﻿PT	AU	BA	BE	GP	AF	BF	CA	TI	SO	SE	BS	LA	DT	CT	CY	CL	SP	HO	DE	ID	AB	C1	C3	RP	EM	RI	OI	FU	FX	CR	NR	TC	Z9	U1	U2	PU	PI	PA	SN	EI	BN	J9	JI	PD	PY	VL	IS	PN	SU	SI	MA	BP	EP	AR	DI	D2	EA	PG	WC	WE	SC	GA	UT	PM	OA	HC	HP	DA
J	Guo, GF; Wang, YX; Zhang, YJ; Chen, XX; Lu, JB; Wang, HH; Jiang, C; Qiu, HQ; Xia, LP				Guo, Gui-Fang; Wang, Yi-Xing; Zhang, Yi-Jun; Chen, Xiu-Xing; Lu, Jia-Bin; Wang, Hao-Hua; Jiang, Chang; Qiu, Hui-Quan; Xia, Liang-Ping			Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3 for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data	WORLD JOURNAL OF GASTROENTEROLOGY			English	Article						4E-binding protein 1; Beclin-1; Microtubule-associated protein 1A/B-light chain 3; Advanced colorectal cancer; Cetuximab efficacy; Prognosis	INCREASES DRUG-RESISTANCE; INDUCED DOWN-REGULATION; ACTIVATING AUTOPHAGY; 1ST-LINE TREATMENT; SURVIVAL; GROWTH; BEVACIZUMAB; THERAPY; KINASE; CELLS	BACKGROUND Colorectal cancer (CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC (ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic. AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005, to October 1, 2015, were studied. Expression of autophagy-related proteins [Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed. RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients, immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3 (0.657, P < 0.001) and 4E-BP1 (0.211, P = 0.042) in ACRC tissues. LC3 was significantly overexpressed in tumor tissues compared to normal tissues (P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1 (P = 0.010) and 4E-BP1 (P = 0.005), pathological grade (P = 0.002), and T stage (P = 0.004) were independent prognostic factors for overall survival (OS). CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy. LC3 is overexpressed in tumor tissues, and Beclin1 and 4E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.	[Guo, Gui-Fang; Wang, Yi-Xing; Chen, Xiu-Xing; Wang, Hao-Hua; Jiang, Chang; Qiu, Hui-Quan; Xia, Liang-Ping] Sun Yat Sen Univ, Canc Ctr, VIP Dept, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China; [Guo, Gui-Fang; Wang, Yi-Xing; Zhang, Yi-Jun; Chen, Xiu-Xing; Lu, Jia-Bin; Wang, Hao-Hua; Jiang, Chang; Qiu, Hui-Quan; Xia, Liang-Ping] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China; [Guo, Gui-Fang; Wang, Yi-Xing; Zhang, Yi-Jun; Chen, Xiu-Xing; Lu, Jia-Bin; Wang, Hao-Hua; Jiang, Chang; Qiu, Hui-Quan; Xia, Liang-Ping] Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Guangdong, Peoples R China; [Zhang, Yi-Jun; Lu, Jia-Bin] Sun Yat Sen Univ, Canc Ctr, Pathol Dept, Guangzhou 510060, Guangdong, Peoples R China		Guo, GF (corresponding author), Sun Yat Sen Univ, Canc Ctr, VIP Dept, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China.	guogf@sysucc.org.cn		guo, gui fang/0000-0002-6283-7266			Alan P, 2016, ESMO C; Allegra CJ, 2009, J CLIN ONCOL, V27, P2091, DOI 10.1200/JCO.2009.21.9170; Alves S, 2015, ONCOTARGET, V6, P30787, DOI 10.18632/oncotarget.5021; Boya P, 2013, NAT CELL BIOL, V15, P713, DOI 10.1038/ncb2788; Choi AMK, 2013, NEW ENGL J MED, V368, P1845, DOI 10.1056/NEJMc1303158; Ekstrand AI, 2010, FAM CANCER, V9, P125, DOI 10.1007/s10689-009-9293-1; Giacchetti S, 2000, J CLIN ONCOL, V18, P136, DOI 10.1200/JCO.2000.18.1.136; 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; Gutierrez MG, 2004, CELL, V119, P753, DOI 10.1016/j.cell.2004.11.038; Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013; Heinemann V, 2014, LANCET ONCOL, V15, P1065, DOI 10.1016/S1470-2045(14)70330-4; Johnson SM, 2010, J AM COLL SURGEONS, V210, P767, DOI 10.1016/j.jamcollsurg.2009.12.008; Kenific CM, 2010, CURR OPIN CELL BIOL, V22, P241, DOI 10.1016/j.ceb.2009.10.008; Koneri K, 2007, ANTICANCER RES, V27, P1453; Li N, 2013, BIOCHEM BIOPH RES CO, V439, P187, DOI 10.1016/j.bbrc.2013.08.065; Li XQ, 2010, AUTOPHAGY, V6, P1066, DOI 10.4161/auto.6.8.13366; Li XQ, 2010, CANCER RES, V70, P5942, DOI 10.1158/0008-5472.CAN-10-0157; Lievre A, 2006, CANCER RES, V66, P3992, DOI 10.1158/0008-5472.CAN-06-0191; Pattingre S, 2005, CELL, V122, P927, DOI 10.1016/j.cell.2005.07.002; PAUSE A, 1994, NATURE, V371, P762, DOI 10.1038/371762a0; Venook AP, 2017, JAMA-J AM MED ASSOC, V317, P2392, DOI 10.1001/jama.2017.7105; Weihua Z, 2008, CANCER CELL, V13, P385, DOI 10.1016/j.ccr.2008.03.015; Wild P, 2014, J CELL SCI, V127, P3, DOI 10.1242/jcs.140426; Xu N, 2012, BIOCHEM BIOPH RES CO, V423, P826, DOI 10.1016/j.bbrc.2012.06.048; Yang MH, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0097242; Yoshioka A, 2008, INT J ONCOL, V33, P461, DOI 10.3892/ijo_00000028; Zhang J, 2013, INT J BIOCHEM CELL B, V45, P745, DOI 10.1016/j.biocel.2012.11.001; Zou ZZ, 2012, AUTOPHAGY, V8, P1798, DOI 10.4161/auto.22110	29	10	11	0	0	BAISHIDENG PUBLISHING GROUP INC	PLEASANTON	8226 REGENCY DR, PLEASANTON, CA 94588 USA	1007-9327	2219-2840		WORLD J GASTROENTERO	World J. Gastroenterol.	APR 21	2019	25	15					1840	1853		10.3748/wjg.v25.i15.1840			14	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	HU2UC	WOS:000465126200005	31057298	Green Published, hybrid, Green Submitted			2022-04-25	
J	Wagh, UR; Rupachandra, S				Wagh, Uttara Ravindra; Rupachandra, S.			New insights of RA-V cyclopeptide as an autophagy inhibitor in human COLO 320DM cancer cell lines	INDIAN JOURNAL OF BIOCHEMISTRY & BIOPHYSICS			English	Article						Apoptosis; Autophagosome; Chloroquine; Colon Cancer; Cyclopeptide; Rapamycin	APOPTOSIS; CISPLATIN; PEPTIDES; PROTEIN	Colon cancer is the leading cause for the malignancy in the gastrointestinal tract. Autophagy is a self-degradation process of the unnecessary, injured and aged organelles and proteins in the cell, which is followed by recovering of degraded products. Apoptosis is a programmed cell death which is characterized by membrane blebbing, chromosome condensation and nuclear fragmentation. Apoptosis and autophagy can occur frequently in a cell, predominantly in a series preceding apoptosis through autophagy by the formation of autophagosomes. In current research, the impact of autophagy inhibition and apoptosis activation were found to be the targeted strategies to treat colon cancer. This study is focused on the apoptotic potential of RA-V, a natural cyclopeptide through the inhibition of protective autophagy in colon cancer cells. Growth inhibitory properties were observed in the RA-V treated (125 mu M) colo 320DM cells using cell viability assay. RA-V induced apoptosis of colo 320DM cells at the maximum concentration of 125 mu M, which was observed using DAPI and Annexin - PI staining methods. In this study we also examined the mechanistic role of RA-V (125 mu M) in and colo 320DM cells in the presence of Rapamycin (mTOR inhibitor) and chloroquine (autophagy inhibitor) using MDC and AO staining methods.	[Wagh, Uttara Ravindra; Rupachandra, S.] SRM Inst Sci & Technol, Dept Biotechnol, Chennai 603203, Tamil Nadu, India		Rupachandra, S (corresponding author), SRM Inst Sci & Technol, Dept Biotechnol, Chennai 603203, Tamil Nadu, India.	rupachas@srmist.edu.in					Bastos M, 2011, BIOPHYS J, V101, pL20, DOI 10.1016/j.bpj.2011.06.038; Chacko SM, 2015, TOXICOL REP, V2, P1213, DOI 10.1016/j.toxrep.2015.08.002; Chen XR, 2017, RSC ADV, V7, P22270, DOI 10.1039/c7ra00056a; Chen X, 2016, FREE RADICAL RES, V50, P744, DOI 10.3109/10715762.2016.1173689; CHUNG J, 1992, CELL, V69, P1227, DOI 10.1016/0092-8674(92)90643-Q; Cooper KF, 2018, OXID MED CELL LONGEV, V2018, DOI 10.1155/2018/4701275; Dahiya R, 2007, ARCH PHARM RES, V30, P1380, DOI 10.1007/BF02977360; de Veer SJ, 2019, CHEM REV, V119, P12375, DOI 10.1021/acs.chemrev.9b00402; Fan JT, 2010, BIOORGAN MED CHEM, V18, P8226, DOI 10.1016/j.bmc.2010.10.019; Fang XY, 2013, TOXICOL APPL PHARM, V267, P95, DOI 10.1016/j.taap.2012.12.010; Fullgrabe J, 2016, J CELL SCI, V129, P3059, DOI 10.1242/jcs.188920; Granados-Romero J, 2017, INT, V5, P4667, DOI [10.18203/2320-6012.ijrms20174914, DOI 10.18203/2320-6012.IJRMS20174914]; Hicks RP, 2016, BIOORGAN MED CHEM, V24, P4056, DOI 10.1016/j.bmc.2016.06.048; Katz SJ, 2011, CURR OPIN RHEUMATOL, V23, P278, DOI 10.1097/BOR.0b013e32834456bf; Klimaszewska-Wisniewska A, 2016, CANCER CELL INT, V16, DOI 10.1186/s12935-016-0288-3; Laplante M, 2012, CELL, V149, P274, DOI 10.1016/j.cell.2012.03.017; Lau JL, 2018, BIOORGAN MED CHEM, V26, P2700, DOI 10.1016/j.bmc.2017.06.052; Lee K, 2016, CURR EYE RES, V41, P1367, DOI 10.3109/02713683.2015.1119856; Lee MS, 2018, MOL CELLS, V41, P1, DOI 10.14348/molcells.2018.0400; Lee YA, 2018, NAT COMMUN, V9, DOI 10.1038/s41467-018-07338-z; Li J, 2016, SCI REP-UK, V6, DOI 10.1038/srep20934; Liu HY, 2013, MOLECULES, V18, P13357, DOI 10.3390/molecules181113357; Liu JJ, 2011, CANCER LETT, V300, P105, DOI 10.1016/j.canlet.2010.10.001; Liu XY, 2016, NEUROSCI LETT, V620, P137, DOI 10.1016/j.neulet.2016.04.001; Lovering F, 2013, MEDCHEMCOMM, V4, P515, DOI 