemotherapeutics against colon cancer cells. In addition, PTEN is activated by inhibition of TRPV4 as indicated by the dephosphorylation and increased nuclear localization. Knockdown of PTEN significantly abrogates TRPV4 silencing induced growth inhibition and recovers the capability of clonogenicity, as well as reduced apoptosis in colon cancer cells. Thus, PTEN regulates the antigrowth effects induced by TRPV4 inhibition through both phosphatase-dependent and independent mechanisms. In conclusion, inhibition of TRPV4 suppresses colon cancer development via activation of PTEN pathway. This finding suggests that downregulation of TPRV4 expression or activity would conceivably constitute a novel approach for the treatment of human colon cancer.	[Liu, Xiaoyu; Zhang, Peng] Longgang ENT Hosp, Shenzhen, Peoples R China; [Liu, Xiaoyu; Zhang, Peng] Inst ENT, Shenzhen Key Lab ENT, Shenzhen, Peoples R China; [Liu, Xiaoyu; Sham, Kathy W. Y.; Chen, Yangchao; Cheng, Christopher H. K.] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China; [Xie, Chuanming] Third Mil Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Army Med Univ, Chongqing, Peoples R China; [Ng, Simon S. M.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Shatin, Hong Kong, Peoples R China		Cheng, CHK (corresponding author), Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China.	chkcheng@cuhk.edu.hk	Ng, Simon S. M./M-1219-2018; Xie, Chuan-Ming/AAT-9557-2021; CHENG, Ki Christopher/R-9641-2018; Chen, Yangchao/AAG-2127-2019; Zhang, Peng/ABB-7193-2020	Ng, Simon S. M./0000-0002-5389-9297; Xie, Chuan-Ming/0000-0003-4362-6612; CHENG, Ki Christopher/0000-0001-8970-9048; Chen, Yangchao/0000-0002-0249-3414; Xiaoyu, LIU/0000-0001-5259-7038; Zhang, Peng/0000-0002-4598-0300; Sham, Kathy Wai-yan/0000-0002-8883-2551	Chinese University of Hong KongChinese University of Hong Kong [4054212];  [81700437]	This work was supported by a Direct Grant (#4054212) (to C.C.) and a graduate studentship (to X.L.) from the Chinese University of Hong Kong; and the National Natural Science Foundation of China (81700437) (to P.Z.).	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JUN 12	2019	10								460	10.1038/s41419-019-1700-4			14	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	IE5RW	WOS:000472436300003	31189890	Green Published, gold			2022-04-25	
J	Guaman-Ortiz, LM; Orellana, MIR; Ratovitski, EA				Miguel Guaman-Ortiz, Luis; Ramirez Orellana, Maria Isabel; Ratovitski, Edward A.			Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells	CURRENT GENOMICS			English	Review						Cancer; Autophagy; Necroptosis; Paraptosis; Natural compounds	NF-KAPPA-B; RESVERATROL INDUCES APOPTOSIS; ORIDONIN-INDUCED APOPTOSIS; INHIBITS AUTOPHAGIC FLUX; MULTIPLE-MYELOMA CELLS; LOW-DOSE EXPOSURES; MOLECULAR-MECHANISMS; COLON-CANCER; BETULINIC ACID; LUNG-CANCER	Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.	[Miguel Guaman-Ortiz, Luis; Ramirez Orellana, Maria Isabel] Univ Tecn Particular Loja, Dept Ciencias Salud, Loja, Ecuador; [Ratovitski, Edward A.] Johns Hopkins Univ, Sch Med, Head & Neck Canc Res Div, Baltimore, MD USA		Guaman-Ortiz, LM; Ratovitski, EA (corresponding author), UTPL, Calle Paris, Loja, Ecuador.	lmguaman@utpl.edu.ec; eratovi1@jhmi.edu	Ortiz, Luis Miguel Guaman/X-9496-2019	Ortiz, Luis Miguel Guaman/0000-0003-2919-4905			Akkoc Y, 2015, BIOMED PHARMACOTHER, V71, P161, DOI 10.1016/j.biopha.2015.02.029; Alexander A, 2010, P NATL ACAD SCI USA, V107, P4153, DOI 10.1073/pnas.0913860107; Altonsy MO, 2011, NUTR CANCER, V63, P1104, DOI 10.1080/01635581.2011.601846; Amagase H, 2006, J NUTR, V136, p716S, DOI 10.1093/jn/136.3.716S; Andrabi SA, 2014, P NATL ACAD SCI USA, V111, P10209, DOI 10.1073/pnas.1405158111; Aoki H, 2007, MOL PHARMACOL, V72, P29, DOI 10.1124/mol.106.033167; Aras A, 2014, ASIAN PAC J CANCER P, V15, P3865, DOI 10.7314/APJCP.2014.15.9.3865; Aredia F, 2014, BIOCHEM PHARMACOL, V92, P157, DOI 10.1016/j.bcp.2014.06.021; 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Genomics		2017	18	2					132	155		10.2174/1389202917666160803150639			24	Biochemistry & Molecular Biology; Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Genetics & Heredity	EU0FD	WOS:000400683600003	28367073	Green Published, Green Submitted			2022-04-25	
J	Lee, Y; Sung, B; Kang, YJ; Kim, DH; Jang, JY; Hwang, SY; Kim, M; Lim, HS; Yoon, JH; Chung, HY; Kim, ND				Lee, Yujin; Sung, Bokyung; Kang, Yong Jung; Kim, Dong Hwan; Jang, Jung-Yoon; Hwang, Seong Yeon; Kim, Minjung; Lim, Hyun Sook; Yoon, Jeong-Hyun; Chung, Hae Young; Kim, Nam Deuk			Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						apigenin; colon cancer cells; cell cycle; apoptosis; autophagy; 3-methyladenine	CYCLE ARREST; IN-VITRO; CARCINOMA; EXPRESSION; PATHWAY; PHOSPHORYLATION; 5-FLUOROURACIL; ACTIVATION; GUIDELINES; ASSAYS	Apigenin (4',5,7-trihydroxyflavone) is a natural flavonoid, shown to have chemopreventive and/or anticancer properties in a variety of human cancer cells. The involvement of autophagy in apigenin-induced apoptotic cell death of HCT116 human colon cancer cells was investigated. Apigenin induced suppression of cell growth in a concentration-dependent manner in HCT116 cells. Flow cytometric analyses indicated that apigenin resulted in G2/M phase arrest. This flavone also suppressed the expression of both cyclin B1 and its activating partners, Cdc2 and Cdc25c, whereas the expression of cell cycle inhibitors, such as p53 and p53-dependent p21(CIP1/WAF1), was increased after apigenin treatment. Apigenin induced poly (ADP-ribose) polymerase (PARP) cleavage and decreased the levels of procaspase-8, -9 and -3. In addition, the apigenin-treated cells exhibited autophagy, as characterized by the appearance of autophagosomes under fluorescence microscopy and the accumulation of acidic vesicular organelles by flow cytometry. Furthermore, the results of the western blot analysis revealed that the levels of LC3-II, the processed form of LC3-I, was increased by apigenin. Treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly enhanced the apoptosis induced by apigenin, which was accompanied by an increase in the levels of PARP cleavage. These results indicate that apigenin has apoptosis-and autophagy-inducing effects in HCT116 colon cancer cells. Autophagy plays a cytoprotective role in apigenin-induced apoptosis, and the combination of apigenin and an autophagy inhibitor may be a promising strategy for colon cancer control.	[Lee, Yujin; Sung, Bokyung; Kang, Yong Jung; Kim, Dong Hwan; Jang, Jung-Yoon; Hwang, Seong Yeon; Kim, Minjung; Lim, Hyun Sook; Yoon, Jeong-Hyun; Chung, Hae Young; Kim, Nam Deuk] Pusan Natl Univ, Coll Pharm, Div Pharm, Mol Inflammat Res Ctr Aging Intervent MRCA, Pusan 609735, South Korea		Kim, ND (corresponding author), Pusan Natl Univ, Coll Pharm, Div Pharm, Pusan 609735, South Korea.	nadkim@pusan.ac.kr	Sung, Bokyung/AAX-5697-2021		Basic Science Research Program through the National Research Foundation of Korea (NRF) - Korea government (MSIP) [NRF-2009-0071649]; National Research Foundation of Korea (NRF) - Korea government (MSIP) [2009-0083538]	This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (NRF-2009-0071649). This study was also financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (no. 2009-0083538). We thank Aging Tissue Bank for providing research information. The authors thank Mr. Kyoung-Pil Lee (Pusan National University) for helping with confocal microscopy.	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J. Oncol.	MAY	2014	44	5					1599	1606		10.3892/ijo.2014.2339			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AJ8IV	WOS:000337947600020	24626522	Bronze			2022-04-25	
J	Kohli, L; Kaza, N; Coric, T; Byer, SJ; Brossier, NM; Klocke, BJ; Bjornsti, MA; Carroll, SL; Roth, KA				Kohli, Latika; Kaza, Niroop; Coric, Tatjana; Byer, Stephanie J.; Brossier, Nicole M.; Klocke, Barbara J.; Bjornsti, Mary-Ann; Carroll, Steven L.; Roth, Kevin A.			4-Hydroxytamoxifen Induces Autophagic Death through K-Ras Degradation	CANCER RESEARCH			English	Article							BREAST-CANCER CELLS; PROTEIN-KINASE-C; NERVE SHEATH TUMORS; TAMOXIFEN-INDUCED APOPTOSIS; ACTIVATION; CALMODULIN; BINDING; INHIBITION; EXPRESSION; PROLIFERATION	Tamoxifen is widely used to treat estrogen receptor-positive breast cancer. Recent findings that tamoxifen and its derivative 4-hydroxytamoxifen (OHT) can exert estrogen receptor-independent cytotoxic effects have prompted the initiation of clinical trials to evaluate its use in estrogen receptor-negative malignancies. For example, tamoxifen and OHT exert cytotoxic effects in malignant peripheral nerve sheath tumors (MPNST) where estrogen is not involved. In this study, we gained insights into the estrogen receptor-independent cytotoxic effects of OHT by studying how it kills MPNST cells. Although caspases were activated following OHT treatment, caspase inhibition provided no protection from OHT-induced death. Rather, OHT-induced death in MPNST cells was associated with autophagic induction and attenuated by genetic inhibition of autophagic vacuole formation. Mechanistic investigations revealed that OHT stimulated autophagic degradation of K-Ras, which is critical for survival of MPNST cells. Similarly, we found that OHT induced K-Ras degradation in breast, colon, glioma, and pancreatic cancer cells. Our findings describe a novel mechanism of autophagic death triggered by OHT in tumor cells that may be more broadly useful clinically in cancer treatment. (C) 2013 AACR.	[Kohli, Latika; Kaza, Niroop; Byer, Stephanie J.; Klocke, Barbara J.; Carroll, Steven L.; Roth, Kevin A.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA; [Kohli, Latika; Brossier, Nicole M.] Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA; [Coric, Tatjana; Bjornsti, Mary-Ann] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL 35294 USA; [Brossier, Nicole M.] Univ Alabama Birmingham, Dept Med Scientist Training Program, Birmingham, AL 35294 USA		Roth, KA (corresponding author), Univ Alabama Birmingham, WP P210 619 South 19th St, Birmingham, AL 35294 USA.	karoth@uab.edu	Brossier, Nicole/AAP-2852-2020	Brossier, Nicole/0000-0002-4197-6283; Roth, Kevin/0000-0002-0643-995X; Kaza, Niroop/0000-0002-7584-1379; Carroll, Steven/0000-0001-6714-4373	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 NS041962, R01 CA134773, R01 CA122804, F30 NS063626, P50CA890919]; Department of DefenseUnited States Department of Defense [X81XWH-09-1-0086, X81XWH-12-1-0164]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA122804, R01CA134773, R01CA058755] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [F30NS063626, R01NS041962] Funding Source: NIH RePORTER	This work was supported by NIH grants R01 NS041962 (K.A. Roth), R01 CA134773 (K.A. Roth. and S.L. Carroll), R01 CA122804 (S.L. Carroll), F30 NS063626 (N.M. Brossier), and P50CA890919 (T. Coric and M.A. Bjornsti); and Department of Defense Grants X81XWH-09-1-0086 and X81XWH-12-1-0164 (S.L. Carroll).	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JUL 15	2013	73	14					4395	4405		10.1158/0008-5472.CAN-12-3765			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	183NR	WOS:000321823600022	23722551	Green Accepted			2022-04-25	