10.1039/c2md20347b; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038/nrm2239; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; Ramadoss DP, 2020, NUTR CANCER, V72, P1422, DOI 10.1080/01635581.2019.1672763; 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; Solomon VR, 2009, EUR J PHARMACOL, V625, P220, DOI 10.1016/j.ejphar.2009.06.063; Song LH, 2017, MOLECULES, V22, DOI 10.3390/molecules22111934; Soysa P, 2018, BMC COMPLEM ALTERN M, V18, DOI 10.1186/s12906-018-2142-8; Swadesh S., 2020, INDIAN J BIOCHEM BIO, V57, P51; Tazehkand MN, 2019, INDIAN J BIOCHEM BIO, V56, P169; Wang ZT, 2015, PLOS ONE, V10, DOI [10.1371/journal.pone.0120843, 10.1371/journal.pone.0141807]; Wani ZA, 2016, FOOD CHEM TOXICOL, V87, P1, DOI 10.1016/j.fct.2015.11.016; Xu DQ, 2015, PLANTA MED, V81, P79, DOI 10.1055/s-0034-1383356; Yang JH, 2018, RSC ADV, V8, P23451, DOI 10.1039/c8ra04241a; Yang YP, 2013, ACTA PHARMACOL SIN, V34, P625, DOI 10.1038/aps.2013.5; Yun CW, 2018, INT J MOL SCI, V19, DOI 10.3390/ijms19113466; Ramirez JAZ, 2020, INT IMMUNOPHARMACOL, V84, DOI 10.1016/j.intimp.2020.106495; Zhang X, 2011, BMC COMPLEM ALTERN M, V11, DOI 10.1186/1472-6882-11-84; Zhong B, 2017, J MOL GRAPH MODEL, V72, P25, DOI 10.1016/j.jmgm.2016.12.004	44	1	1	0	0	NATL INST SCIENCE COMMUNICATION-NISCAIR	NEW DELHI	DR K S KRISHNAN MARG, PUSA CAMPUS, NEW DELHI 110 012, INDIA	0301-1208	0975-0959		INDIAN J BIOCHEM BIO	Indian J. Biochem. Biophys.	OCT	2021	58	5					426	433					8	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	WD4EC	WOS:000704895000004					2022-04-25	
J	Mosca, L; Pagano, M; Pecoraro, A; Borzacchiello, L; Mele, L; Cacciapuoti, G; Porcelli, M; Russo, G; Russo, A				Mosca, Laura; Pagano, Martina; Pecoraro, Annalisa; Borzacchiello, Luigi; Mele, Luigi; Cacciapuoti, Giovanna; Porcelli, Marina; Russo, Giulia; Russo, Annapina			S-Adenosyl-l-Methionine Overcomes uL3-Mediated Drug Resistance in p53 Deleted Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						uL3; drug resistance; AdoMet; autophagy; apoptosis; colon cancer	GASTRIC-CANCER; HNRNP H1; ADENOSYLMETHIONINE; RPL3; APOPTOSIS; LIVER; METHYLTHIOADENOSINE; EXPRESSION; PROTEIN; GROWTH	Purpose: In order to study novel therapeutic approaches taking advantage of natural compounds showing anticancer and anti-proliferative effects, we focused our interest on S-adenosyl-l-methionine, a naturally occurring sulfur-containing nucleoside synthesized from adenosine triphosphate and methionine by methionine adenosyltransferase, and its potential in overcoming drug resistance in colon cancer cells devoid of p53. Results: In the present study, we demonstrated that S-adenosyl-l-methionine overcomes uL3-mediated drug resistance in p53 deleted colon cancer cells. In particular, we demonstrated that S-adenosyl-l-methionine causes cell cycle arrest at the S phase; inhibits autophagy; augments reactive oxygen species; and induces apoptosis in these cancer cells. Conclusions: Results reported in this paper led us to propose S-adenosyl-l-methionine as a potential promising agent for cancer therapy by examining p53 and uL3 profiles in tumors to yield a better clinical outcomes.	[Mosca, Laura; Borzacchiello, Luigi; Cacciapuoti, Giovanna; Porcelli, Marina] Univ Campania Luigi Vanvitelli, Dept Precis Med, Via Luigi De Crecchio, I-80138 Naples, Italy; [Pagano, Martina; Pecoraro, Annalisa; Russo, Giulia; Russo, Annapina] Univ Naples Federico II, Dept Pharm, Via Domenico Montesano 49, I-80131 Naples, Italy; [Mele, Luigi] Univ Campania Luigi Vanvitelli, Dept Expt Med, Via Luciano Armanni 5, I-80138 Naples, Italy		Porcelli, M (corresponding author), Univ Campania Luigi Vanvitelli, Dept Precis Med, Via Luigi De Crecchio, I-80138 Naples, Italy.; Russo, G; Russo, A (corresponding author), Univ Naples Federico II, Dept Pharm, Via Domenico Montesano 49, I-80131 Naples, Italy.	laura.mosca@unicampania.it; martina.pagano@unicampania.it; annalisa.pecoraro@unina.it; luigi.borzacchiello@unicampania.it; luigi.mele@unicampania.it; giovanna.cacciapuoti@unicampania.it; marina.porcelli@unicampania.it; giulia.russo@unina.it; annapina.russo@unina.it	Pecoraro, Annalisa/AFQ-5507-2022; Mele, Luigi/AAC-9887-2019; Russo, Annapina/O-7545-2015	Mele, Luigi/0000-0002-6008-0802; Russo, Annapina/0000-0002-7509-3702	Regione Campania-POR Campania FESR 2014/2020 "Combattere la resistenza tumorale: piattaforma integrata multidisciplinare 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); Programme Valere 2020 (Vanvitelli per la Ricerca; Universita della Campania "Luigi Vanvitelli"); Department of Precision Medicine, Universita della Campania "Luigi Vanvitelli"	This research was funded by a grant from Regione Campania-POR Campania FESR 2014/2020 "Combattere la resistenza tumorale: piattaforma integrata multidisciplinare per un approccio tecnologico innovativo alle oncoterapie-Campania Oncoterapie" Project No. B61G18000470007 (to A. Russo); Fondo di ricerca di base FFABR-2017 (to A. Russo and G. Russo); Ministero della Universita e della Ricerca (MIUR); Programme Valere 2020 (Vanvitelli per la Ricerca; Universita della Campania "Luigi Vanvitelli"); and by Intradepartmental Projects, Department of Precision Medicine, Universita della Campania "Luigi Vanvitelli" (to M.Porcelli).	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J. Mol. Sci.	JAN	2021	22	1							103	10.3390/ijms22010103			18	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	PP8VJ	WOS:000606133200001	33374288	gold, Green Published			2022-04-25	
J	Taniguchi, K; Sakai, M; Sugito, N; Kumazaki, M; Shinohara, H; Yamada, N; Nakayama, T; Ueda, H; Nakagawa, Y; Ito, Y; Futamura, M; Uno, B; Otsuki, Y; Yoshida, K; Uchiyama, K; Akao, Y				Taniguchi, Kohei; Sakai, Miku; Sugito, Nobuhiko; Kumazaki, Minami; Shinohara, Haruka; Yamada, Nami; Nakayama, Tatsushi; Ueda, Hiroshi; Nakagawa, Yoshihito; Ito, Yuko; Futamura, Manabu; Uno, Bunji; Otsuki, Yoshinori; Yoshida, Kazuhiro; Uchiyama, Kazuhisa; Akao, Yukihiro			PTBP1-associated microRNA-1 and-133b suppress the Warburg effect in colorectal tumors	ONCOTARGET			English	Article						miR-1; miR-133; Warburg effect; PTBP1; PKM	TRACT-BINDING-PROTEIN; KINASE MESSENGER-RNA; CANCER-CELL-GROWTH; PYRUVATE-KINASE; ISOFORM EXPRESSION; DOWN-REGULATION; PTB; METABOLISM; FEEDBACK; HYPOXIA	It is known that pyruvate kinase in muscle (PKM), which is a rate-limiting glycolytic enzyme, has essential roles in the Warburg effect and that expression of cancer-dominant PKM2 is increased by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the PKM gene. In other words, PKM2 acts as a promoter of the Warburg effect. Previously, we demonstrated that the Warburg effect was partially established by down-regulation of several microRNAs (miRs) that bind to PTBP1 and that ectopic expression of these miRs suppressed the Warburg effect. In this study, we investigated the functions of miR-1 and -133b, which are well known as muscle-specific miRs, from the viewpoint of the Warburg effect in colorectal tumors. The expression levels of miR-1 and -133b were relatively high in colon tissue except muscle and very frequently down-regulated in 75 clinical colorectal tumors samples, even in adenomas, compared with those of the adjacent normal tissue samples. The ectopic expression of these miRs induced growth suppression and autophagic cell death through the switching of PKM isoform expression from PKM2 to PKM1 by silencing PTBP1 expression both in vitro and in vivo. Also, we showed that the resultant increase in the intracellular level of reactive oxygen species (ROS) was involved in this mechanism. Furthermore, PTBP1 was highly expressed in most of the 30 clinical colorectal tumor samples examined, even in adenomas. Our results suggested that PTBP1 and PTBP1-associated miR-1 and -133b are crucial molecules for the maintenance of the Warburg effect in colorectal tumors.	[Taniguchi, Kohei; Sakai, Miku; Sugito, Nobuhiko; Kumazaki, Minami; Shinohara, Haruka; Yamada, Nami; Nakayama, Tatsushi; Ueda, Hiroshi; 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, Dept Gastroenterol, Sch Med, Kutsukake Cho, Toyoake, Aichi 4701192, Japan; [Ito, Yuko; Otsuki, Yoshinori] Osaka Med Coll, Div Life Sci, Dept Anat & Cell Biol, Takatsuki, Osaka 5698686, Japan; [Futamura, Manabu; Yoshida, Kazuhiro] Gifu Univ, Dept Surg Oncol, Sch Med, Gifu 5011193, Japan		Taniguchi, K (corresponding author), Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Gifu 5011193, Japan.; Taniguchi, K (corresponding author), Osaka Med Coll, Dept Gen & Gastroenterol Surg, Takatsuki, Osaka 5698686, Japan.	sur144@osaka-med.ac.jp	Nakayama, Tatsushi/AAE-8723-2022	Nakayama, Tatsushi/0000-0002-0346-2089; Yamada, Nami/0000-0002-1220-0814; Shinohara, Haruka/0000-0001-8326-1203; Taniguchi, Kohei/0000-0003-0648-1370	Ministry of Education, Science, Sports, and Culture of JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [YA-24659157, KU-15K10120]	The work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan (YA-24659157 and KU-15K10120).	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J	Adacan, K; Obakan Yerlikaya, P				Adacan, Kaan; Obakan Yerlikaya, Pinar			Epibrassinolide activates AKT to trigger autophagy with polyamine metabolism in SW480 and DLD-1 colon cancer cell lines	TURKISH JOURNAL OF BIOLOGY			English	Article						Autophagy; epibrassinolide; polyamines; LC3; spermidine	ENDOPLASMIC-RETICULUM STRESS; APOPTOSIS; KINASE	Epibrassinolide (EBR), a plant-derived polyhydroxylated derivative of 5 alpha-cholestane, structurally shows similarities to animal steroid hormones. According to the present study, EBR treatment triggered a significant stress response via activating ER stress, autophagy, and apoptosis in cancer cells. EBR could also increase Akt phosphorylation in vitro. While the activation of Akt resulted in cellular metabolic activation in normal cells to proceed with cell survival, a rapid stress response was induced in cancer cells to reduce survival. Therefore, Akt as a mediator of cellular survival and death decision pathways is a crucial target in cancer cells. In this study, we determined that EBR induces stress responses through activating Akt, which reduced the mTOR complex I (mTORC1) activation in SW480 and DLD-1 colon cancer cells. As a consequence, EBR triggered macroautophagy and led to lipidation of LC3 most efficiently in SW480 cells. The cotreatment of spermidine (Spd) with EBR increased lipidation of LC3 synergistically in both cell lines. We also found that EBR promoted polyamine catabolism in SW480 cells. The retention of polyamine biosynthesis was remarkable following EBR treatment. We suggested that EBR-mediated Akt activation might determine the downstream cellular stress responses to induce autophagy related to polyamines.	[Adacan, Kaan; Obakan Yerlikaya, Pinar] Istanbul Kultur Univ, Sci & Literature Fac, Dept Mol Biol & Genet, Istanbul, Turkey		Obakan Yerlikaya, P (corresponding author), Istanbul Kultur Univ, Sci & Literature Fac, Dept Mol Biol & Genet, Istanbul, Turkey.	p.obakan@iku.edu.tr		OBAKAN YERLIKAYA, PINAR/0000-0001-7058-955X	Istanbul Kultur University Scientific Project CenterIstanbul Kultur University	This study was supported by the Istanbul Kultur University Scientific Project Center. We gratefully thank Utku Ozbey for his technical assistance for the HPLC analysis.	Akkoc Y, 2018, TURK J GASTROENTEROL, V29, P270, DOI 10.5152/tjg.2018.150318; Banerjee IA, 2019, MAT SCI ENG C-MATER, V97, P451, DOI 10.1016/j.msec.2018.12.037; Coskun D, 2015, EXP CELL RES, V338, P10, DOI 10.1016/j.yexcr.2015.08.015; Cybulsky AV, 2017, NAT REV NEPHROL, V13, P681, DOI 10.1038/nrneph.2017.129; DeBerardinis RJ, 2008, CELL METAB, V7, P11, DOI 10.1016/j.cmet.2007.10.002; Eisenberg T, 2009, NAT CELL BIOL, V11, P1305, DOI 10.1038/ncb1975; Esposito D, 2011, J MED CHEM, V54, P4057, DOI 10.1021/jm200028h; Franke TF, 2008, ONCOGENE, V27, P6473, DOI 10.1038/onc.2008.313; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Gozuacik D, 2007, CURR TOP DEV BIOL, V78, P217, DOI 10.1016/S0070-2153(06)78006-1; Hai Y, 2017, NAT COMMUN, V8, DOI 10.1038/ncomms15368; Jung CH, 2010, FEBS LETT, V584, P1287, DOI 10.1016/j.febslet.2010.01.017; Kahana C, 2009, CELL MOL LIFE SCI, V66, P2479, DOI 10.1007/s00018-009-0033-3; Kocaturk NM, 2019, EUR J PHARM SCI, V134, P116, DOI 10.1016/j.ejps.2019.04.011; Kuryayeva F, 2019, EPIBRASSINOLIDE PROM, V40, P10; Lee ST, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0057708; Liu HY, 2009, J BIOL CHEM, V284, P31484, DOI 10.1074/jbc.M109.033936; Menon D, 2017, J BIOL CHEM, V292, P6303, DOI 10.1074/jbc.M116.772988; Obakan P, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0135788; Obakan P, 2014, AMINO ACIDS, V46, P553, DOI 10.1007/s00726-013-1574-1; Obakan-Yerlikaya P, 2017, MOL CARCINOGEN, V56, P1603, DOI 10.1002/mc.22616; Palavan-Unsal N., 2006, Experimental Oncology, V28, P178; Palmieri M, 2017, CELL CYCLE, V16, P1237, DOI 10.1080/15384101.2017.1337968; Persad S, 2001, J BIOL CHEM, V276, P27462, DOI 10.1074/jbc.M102940200; Pietrocola F, 2015, CELL DEATH DIFFER, V22, P509, DOI 10.1038/cdd.2014.215; Rueden CT, 2017, BMC BIOINFORMATICS, V18, DOI 10.1186/s12859-017-1934-z; SINGH S, 1990, ANAL BIOCHEM, V187, P212, DOI 10.1016/0003-2697(90)90446-G; Song S, J CELLULAR PHYSL, V233, P3867; Wang Tian, 2005, Zhiwu Shengli yu Fenzi Shengwuxue Xuebao, V31, P637; Yue F, 2017, CANCER RES, V77, P2938, DOI 10.1158/0008-5472.CAN-16-3462; Zhang Z, 2012, MOL CELL BIOCHEM, V361, P249, DOI 10.1007/s11010-011-1110-0	31	0	0	1	3	TUBITAK SCIENTIFIC & TECHNICAL RESEARCH COUNCIL TURKEY	ANKARA	ATATURK BULVARI NO 221, KAVAKLIDERE, ANKARA, 00000, TURKEY	1300-0152	1303-6092		TURK J BIOL	Turk. J. Biol.		2020	44	6					417	426		10.3906/biy-2005-37			10	Biology	Science Citation Index Expanded (SCI-EXPANDED)	Life Sciences & Biomedicine - Other Topics	PI9FM	WOS:000601387600007	33402868	Green Published, gold			2022-04-25	
J	An, N; Sun, Y; Ma, L; Shi, SL; Zheng, X; Feng, WS; Shan, ZM; Han, YG; Zhao, L; Wu, HM				An, Na; Sun, Ying; Ma, Ligang; Shi, Shengli; Zheng, Xiaoke; Feng, Weisheng; Shan, Zhiming; Han, Yongguang; Zhao, Le; Wu, Huiming			Helveticoside Exhibited p53-dependent Anticancer Activity Against Colorectal Cancer	ARCHIVES OF MEDICAL RESEARCH			English	Article						Colorectal cancer; Helveticoside; Apoptosis; Mitochondrial membrane potential; p53	ROS-DEPENDENT APOPTOSIS; COLON-CANCER; NATURAL-PRODUCTS; TANSHINONE IIA; GROWTH; CELLS; MECHANISMS; GLYCOSIDES; AUTOPHAGY; MILTIRONE	Background. Investigation into the anti-cancer activities of natural products and their derivatives represents an efficient approach to develop safe and effective chemotherapeutic agents for the treatment of colorectal cancer. Helveticoside is a biologically active component of the seed extract of Descurainia sophia. This compound has been reported to regulate the genes related to cell proliferation and apoptosis in lung cancer cells, however its anticancer activity has not been fully explored yet. Methods. Cell viability was evaluated by MTT and Trypan blue exclusion assay; cell apoptosis was measured by flow cytometry; mitochondrial membrane potential was determined by using JC1-mitochondrial membrane potential assay kit; protein levels were determined by western blot assay; in vivo tumor growth was assessed in a xenograft nude mice model. Results. The current study demonstrated the in vitro anti-cancer activity of helveticoside against colorectal cancer using colorectal cancer cells SW480 and HCT116. Moreover, induction of apoptosis was found to mediate the cytotoxic action of helveticoside on SW480 and HCT116 cells. Based on the decrease in the mitochondrial membrane potential, upregulation of Bax, downregulation of Bcl-2 and cleavage of caspase-3 and 9, apoptosis was induced by helveticoside via mitochondria-mediated intrinsic apoptotic signaling pathways in colorectal cancer cells. Besides, using p53-knockout SW480 cells, the cytotoxic action of helveticoside was found to be p53-dependent. More importantly, administration of helveticoside inhibited the growth of HCT116 cells derived-colorectal cancer xenograft in mice via activation of apoptosis. Conclusions. Helveticoside might be a potential candidate for the development of novel chemotherapeutic agents for the treatment of colorectal cancer, while the potential toxic effects of helveticoside may be worthy of further investigations. (C) 2020 IMSS. Published by Elsevier Inc.	[An, Na; Ma, Ligang; Shi, Shengli; Zheng, Xiaoke; Feng, Weisheng; Han, Yongguang; Zhao, Le; Wu, Huiming] Henan Univ Chinese Med, Coll Pharm, Zhengzhou 450046, Henan, Peoples R China; [Sun, Ying] Henan Univ Chinese Med, Basic Med Coll, Zhengzhou, Henan, Peoples R China; [Zheng, Xiaoke; Feng, Weisheng] Henan Univ Chinese Med, Coconstruct Collaborat Innovat Ctr Chinese Med &, Zhengzhou, Henan, Peoples R China; [Shan, Zhiming] Zhengzhou Univ, Henan Childrens Hosp, Zhengzhou Childrens Hosp, Clin Lab,Childrens Hosp, Zhengzhou, Henan, Peoples R China		Zheng, X (corresponding author), Henan Univ Chinese Med, Coll Pharm, Zhengzhou 450046, Henan, Peoples R China.	zhengxk.2006@163.com	Ma, Ligang/O-9603-2014	Ma, Ligang/0000-0003-3451-5291	National Key Research and Development Project (The Major Project for Research of the Modernization of TCM) [2019YFC1708802]; Henan province high-level personnel special support "ZhongYuan One Thousand People Plan''-Zhongyuan Leading Talent [ZYQR201810080]; Doctoral Scientific Fund Project of Henan University of Chinese Medicine [BSJJ2014-13]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2017M622352]; Henan Province Postdoctoral Science Foundation [00104341]	This study was supported by The National Key Research and Development Project (The Major Project for Research of the Modernization of TCM; No. 2019YFC1708802), Henan province high-level personnel special support ``ZhongYuan One Thousand People Plan''-Zhongyuan Leading Talent (No. ZYQR201810080), The Doctoral Scientific Fund Project of Henan University of Chinese Medicine (No. BSJJ2014-13), China Postdoctoral Science Foundation (No. 2017M622352), and Henan Province Postdoctoral Science Foundation (No. 00104341).	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Med. Res.	APR	2020	51	3					224	232		10.1016/j.arcmed.2020.02.007			9	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	LS1GC	WOS:000536139200005	32147288				2022-04-25	