J	Sipos, F; Szekely, H; Kis, ID; Tulassay, Z; Muzes, G				Sipos, Ferenc; Szekely, Hajnal; Kis, Imre Daniel; Tulassay, Zsolt; Muzes, Gyorgyi			Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer	WORLD JOURNAL OF GASTROENTEROLOGY			English	Review						Insulin-like growth factor; IGF1R; Autophagy; Colitis; Colorectal cancer; Metabolic syndrome	GROWTH-FACTOR RECEPTOR; FACTOR-I RECEPTOR; CELL-DEATH; INSULIN-RESISTANCE; THERAPEUTIC TARGET; KAPPA-B; IGF-I; COLON; APOPTOSIS; EXPRESSION	Metabolic syndrome (MetS), as a chronic inflammatory disorder has a potential role in the development of inflammatory and cancerous complications of the colonic tissue. The interaction of DNA damage and inflammation is affected by the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. The IGF1R pathway has been reported to regulate autophagy, as well, but sometimes through a bidirectional context. Targeting the IGF1R-autophagy crosstalk could represent a promising strategy for the development of new antiinflammatory and anticancer therapies, and may help for subjects suffering from MetS who are at increased risk of colorectal cancer. However, therapeutic responses to targeted therapies are often shortlived, since a signaling crosstalk of IGF1R with other receptor tyrosine kinases or autophagy exists, leading to acquired cellular resistance to therapy. From a pharmacological point of view, it is attractive to speculate that synergistic benefits could be achieved by inhibition of one of the key effectors of the IGF1R pathway, in parallel with the pharmacological stimulation of the autophagy machinery, but cautiousness is also required, because pharmacologic IGF1R modulation can initiate additional, sometimes unfavorable biologic effects.	[Sipos, Ferenc; Szekely, Hajnal; Muzes, Gyorgyi] Semmelweis Univ, Dept Internal Med 2, H-1088 Budapest, Hungary; [Kis, Imre Daniel] Semmelweis Univ, Fac Med, H-1088 Budapest, Hungary; [Tulassay, Zsolt] Hungarian Acad Sci, Mol Med Res Grp, H-1088 Budapest, Hungary		Sipos, F (corresponding author), Semmelweis Univ, Dept Internal Med 2, Immunol & Med, Szentkiralyi St 46, H-1088 Budapest, Hungary.	dr.siposf@gmail.com			Hungarian Scientific Research FundOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA-K111743]	Supported by the Hungarian Scientific Research Fund (No. OTKA-K111743) to Tulassay Z. The funders had no role in data collection, decision to publish, or preparation of the manuscript.	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Gastroenterol.	DEC 14	2017	23	46					8109	8119		10.3748/wjg.v23.i46.8109			11	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	FP8XL	WOS:000417929300001	29290648	Green Published, Green Submitted, hybrid			2022-04-25	
J	Garcia-Maurino, S; Alcaide, A; Dominguez, C				Garcia-Maurino, Sofia; Alcaide, Antonio; Dominguez, Cecilia			Pharmacological Control of Autophagy: Therapeutic Perspectives in Inflammatory Bowel Disease and Colorectal Cancer	CURRENT PHARMACEUTICAL DESIGN			English	Review						AMP-dependent kinase; autophagy; colorectal cancer; Endoplasmic Reticulum stress; inflammatory bowel disease; mammalian target of rapamycin	ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; HUMAN COLON-CANCER; ADVANCED SOLID TUMORS; FACTOR-KAPPA-B; HISTONE DEACETYLASE INHIBITORS; ISOLATED RAT HEPATOCYTES; AIRWAY EPITHELIAL-CELLS; INTESTINAL PANETH CELLS; CLASS-II PRESENTATION	Autophagy, an intracellular process involved in removing and recycling cellular components, plays a major role in growth, development, and responses to stress and pathogens. Autophagy is compromised in many human diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). Autophagy malfunction is associated to an alteration of both innate and adaptative immune responses, defects in bacterial clearance, and malfunction of goblet and Paneth cells; all these perturbations are related to IBD and CRC pathogenesis. Preclinical data show that both inhibition and induction of autophagy have significant potential to be translated into the clinic. Inhibitors of TORC1 (rapamycin and rapalogs) have proven to be effective in IBD and in many models for CRCs; however, their clinical use has produced only modest success. Second generations of mTOR inhibitors, which target its kinase domain, have been more effective. Optimal antitumor efficacy is achieved by combination of agents with different molecular targets, such as proteasome or histone deacetylase inhibitors combined with autophagy inhibitors (hydroxychloroquine) or activators (everolimus). Clinical trials in course are assaying the effect of these compounds in combination with standard treatments of CRC. This review summarizes current knowledge about the autophagic machinery and its regulation, then it explores the relevance and impact of the malfunction of autophagy on the pathogenesis of IBD and CRC, and, finally, it discusses the therapeutic potential of molecules that regulate autophagy and their use for the treatment of these two diseases.	[Garcia-Maurino, Sofia] Univ Seville, Fac Biol, Dept Plant Biol & Ecol, E-41012 Seville, Spain; [Alcaide, Antonio; Dominguez, Cecilia] Univ Seville, Dept Pharmacol, Seville, Spain		Garcia-Maurino, S (corresponding author), Univ Seville, Fac Biol, Dept Plant Biol & Ecol, Ave Reina Mercedes 6, E-41012 Seville, Spain.	sgarma@us.es	García-Mauriño, Sofía/E-6707-2010	García-Mauriño, Sofía/0000-0002-7698-5112	Junta de Andalucia, SpainJunta de Andalucia [CTS658, BIO298]	This work was supported by the Junta de Andalucia (PAI groups CTS658 and BIO298). A. Alcaide was in receipt of a FPI fellowship from the Junta de Andalucia, Spain.	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Pharm. Design	SEP	2012	18	26					3853	3873		10.2174/138161212802083653			21	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	993OV	WOS:000307870100004	22632751				2022-04-25	
J	Tang, SN; Cai, SN; Ji, S; Yan, XJ; Zhang, WJ; Qiao, X; Zhang, HQ; Ye, M; Yu, SW				Tang, Shunan; Cai, Sina; Ji, Shuai; Yan, Xiaojin; Zhang, Weijia; Qiao, Xue; Zhang, Hongquan; Ye, Min; Yu, Siwang			Isoangustone A induces autophagic cell death in colorectal cancer cells by activating AMPK signaling	FITOTERAPIA			English	Article						Prenylated flavonoids; Isoangustone A; Autophagy; Apoptosis; AMPK	BIOLOGICAL-ACTIVITIES; ADENOCARCINOMA CELLS; DUAL ROLE; MTOR; INHIBITION; MODULATION; FLAVONOIDS; APOPTOSIS; PROTEIN; TARGET	Phytochemicals, especially flavonoids, have been widely investigated for their diversified pharmacological activities including anticancer activities. Previously we identified isoangustone A from licorice-derived compounds as a potent inducer of cell death. In the present study, the exact mechanism by which isoangustone A induced cell death was further investigated, with autophagy as an indispensible part of this process. Isoangustone A treatment activated autophagic signaling and induced a complete autophagic flux in colorectal cancer cells. Knockdown of ATG5 or pre-treatment with autophagy inhibitors significantly reversed isoangustone A-induced apoptotic signaling and loss of cell viability, suggesting autophagy plays an important role in isoangustone A-induced cell death. Isoangustone A inhibited Akt/mTOR signaling, and overexpressing of a constitutively activated Akt mildly suppressed isoangustone A-induced cell death. More importantly, isoangustone A inhibited cellular ATP level and activated AMPK, and pre-treatment with AMPK inhibitor or overexpression of dominant negative AMPK alpha 2 significantly reversed isoangustone A-induced autophagy and cell death. Further study shows isoangustone A dose-dependently inhibited mitochondrial respiration, which could be responsible for isoangustone A-induced activation of AMPK. Finally, isoangustone A at a dosage of 10 mg/kg potently activated AMPK and autophagic signaling in and inhibited the growth of SW480 human colorectal xenograft in vivo. Taken together, induction of autophagy through activation of AMPK is an important mechanism by which isoangustone A inhibits tumor growth, and isoangustone A deserves further investigation as a promising anti-cancer agent.	[Tang, Shunan; Cai, Sina; Ji, Shuai; Yan, Xiaojin; Zhang, Weijia; Qiao, Xue; Zhang, Hongquan; Ye, Min; Yu, Siwang] Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100191, Peoples R China; [Tang, Shunan; Cai, Sina; Yan, Xiaojin; Zhang, Weijia; Yu, Siwang] Peking Univ, Dept Mol & Cellular Pharmacol, Sch Pharmaceut Sci, Beijing 100191, Peoples R China; [Ji, Shuai; Qiao, Xue; Ye, Min] Peking Univ, Dept Nat Med, Sch Pharmaceut Sci, Beijing 100191, Peoples R China; [Zhang, Hongquan] Peking Univ, Dept Anat Histol & Embryol, Sch Basic Med Sci, Beijing, Peoples R China		Ye, M; Yu, SW (corresponding author), Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100191, Peoples R China.	yemin@bjmu.edu.cn; swang_yu@hsc.pku.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472657, 81891011, 81730071]	This research was supported by the National Natural Science Foundation of China (81472657, 81891011 and 81730071) , and the funding source has not been involved in the study design, the collection, analysisFitoterapia (2021) and interpretation of data, or in the writing of the report. The authors thank Dr. AhNg Tony Kong at Rutgers, the State University of New Jersey for providing necessary plasmids, and all the members of Yu's group for technical assistance and critical discussions.	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J	Wu, JC; Lai, CS; Badmaev, V; Nagabhushanam, K; Ho, CT; Pan, MH				Wu, Jia-Ching; Lai, Ching-Shu; Badmaev, Vladimir; Nagabhushanam, Kalyanam; Ho, Chi-Tang; Pan, Min-Hsiung			Tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death through coordinative modulation of PI3K/Akt-mTOR and MAPK signaling pathways in human leukemia HL-60 cells	MOLECULAR NUTRITION & FOOD RESEARCH			English	Article						Autophagy; Curcumin; Tetrahydrocurcumin	MALIGNANT GLIOMA-CELLS; CANCER; RADIATION; APOPTOSIS; AKT	Scope: Autophagy (type II programmed cell death) is crucial for maintaining cellular homeostasis. Several autophagy-deficient or knockout studies indicate that autophagy is a tumor suppressor. Tetrahydrocurcumin (THC), a major metabolite of curcumin, has been demonstrated with anti-colon carcinogenesis and antioxidation in vivo. Methods and results: In the present study, we found that treatment with THC induced autophagic cell death in human HL-60 promyelocytic leukemia cells by increasing autophage marker acidic vascular organelle (AVO) formation. Flow cytometry also confirmed that THC treatment did not increase sub-G1 cell population whereas curcumin did with strong apoptosis-inducing activity. At the molecular levels, the results from Western blot analysis showed that THC significantly down-regulated phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase signalings including decreasing the phosphorylation of mammalian target of rapamycin, glycogen synthase kinase 3 beta and p70 ribosomal protein S6 kinase. Further molecular analysis exhibited that the pretreatment of 3-methyladenine (an autophagy inhibitor) also significantly reduced acidic vascular organelle production in THC-treated cells. Conclusion: Taken together, these results demonstrated the anticancer efficacy of THC by inducing autophagy as well as provided a potential application for the prevention of human leukemia.	[Wu, Jia-Ching; Lai, Ching-Shu; Pan, Min-Hsiung] Natl Kaohsiung Marine Univ, Dept Seafood Sci, Kaohsiung 81143, Taiwan; [Badmaev, Vladimir] Lab Appl Pharmacol, Staten Isl, NY USA; [Nagabhushanam, Kalyanam] Sabinsa Corp, E Windsor, NJ USA; [Ho, Chi-Tang] Rutgers State Univ, Dept Food Sci, New Brunswick, NJ 08903 USA		Pan, MH (corresponding author), Natl Kaohsiung Marine Univ, Dept Seafood Sci, 142 Haijhuan Rd, Kaohsiung 81143, Taiwan.	mhpan@mail.nkmu.edu.tw	Pan, Min-Hsiung/AAT-8865-2021	Pan, Min-Hsiung/0000-0002-5188-7030	National Science Council NSCMinistry of Science and Technology, Taiwan [98-2313-B-022-002-MY3, 98-2321-B-022-001, 100-2918-I-022-005]	This study was supported by the National Science Council NSC 98-2313-B-022-002-MY3, 98-2321-B-022-001, and 100-2918-I-022-005.	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Nutr. Food Res.	NOV	2011	55	11					1646	1654		10.1002/mnfr.201100454			9	Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology	855RI	WOS:000297581500005	21928294				2022-04-25	