J	Lee, SH; Lee, HS; Lee, J; Amarakoon, D; Lou, ZY; Noronha, LE; Herald, TJ; Perumal, R; Smolensky, D				Lee, Seong-Ho; Lee, Hee-Seop; Lee, Jihye; Amarakoon, Darshika; Lou, Zhiyuan; Noronha, Leela E.; Herald, Thomas J.; Perumal, Ramasamy; Smolensky, Dmitriy			Polyphenol Containing Sorghum Brans Exhibit an Anti-Cancer Effect in Apc Min/ plus Mice Treated with Dextran Sodium Sulfate	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						high phenolic sorghum bran; colon cancer; PI3K; AMPK; autophagy; Apc Min; + mouse	GENOME-WIDE ASSOCIATION; CANCER-CELL GROWTH; NF-KAPPA-B; POTENTIAL IMPACT; PHYTOCHEMICALS; EXPRESSION; AUTOPHAGY; PATHWAY; ACID; LINE	Colon cancer (CC) is considered a high-risk cancer in developed countries. Its etiology is correlated with a high consumption of red meat and low consumption of plant-based foods, including whole grains. Sorghum bran is rich in polyphenols. This study aimed to determine whether different high-phenolic sorghum brans suppress tumor formation in a genetic CC rodent model and elucidate mechanisms. Tissue culture experiments used colorectal cancer cell lines SW480, HCT-116 and Caco-2 and measured protein expression, and protein activity. The animal model used in this study was APC Min+/mouse model combined with dextram sodium sulfate. High phenolic sorghum bran extract treatment resulted in the inhibition of proliferation and induced apoptosis in CC cell lines. Treatment with high phenolic sorghum bran extracts repressed TNF-alpha-stimulated NF-kappa B transactivation and IGF-1-stimulated PI3K/AKT pathway via the downregulation of beta-catenin transactivation. Furthermore, high-phenolic sorghum bran extracts activated AMPK and autophagy. Feeding with high-phenolic sorghum bran for 6 weeks significantly suppressed tumor formation in an APC Min/+ dextran sodium sulfate promoted CC mouse model. Our data demonstrates the potential application of high-phenolic sorghum bran as a functional food for the prevention of CC.	[Lee, Seong-Ho; Lee, Hee-Seop; Lee, Jihye; Amarakoon, Darshika; Lou, Zhiyuan] Univ Maryland, Coll Agr & Nat Resources, Dept Nutr & Food Sci, College Pk, MD 20742 USA; [Noronha, Leela E.] ARS, Arthropod Borne Anim Dis Res Unit, USDA, Manhattan, KS 66502 USA; [Herald, Thomas J.; Smolensky, Dmitriy] ARS, Grain Qual & Struct Res Unit, USDA, Manhattan, KS 66502 USA; [Perumal, Ramasamy] Kansas State Univ, Agr Res Ctr, Hays, KS 67601 USA		Lee, SH (corresponding author), Univ Maryland, Coll Agr & Nat Resources, Dept Nutr & Food Sci, College Pk, MD 20742 USA.; Smolensky, D (corresponding author), ARS, Grain Qual & Struct Res Unit, USDA, Manhattan, KS 66502 USA.	slee2000@umd.edu; hslee123@umd.edu; jlee1232@terpmail.umd.edu; darshika@umd.edu; zhiyuanlou@hotmail.com; Leela.noronha@usda.gov; thomasherald98@gmail.com; perumal@ksu.edu; dmitriy.smolensky@usda.gov	Smolensky, Dmitriy/AAD-2009-2019; Lee, Jihye/AAY-2441-2021	Smolensky, Dmitriy/0000-0002-8128-2681; Lee, Jihye/0000-0002-7007-7498; Lee, Hee-Seop/0000-0002-8500-9607; Noronha, Leela/0000-0003-2330-2215	USDA-ARSUnited States Department of Agriculture (USDA)USDA Agricultural Research Service [3020-43440-002-000-D]	This research and APC was funded by USDA-ARS in-house appropriated project number 3020-43440-002-000-D.	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J. Mol. Sci.	AUG	2021	22	15							8286	10.3390/ijms22158286			15	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	TV5WV	WOS:000681794600001	34361052	gold, Green Published			2022-04-25	
J	Rudolf, E; Rezacova, K; Cervinka, M				Rudolf, Emil; Rezacova, Katerina; Cervinka, Miroslav			Activation of p38 and changes in mitochondria accompany autophagy to premature senescence-like phenotype switch upon chronic exposure to selenite in colon fibroblasts	TOXICOLOGY LETTERS			English	Article						Sodium selenite; Colonic fibroblasts; p38; Premature senescence; Mitochondria; Autophagy	COLORECTAL-CANCER CELLS; OXIDATIVE STRESS; INDUCED APOPTOSIS; SIGNALING PATHWAY; PROSTATE-CANCER; SODIUM-SELENITE; PROTEIN-KINASE; PHOSPHORYLATION; CHEMOPREVENTION; INVOLVEMENT	Effects of chronic exposure to supranutritional sodium selenite (Se) were investigated in colonic fibroblasts. Initially, Se did not produce any gross changes in exposed cells; however, basal levels of autophagy were transiently increased and p38 activity was stimulated. From the 3rd week onwards, Se decreased cell proliferation, with corrensponding changes in cell cycle distribution. Also, in exposed cells oxidative stress and DNA damage slowly but gradually increased along with decreasing mitochondrial function and upon continued elevated activity of p38 kinase. Towards the end of the experiment, premature senescence features became more prominent in treated cells. Pharmacological inhibition as well as gene knockdown of these processes confirmed the involvement of p38 in balancing autophagy and premature senescence in cells exposed to Se and suggests that this element may in a given time frame compromise selected cell populations in digestive system. (C) 2014 Elsevier Ireland Ltd. All rights reserved.	[Rudolf, Emil; Rezacova, Katerina; Cervinka, Miroslav] Charles Univ Prague, Dept Med Biol & Genet, Fac Med Hradec Kralove, Hradec Kralove 50038, Czech Republic		Rudolf, E (corresponding author), Charles Univ Prague, Dept Med Biol & Genet, Fac Med Hradec Kralove, Simkova 870, Hradec Kralove 50038, Czech Republic.	rudolf@lfhk.cuni.cz	Rudolf, Emil/B-5956-2017; Cervinka, Miroslav/R-7387-2016	Rudolf, Emil/0000-0002-9526-3174; Cervinka, Miroslav/0000-0001-8602-4756	PRVOUK [P37/01]	This work was supported by the program PRVOUK P37/01.	Campisi J, 2013, ANNU REV PHYSIOL, V75, P685, DOI 10.1146/annurev-physiol-030212-183653; Chen YR, 1996, J BIOL CHEM, V271, P631, DOI 10.1074/jbc.271.2.631; Choi CH, 2012, BIOCHEM BIOPH RES CO, V418, P759, DOI 10.1016/j.bbrc.2012.01.095; Clark LC, 1996, JAMA-J AM MED ASSOC, V276, P1957, DOI 10.1001/jama.276.24.1957; Combs GF, 2001, BRIT J NUTR, V85, P517, DOI 10.1079/BJN2000280; Cui Q, 2007, J PHARMACOL SCI, V105, P317, DOI 10.1254/jphs.FP0070336; Dasari A, 2006, CANCER RES, V66, P10805, DOI 10.1158/0008-5472.CAN-06-1236; Davis CD, 2000, J NUTR, V130, P2903, DOI 10.1093/jn/130.12.2903; Debacq-Chainiaux F, 2010, ADV EXP MED BIOL, V694, P126; El-Bayoumy K, 2005, MUTAT RES-FUND MOL M, V591, P224, DOI 10.1016/j.mrfmmm.2005.04.021; Harrison PR, 1997, BIOMED ENVIRON SCI, V10, P235; Hu YJ, 2005, J NUTR, V135, p3021S, DOI 10.1093/jn/135.12.3021S; Huang F, 2009, FREE RADICAL BIO MED, V46, P1186, DOI 10.1016/j.freeradbiomed.2009.01.026; Irons R, 2006, J NUTR, V136, P1311, DOI 10.1093/jn/136.5.1311; Ito M, 2011, AGING-US, V3, P1213, DOI 10.18632/aging.100418; Jacobs ET, 2004, J NATL CANCER I, V96, P1669, DOI 10.1093/jnci/djh310; Keil E, 2013, CELL DEATH DIFFER, V20, P321, DOI 10.1038/cdd.2012.129; Kim YS, 2004, EXP MOL MED, V36, P157, DOI 10.1038/emm.2004.22; Krishna M, 2008, CELL MOL LIFE SCI, V65, P3525, DOI 10.1007/s00018-008-8170-7; Li J, 2003, J TRACE ELEM MED BIO, V17, P19, DOI 10.1016/S0946-672X(03)80041-X; Luo H, 2012, CANCER LETT, V315, P78, DOI 10.1016/j.canlet.2011.10.014; Meuillet E, 2004, J CELL BIOCHEM, V91, P443, DOI 10.1002/jcb.10728; Rayman MP, 2005, P NUTR SOC, V64, P527, DOI 10.1079/PNS2005467; Rocourt CRB, 2013, J NUTR BIOCHEM, V24, P781, DOI 10.1016/j.jnutbio.2012.04.011; SHAMBERGER RJ, 1969, CAN MED ASSOC J, V100, P682; Shilo S, 2003, ANTIOXID REDOX SIGN, V5, P273, DOI 10.1089/152308603322110850; Ye YC, 2011, J PHARMACOL SCI, V117, P160, DOI 10.1254/jphs.11105FP; Yu RA, 2006, BIOMED ENVIRON SCI, V19, P197; Zhang YM, 2009, FASEB J, V23, P1358, DOI 10.1096/fj.08-110296; Zhong WX, 2001, CANCER RES, V61, P7071; Zou YF, 2008, CANCER BIOL THER, V7, P689, DOI 10.4161/cbt.7.5.5688	31	3	3	0	11	ELSEVIER IRELAND LTD	CLARE	ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND	0378-4274	1879-3169		TOXICOL LETT	Toxicol. Lett.	NOV 18	2014	231	1					29	37		10.1016/j.toxlet.2014.09.006			9	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	AT1LU	WOS:000344696100004	25204997				2022-04-25	
J	Gorgulho, CM; Krishnamurthy, A; Lanzi, A; Galon, J; Housseau, F; Kaneno, R; Lotze, MT				Gorgulho, Carolina Mendonca; Krishnamurthy, Anuradha; Lanzi, Anastasia; Galon, Jerome; Housseau, Franck; Kaneno, Ramon; Lotze, Michael T.			Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer	JOURNAL OF IMMUNOTHERAPY			English	Review						colorectal cancer; immunotherapy; Immunoscore; autophagy; chemoresistance; DAMPs; HMGB1; dendritic cells; T cells; microbiome		Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%-6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current "state-of-the-art" immunotherapies and define those areas with greatest therapeutic promise for the future.	[Gorgulho, Carolina Mendonca; Kaneno, Ramon] Sao Paulo State Univ, UNESP, Dept Chem & Biol Sci, Inst Biosci Botucatu, Botucatu, SP, Brazil; [Gorgulho, Carolina Mendonca; Kaneno, Ramon] Sao Paulo State Univ, UNESP, Dept Pathol, Sch Med Botucatu, Botucatu, SP, Brazil; [Gorgulho, Carolina Mendonca; Lotze, Michael T.] Univ Pittsburgh, DAMP Lab, Dept Surg, Pittsburgh, PA 15213 USA; [Krishnamurthy, Anuradha] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA; [Lanzi, Anastasia; Galon, Jerome] Sorbonne Univ, Cordeliers Res Ctr, Lab Integrat Canc Immunol, League Against Canc,INSERM, Paris, France; [Housseau, Franck] Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA		Lotze, MT (corresponding author), Univ Pittsburgh, Dept Surg, G-27A Hillman Canc,5117 Ctr Ave, Pittsburgh, PA 15213 USA.	lotzemt@upmc.edu	Mendonca Gorgulho, Carolina/L-9511-2017	Mendonca Gorgulho, Carolina/0000-0001-6569-8647	NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01 CA181450] Funding Source: Medline		Abraha AM, 2016, WORLD J GASTRO ONCOL, V8, P583, DOI 10.4251/wjgo.v8.i8.583; 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Immunother.	FEB-MAR	2021	44	2					49	62		10.1097/CJI.0000000000000357			14	Oncology; Immunology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Immunology; Research & Experimental Medicine	QN3DY	WOS:000622345900001	33416261	Green Accepted			2022-04-25	
J	Rajendran, P; Kidane, AI; Yu, TW; Dashwood, WM; Bisson, WH; Lohr, CV; Ho, E; Williams, DE; Dashwood, RH				Rajendran, Praveen; Kidane, Ariam I.; Yu, Tian-Wei; Dashwood, Wan-Mohaiza; Bisson, William H.; Loehr, Christiane V.; Ho, Emily; Williams, David E.; Dashwood, Roderick H.			HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates	EPIGENETICS			English	Article						CtIP acetylation; DNA damage; HDAC inhibition; HDAC3; SIRT6; colon cancer; epigenetics; repair	HISTONE DEACETYLASE INHIBITORS; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; CRUCIFEROUS VEGETABLES; KU70 ACETYLATION; CHEMOPREVENTION; THERAPY; PROLIFERATION; INSTABILITY; REPRESSOR	Histone deacetylases (HDACs) and acetyltransferases have important roles in the regulation of protein acetylation, chromatin dynamics and the DNA damage response. Here, we show in human colon cancer cells that dietary isothiocyanates (ITCs) inhibit HDAC activity and increase HDAC protein turnover with the potency proportional to alkyl chain length, i.e., AITC < sulforaphane (SFN) < 6-SFN < 9-SFN. Molecular docking studies provided insights into the interactions of ITC metabolites with HDAC3, implicating the allosteric site between HDAC3 and its co-repressor. ITCs induced DNA double-strand breaks and enhanced the phosphorylation of histone H2AX, ataxia telangiectasia and Rad3-related protein (ATR) and checkpoint kinase-2 (CHK2). Depending on the ITC and treatment conditions, phenotypic outcomes included cell growth arrest, autophagy and apoptosis. Coincident with the loss of HDAC3 and HDAC6, as well as SIRT6, ITCs enhanced the acetylation and subsequent degradation of critical repair proteins, such as CtIP, and this was recapitulated in HDAC knockdown experiments. Importantly, colon cancer cells were far more susceptible than non-cancer cells to ITC-induced DNA damage, which persisted in the former case but was scarcely detectable in non-cancer colonic epithelial cells under the same conditions. Future studies will address the mechanistic basis for dietary ITCs preferentially exploiting HDAC turnover mechanisms and faulty DNA repair pathways in colon cancer cells vs. normal cells.	[Rajendran, Praveen; Kidane, Ariam I.; Yu, Tian-Wei; Dashwood, Wan-Mohaiza; Ho, Emily; Williams, David E.; Dashwood, Roderick H.] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA; [Bisson, William H.; Williams, David E.; Dashwood, Roderick H.] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA; [Loehr, Christiane V.] Oregon State Univ, Coll Vet Med, Corvallis, OR 97331 USA; [Ho, Emily] Oregon State Univ, Sch Biol & Populat Hlth Sci, Corvallis, OR 97331 USA		Rajendran, P (corresponding author), Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA.	praveen.rajendran@oregonstate.edu	Löhr, C. V./AAU-4902-2020; Dashwood, Roderick/AAF-2025-2020; Rajendran, Praveen/AAK-9963-2021	Löhr, C. V./0000-0003-3787-5583; Rajendran, Praveen/0000-0002-6221-7366	US National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA090890, CA65525, CA122906, CA122959, CA80176, ES00210]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA122906, R01CA065525, R01CA122959, R29CA065525, P01CA090890, R01CA080176] 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) [P30ES000210] Funding Source: NIH RePORTER	Supported by US National Institutes of Health grants CA090890, CA65525, CA122906, CA122959, CA80176 and ES00210. We thank Teresa Sawyer for help with EM, Andrew Hau for autophagy antibodies and the Cell Imaging and Analysis Core for assistance with immunocytochemistry.	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J	Kim, MS; Jeong, EG; Ahn, CH; Kim, SS; Lee, SH; Yoo, NJ				Kim, Min Sung; Jeong, Eun Goo; Ahn, Chang Hyeok; Kim, Sung Soo; Lee, Sug Hyung; Yoo, Nam Jin			Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability	HUMAN PATHOLOGY			English	Article						UVRAG; MSI; gastric cancer; mutation	TUMOR-SUPPRESSOR; INACTIVATING MUTATIONS; BECLIN-1; CANCER; TUMORIGENESIS; PROTEINS; DEATH; CELLS; BIF-1	Alteration of autophagy is involved in tumor development. Beclin 1, an important regulator of autophagy, acts as a tumor suppressor. Ultraviolet (UV) radiation resistance-associated gene (UVRAG) binds with Beclin1 and induces autophagy. There is a polyadenine tract in UVRAG gene (A10 in exon 8) that is a target for frameshift mutations in colorectal carcinomas with microsatellite instability (MSI). Functionally, colon cancer cells with the frameshift mutation of UFRAG show reduced autophagy formation and increased tumorigenicity. The aim of this study was to determine whether the frameshift mutations of UVRAG are also present in gastric carcinomas with MSI. For this, we analyzed human UVRAG exon 8 in 45 gastric carcinomas with MSI and 92 gastric carcinomas without MSI by a single-strand conformation polymorphism analysis. Overall, we detected 3 frameshift mutations of UVRAG in the polyadenine tract (3/45; 6.7%), and all of them were found in MSH-high (H) subtypes (3/32; 9.4%). The 3 mutations consisted of 2 c.708_709delA and 1 c.709delA which would result in premature stops of the UVRAG protein synthesis. The present data indicate that frameshilft mutations in the polyadenine tract in UVRAG gene are present in gastric carcinomas as well and suggest that the affected gastric cancer cells with the mutations may have a reduced autophagy activity. (c) 2008 Elsevier Inc. All rights reserved.	[Kim, Min Sung; Jeong, Eun Goo; Lee, Sug Hyung; Yoo, Nam Jin] Catholic Univ Korea, Coll Med, Dept Pathol, Seoul 137701, South Korea; [Ahn, Chang Hyeok] Catholic Univ Korea, Coll Med, Dept Gen Surg, Seoul 137701, South Korea; [Kim, Sung Soo] Catholic Univ Korea, Coll Med, Dept Internal Med, Seoul 137701, South Korea		Yoo, NJ (corresponding author), Catholic Univ Korea, Coll Med, Dept Pathol, Seoul 137701, South Korea.	goldfish@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; Boland CR, 1998, CANCER RES, V58, P5248; Edinger AL, 2004, CURR OPIN CELL BIOL, V16, P663, DOI 10.1016/j.ceb.2004.09.011; Ionov Y, 2004, ONCOGENE, V23, P639, DOI 10.1038/sj.onc.1207178; 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; Krajewska M, 1996, AM J PATHOL, V149, P1449; Lee JW, 2007, APMIS, V115, P750, DOI 10.1111/j.1600-0463.2007.apm_640.x; Lee JW, 2006, PATHOLOGY, V38, P312, DOI 10.1080/00313020600820880; Lee JW, 2004, CARCINOGENESIS, V25, P1371, DOI 10.1093/carcin/bgh145; 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; 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; Schwartz S, 1999, CANCER RES, V59, P2995; Shin MS, 2002, BLOOD, V99, P4094, DOI 10.1182/blood.V99.11.4094; Simpson AJG, 2001, TRENDS MOL MED, V7, P76, DOI 10.1016/S1471-4914(01)01916-5; Takahashi Y, 2007, NAT CELL BIOL, V9, P1142, DOI 10.1038/ncb1634; TEITZ T, 1990, GENE, V87, P295, DOI 10.1016/0378-1119(90)90316-J; Wu MS, 2000, GENE CHROMOSOME CANC, V27, P403, DOI 10.1002/(SICI)1098-2264(200004)27:4<403::AID-GCC10>3.3.CO;2-T; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	25	120	131	1	12	W B SAUNDERS CO-ELSEVIER INC	PHILADELPHIA	1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA	0046-8177	1532-8392		HUM PATHOL	Hum. Pathol.	JUL	2008	39	7					1059	1063		10.1016/j.humpath.2007.11.013			5	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	320VX	WOS:000257264300011	18495205				2022-04-25	