J	Wu, YC; Wang, XJ; Yu, L; Chan, FKL; Cheng, ASL; Yu, J; Sung, JJY; Wu, WKK; Cho, CH				Wu, Ya C.; Wang, Xiao J.; Yu, Le; Chan, Francis K. L.; Cheng, Alfred S. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.; Cho, Chi H.			Hydrogen Sulfide Lowers Proliferation and Induces Protective Autophagy in Colon Epithelial Cells	PLOS ONE			English	Article							ULCERATIVE-COLITIS; IN-VITRO; CANCER; PROTEIN; HUMANS	Hydrogen sulfide (H2S) is a gaseous bacterial metabolite that reaches high levels in the large intestine. In the present study, the effect of H2S on the proliferation of normal and cancerous colon epithelial cells was investigated. An immortalized colon epithelial cell line (YAMC) and a panel of colon cancer cell lines (HT-29, SW1116, HCT116) were exposed to H2S at concentrations similar to those found in the human colon. H2S inhibited normal and cancerous colon epithelial cell proliferation as measured by MTT assay. The anti-mitogenic effect of H2S was accompanied by G(1)-phase cell cycle arrest and the induction of the cyclin-dependent kinase inhibitor p21(Cip). Moreover, exposure to H2S led to features characteristic of autophagy, including increased formation of LC3B(+) autophagic vacuoles and acidic vesicular organelles as determined by immunofluorescence and acridine orange staining, respectively. Abolition of autophagy by RNA interference targeting Vps34 or Atg7 enhanced the anti-proliferative effect of H2S. Further mechanistic investigation revealed that H2S stimulated the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase. Inhibition of AMPK significantly reversed H2S-induced autophagy and inhibition of cell proliferation. Collectively, we demonstrate that H2S inhibits colon epithelial cell proliferation and induces protective autophagy via the AMPK pathway.	[Wu, Ya C.; Yu, Le; Cho, Chi H.] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China; [Wang, Xiao J.; Chan, Francis K. L.; Cheng, Alfred S. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.] Chinese Univ Hong Kong, Inst Digest Dis, LKS Inst Hlth Sci, Shatin, Hong Kong, Peoples R China; [Wang, Xiao J.; Chan, Francis K. L.; Cheng, Alfred S. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.] Chinese Univ Hong Kong, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China		Wu, YC (corresponding author), Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China.	wukakei@cuhk.edu.hk	Wu, William K.K./A-3277-2009; Cho, Chi Hin/C-6543-2014; Chan, Francis K. L./F-4851-2010; Cheng, Alfred SL/C-3327-2014; Sung, Joseph J. Y./R-3203-2018; Yu, Jun/D-8569-2015	Wu, William K.K./0000-0002-5662-5240; Cho, Chi Hin/0000-0002-7658-3260; Chan, Francis K. L./0000-0001-7388-2436; Cheng, Alfred SL/0000-0003-2345-6951; Sung, Joseph J. Y./0000-0003-3125-5199; Yu, Jun/0000-0001-5008-2153			Bian JS, 2006, J PHARMACOL EXP THER, V316, P670, DOI 10.1124/jpet.105.092023; Diaz-Troya S, 2008, AUTOPHAGY, V4, P851, DOI 10.4161/auto.6555; Fiorucci S, 2007, BRIT J PHARMACOL, V150, P996, DOI 10.1038/sj.bjp.0707193; FLORIN T, 1991, GUT, V32, P766, DOI 10.1136/gut.32.7.766; Gwinn DM, 2008, MOL CELL, V30, P214, DOI 10.1016/j.molcel.2008.03.003; Kawabata A, 2007, PAIN, V132, P74, DOI 10.1016/j.pain.2007.01.026; Kimura Y, 2004, FASEB J, V18, P1165, DOI 10.1096/fj.04-1815fje; Levine J, 1998, AM J GASTROENTEROL, V93, P83, DOI 10.1111/j.1572-0241.1998.083_c.x; MACFARLANE GT, 1992, J APPL BACTERIOL, V72, P57, DOI 10.1111/j.1365-2672.1992.tb05187.x; Magee EA, 2000, AM J CLIN NUTR, V72, P1488; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038/nrm2239; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Meijer AJ, 2007, AUTOPHAGY, V3, P238, DOI 10.4161/auto.3710; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Picton R, 2007, DIGEST DIS SCI, V52, P373, DOI 10.1007/s10620-006-9529-y; Ramasamy S, 2006, AM J PHYSIOL-GASTR L, V291, pG288, DOI 10.1152/ajpgi.00324.2005; Sato K, 2007, CANCER RES, V67, P9677, DOI 10.1158/0008-5472.CAN-07-1462; Schicho R, 2006, GASTROENTEROLOGY, V131, P1542, DOI 10.1053/j.gastro.2006.08.035; Teague B, 2002, BRIT J PHARMACOL, V137, P139, DOI 10.1038/sj.bjp.0704858; Tripatara P, 2008, LAB INVEST, V88, P1038, DOI 10.1038/labinvest.2008.73; Turk HF, 2011, INT J CANCER, V128, P63, DOI 10.1002/ijc.25323; Wallace JL, 2007, FASEB J, V21, P4070, DOI 10.1096/fj.07-8669com; Wallace JL, 2007, TRENDS PHARMACOL SCI, V28, P501, DOI 10.1016/j.tips.2007.09.003; Wu WKK, 2012, ONCOGENE, V31, P939, DOI 10.1038/onc.2011.295	24	74	81	1	25	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1932-6203			PLOS ONE	PLoS One	MAY 29	2012	7	5							e37572	10.1371/journal.pone.0037572			9	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	959WT	WOS:000305349600021	22679478	Green Submitted, Green Published, gold			2022-04-25	
J	Lin, XT; Wu, QN; Qin, S; Fan, DJ; Lv, MY; Chen, X; Cai, JW; Weng, JR; Zou, YF; Rong, YM; Gao, F				Lin, Xu-tao; Wu, Qiu-ning; Qin, Si; Fan, De-jun; Lv, Min-yi; Chen, Xi; Cai, Jia-wei; Weng, Jing-rong; Zou, Yi-feng; Rong, Yu-ming; Gao, Feng			Identification of an Autophagy-Related Gene Signature for the Prediction of Prognosis in Early-Stage Colorectal Cancer	FRONTIERS IN GENETICS			English	Article						colorectal cancer; prognosis; early stage; disease-free survival; autophagy-related gene	II COLON-CANCER; ADJUVANT CHEMOTHERAPY; IMMUNE-RESPONSES; ALPHA; TUMOR; INTERFERON; VALIDATION; STAT3	Purpose: A certain number of early-stage colorectal cancer (CRC) patients suffer tumor recurrence after initial curative resection. In this context, an effective prognostic biomarker model is constantly in need. Autophagy exhibits a dual role in tumorigenesis. Our study aims to develop an autophagy-related gene (ATG) signature-based on high-throughput data analysis for disease-free survival (DFS) prognosis of patients with stage I/II CRC.Methods: Gene expression profiles and clinical information of CRC patients extracted from four public datasets were distributed to discovery and training cohort (GSE39582), validation cohort (TCGA CRC, n = 624), and meta-validation cohort (GSE37892 and GSE14333, n = 420). Autophagy genes significantly associated with prognosis were identified.Results: Among 655 autophagy-related genes, a 10-gene ATG signature, which was significantly associated with DFS in the training cohort (HR, 2.76[1.56-4.82]; p = 2.06 x 10-4), was constructed. The ATG signature, stratifying patients into high and low autophagy risk groups, was validated in the validation (HR, 2.29[1.15-4.55]; p = 1.5 x 10-2) and meta-validation cohorts (HR, 2.5[1.03-6.06]; p = 3.63 x 10-2) and proved to be prognostic in a multivariate analysis. Functional analysis revealed enrichment of several immune/inflammatory pathways in the high autophagy risk group, where increased infiltration of T regulatory cells (Tregs) and decreased infiltration of M1 macrophages were observed.Conclusion: Our study established a prognostic ATG signature that effectively predicted DFS for early-stage CRC patients. Meanwhile, the study also revealed the possible relationship among autophagy process, immune/inflammatory response, and tumorigenesis.	[Lin, Xu-tao; Wu, Qiu-ning; Fan, De-jun] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Gastrointestinal Endoscopy, Guangzhou, Peoples R China; [Lin, Xu-tao; Wu, Qiu-ning; Qin, Si; Fan, De-jun; Lv, Min-yi; Chen, Xi; Cai, Jia-wei; Weng, Jing-rong; Zou, Yi-feng; Gao, Feng] Sun Yat Sen Univ, Affiliated Hosp 6, Guangdong Prov Key Lab Colorectal & Pelv Floor Di, Guangdong Inst Gastroenterol, Guangzhou, Peoples R China; [Qin, Si] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Med Ultrason, Guangzhou, Peoples R China; [Lv, Min-yi; Chen, Xi; Cai, Jia-wei; Weng, Jing-rong; Zou, Yi-feng; Gao, Feng] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou, Peoples R China; [Rong, Yu-ming] Sun Yat Sen Univ, Ctr Canc, Dept VIP Reg, Guangzhou, Peoples R China		Gao, F (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 6, Guangdong Prov Key Lab Colorectal & Pelv Floor Di, Guangdong Inst Gastroenterol, Guangzhou, Peoples R China.; Gao, F (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou, Peoples R China.; Rong, YM (corresponding author), Sun Yat Sen Univ, Ctr Canc, Dept VIP Reg, Guangzhou, Peoples R China.	rongym@sysucc.org.cn; gaof57@mail.sysu.edu.cn			National Key Clinical Discipline; "5010 Clinical Research Program" of Sun Yat-sen University [2010012]; Natural Science Foundation of Guangdong Province, ChinaNational Natural Science Foundation of Guangdong Province [2020A1515010428]; Medical Science Research Grant from the Health Department of Guangdong Province [A2018007]	This work was supported by National Key Clinical Discipline; and "5010 Clinical Research Program" of Sun Yat-sen University (grant number 2010012); and Natural Science Foundation of Guangdong Province, China (grant number 2020A1515010428); and Medical Science Research Grant from the Health Department of Guangdong Province (grant number A2018007).	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Genet.	NOV 25	2021	12								755789	10.3389/fgene.2021.755789			14	Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Genetics & Heredity	XM7CJ	WOS:000728980000001	34899841	Green Published, gold			2022-04-25	
J	Dukel, M; Tavsan, Z; Kayali, HA				Dukel, Muzaffer; Tavsan, Zehra; Kayali, Hulya Ayar			Flavonoids regulate cell death-related cellular signaling via ROS in human colon cancer cells	PROCESS BIOCHEMISTRY			English	Article						Colon cancer; Flavonoid; ROS; CAM; PKC; Cell death		Although several studies investigated effects of flavonoids on proliferation and apoptosis, yet no study has correlated the cellular damage caused by reactive oxygen species (ROS) production, cell death related pathways and cell adhesion molecules (CAM) expression with cell survival. Here, we investigate cytotoxic effect of catechin, epicatechin and naringenin on colon cancer cells. While especially naringenin demonstrated most significant inhibition of colon cancer cell viability, high concentrations treatment did not exhibit more pronounced effect in colon epithelial cells. In addition, these flavonoids caused excessive ROS generation resulting in the impairment of lipid and protein, followed by the induction of apoptosis and autophagy. In details, mechanism studies revealed that elevated ROS production leads to caspase activation and pretreated NAC, an antioxidant, blocks catechins and naringenin induced apoptosis and autophagy. PKC activity assay data also showed that catechin and naringenin treatment decreases PKC activity that leads to cell death. Moreover, studied flavonoids, especially naringenin, induced G2/M cell cycle arrest in a ROS-independent manner. Furthermore, the studied flavonoids suppressed or decreased the expression of the cancer progression and metastasis-related cell adhesion molecules. Taken together, our results indicate that studied flavonoids suppress colon cancer cell growth via inducing cell death in ROS dependent manner.	[Dukel, Muzaffer] Mehmet Akif Ersoy Univ, Fac Art & Sci, Mol Biol & Genet Dept, TR-15100 Burdur, Turkey; [Dukel, Muzaffer; Tavsan, Zehra; Kayali, Hulya Ayar] Izmir Biomed & Genome Ctr, TR-35340 Izmir, Turkey; [Kayali, Hulya Ayar] Dokuz Eylul Univ, Sci Fac, Chem Dept, Biochem Div, TR-35390 Izmir, Turkey		Kayali, HA (corresponding author), Izmir Biomed & Genome Ctr, TR-35340 Izmir, Turkey.	hulya.ayarkayali@ibg.edu.tr	Tavsan, Zehra/AAR-6576-2021		Dokuz Eylul University, Department of Scientific Research ProjectsDokuz Eylul University [KB.FEN.001]	This work was supported by the Dokuz Eylul University, Department of Scientific Research Projects (2016.KB.FEN.001). We thank to Technician Birgul Kehlibar who helps MTT analysis. Elcin Ca.gatay carried out the cell culture experiments of Annexin-V and cell cycle analysis. Duygu Erdo.gan helped in revising the manuscript. The authors declare that they have no competing interests.	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Neilson AP, 2010, NUTR RES, V30, P327, DOI 10.1016/j.nutres.2010.05.006; Okegawa T, 2004, ACTA BIOCHIM POL, V51, P445; Patel K, 2018, CHIN J INTEGR MED, V24, P551, DOI 10.1007/s11655-014-1960-x; Perez-Vizcaino F, 2009, PHARMACOL REP, V61, P67, DOI 10.1016/S1734-1140(09)70008-8; Pericleous M, 2013, J GASTROINTEST ONCOL, V4, P409, DOI 10.3978/j.issn.2078-6891.2013.003; Plaumann B, 1996, ONCOGENE, V13, P1605; Prochazkova D, 2011, FITOTERAPIA, V82, P513, DOI 10.1016/j.fitote.2011.01.018; Rabik CA, 2007, CANCER TREAT REV, V33, P9, DOI 10.1016/j.ctrv.2006.09.006; Ravindranath MH, 2006, EVID-BASED COMPL ALT, V3, P237, DOI 10.1093/ecam/nel003; Reyland ME, 2016, PHARMACOL THERAPEUT, V165, P1, DOI 10.1016/j.pharmthera.2016.05.001; Rhouma HE, 2021, NAT PROD RES, V35, P1836, DOI 10.1080/14786419.2019.1637867; Ryan-Harshman M, 2007, CAN FAM PHYSICIAN, V53, P1913; Saralamma VVG, 2017, ONCOL LETT, V14, P607, DOI 10.3892/ol.2017.6184; Shao JW, 2016, SCI REP-UK, V6, DOI 10.1038/srep30549; Shi Q, 2017, AAPS J, V19, P1779, DOI 10.1208/s12248-017-0134-0; 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FEB	2021	101						11	25		10.1016/j.procbio.2020.10.002			15	Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Engineering, Chemical	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Engineering	QE1MW	WOS:000615974400002					2022-04-25	
J	Mesas, C; Martinez, R; Ortiz, R; Galisteo, M; Lopez-Jurado, M; Cabeza, L; Perazzoli, G; Melguizo, C; Porres, JM; Prados, J				Mesas, Cristina; Martinez, Rosario; Ortiz, Raul; Galisteo, Milagros; Lopez-Jurado, Maria; Cabeza, Laura; Perazzoli, Gloria; Melguizo, Consolacion; Porres, Jesus M.; Prados, Jose			Antitumor Effect of the Ethanolic Extract from Seeds of Euphorbia lathyris in Colorectal Cancer	NUTRIENTS			English	Article						colon cancer; Euphorbia lathyris; ethanolic extract; apoptosis; antiangiogenic effect; cancer stem cells		The seeds of Euphorbia lathyris have been used in traditional medicine to treat various medical conditions. However, neither all of their active biocompounds nor the molecular mechanisms underlying their therapeutic effects have been described. A new ethanolic extract of defatted flour from mature seeds of Euphorbia lathyris showed a high total polyphenol content and significant antioxidant activity. Chromatographic analysis showed that esculetin, euphorbetin, gaultherin, and kaempferol-3-rutinoside were the most abundant polyphenolic bioactive compounds. Antiproliferative assays showed a high and selective antitumor activity against colon cancer cell lines (T84 and HCT-15). In addition, a significant antiproliferative activity against glioblastoma multiforme cells was also demonstrated. Its mechanism of action to induce cell death was mediated by the overexpression of caspases 9, 3, and 8, and by activation of autophagy. Interestingly, a reduction in the migration capacity of colon cancer cells and a significant antiangiogenic effect on human umbilical vein endothelial cells were also demonstrated. Finally, the extract significantly reduced the subpopulations of cancer stem cells. This extract could be the basis to develop new therapeutic strategies for the treatment of colon cancer, although further experiments will be necessary to determine its in vivo effects.	[Mesas, Cristina; Ortiz, Raul; Cabeza, Laura; Perazzoli, Gloria; Melguizo, Consolacion; Prados, Jose] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain; [Mesas, Cristina; Ortiz, Raul; Cabeza, Laura; Perazzoli, Gloria; Melguizo, Consolacion; Prados, Jose] Univ Granada, Fac Med, Dept Anat & Embryol, Granada 18071, Spain; [Mesas, Cristina; Ortiz, Raul; Cabeza, Laura; Perazzoli, Gloria; Melguizo, Consolacion; Prados, Jose] Inst Biosanitario Granada Ibs GRANADA, Granada 18014, Spain; [Martinez, Rosario; Lopez-Jurado, Maria; Porres, Jesus M.] Univ Granada, Biomed Res Ctr CIBM, Inst Nutr & Food Technol INyTA, Dept Physiol, Granada 18100, Spain; [Galisteo, Milagros] Univ Granada, Sch Pharm, Dept Pharmacol, Granada 18071, Spain		Melguizo, C (corresponding author), Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain.; Melguizo, C (corresponding author), Univ Granada, Fac Med, Dept Anat & Embryol, Granada 18071, Spain.; Melguizo, C (corresponding author), Inst Biosanitario Granada Ibs GRANADA, Granada 18014, Spain.	cristinam@correo.ugr.es; rosariomz@ugr.es; roquesa@ugr.es; mgalist@ugr.es; mlopezj@ugr.es; lautea@ugr.es; gperazzoli@ugr.es; melguizo@ugr.es; jmporres@ugr.es; jcprados@ugr.es	Mesas, Cristina/AAO-3126-2021; Ortiz Quesada, Raul/J-7256-2017; Prados, Jose/J-7116-2017; Porres Foulquie, Jesus Maria/B-6442-2018; Melguizo Alonso, Consolacion/E-9842-2016	Ortiz Quesada, Raul/0000-0001-8409-5235; Prados, Jose/0000-0003-4303-7746; Porres Foulquie, Jesus Maria/0000-0001-5657-0764; Mesas, Cristina/0000-0001-6369-5485; Melguizo Alonso, Consolacion/0000-0003-3990-806X	Granada University [PSE/17/002]; Ministerio de Ciencia e InnovacionInstituto de Salud Carlos IIISpanish GovernmentEuropean Commission [RTC-2017-6540-1]; CTS-107 Group; AGR145 Group	This research was funded by the Granada University (project PSE/17/002), Ministerio de Ciencia e Innovacion (project RTC-2017-6540-1) and by the CTS-107 and AGR145 Groups.	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J	Xu, MY; Kim, YS				Xu, Mei-Ying; Kim, Yeong Shik			Antitumor activity of glycyrol via induction of cell cycle arrest, apoptosis and defective autophagy	FOOD AND CHEMICAL TOXICOLOGY			English	Article						Glycyrol; Apoptosis; Cell cycle arrest; Defective autophagy; JNK; AMPK	COLON-CANCER CELLS; BREAST-CANCER; MAPK PATHWAYS; PHASE ARREST; DNA-DAMAGE; DEATH; INHIBITION; GROWTH; JNK; ACTIVATION	Glycyrol is a coumestan isolated from Glycyrrhiza uralensis and synthesized to use. In this study, the antitumor activity and the underlying mechanism of glycyrol were evaluated in vitro and in vivo. It was shown that glycyrol induced cell death associated with apoptosis and autophagy as evidenced by morphological changes in AGS and HCT 116 cells. The apoptosis-inducing effect was characterized by increase in ratio of sub-G1 phase, poly (ADP-ribose) polymerase-1 (PARP-1) cleavage and caspase-3 activation. Mechanistic studies showed that glycyrol induced G0/G1 phase cell cycle arrest as indicated by increase in p21. Furthermore, c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (MAPKs) activation induced caspase-dependent apoptosis accompanied by adenosine monophosphate-activated protein kinase (AMPK) activation. Defective autophagy was triggered, which stopped the autophagic flux by the slowing of lysosomal degradation. In addition, glycyrol suppressed tumor growth in a nude mouse tumor xenograft model bearing HCT 116 cells. Taken together, glycyrol is demonstrated to have antitumor activity, and might potentially serve as potential candidate for cancer therapy. (C) 2014 Elsevier Ltd. All rights reserved.	[Xu, Mei-Ying; Kim, Yeong Shik] Seoul Natl Univ, Coll Pharm, Nat Prod Res Inst, Seoul 151742, South Korea		Kim, YS (corresponding author), Seoul Natl Univ, Coll Pharm, Nat Prod Res Inst, 1 Gwanak Ro, Seoul 151742, South Korea.	kims@snu.ac.kr			MRC - Korean Government (NRF) [2009-93146]	This work was supported by an MRC grant funded by the Korean Government (NRF, No. 2009-93146).	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Toxicol.	DEC	2014	74						311	319		10.1016/j.fct.2014.10.023			9	Food Science & Technology; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology; Toxicology	AY0GD	WOS:000347274600048	25445757				2022-04-25	