J	Ling, LU; Tan, KB; Lin, H; Chiu, GNC				Ling, L-U; Tan, K-B; Lin, H.; Chiu, G. N. C.			The role of reactive oxygen species and autophagy in safingol-induced cell death	CELL DEATH & DISEASE			English	Article						ROS; autophagy; necrosis; safingol; glucose uptake inhibition	PROTEIN-KINASE-C; INHIBITOR SAFINGOL; CANCER CELLS; ARSENIC TRIOXIDE; CARCINOMA-CELLS; ENDONUCLEASE G; PHORBOL ESTER; GLIOMA-CELLS; COLON-CANCER; APOPTOSIS	Safingol is a sphingolipid with promising anticancer potential, which is currently in phase I clinical trial. Yet, the underlying mechanisms of its action remain largely unknown. We reported here that safingol-induced primarily accidental necrotic cell death in MDA-MB-231 and HT-29 cells, as shown by the increase in the percentage of cells stained positive for 7-aminoactinomycin D, collapse of mitochondria membrane potential and depletion of intracellular ATP. Importantly, safingol treatment produced time-and concentration-dependent reactive oxygen species (ROS) generation. Autophagy was triggered following safingol treatment, as reflected by the formation of autophagosomes, acidic vacuoles, increased light chain 3-II and Atg biomarkers expression. Interestingly, scavenging ROS with N-acetyl-L-cysteine could prevent the autophagic features and reverse safingol-induced necrosis. Our data also suggested that autophagy was a cell repair mechanism, as suppression of autophagy by 3-methyladenine or bafilomycin A1 significantly augmented cell death on 2-5 mu M safingol treatment. In addition, Bcl-xL and Bax might be involved in the regulation of safingol-induced autophagy. Finally, glucose uptake was shown to be inhibited by safingol treatment, which was associated with an increase in p-AMPK expression. Taken together, our data suggested that ROS was the mediator of safingol-induced cancer cell death, and autophagy is likely to be a mechanism triggered to repair damages from ROS generation on safingol treatment. Cell Death and Disease (2011) 2, e129; doi: 10.1038/cddis.2011.12; published online 10 March 2011	[Ling, L-U; Tan, K-B; Lin, H.; Chiu, G. N. C.] Natl Univ Singapore, Dept Pharm, Fac Sci, Singapore 117543, Singapore		Chiu, GNC (corresponding author), Natl Univ Singapore, Dept Pharm, Fac Sci, Block S4,02-09,18 Sci Dr 4, Singapore 117543, Singapore.	phacncg@nus.edu.sg	Tan, Kuan Boone/J-9756-2013; Chiu, Gigi/I-6250-2013	Tan, Kuan Boone/0000-0002-6523-6941; Chiu, Gigi/0000-0003-1734-3512	Singapore's Ministry of Education through the National University of Singapore (NUS)National University of Singapore [R-148-000-098-112]; NUSNational University of Singapore	This work was supported by Singapore's Ministry of Education through the National University of Singapore (NUS) Academic Research Fund FRC-Tier 1 grant (R-148-000-098-112). LU Ling and KB Tan are supported by NUS graduate research scholarship.	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MAR	2011	2								e129	10.1038/cddis.2011.12			12	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	742UE	WOS:000288969700006	21390063	Green Published, gold			2022-04-25	
J	Singh, MP; Park, KH; Khaket, TP; Kang, SC				Singh, Mahendra Pal; Park, Ki Hun; Khaket, Tejinder Pal; Kang, Sun Chul			CJK-7, a Novel Flavonoid from Paulownia tomentosa Triggers Cell Death Cascades in HCT-116 Human Colon Carcinoma Cells via Redox Signaling	ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY			English	Article						Apoptosis; autophagy; colon cancer; natural compounds; oxidative stress; redox signaling	OXIDATIVE STRESS; GASTRIC-CANCER; APOPTOSIS; AUTOPHAGY; DAMAGE; MITOCHONDRIA; ACTIVATION; MECHANISMS; PREVENTION; SURVIVAL	Background: Colon cancer is the second most common cancer to cause death worldwide. About halfof colon cancers patients require adjuvant therapy to control relapse following surgical resection. Therefore, abolition of tumor cell progression using an effective chemotherapeutic agent holds a feasible approach to treat patients suffering from colon cancer. In the present study, we evaluated the effects of geranylated flavonoid CJK-7, isolated from Paulownia tomentosa on HCT-116 human colon carcinoma cells. Materials and Methods: The effects of CJK-7 as an active component on HCT-116 cells programmed cell death and its underlying molecular mechanism were examined by using MTT assay, morphological assessment, H(2)DCFDA staining, Fura-2AM staining, Hoechst-33342 staining, comet assay, Acridine orange staining, mitochondrial membrane potential (Delta Psi m) assay and Western blot analyses. Results and Conclusion: The results revealed that, CJK-7 was capable of inducing caspase-dependent cell death events in cancer cells. Moreover, it was involved in up-regulation of autophagy signaling as evidenced by enhanced expression of LC3I/II. We also noticed stimulated expression of endoplasmic reticulum stress markers and phosphorylation of c-Jun NH2-terminal kinase (JNK), which was associated with up-regulated expression of p53, PUMA, Atg5 and Beclin-1, and down-regulation of Bcl-2, stressing the interaction of ROS on the aforementioned signaling. Furthermore, exposure to ROS scavengers (N-acetyl-l-cysteine (NAC), and JNK-specific inhibitor SP600125) significantly reversed the effects of CJK-7 by down-regulating apoptosis and autophagy signatures in HCT-116 cancer cells. Collectively our findings clarify the ROS-dependent regulatory effect of CJK-7 on programmed cell death signaling events in HCT-116 cancer cells while depicting its virile pro-oxidant capacity.	[Singh, Mahendra Pal; Khaket, Tejinder Pal; Kang, Sun Chul] Daegu Univ, Collage Engn, Dept Biotechnol, Gyongsan 38453, Gyeongbuk, South Korea; [Park, Ki Hun] Gyeongsan Natl Univ, Div Appl Sci, IALS, Jinju 660701, South Korea		Kang, SC (corresponding author), Daegu Univ, Collage Engn, Coll Engn, Dept Biotechnol, Gyongsan 38453, Gyeongbuk, South Korea.	sckang@daegu.ac.kr	Khaket, Tej/I-6260-2015; Singh, Mahendra Pal/J-8391-2019		National Research Foundation of Korea (NRF)National Research Foundation of Korea [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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Chem.		2018	18	3					428	437		10.2174/1871520617666171026170009			10	Oncology; Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	GJ0UF	WOS:000434969100012	29076434				2022-04-25	
J	Menon, MB; Kotlyarov, A; Gaestel, M				Menon, Manoj B.; Kotlyarov, Alexey; Gaestel, Matthias			SB202190-Induced Cell Type-Specific Vacuole Formation and Defective Autophagy Do Not Depend on p38 MAP Kinase Inhibition	PLOS ONE			English	Article							PROTEIN-KINASE; CANCER-CELL; IN-VIVO; MATURATION STEP; SB 203580; P38-ALPHA; STRESS; GROWTH; SENSITIVITY; METABOLISM	SB202190, a widely used inhibitor of p38 MAPK alpha and beta, was recently described to induce autophagic vacuoles and cell death in colon and ovarian cancer cells lines and, therefore, this effect was supposed to be specific for transformed cells and to open therapeutic options. Here, we demonstrate that SB202190 and the structurally related inhibitor SB203580 induce pro-autophagic gene expression and vacuole formation in various cancer and non-cancer cell lines of human, rat, mouse and hamster origin. This effect seems to induce defective autophagy leading to the accumulation of acidic vacuoles, p62 protein and lipid conjugated LC3. Using further p38 inhibitors we show that p38 MAPK inhibition is not sufficient for the autophagic response. In line with these results, expression of a SB202190-resistant mutant of p38 alpha, which significantly increases activity of the p38 pathway under inhibitory conditions, does not block SB202190-dependent vacuole formation, indicating that lack of p38 alpha activity is not necessary for this effect. Obviously, the induction of autophagic vacuole formation by SB203580 and SB202190 is due to off-target effects of these inhibitors on post-translational protein modifications, such as phosphorylation of the MAPKs ERK1/2 and JNK1/2, ribosomal protein S6, and PKB/Akt. Interestingly, the PI3K-inhibitor wortmannin induces transient vacuole formation indicating that the PI3K-PKB/Akt-mTOR pathway is essential for preventing autophagy and that cross-inhibition of this pathway by SB202190 could be the reason for the early part of the effect observed.	