J	Das, S; Nayak, A; Siddharth, S; Nayak, D; Narayan, S; Kundu, CN				Das, Sarita; Nayak, Anmada; Siddharth, Sumit; Nayak, Deepika; Narayan, Satya; Kundu, Chanakya Nath			TRAIL enhances quinacrine-mediated apoptosis in breast cancer cells through induction of autophagy via modulation of p21 and DR5 interactions	CELLULAR ONCOLOGY			English	Article						QC; TRAIL; p21; DR5; Autophagy; Apoptosis; Breast cancer	LIPID RAFTS; DEATH RECEPTORS; TUMOR-CELLS; RESISTANCE; INHIBITION; CARCINOMA; CASCADE; SENSITIVITY; ACTIVATION; EXPRESSION	Previously, we reported that quinacrine (QC) may cause apoptosis in breast and colon cancer cells by activating the death receptor 5 (DR5), resulting in autophagic cell death through p21 modulation. Here, we systematically evaluated the combined role of p21 and DR5 and their crosstalk in QC-mediated autophagy and apoptosis in breast cancer cells using in vitro and in vivo models. Multiple breast cancer-derived cell lines (MCF-7, ZR-75-1, T47D, MDA-MB-231 and MCF-10A-Tr) and a mouse xenograft model were used. Also, multiple assays, including Western blotting, immunoprecipitation, staining for autophagy and apoptosis, gene silencing, hematoxylin and eosin staining, immunohistochemistry, cell viability assessment, fluorescence imaging and cell sorting were used. We found that QC activates p21 and DR5 in combination with the apoptosis inducer TRAIL in the breast cancer-derived cells tested. Combined TRAIL and QC treatment increased autophagy and apoptosis by increasing the interaction between, and co-localization of, p21 and DR5 in the death-inducing signaling complex (DISC). We found that this combination also inhibited the mTOR/PI3K/AKT signaling cascade and modulated reactive oxygen species (ROS) and nitric oxide (NO) production. Reductions in autophagy and apoptosis in DR5-knockout cells and a lack of change in p21-DR5-silenced cells were noted after TRAIL + QC treatment. This result explains dependence of the death (autophagy and apoptosis) cascade on these two key regulatory proteins. In addition, we found in an in vivo mouse xenograft model that increased expression and enhanced co-localization of p21 and DR5 after TRAIL + QC treatment supported a joint regulatory role of these proteins in the co-prevalence of autophagy and apoptosis. Our data suggest that a combined treatment of TRAIL and QC causes cell death in breast cancer-derived cells via autophagy and apoptosis by increasing the interaction of p21 and DR5, as indicated by both in vitro and in vivo studies.	[Das, Sarita; Nayak, Anmada; Siddharth, Sumit; Nayak, Deepika; Kundu, Chanakya Nath] KIIT Univ, KIIT Sch Biotechnol, Div Canc Biol, Campus 11, Bhubaneswar 751024, Orissa, India; [Narayan, Satya] Univ Florida, Dept Anat & Cell Biol, Coll Med, Gainesville, FL 32610 USA		Kundu, CN (corresponding author), KIIT Univ, KIIT Sch Biotechnol, Div Canc Biol, Campus 11, Bhubaneswar 751024, Orissa, India.	cnkundu@gmail.com	Siddharth, Sumit/AFL-4204-2022	Kundu, Chanakya/0000-0003-0297-1030	Department of Science and Technology (DST)Department of Science & Technology (India); Indian Council of Medical Research (ICMR), Government of IndiaIndian Council of Medical Research (ICMR)	We sincerely acknowledge the Department of Science and Technology (DST) and the Indian Council of Medical Research (ICMR), Government of India, for providing fellowships to SD, AN and SS, respectively. In addition, we sincerely thank Mark Zakshevsky, Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida, USA, for proofreading the manuscript.	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Oncol.	DEC	2017	40	6					593	607		10.1007/s13402-017-0347-3			15	Oncology; Cell Biology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology; Pathology	FO0RK	WOS:000416454200005	28936683				2022-04-25	
J	Son, Y; An, Y; Jung, J; Shin, S; Park, I; Gwak, J; Ju, BG; Chung, YH; Na, M; Oh, S				Son, Younglim; An, Younju; Jung, Jaeyeon; Shin, Sora; Park, InWha; Gwak, Jungsug; Ju, Bong Gun; Chung, Young-Hwa; Na, MinKyun; Oh, Sangtaek			Protopine isolated from Nandina domestica induces apoptosis and autophagy in colon cancer cells by stabilizing p53	PHYTOTHERAPY RESEARCH			English	Article						apoptosis; autophagy; colon cancer; Nandina domestica; p53 signaling; protopine	PHOSPHORYLATION; ACTIVATION; FUMARIA; DEATH	The tumor suppressor p53 plays essential roles in cellular protection mechanisms against a variety of stress stimuli and its activation induces apoptosis or autophagy in certain cancer cells. Here, we identified protopine, an isoquinoline alkaloid isolated from Nandina domestica, as an activator of the p53 pathway from cell-based natural compound screening based on p53-responsive transcription. Protopine increased the p53-mediated transcriptional activity and promoted p53 phosphorylation at the Ser15 residue, resulting in stabilization of p53 protein. Moreover, protopine up-regulated the expression of p21(WAF1/CIP1) and BAX, downstream genes of p53, and inhibited the proliferation of HCT116 colon cancer cells. Apoptosis was elicited by protopine as indicated by caspase-3/7 activation, poly ADP ribose polymerase cleavage, and increased population of Annexin V-FITC-positive cells. Furthermore, protopine induced the formation of microtubule-associated protein 1 light chain 3 (LC3) puncta and LC3-II turnover, typical biochemical markers of autophagy, in HCT116 cells. Our findings suggest that protopine exerts its antiproliferative activity by stimulating the p53 pathway and may have potential as a chemopreventive agent for human colon cancer.	[Son, Younglim; An, Younju; Jung, Jaeyeon; Shin, Sora; Oh, Sangtaek] Kookmin Univ, Dept Bio & Fermentat Convergence Technol, BK21 PLUS Program, Seoul, South Korea; [Park, InWha; Na, MinKyun] Chungnam Natl Univ, Coll Pharm, Daejeon 34134, South Korea; [Gwak, Jungsug; Ju, Bong Gun] Sogang Univ, Dept Life Sci, Seoul, South Korea; [Chung, Young-Hwa] Pusan Natl Univ, Dept Cognomechatron Engn, BK21, Busan, South Korea		Na, M (corresponding author), Chungnam Natl Univ, Coll Pharm, Daejeon 34134, South Korea.; Oh, S (corresponding author), Kookmin Univ, Dept Bio & Fermentat Convergence Technol, Seoul 02707, South Korea.	mkna@cnu.ac.kr; ohsa@kookmin.ac.kr			Basic Science Research Program through the National Research Foundation of Korea (NRF) - Korean government [NRF-2018R1D1A1B07048208, NRF-2017R1A2A2A05001340]	This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2018R1D1A1B07048208, NRF-2017R1A2A2A05001340).	Altman BJ, 2012, CSH PERSPECT BIOL, V4, DOI 10.1101/cshperspect.a008763; Bae DS, 2012, BMB REP, V45, P108, DOI 10.5483/BMBRep.2012.45.2.108; Bae SK, 2011, BIOCHEM BIOPH RES CO, V409, P75, DOI 10.1016/j.bbrc.2011.04.108; Brooks CL, 2003, CURR OPIN CELL BIOL, V15, P164, DOI 10.1016/S0955-0674(03)00003-6; Broz P, 2013, NAT REV IMMUNOL, V13, P551, DOI 10.1038/nri3479; Chen CH, 2012, CANCER LETT, V315, P1, DOI 10.1016/j.canlet.2011.09.042; CordonCardo C, 1997, CANCER RES, V57, P1217; DAMERON KM, 1994, SCIENCE, V265, P1582, DOI 10.1126/science.7521539; Gottlieb TM, 1996, BBA-REV CANCER, V1287, P77, DOI 10.1016/0304-419X(95)00019-C; Gump JM, 2011, TRENDS CELL BIOL, V21, P387, DOI 10.1016/j.tcb.2011.03.007; Haberlein H, 1996, PLANTA MED, V62, P227, DOI 10.1055/s-2006-957865; Haggar Fatima A, 2009, Clin Colon Rectal Surg, V22, P191, DOI 10.1055/s-0029-1242458; He K, 2014, AFR J TRADIT COMPLEM, V11, P415, DOI 10.4314/ajtcam.v11i2.28; Jiang B, 2004, EUR J PHARMACOL, V506, P93, DOI 10.1016/j.ejphar.2004.11.004; Kim BJ, 2006, J BIOL CHEM, V281, P21256, DOI 10.1074/jbc.M510644200; Kim SR, 1999, PLANTA MED, V65, P218, DOI 10.1055/s-1999-13983; Lee HY, 2015, MAR DRUGS, V13, P543, DOI 10.3390/md13010543; LEVINE AJ, 1994, J LAB CLIN MED, V123, P817; Levine AJ, 2009, NAT REV CANCER, V9, P749, DOI 10.1038/nrc2723; Okada H, 2004, NAT REV CANCER, V4, P592, DOI 10.1038/nrc1412; Orhan I, 2007, Z NATURFORSCH C, V62, P19; Park S, 2006, MOL PHARMACOL, V70, P960, DOI 10.1124/mol.106.024729; Rathi A, 2008, PHYTOMEDICINE, V15, P470, DOI 10.1016/j.phymed.2007.11.010; Saeed SA, 1997, PHARMACOL RES, V36, P1, DOI 10.1006/phrs.1997.0195; Speidel D, 2010, TRENDS CELL BIOL, V20, P14, DOI 10.1016/j.tcb.2009.10.002; Tzifi Flora, 2012, Adv Hematol, V2012, P524308, DOI 10.1155/2012/524308; Xiao XH, 2007, BASIC CLIN PHARMACOL, V101, P85, DOI 10.1111/j.1742-7843.2007.00075.x	27	15	17	2	12	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0951-418X	1099-1573		PHYTOTHER RES	Phytother. Res.	JUN	2019	33	6					1689	1696		10.1002/ptr.6357			8	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	ID7ZJ	WOS:000471901200010	30932278				2022-04-25	
J	Lu, XY; Wei, HB; Zhang, XJ; Zheng, WX; Chang, C; Gu, JY				Lu, Xueying; Wei, Haibo; Zhang, Xiaojin; Zheng, Wenxin; Chang, Cheng; Gu, Jinyu			Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis	ONCOLOGY LETTERS			English	Article						rapamycin; oxaliplatin; colon cancer; apoptosis; autophagy	CHEMOTHERAPY-INDUCED CYTOTOXICITY; MAMMALIAN TARGET; MTOR INHIBITOR; COLORECTAL-CANCER; MULTIPLE-MYELOMA; COMBINATION; AUTOPHAGY; NEUROTOXICITY; PACLITAXEL; RADIATION	The present study aimed to examine the combined effects of oxaliplatin (L-OHP) and rapamycin (RAPA) in the HCT116 colon cancer cell line. The growth inhibitory effect was evaluated by MTT assay as a monotherapy or combination therapy. IC50 values were determined using CalcuSyn 2.0 software. To determine the interaction of the drugs, the combination index (CI) was calculated using the Chou-Talalay method. Apoptosis was investigated using flow cytometry and Western blotting. Acridine orange staining was employed to observe morphological changes. The results showed the IC50 values of L-OHP and RAPA to be 8.35 +/- 0.78 mu M (r=0.99) and 223.44 +/- 38.10 nM (r=0.94), respectively. Cl was when L-OHP was used at doses ranging from 1 to 5 mu M plus RAPA at a dose of 10 nM, suggesting synergistic or additive effects. CI was >= 1 when 100 nM RAPA was used in combination with low-dose L-OHP, showing additive to antagonistic effects. The combination of L-OHP (1 mu M) and RAPA (10 nM) induced 19.76% Annexin V-positive cells, which was found to be higher than L-OHP (11.45%, p < 0.01) or RAPA (6.89%, p < 0.01) alone. The cleaved PARP protein expression levels were highest after 48 h of combination treatment. Acridine orange staining showed typical bright red Acidic vesicular organdies in the RAPA group, whereas the green condensed chromatin in the apoptotic bodies was found in both the L-OHP and combination groups. In conclusion, at a cytostatic concentration, RAPA was found to potentiate the anti-tumor effects of low-dose L-OHP in the HCT116 colon cancer cell by inducing enhanced apoptosis.	[Chang, Cheng; Gu, Jinyu] Harbin Med Univ, Dept Gen Surg, Affiliated Hosp 2, Harbin 150086, Heilongjiang, Peoples R China; [Lu, Xueying; Wei, Haibo; Zhang, Xiaojin; Zheng, Wenxin] Harbin Med Univ, Dept Immunol, Basic Med Sci Coll, Harbin 150081, Heilongjiang, Peoples R China		Gu, JY (corresponding author), Harbin Med Univ, Dept Gen Surg, Affiliated Hosp 2, 246 Baojian Rd, Harbin 150086, Heilongjiang, Peoples R China.	gujinyu@hotmail.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30700997]; Heilongjiang overseas fund [LC06C27]	This study was funded by grants from the National Natural Science Foundation of China (No. 30700997) to Dr Xueying Lu and from the Heilongjiang overseas fund (No. LC06C27) to Dr Jinyu Gu.	Bae-Jump VL, 2009, CANCER-AM CANCER SOC, V115, P3887, DOI 10.1002/cncr.24431; Eisenberg-Lerner A, 2009, CELL DEATH DIFFER, V16, P966, DOI 10.1038/cdd.2009.33; Francis LK, 2006, CLIN CANCER RES, V12, P6826, DOI 10.1158/1078-0432.CCR-06-1331; Fung AS, 2009, CLIN CANCER RES, V15, P5389, DOI 10.1158/1078-0432.CCR-08-3007; Gerber DE, 2010, CANCER METAST REV, V29, P171, DOI 10.1007/s10555-010-9215-6; Gu JY, 2006, DIGESTION, V74, P19, DOI 10.1159/000095826; Houghton PJ, 2010, MOL CANCER THER, V9, P101, DOI 10.1158/1535-7163.MCT-09-0952; Johnson SM, 2010, J AM COLL SURGEONS, V210, P767, DOI 10.1016/j.jamcollsurg.2009.12.008; Kondo Y, 2006, AUTOPHAGY, V2, P85, DOI 10.4161/auto.2.2.2463; McWhinney SR, 2009, MOL CANCER THER, V8, P10, DOI 10.1158/1535-7163.MCT-08-0840; Merimsky O, 2007, INT J ONCOL, V31, P225; Mondesire WH, 2004, CLIN CANCER RES, V10, P7031, DOI 10.1158/1078-0432.CCR-04-0361; Nagata Y, 2010, INT J ONCOL, V37, P1001, DOI 10.3892/ijo_00000751; Paglin S, 2001, CANCER RES, V61, P439; Park SB, 2009, J CLIN ONCOL, V27, P1243, DOI 10.1200/JCO.2008.19.3425; Parkin DM, 2005, CA-CANCER J CLIN, V55, P74, DOI 10.3322/canjclin.55.2.74; Pencreach E, 2009, CLIN CANCER RES, V15, P1297, DOI 10.1158/1078-0432.CCR-08-0889; Perotti A, 2010, J CLIN ONCOL, V28, P4554, DOI 10.1200/JCO.2009.27.5867; Raje N, 2004, BLOOD, V104, P4188, DOI 10.1182/blood-2004-06-2281; Rodriguez J, 2007, WORLD J GASTROENTERO, V13, P5867, DOI 10.3748/wjg.v13.i44.5867; Shafer A, 2010, INT J CANCER, V126, P1144, DOI 10.1002/ijc.24837; Shigematsu H, 2010, INT J CANCER, V126, P2716, DOI 10.1002/ijc.24990; Silvestris N, 2009, ONCOLOGY-BASEL, V77, P69, DOI 10.1159/000258498; Wadlow RC, 2010, CANCER-AM CANCER SOC, V116, P3537, DOI 10.1002/cncr.25155	24	7	8	1	9	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-1074	1792-1082		ONCOL LETT	Oncol. Lett.	JUL-AUG	2011	2	4					643	647		10.3892/ol.2011.299			5	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	775ZD	WOS:000291503300011	22848242	Green Published, gold			2022-04-25	
J	Wiener, Z; Hogstrom, J; Hyvonen, V; Band, AM; Kallio, P; Holopainen, T; Dufva, O; Haglund, C; Kruuna, O; Oliver, G; Ben-Neriah, Y; Alitalo, K				Wiener, Zoltan; Hogstrom, Jenny; Hyvonen, Ville; Band, Arja M.; Kallio, Pauliina; Holopainen, Tanja; Dufva, Olli; Haglund, Caj; Kruuna, Olli; Oliver, Guillermo; Ben-Neriah, Yinon; Alitalo, Kari			Prox1 Promotes Expansion of the Colorectal Cancer Stem Cell Population to Fuel Tumor Growth and Ischemia Resistance	CELL REPORTS			English	Article							INTESTINAL EPITHELIUM; BETA-CATENIN; COLON; IDENTIFICATION; AUTOPHAGY; ORIGIN	Colorectal cancer (CRC) initiation and growth is often attributed to stem cells, yet little is known about the regulation of these cells. We show here that a sub-population of Prox1-transcription-factor-expressing cells have stem cell activity in intestinal adenomas, but not in the normal intestine. Using in vivo models and 3D ex vivo organoid cultures of mouse adenomas and human CRC, we found that Prox1 deletion reduced the number of stem cells and cell proliferation and decreased intestinal tumor growth via induction of annexin A1 and reduction of the actin-binding protein filamin A, which has been implicated as a prognostic marker in CRC. Loss of Prox1 also decreased autophagy and the survival of hypoxic tumor cells in tumor transplants. Thus, Prox1 is essential for the expansion of the stem cell pool in intestinal adenomas and CRC without being critical for the normal functions of the gut.	[Wiener, Zoltan; Hogstrom, Jenny; Hyvonen, Ville; Band, Arja M.; Kallio, Pauliina; Holopainen, Tanja; Dufva, Olli; Alitalo, Kari] Univ Helsinki, Translat Canc Biol Program, FIN-00014 Helsinki, Finland; [Alitalo, Kari] Biomedicum Helsinki, Wihuri Res Inst, Helsinki 00014, Finland; [Haglund, Caj; Kruuna, Olli] Univ Helsinki, Cent Hosp, Dept Surg, Helsinki 00029, Finland; [Oliver, Guillermo] St Jude Childrens Res Hosp, Dept Genet, Memphis, TN 38105 USA; [Ben-Neriah, Yinon] Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Immunol, IL-91120 Jerusalem, Israel		Alitalo, K (corresponding author), Univ Helsinki, Translat Canc Biol Program, FIN-00014 Helsinki, Finland.	kari.alitalo@helsinki.fi	Dufva, Olli/X-7225-2019; Haglund, Caj/N-1240-2019; Ben-Neriah, Yinon/L-6285-2019; Alitalo, Kari K/J-5013-2014	Alitalo, Kari K/0000-0002-7331-0902; Kallio, Pauliina/0000-0001-6374-6203; Dufva, Olli/0000-0002-8084-0282	Sigrid Juselius FoundationSigrid Juselius Foundation; Finnish Cancer Organizations; Academy of FinlandAcademy of Finland [262976]; Marie-Curie Intra-European FellowshipEuropean Commission [PIEF-GA-2009-236695]	We thank Dr. Leif Andersson for the consultations on histopathology, Dr. Taija Ma kinen for the Prox1-Cre<SUP>ER</SUP> mice, Dr. Darren Tyson for the ANXA1-modulating constructs, Dr. David Calderwood for the FLNA antibody, Dr. Meenhard Herlyn (Wistar Institute) for the SW1222 cell line, Dr. Tatiana Petrova for discussions of PROX1 functions in CRC, Dr. Pekka Katajisto, Dr. Tuomas Tammela, and Dr. Timo Otonkoski for comments on the manuscript, and Lari Pyoria , Kirsi Lintula, Katja Salo, Laura Raitanen, and Tapio Tainola for their help with the experiments. The Biomedicum Imaging Unit is acknowledged for microscopy services. This work was funded by the Sigrid Juselius Foundation, the Finnish Cancer Organizations, and the Academy of Finland (262976). Z.W. was supported by the Sigrid Juselius Foundation and by the Marie-Curie Intra-European Fellowship (PIEF-GA-2009-236695).	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J	Liu, YQ; Cheng, X; Guo, LX; Mao, C; Chen, YJ; Liu, HX; Xiao, QC; Jiang, S; Yao, ZJ; Zhou, GB				Liu, Yong-Qiang; Cheng, Xin; Guo, Liang-Xia; Mao, Chan; Chen, Yi-Jie; Liu, Hai-Xia; Xiao, Qi-Cai; Jiang, Sheng; Yao, Zhu-Jun; Zhou, Guang-Biao			Identification of an Annonaceous Acetogenin Mimetic, AA005, as an AMPK Activator and Autophagy Inducer in Colon Cancer Cells	PLOS ONE			English	Article							PROTEIN-KINASE; MAMMALIAN TARGET; RAT-LIVER; METFORMIN; ANTICANCER; INHIBITION; METABOLISM; PHOSPHORYLATION; 2-DEOXYGLUCOSE; MITOCHONDRIA	Annonaceous acetogenins, a large family of naturally occurring polyketides isolated from various species of the plant genus Annonaceae, have been found to exhibit significant cytotoxicity against a variety of cancer cells. Previous studies showed that these compounds could act on the mitochondria complex-I and block the corresponding electron transport chain and terminate ATP production. However, more details of the mechanisms of action remain ambiguous. In this study we tested the effects of a set of mimetics of annonaceous acetogenin on some cancer cell lines, and report that among them AA005 exhibits the most potent antitumor activity. AA005 depletes ATP, activates AMP-activated protein kinase (AMPK) and inhibits mTOR complex 1 (mTORC1) signal pathway, leading to growth inhibition and autophagy of colon cancer cells. AMPK inhibitors compound C and inosine repress, while AMPK activator AICAR enhances, AA005-caused proliferation suppression and subsequent autophagy of colon cancer cells. AA005 enhances the ATP depletion and AMPK activation caused by 2-deoxyglucose, an inhibitor of mitochondrial respiration and glycolysis. AA005 also inhibits chemotherapeutic agent cisplatin-triggered up-regulation of mTOR and synergizes with this drug in suppression of proliferation and induction of apoptosis of colon cancer cells. These data indicate that AA005 is a new metabolic inhibitor which exhibits therapeutic potentials in colon cancer.	[Mao, Chan; Chen, Yi-Jie; Liu, Hai-Xia; Yao, Zhu-Jun] Nanjing Univ, State Key Lab Coordinat Chem, Nanjing Natl Lab Microstruct, Sch Chem & Chem Engn, Nanjing, Jiangsu, Peoples R China; [Xiao, Qi-Cai; Jiang, Sheng] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou, Guangdong, Peoples R China; [Liu, Yong-Qiang; Cheng, Xin; Guo, Liang-Xia; Zhou, Guang-Biao] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Div Mol Carcinogenesis & Targeted Therapy Canc, Beijing, Peoples R China; [Liu, Yong-Qiang] Chinese Acad Sci, Grad Univ, Beijing, Peoples R China		Yao, ZJ (corresponding author), Nanjing Univ, State Key Lab Coordinat Chem, Nanjing Natl Lab Microstruct, Sch Chem & Chem Engn, Nanjing, Jiangsu, Peoples R China.	yaoz@nju.edu.cn; gbzhou@ioz.ac.cn	Zhou, Guang-Biao/ABG-5795-2021; Yao, Zhu-Jun/E-7635-2015	Xiao, Qicai/0000-0001-9383-4052; Zhou, Guang-Biao/0000-0001-6778-7133; Zhou, Guang-Biao/0000-0002-6327-2316	National Key Program for Basic ResearchNational Basic Research Program of China [2012CB910800, 2010CB833200, 2009CB940900]; National Natural Science FoundationNational Natural Science Foundation of China (NSFC) [81071930, 81171925, 20972160, 21172220]; Special Foundation of President; Key Project of Knowledge Innovation Program of the Chinese Academy of SciencesChinese Academy of Sciences [KSCX1-YW-R-26, KSCX2-YW-R-235]; National Major Scientific and Technological Program for Drug Discovery [2009ZX09103-101]	This work was supported in part by the National Key Program for Basic Research (2012CB910800, 2010CB833200 and 2009CB940900), the National Natural Science Foundation (No. 81071930, 81171925, 20972160 and 21172220), the Special Foundation of President and the Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX1-YW-R-26 and KSCX2-YW-R-235), and the National Major Scientific and Technological Program for Drug Discovery (2009ZX09103-101). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Long, JL; He, QL; Yin, YT; Lei, X; Li, ZQ; Zhu, W				Long, Jiali; He, Qinglian; Yin, Yuting; Lei, Xue; Li, Ziqi; Zhu, Wei			The effect of miRNA and autophagy on colorectal cancer	CELL PROLIFERATION			English	Review						autophagy; colorectal cancer; microRNA; therapy	CONFERS 5-FLUOROURACIL RESISTANCE; INFLAMMATORY-BOWEL-DISEASE; NF-KAPPA-B; COLON-CANCER; STEM-CELLS; REGULATES AUTOPHAGY; INHIBIT AUTOPHAGY; MAMMALIAN TARGET; EPITHELIAL-CELLS; DRUG-RESISTANCE	Colorectal cancer (CRC) has become a concern because of its high recurrence rate and metastasis rate, low early diagnosis rate and poor therapeutic effect. At present, various studies have shown that autophagy is closely connected with the occurrence and progression of CRC. Autophagy is a highly cytosolic catabolic process involved in lysosomes in biological evolution. Cells degrade proteins and damaged organelles by autophagy to achieve material circulation and maintain cell homeostasis. Moreover, microRNAs are key regulators of autophagy, and their mediated regulation of transcriptional and post-transcriptional levels plays an important role in autophagy in CRC cells. This review focuses on the recent research advances of how autophagy and related microRNAs are involved in affecting occurrence and progression of CRC and provides a new perspective for the study of CRC treatment strategies.	[Long, Jiali; He, Qinglian; Yin, Yuting; Lei, Xue; Li, Ziqi; Zhu, Wei] Guangdong Med Univ, Dept Pathol, 1 Xincheng Rd, Dongguan 523808, Guangdong, Peoples R China; [Long, Jiali] Sun Yat Sen Univ, Affiliated Hosp 8, Dept Pathol, Shenzhen, Peoples R China		Zhu, W (corresponding author), Guangdong Med Univ, Dept Pathol, 1 Xincheng Rd, Dongguan 523808, Guangdong, Peoples R China.	zhuwei@gdmu.edu.cn		Zhu, Wei/0000-0002-1217-1718	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472275]; Guangdong Basic and Applied Basic Research Foundation [2020A151501303, 2014A030313542]	This work was supported by National Natural Science Foundation of China (81472275), Guangdong Basic and Applied Basic Research Foundation (2020A151501303, 2014A030313542).	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OCT	2020	53	10							e12900	10.1111/cpr.12900		SEP 2020	10	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	OI6MM	WOS:000568854000001	32914514	Green Published, gold			2022-04-25	