[Menon, Manoj B.; Kotlyarov, Alexey; Gaestel, Matthias] Hannover Med Sch, Inst Biochem, D-3000 Hannover, Germany		Menon, MB (corresponding author), Hannover Med Sch, Inst Biochem, D-3000 Hannover, Germany.	gaestel.matthias@mh-hannover.de	Gaestel, Matthias/A-6560-2013; Menon, Manoj B./P-1543-2015	Gaestel, Matthias/0000-0002-4944-4652; Menon, Manoj B./0000-0001-5859-0347	Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG); Hannover Medical School	This work was supported by Deutsche Forschungsgemeinschaft and the PhD-Program of the Hannover Medical School. 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	Akkoc, Y; Berrak, O; Arisan, ED; Obakan, P; Coker-Gurkan, A; Palavan-Unsal, N				Akkoc, Yunus; Berrak, Ozge; Arisan, Elif Damla; Obakan, Pinar; Coker-Gurkan, Ajda; Palavan-Unsal, Narcin			Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl-2 through activation of autophagy in MCF-7 cells	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Curcumin; Breast cancer; Apoptosis; PI3K; LY294002	COLON-CANCER CELLS; DOWN-REGULATION; BREAST-CANCER; CHEMOTHERAPEUTIC DRUGS; FAMILY-MEMBERS; LEUKEMIA-CELLS; KAPPA-B; DEATH; EXPRESSION; PATHWAYS	Curcumin is a natural anti-cancer agent derived from turmeric (Curcuma longa). Curcumin triggers intrinsic apoptotic cell death by activating mitochondrial permeabilization due to the altered expression of pro-and anti-apoptotic Bcl-2 family members. Phosphoinositol-3-kinase (PI3K) and Akt, key molecular players in the survival mechanism, have been shown to be associated with the Bcl-2 signaling cascade; therefore, evaluating the therapeutic efficiency of drugs that target both survival and the apoptosis mechanism has gained importance in cancer therapy. We found that Bcl-2 overexpression is a limiting factor for curcumin-induced apoptosis in highly metastatic MCF-7 breast cancer cells. Forced overexpression of Bcl-2 also blocked curcumin-induced autophagy in MCF-7 cells, through its inhibitory interactions with Beclin-1. Pre-treatment of PI3K inhibitor LY294002 enhanced curcumin-induced cell death, apoptosis, and autophagy via modulating the expression of Bcl-2 family members and autophagosome formation in MCF-7 breast cancer cells. Atg7 silencing further increased apoptotic potential of curcumin in the presence or absence of LY294002 in wt and Bcl-2+ MCF-7 cells. The findings of this study support the hypothesis that blocking the PI3K/Akt pathway may further increased curcumin-induced apoptosis and overcome forced Bcl-2 expression level mediated autophagic responses against curcumin treatment in MCF-7 cells. (C) 2015 Elsevier Masson SAS. All rights reserved.	[Akkoc, Yunus; Berrak, Ozge; Arisan, Elif Damla; Obakan, Pinar; Coker-Gurkan, Ajda; Palavan-Unsal, Narcin] Istanbul Kultur Univ, Dept Mol Biol & Genet, TR-34156 Bakirkoy Istanbul, Turkey		Arisan, ED (corresponding author), Istanbul Kultur Univ, Dept Mol Biol & Genet, Atakoy Campus, TR-34156 Bakirkoy Istanbul, Turkey.	d.arisan@iku.edu.tr	OBAKAN, PINAR/D-2836-2015; Arisan, Elif Damla/W-8682-2019; Rencuzogullari, Ozge/X-9954-2019; AKKOC, Yunus/AAK-8853-2020	Arisan, Elif Damla/0000-0002-4844-6381; AKKOC, Yunus/0000-0001-5379-6151; Gurkan, Ajda/0000-0003-1475-2417; Unsal Palavan, Narcin/0000-0002-2945-540X	Istanbul Kultur University Scientific Projects Support CenterIstanbul Kultur University	We are thankful to the Istanbul Kultur University Scientific Projects Support Center and Merve Celik for her technical assistance.	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Pharmacother.	APR	2015	71						161	171		10.1016/j.biopha.2015.02.029			11	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	CH6XK	WOS:000354179500026	25960232				2022-04-25	
J	Liu, ZY; Liu, Y; Long, YP; Liu, BH; Wang, XF				Liu, Zhengyong; Liu, Yi; Long, Yupeng; Liu, Baohua; Wang, Xiangfeng			Role of HSP27 in the multidrug sensitivity and resistance of colon cancer cells	ONCOLOGY LETTERS			English	Article						heat shock 27 kD protein 1; notch receptor 1-Akt-mTOR pathway; multidrug sensitivity; colon cancer	SHOCK-PROTEIN 27; DRUG-RESISTANCE; MOLECULAR CHAPERONE; GASTRIC-CANCER; VINCRISTINE; SUPPRESSION; APOPTOSIS; STATISTICS; AUTOPHAGY; AKT/MTOR	Multidrug resistance in cancer cells is a primary factor affecting therapeutic efficacy. Heat shock 27 kD protein 1 (HSP27) is associated with cell apoptosis and resistance to chemotherapy. However, the mechanisms underlying HSP27-associated pathways in colon cancer cells remain unclear. Therefore, the present study used short hairpin (sh) RNA to inhibit HSP27 expression in colon cancer cells in order to investigate the effects in vitro and in vivo. Flow cytometry was used to investigate cell apoptosis and a xenograft model was employed to examine the tumorigenesis. Protein expression was measured by Western blotting. The results revealed that suppression of HSP27 expression significantly increased cell apoptosis, inhibited tumor growth and enhanced sensitivity to the anti-cancer agents 5-fluorouracil (5-FU) and vincristine (VCR). shHSP27 significantly decreased the expression of notch receptor 1 and the phosphorylation level of Akt and mTOR, and enhanced the effect of 5-FU and VCR. In conclusion, HSP27 suppression enhanced the sensitivity of colon cancer cells to 5-FU and VCR, and increased colon cancer cell apoptosis with and without chemotherapy. Therefore, the development of novel therapeutic agents that inhibit the expression of HSP27 may offer a new treatment option for colon cancer.	[Liu, Zhengyong; Liu, Baohua; Wang, Xiangfeng] Army Med Univ, Daping Hosp, Dept Gen Surg, 10 Changjiangzhilu Rd, Chongqing 400042, Peoples R China; [Liu, Yi] Army Med Univ, Daping Hosp, Dept Informat, Chongqing 400042, Peoples R China; [Long, Yupeng] Chinese Peoples Liberat Army, Army Hosp 958, Dept Clin Lab, Chongqing 400020, Peoples R China		Liu, BH; Wang, XF (corresponding author), Army Med Univ, Daping Hosp, Dept Gen Surg, 10 Changjiangzhilu Rd, Chongqing 400042, Peoples R China.	LBH57268@163.com; xiangfengwang@tmmu.edu.cn			Chongqing Science and Technology Commission of China [cstc2017j-cyjAX0360]	The present study was supported by the Chongqing Science and Technology Commission of China (grant no. cstc2017j-cyjAX0360).	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Lett.	MAR	2020	19	3					2021	2027		10.3892/ol.2020.11255			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	KU8AI	WOS:000519933800043	32194698	gold, Green Published			2022-04-25	
J	Zhang, SL; Yang, ZW; Bao, WL; Liu, LX; You, Y; Wang, X; Shao, LM; Fu, W; Kou, XH; Shen, WX; Yuan, CM; Hu, B; Dang, WZ; Nandakumar, KS; Jiang, HL; Zheng, MY; Shen, XY				Zhang, Sulin; Yang, Zhiwen; Bao, Weilian; Liu, Lixin; You, Yan; Wang, Xu; Shao, Liming; Fu, Wei; Kou, Xinhui; Shen, Weixing; Yuan, Congmin; Hu, Bin; Dang, Wenzhen; Nandakumar, Kutty Selva; Jiang, Hualiang; Zheng, Mingyue; Shen, Xiaoyan			SNX10 (sorting nexin 10) inhibits colorectal cancer initiation and progression by controlling autophagic degradation of SRC	AUTOPHAGY			English	Article						Colorectal cancer; macroautophagy; SNX10; SRC; tumor growth	CHAPERONE-MEDIATED AUTOPHAGY; STAT3; EXPRESSION; INFLAMMATION; ACTIVATION; REVEALS; ROLES; CELLS; MODEL; IL-6	The non-receptor tyrosine kinase SRC is a key mediator of cellular protumorigenic signals. SRC is aberrantly over-expressed and activated in more than 80% of colorectal cancer (CRC) patients, therefore regulation of its stability and activity is essential. Here, we report a significant down regulation of SNX10 (sorting nexin 10) in human CRC tissues, which is closely related to tumor differentiation, TNM stage, lymph node metastasis and survival period. SNX10 deficiency in normal and neoplastic colorectal epithelial cells promotes initiation and progression of CRC in mice. SNX10 controls SRC levels by mediating autophagosome-lysosome fusion and SRC recruitment for autophagic degradation. These mechanisms ensure proper controlling of the activities of SRC-STAT3 and SRC-CTNNB1 signaling pathways by up-regulating SNX10 expression under stress conditions. These findings suggest that SNX10 acts as a tumor suppressor in CRC and it could be a potential therapeutic target for future development.	[Zhang, Sulin; Bao, Weilian; Liu, Lixin; You, Yan; Wang, Xu; Shao, Liming; Fu, Wei; Kou, Xinhui; Yuan, Congmin; Hu, Bin; Dang, Wenzhen; Shen, Xiaoyan] Fudan Univ, Sch Pharm, Dept Pharmacol, 826 Zhangheng Rd, Shanghai 201203, Peoples R China; [Zhang, Sulin; Jiang, Hualiang; Zheng, Mingyue] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zuchongzhi 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, Weixing] Nanjing Univ Tradit Chinese Med, Translat Med Res Ctr, Nanjing, Jiangsu, Peoples R China; [Nandakumar, Kutty Selva] Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China		Shen, XY (corresponding author), Fudan Univ, Sch Pharm, Dept Pharmacol, 826 Zhangheng Rd, Shanghai 201203, Peoples R China.; Zheng, MY (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China.	