J	Campos, T; Ziehe, J; Palma, M; Escobar, D; Tapia, JC; Pincheira, R; Castro, AF				Campos, Tania; Ziehe, Javiera; Palma, Mario; Escobar, David; Tapia, Julio C.; Pincheira, Roxana; Castro, Ariel F.			Rheb Promotes Cancer Cell Survival Through p27Kip1-Dependent Activation of Autophagy	MOLECULAR CARCINOGENESIS			English	Article						Rheb GTPase; N-terminal of p27; mTORC1-independent	MAMMALIAN TARGET; COMPLEX; INHIBITION; APOPTOSIS; P27(KIP1); MTORC1; P27; PHOSPHORYLATION; PROLIFERATION; MECHANISMS	We previously found that the small GTPase Rheb regulates the cell-cycle inhibitor p27KIP1 (p27) in colon cancer cells by a mTORC1-independent mechanism. However, the biological function of the Rheb/p27 axis in cancer cells remains unknown. Here, we show that siRNA-mediated depletion of Rheb decreases survival of human colon cancer cells under serum deprivation. As autophagy can support cell survival, we analyzed the effect of Rheb on this process by detecting the modification of the autophagy marker protein LC3 by western blot and imunofluorescence. We found that Rheb promotes autophagy in several human cancer cell lines under serum deprivation. Accordingly, blocking autophagy inhibited the pro-survival effect of Rheb in colon cancer cells. We then analyzed whether p27 was involved in the biological effect of Rheb. Depletion of p27 inhibited colon cancer cell survival, and Rheb induction of autophagy. These results suggest that p27 has an essential role in the effect of Rheb in response to serum deprivation. In addition, we demonstrated that the role of p27 in autophagy stands on the N-terminal portion of the protein, where the CDK-inhibitory domain is located. Our results indicate that a Rheb/p27 axis accounts for the activation of autophagy that supports cancer cell survival. Our work therefore highlights a biological function of Rheb and prompts the need for future studies to address whether the mTORC1-independent Rheb/p27 axis could contribute to tumorigenesis and/or resistance to mTOR inhibitors. (C) 2015 Wiley Periodicals, Inc.	[Campos, Tania; Ziehe, Javiera; Palma, Mario; Escobar, David; Pincheira, Roxana; Castro, Ariel F.] Univ Concepcion, Fac Ciencias Biol, Lab Transducc Senales & Canc, Dept Bioquim & Biol Mol, Concepcion, Chile; [Tapia, Julio C.] Univ Chile, ICBM, Fac Med, Lab Transformac Celular, Santiago, Chile		Castro, AF (corresponding author), Univ Concepcion, Fac Ciencias Biol, Dept Bioquim & Biol Mol, Barrio Univ S-N, Concepcion 4030000, Region Bio Bio, Chile.		Tapia, Julio/A-7436-2012	Pincheira, Roxana/0000-0003-4277-5245	Universidad de Concepcion [DIUC 210.037.011-1.0]; CONICYT/FONDECYTComision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)CONICYT FONDECYT [Regular 1120923, Regular 1120132, Regular 1110821]; CONICYTComision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)	Grant sponsor: Universidad de Concepcion; Grant number: DIUC 210.037.011-1.0; Grant sponsor: CONICYT/FONDECYT; Grant number: Regular 1120923; Grant sponsor: CONICYT/FONDECYT; Grant number: Regular 1120132; Grant sponsor: CONICYT/FONDECYT; Grant number: Regular 1110821; Grant sponsor: CONICYT	Alers S, 2012, MOL CELL BIOL, V32, P2, DOI 10.1128/MCB.06159-11; Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Barth S, 2010, J PATHOL, V221, P117, DOI 10.1002/path.2694; Borriello A, 2007, CELL CYCLE, V6, P1053, DOI 10.4161/cc.6.9.4142; Castro AF, 2003, J BIOL CHEM, V278, P32493, DOI 10.1074/jbc.C300226200; Chen N, 2010, FEBS LETT, V584, P1427, DOI 10.1016/j.febslet.2009.12.034; Choo AY, 2008, P NATL ACAD SCI USA, V105, P17414, DOI 10.1073/pnas.0809136105; Chu IM, 2008, NAT REV CANCER, V8, P253, DOI 10.1038/nrc2347; Criollo A, 2010, EMBO J, V29, P619, DOI 10.1038/emboj.2009.364; Ducker GS, 2014, ONCOGENE, V33, P1590, DOI 10.1038/onc.2013.92; Furuya T, 2010, MOL CELL, V38, P500, DOI 10.1016/j.molcel.2010.05.009; Garami A, 2003, MOL CELL, V11, P1457, DOI 10.1016/S1097-2765(03)00220-X; Giansanti V, 2011, APOPTOSIS, V16, P321, DOI 10.1007/s10495-011-0589-x; Gordy C, 2012, PROTEIN CELL, V3, P17, DOI 10.1007/s13238-011-1127-x; Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013; Hippert MM, 2006, CANCER RES, V66, P9349, DOI 10.1158/0008-5472.CAN-06-1597; Holohan C, 2013, NAT REV CANCER, V13, P714, DOI 10.1038/nrc3599; Huang J, 2008, BIOCHEM J, V412, P179, DOI 10.1042/BJ20080281; Kelsey I, 2013, SCI SIGNAL, V6, DOI 10.1126/scisignal.2004632; Kim JH, 2011, AUTOPHAGY, V7, P1187, DOI 10.4161/auto.7.10.16643; Komata T, 2003, BRIT J CANCER, V88, P1277, DOI 10.1038/sj.bjc.6600862; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Lacher MD, 2010, ONCOGENE, V29, P6543, DOI 10.1038/onc.2010.393; Lacher Markus D, 2011, Small GTPases, V2, P211; Larrea MD, 2009, CELL CYCLE, V8, P3455, DOI 10.4161/cc.8.21.9789; Lee J, 2009, EXP MOL MED, V41, P765, DOI 10.3858/emm.2009.41.11.102; Liang JY, 2007, NAT CELL BIOL, V9, P218, DOI 10.1038/ncb1537; Lu KH, 2008, CLIN CANCER RES, V14, P2543, DOI 10.1158/1078-0432.CCR-07-0321; Mathew R, 2011, COLD SH Q B, V76, P389, DOI 10.1101/sqb.2012.76.011015; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Mavrakis KJ, 2008, GENE DEV, V22, P2178, DOI 10.1101/gad.1690808; Melser S, 2013, CELL METAB, V17, P719, DOI 10.1016/j.cmet.2013.03.014; Nardella C, 2008, GENE DEV, V22, P2172, DOI 10.1101/gad.1699608; Neuman NA, 2011, EMBO MOL MED, V3, P189, DOI 10.1002/emmm.201100131; Rubinsztein DC, 2012, CURR BIOL, V22, pR29, DOI 10.1016/j.cub.2011.11.034; Saito K, 2005, J BIOCHEM, V137, P423, DOI 10.1093/jb/mvi046; Sancak Y, 2010, CELL, V141, P290, DOI 10.1016/j.cell.2010.02.024; Short JD, 2010, MOL CARCINOG, V49, P14; Short JD, 2008, CANCER RES, V68, P6496, DOI 10.1158/0008-5472.CAN-07-5756; Sun XT, 2014, J BIOL CHEM, V289, P16924, DOI 10.1074/jbc.M113.542795; Tapia JC, 2004, J CELL BIOCHEM, V91, P865, DOI 10.1002/jcb.20027; Wong PM, 2013, AUTOPHAGY, V9, P124, DOI 10.4161/auto.23323; Wu YC, 2009, BIOCHEM BIOPH RES CO, V382, P451, DOI 10.1016/j.bbrc.2009.03.051	43	22	23	1	8	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0899-1987	1098-2744		MOL CARCINOGEN	Mol. Carcinog.	FEB	2016	55	2					220	229		10.1002/mc.22272			10	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	DB9BT	WOS:000368811700009	25594310				2022-04-25	
J	Wang, WK; Lin, ST; Chang, WW; Liu, LW; Li, TYT; Kuo, CY; Hsieh, JL; Lee, CH				Wang, Wei-Kuang; Lin, Song-Tao; Chang, Wen-Wei; Liu, Li-Wen; Li, Tom Yu-Tung; Kuo, Chun-Yu; Hsieh, Jeng-Long; Lee, Che-Hsin			Hinokitiol induces autophagy in murine breast and colorectal cancer cells	ENVIRONMENTAL TOXICOLOGY			English	Article						hinokitiol; antitumor; autophagy	APOPTOSIS; DEATH; INDUCTION; PATHWAY; INHIBITION; CARCINOMA	Hinokitiol is found in the heartwood of cupressaceous plants and possesses several biological activities. Hinokitiol may play an important role in anti-inflammation and antioxidant processes, making it potentially useful in therapies for inflammatory-mediated disease. Previously, the suppression of tumor growth by hinokitiol has been shown to occur through apoptosis. Programmed cell death can also occur through autophagy, but the mechanism of hinokitiol-induced autophagy in tumor cells is poorly defined. We used an autophagy inhibitor (3-methyladenine) to demonstrate that hinokitiol can induce cell death via an autophagic pathway. Further, we suggest that hinokitiol induces autophagy in a dose-dependent manner. Markers of autophagy were increased after tumor cells were treated with hinokitiol. In addition, immunoblotting revealed that the levels of phosphoprotein kinase B (P-AKT), phosphomammalian target of rapamycin (P-mTOR), and phospho-p70 ribosomal s6 kinase (P-p70S6K) in tumor cells were decreased after hinokitiol treatment. In conclusion, our results indicate that hinokitiol induces the autophagic signaling pathway via downregulation of the AKT/mTOR pathway. Therefore, our findings show that hinokitiol may control tumor growth by inducing autophagic signaling. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 77-84, 2016.	[Wang, Wei-Kuang] Feng Chia Univ, Dept Environm Engn & Sci, Taichung 40724, Taiwan; [Lin, Song-Tao; Kuo, Chun-Yu; Lee, Che-Hsin] China Med Univ, Sch Med, Dept Microbiol, Taichung, Taiwan; [Chang, Wen-Wei] Chung Shan Med Univ, Coll Med Sci & Technol, Dept Biomed Sci, Taichung, Taiwan; [Chang, Wen-Wei] Chung Shan Med Univ Hosp, Dept Med Res, Taichung 40201, Taiwan; [Liu, Li-Wen; Li, Tom Yu-Tung] Osaka Univ, Grad Sch Med, Div Gene Therapy Sci, Osaka, Japan; [Hsieh, Jeng-Long] Chung Hwa Univ Med Technol, Dept Nursing, Tainan, Taiwan		Lee, CH (corresponding author), China Med Univ, Sch Med, Dept Microbiol, Taichung, Taiwan.	chlee@mail.cmu.edu.tw	Wang, Wei-Kuang/Q-3662-2018	Chang, Wen-Wei/0000-0003-2283-1377; Li, Yu-Tung/0000-0002-0718-7344	National Science Council, TaiwanMinistry of Science and Technology, Taiwan; Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence [NSC 101-2320-B-039-012-MY3, DOH102-TD-B-111-004]	Contract grant sponsors: National Science Council, Taiwan; Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence.; Contract grant numbers: NSC 101-2320-B-039-012-MY3; DOH102-TD-B-111-004	Bjorkoy G, 2005, J CELL BIOL, V171, P603, DOI 10.1083/jcb.200507002; Castle JC, 2014, BMC GENOMICS, V15, DOI 10.1186/1471-2164-15-190; Chen YL, 2014, CELL DEATH DIS, V5, DOI 10.1038/cddis.2014.159; Eisenberg-Lerner A, 2009, CELL DEATH DIFFER, V16, P966, DOI 10.1038/cdd.2009.33; Ido Y, 1999, CELL PROLIFERAT, V32, P63, DOI 10.1046/j.1365-2184.1999.00133.x; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Lee CH, 2014, GENE THER, V21, P309, DOI 10.1038/gt.2013.86; Lee YR, 2013, J BIOMED SCI, V20, DOI 10.1186/1423-0127-20-65; Lee YS, 2013, J NAT PROD, V76, P2195, DOI 10.1021/np4005135; Liu WS, 2013, MAR DRUGS, V11, P1899, DOI 10.3390/md11061899; Lockshin RA, 2004, INT J BIOCHEM CELL B, V36, P2405, DOI 10.1016/j.biocel.2004.04.011; Lu CH, 2012, BIOMED PHARMACOTHER, V66, P642, DOI 10.1016/j.biopha.2012.08.001; Pattingre S, 2006, CANCER RES, V66, P2885, DOI 10.1158/0008-5472.CAN-05-4412; Shiau AL, 2014, ENVIRON TOXICOL, V29, P363, DOI 10.1002/tox.21763; Shih YH, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0094941; Sun PH, 2011, CANCER LETT, V310, P170, DOI 10.1016/j.canlet.2011.06.037; Yo YT, 2009, J AGR FOOD CHEM, V57, P8266, DOI 10.1021/jf901054c; Zhang HY, 2009, TOXICOL SCI, V110, P376, DOI 10.1093/toxsci/kfp101; Zhu WY, 2014, INT J MOL SCI, V15, P3336, DOI 10.3390/ijms15023336	19	17	19	0	20	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	1520-4081	1522-7278		ENVIRON TOXICOL	Environ. Toxicol.	JAN	2016	31	1					77	84		10.1002/tox.22023			8	Environmental Sciences; Toxicology; Water Resources	Science Citation Index Expanded (SCI-EXPANDED)	Environmental Sciences & Ecology; Toxicology; Water Resources	CY7JT	WOS:000366585300007	25044443				2022-04-25	
J	Fujiwara, K; Daido, S; Yamamoto, A; Kobayashi, R; Yokoyama, T; Aoki, H; Iwado, E; Shinojima, N; Kondo, Y; Kondo, S				Fujiwara, Keishi; Daido, Shigeru; Yamamoto, Akitsugu; Kobayashi, Ryuji; Yokoyama, Tomohisa; Aoki, Hiroshi; Iwado, Eiji; Shinojima, Naoki; Kondo, Yasuko; Kondo, Seiji			Pivotal role of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in apoptosis and autophagy	JOURNAL OF BIOLOGICAL CHEMISTRY			English	Article							PROGRAMMED CELL-DEATH; MALIGNANT GLIOMA-CELLS; HUMAN COLON-CANCER; CARCINOMA CELLS; P21 WAF1/CIP1; CERAMIDE; P53; BCL-2; MACROAUTOPHAGY; CAMPTOTHECIN	Programmed cell death (PCD) is involved in a variety of biologic events. Based on the morphologic appearance of the cells, there are two types of PCD as follows: apoptotic(type I) and autophagic(type II). However, the molecular machinery that determines the type of PCD is poorly defined. The purpose of this study was to show whether the presence of the cyclin-dependent kinase (CDK) inhibitor p21(WAF1/CIP1), a modulator of apoptosis, determines which type of PCD the cell undergoes. Treatment with C-2-ceramide was associated with both the cleavage of caspase-3 and poly(ADP- ribose) polymerase and the degradation of autophagy-related Beclin 1 and Atg5 proteins, without a change in the cyclin-CDK activity, which culminated in apoptosis in p21(+/+) mouse embryonic fibroblasts (MEFs). On the other hand, C-2-ceramide did not cleave caspase-3 or poly(ADP- ribose) polymerase and kept Beclin 1 and Atg5 proteins stable in p21(+/+) MEFs, events that this time culminated in autophagy. When expression of the p21 protein was inhibited by small interfering RNA or when the overexpression of Beclin 1 or Atg5 was induced, autophagy rather than apoptosis was initiated in the p21(+/+) MEFs treated with C-2-ceramide. In contrast, the exogenous expression of p21 or the silencing of Beclin 1 and Atg5 with small interfering RNA increased the number of apoptotic cells and decreased the number of autophagic cells among C-2-ceramide-treated p21(+/+) MEFs. gamma-Irradiation, which endogenously generates ceramide, induced a similar tendency in these MEFs. These results suggest that p21 plays an essential role in determining the type of cell death, positively for apoptosis and negatively for autophagy.	[Fujiwara, Keishi; Daido, Shigeru; Yokoyama, Tomohisa; Aoki, Hiroshi; Iwado, Eiji; Shinojima, Naoki; Kondo, Yasuko; Kondo, Seiji] Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA; [Yamamoto, Akitsugu] Nagahama Inst Biosci & Technol, Dept Cell Biol & Biosci, Shiga 5260829, Japan; [Kobayashi, Ryuji] Univ Texas, MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA; [Kondo, Seiji] Univ Texas, Grad Sch Biomed Sci, Houston, TX 77030 USA; [Kondo, Seiji] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA		Kondo, S (corresponding author), Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, 1515 Holcombe Blvd,Unit BSRB 1004, Houston, TX 77030 USA.	seikondo@mdanderson.org	Shinojima, Naoki/AAW-3038-2021	Shinojima, Naoki/0000-0003-3352-7936	NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA 16672] Funding Source: Medline; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016672] Funding Source: NIH RePORTER		Bursch W, 2000, ANN NY ACAD SCI, V926, P1, DOI 10.1111/j.1749-6632.2000.tb05594.x; 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J	Li, JQ; Song, P; Zhu, LY; Aziz, N; Zhou, QY; Zhang, YL; Xu, WX; Feng, LF; Chen, DW; Wang, X; Jin, HC				Li, Jiaqiu; Song, Ping; Zhu, Liyuan; Aziz, Neelum; Zhou, Qiyin; Zhang, Yulong; Xu, Wenxia; Feng, Lifeng; Chen, Dingwei; Wang, Xian; Jin, Hongchuan			Synthetic lethality of glutaminolysis inhibition, autophagy inactivation and asparagine depletion in colon cancer	ONCOTARGET			English	Article						colorectal cancer; glutaminolysis; glutamine; synthetic lethality	COLORECTAL-CANCER; ANTITUMOR-ACTIVITY; METABOLISM; CELLS; PROLIFERATION; MUTATIONS; ADDICTION; XENOGRAFT; SURVIVAL; EFFICACY	Cancer cells reprogram metabolism to coordinate their rapid growth. They addict on glutamine metabolism for adenosine triphosphate generation and macromolecule biosynthesis. In this study, we report that glutamine deprivation retarded cell growth and induced prosurvival autophagy. Autophagy inhibition by chloroquine significantly enhanced glutamine starvation induced growth inhibition and apoptosis activation. Asparagine deprivation by L-asparaginase exacerbated growth inhibition induced by glutamine starvation and autophagy blockage. Similar to glutamine starvation, inhibition of glutamine metabolism with a chemical inhibitor currently under clinical evaluation was synthetically lethal with chloroquine and L-asparaginase, drugs approved for the treatment of malaria and leukemia, respectively. In conclusion, inhibiting glutaminolysis was synthetically lethal with autophagy inhibition and asparagine depletion. Therefore, targeting glutaminolysis could be a promising approach for colorectal cancer treatment.	[Li, Jiaqiu; Song, Ping; Aziz, Neelum; Zhou, Qiyin; Wang, Xian] Zhejiang Univ, Med Sch, Dept Med Oncol, Sir Runrun Shaw Hosp, Hangzhou, Zhejiang, Peoples R China; [Li, Jiaqiu; Zhu, Liyuan; Zhang, Yulong; Xu, Wenxia; Feng, Lifeng; Jin, Hongchuan] Zhejiang Univ, Sir Runrun Shaw Hosp, Key Lab Biotherapy Zhejiang, Lab Canc Biol,Med Sch, Hangzhou, Zhejiang, Peoples R China; [Chen, Dingwei] Zhejiang Univ, Sir Runrun Shaw Hosp, Dept Surg, Med Sch, Hangzhou, Zhejiang, Peoples R China		Wang, X (corresponding author), Zhejiang Univ, Med Sch, Dept Med Oncol, Sir Runrun Shaw Hosp, Hangzhou, Zhejiang, Peoples R China.; Jin, HC (corresponding author), Zhejiang Univ, Sir Runrun Shaw Hosp, Key Lab Biotherapy Zhejiang, Lab Canc Biol,Med Sch, Hangzhou, Zhejiang, Peoples R China.; Chen, DW (corresponding author), Zhejiang Univ, Sir Runrun Shaw Hosp, Dept Surg, Med Sch, Hangzhou, Zhejiang, Peoples R China.	dwyf@hotmail.com; wangxzju@163.com; jinhc@zju.edu.cn	Jin, Hongchuan/C-3686-2009	Jin, Hongchuan/0000-0002-6697-3097	High Level Talents Program from the Department of Health, Natural Science foundation of Zhejiang [LZ17H160003]; Natural Science foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672723, 81672360]; Department of Health in Zhejiang Province [WKJ-ZJ-1520, WKJ-ZJ-1720]	This work was supported by High Level Talents Program from the Department of Health, Natural Science foundation of Zhejiang (LZ17H160003), Natural Science foundation of China (81672723; 81672360), and the Department of Health in Zhejiang Province (WKJ-ZJ-1520; WKJ-ZJ-1720).	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J	Chang, CT; Hseu, YC; Thiyagarajan, V; Lin, KY; Way, TD; Korivi, M; Liao, JW; Yang, HL				Chang, Chia-Ting; Hseu, You-Cheng; Thiyagarajan, Varadharajan; Lin, Kai-Yuan; Way, Tzong-Der; Korivi, Mallikarjuna; Liao, Jiuun-Wang; Yang, Hsin-Ling			Chalcone flavokawain B induces autophagic-cell death via reactive oxygen species-mediated signaling pathways in human gastric carcinoma and suppresses tumor growth in nude mice	ARCHIVES OF TOXICOLOGY			English	Article						Flavokawain B; AGS cells; Autophagy; ROS; ATG4B	COLON-CANCER CELLS; KAVA EXTRACT; DOWN-REGULATION; ROS GENERATION; BREAST-CANCER; CYCLE ARREST; P38 MAPK; IN-VIVO; APOPTOSIS; RATS	Flavokawain B (FKB), a naturally occurring chalcone in kava extracts, has been reported to possess anticancer activity. However, the effect of FKB on gastric cancer remains unclear. We examined the in vitro and in vivo anticancer activity and autophagy involvement of FKB and determined the underlying molecular mechanisms. FKB is potently cytotoxic to human gastric cancer cells (AGS/NCI-N87/KATO-III/TSGH9201) and mildly toxic towards normal (Hs738) cells and primary mouse hepatocytes. FKB-induced AGS cell death was characterized by autophagy, not apoptosis, as evidenced by increased LC3-II accumulation, GFP-LC3 puncta and acidic vesicular organelles (AVOs) formation, without resulting procaspase-3/PARP cleavage. FKB further caused p62/SQSTM1 activation, mTOR downregulation, ATG4B inhibition, and Beclin-1/Bcl-2 dysregulation. Silencing autophagy inhibitors CQ/3-MA and LC3 (shRNA) significantly reversed the FKB-induced cell death of AGS cells. FKB-triggered ROS generation and ROS inhibition by NAC pre-treatment diminished FKB-induced cell death, LC3 conversion, AVO formation, p62/SQSTM1 activation, ATG4B inhibition and Beclin-1/Bcl-2 dysregulation, which indicated ROS-mediated autophagy in AGS cells. Furthermore, FKB induces G(2)/M arrest and alters cell-cycle proteins through ROS-JNK signaling. Interestingly, FKB-induced autophagy is associated with the suppression of HER-2 and PI3K/AKT/mTOR signaling cascades. FKB inhibits apoptotic Bax expression, and Bax-transfected AGS cells exhibit both apoptosis and autophagy; thus, FKB-inactivated Bax results in apoptosis inhibition. In vivo data demonstrated that FKB effectively inhibited tumor growth, prolonged the survival rate, and induced autophagy in AGS-xenografted mice. Notably, silencing of LC3 attenuated FKB-induced autophagy in AGS-xenografted tumors. FKB may be a potential chemopreventive agent in the activation of ROS-mediated autophagy of gastric cancer cells.	[Chang, Chia-Ting; Korivi, Mallikarjuna; Yang, Hsin-Ling] China Med Univ, Coll Biopharmaceut & Food Sci, Inst Nutr, 91 Hsueh Shih Rd, Taichung 40402, Taiwan; [Hseu, You-Cheng; Thiyagarajan, Varadharajan] China Med Univ, Coll Biopharmaceut & Food Sci, Dept Cosmeceut, 91 Hsueh Shih Rd, Taichung 40402, Taiwan; [Hseu, You-Cheng] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 41354, Taiwan; [Lin, Kai-Yuan] Chi Mei Med Ctr, Dept Med Res, Tainan 710, Taiwan; [Way, Tzong-Der] China Med Univ, Coll Biopharmaceut & Food Sci, Dept Life Sci, Taichung 40402, Taiwan; [Liao, Jiuun-Wang] Natl Chung Hsing Univ, Grad Inst Vet Pathol, Taichung 402, Taiwan		Yang, HL (corresponding author), China Med Univ, Coll Biopharmaceut & Food Sci, Inst Nutr, 91 Hsueh Shih Rd, Taichung 40402, Taiwan.; Hseu, YC (corresponding author), China Med Univ, Coll Biopharmaceut & Food Sci, Dept Cosmeceut, 91 Hsueh Shih Rd, Taichung 40402, Taiwan.; Hseu, YC (corresponding author), Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 41354, Taiwan.	ychseu@mail.cmu.edu.tw; hlyang@mail.cmu.edu.tw	Korivi, Mallikarjuna/C-7952-2012	Korivi, Mallikarjuna/0000-0002-4038-1368; Liao, Jiunn-Wang/0000-0001-7374-1203	Ministry of Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [MOST-104-2320-B-039-040-MY3, MOST-103-2320-B-039-038 -MY3, NSC-103-2622-B-039-001-CC2, CMU103-ASIA-12, CMU 103-ASIA-09]; Asia University; China Medical University, TaiwanChina Medical University; China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan [CHM106-5-3]	This work was supported by Grants MOST-104-2320-B-039-040-MY3, MOST-103-2320-B-039-038 -MY3, NSC-103-2622-B-039-001-CC2, CMU103-ASIA-12, and CMU 103-ASIA-09 from the Ministry of Science and Technology, Asia University, and China Medical University, Taiwan to Dr. Hsin-Ling Yang and Dr. You-Cheng Hseu. This study was supported by China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan (CHM106-5-3).	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