myzheng@simm.ac.cn; shxiaoy@fudan.edu.cn	Nandakumar, Kutty Selva/D-5438-2011; Bao, Weilian/AAU-5822-2021; Zheng, Mingyue/Z-3582-2019; Zheng, Mingyue/AAJ-8027-2020	Nandakumar, Kutty Selva/0000-0001-7790-8197; Zheng, Mingyue/0000-0002-3323-3092	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773744, 81573441, 81371923]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2018M642122]; Shanghai Sailing Program [19YF1457800]	This study was supported by National Natural Science Foundation of China (No. 81773744, 81573441 and 81371923), China Postdoctoral Science Foundation (NO. 2018M642122), and Shanghai Sailing Program (NO. 19YF1457800); China Postdoctoral Science Foundation [2018M642122].	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J	Wang, X; Yang, DY; Yang, LQ; Zhao, WZ; Cai, LY; Shi, HP				Wang, Xin; Yang, De-Yi; Yang, Liu-Qing; Zhao, Wen-Zhi; Cai, Li-Ya; Shi, Han-Ping			Anthocyanin Consumption and Risk of Colorectal Cancer: A Meta-Analysis of Observational Studies	JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION			English	Review						Anthocyanins; colorectal cancer; meta-analysis	DIETARY FLAVONOID INTAKE; COLON-CANCER; RICH EXTRACT; CELLS; DELPHINIDIN; MECHANISMS; VEGETABLES; QUALITY; FRUITS; BIAS	This meta-analysis aimed to summarize the association between anthocyanin consumption and the risk of colorectal cancer. All relative articles were located on online databases, including PubMed, Embase, and the Cochrane Library as of June 11, 2018. Risk ratios (RRs) or odds ratio and their 95% confidence intervals (CIs) were calculated through the STATA 12.0 software package. A total of seven studies were included in the meta-analysis. A significant inverse association was found between total anthocyanin consumption and colorectal cancer risk (RR = 0.78; 95% CI, 0.64-0.95). Likewise, there was significant evidence of a relationship between anthocyanin intake and colorectal cancer in the colon site (RR = 0.81; 95% CI, 0.71-0.92); men (RR = 0.88; 95% CI, 0.81-0.95), and case-control studies (RR = 0.69; 95% CI, 0.60-0.78). A dose-response relationship was not found in this meta-analysis. The Grades of Recommendations Assessment, Development, and Evaluation quality in our study was very low. This meta-analysis indicates that anthocyanin consumption is inversely associated with the risk of colorectal cancer. Anthocyanins may play an active role in the prevention of colorectal cancer. Key teaching points: Some epidemiological studies found an inverse correlation between the high consumption of anthocyanins and low risk of colorectal cancer. Because of this structure, anthocyanins/anthocyanidins have a powerful capability of donating electrons, which can be characterized as antioxidant properties. Anthocyanins can also inhibit colon cancer by interfering in the cell cycle and inducing the effect of anti-proliferation and apoptosis. The formation of cytoplasmic vacuoles in cells also indicates that anthocyanins may induce autophagy. From the findings of nonrandomized controlled trials, anthocyanins may play an active role in the prevention of colorectal cancer.	[Wang, Xin; Yang, Liu-Qing; Zhao, Wen-Zhi; Cai, Li-Ya; Shi, Han-Ping] Capital Med Univ, Dept Gastrointestinal Surg, Beijing Shijitan Hosp, Dept Oncol, Beijing, Peoples R China; [Wang, Xin; Yang, Liu-Qing; Zhao, Wen-Zhi; Cai, Li-Ya; Shi, Han-Ping] Capital Med Univ, Dept Clin Nutr, Beijing Shijitan Hosp, Dept Oncol, Beijing, Peoples R China; [Wang, Xin; Yang, Liu-Qing; Zhao, Wen-Zhi; Cai, Li-Ya; Shi, Han-Ping] Peking Univ, Clin Med Coll 9, Beijing, Peoples R China; [Yang, De-Yi] Cent S Univ, Dept Gastrointestinal Surg, Xiangya Hosp, Changsha, Hunan, Peoples R China		Shi, HP (corresponding author), Capital Med Univ, Dept Gastrointestinal Surg, Dept Clin Nutr, Beijing Shijitan Hosp, 10 Tieyi Rd, Beijing 100038, Peoples R China.	shihp@vip.163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672888]; National Key Research and Development Program of China [2017YFC1309200]	This work was supported by the National Natural Science Foundation of China (grant numbers 81672888) and the National Key Research and Development Program of China (Project No. 2017YFC1309200).	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Am. Coll. Nutr.	JUL 4	2019	38	5					470	477		10.1080/07315724.2018.1531084			8	Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Nutrition & Dietetics	IF3GV	WOS:000472969800011	30589398				2022-04-25	
J	Shang, M; Sun, J				Shang, Mei; Sun, Jun			Vitamin D/VDR, Probiotics, and Gastrointestinal Diseases	CURRENT MEDICINAL CHEMISTRY			English	Review						Autophagy; bacteria; colon cancer; colitis; lactic acid bacteria; IBD; inflammation; probiotics; NF-kappa B; vitamin D; VDR	ENTEROTOXIGENIC ESCHERICHIA-COLI; EPITHELIAL BARRIER DYSFUNCTION; ANTIBIOTIC-ASSOCIATED DIARRHEA; INFLAMMATORY-BOWEL-DISEASE; D-RECEPTOR; LACTOBACILLUS-RHAMNOSUS; COLORECTAL-CANCER; TIGHT JUNCTION; D DEFICIENCY; GUT MICROBIOME	Vitamin D is an important factor in regulating inflammation, immune responses, and carcinoma inhibition via action of its receptor, vitamin D receptor (VDR). Recent studies have demonstrated the role of vitamin D/VDR in regulating host-bacterial interactions. Probiotics are beneficial bacteria with the power of supporting or favoring life on the host. In the current review, we will discuss the recent progress on the roles of vitamin D/VDR in gut microbiome and inflammation. We will summarize evidence of probiotics in modulating vitamin D/VDR and balancing gut microbiota in health and gastrointestinal diseases. Moreover, we will review the clinical application of probiotics in prevention and therapy of IBD or colon cancer. Despite of the gains, there remain several barriers to advocate broad use of probiotics in clinical therapy. We will also discuss the limits and future direction in scientific understanding of probiotics, vitamin D/VDR, and host responses.	[Shang, Mei] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou, Guangdong, Peoples R China; [Shang, Mei; Sun, Jun] Univ Illinois, Dept Med, Chicago, IL USA		Sun, J (corresponding author), Univ Illinois, Dept Med, Div Gastroenterol & Hepatol, 840 S Wood St,Room 704 CSB, Chicago, IL 60612 USA.	junsun7@uic.edu	Sun, Jun/S-7440-2019	Sun, Jun/0000-0001-7465-3133	NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01 DK105118]; International Program for Ph.D. Candidates, Sun Yat-Sen University; 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) [R03DK089010, R01DK105118] Funding Source: NIH RePORTER	We would like to acknowledge the NIDDK grant R01 DK105118 (JS). Mei Shang is partially supported by the International Program for Ph.D. Candidates, Sun Yat-Sen University. We would like to thank Annika Agrawal for her help with proofreading of this manuscript.	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Med. Chem.		2017	24	9					876	887		10.2174/0929867323666161202150008			12	Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy	EU0JO	WOS:000400697700004	27915988	Green Accepted			2022-04-25	
J	Hu, XT; Sui, XB; Li, LL; Huang, XF; Rong, R; Su, XW; Shi, QL; Mo, LJ; Shu, XS; Kuang, YY; Tao, Q; He, C				Hu, Xiaotong; Sui, Xinbing; Li, Lili; Huang, Xuefeng; Rong, Rong; Su, Xianwei; Shi, Qinglan; Mo, Lijuan; Shu, Xingsheng; Kuang, Yeye; Tao, Qian; He, Chao			Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers	JOURNAL OF PATHOLOGY			English	Article						PCDH17; tumour suppressor gene; methylation; apoptosis; autophagy	CANDIDATE; MULTIPLE; DIVERSITY; GENE; NASOPHARYNGEAL; CARCINOMAS; ESOPHAGEAL; MECHANISM; PROTEIN; DEATH	Gastric and colorectal cancers are among the most common cancers worldwide and cause serious cancer mortality. Both epigenetic and genetic disruptions of tumour suppressor genes (TSGs) are frequently involved in their pathogenesis. Here, we studied the epigenetic and genetic alterations of a novel TSG-PCDH17 and its functions in the pathogenesis of these tumours. We found that PCDH17 was frequently silenced and methylated in almost all gastric and colorectal tumour cell lines as well as in similar to 95% of primary tumours, but not in normal gastric and colonic mucosa. Moreover, its deletion was detected in only 18% of gastric and 12% of colorectal cancer tissues, suggesting that epigenetic and genetic inactivation of PCDH17 are both involved in gastric and colorectal tumourigenesis. PCDH17 protein expression was significantly correlated with low tumour stage and less lymph node metastasis of gastric and colorectal cancer patients, indicating its potential as a tumour marker. Restoring PCDH17 expression inhibited tumour cell growth in vitro and in vivo through promoting apoptosis, as evidenced by increased TUNEL staining and caspase-3 activation. Furthermore, PCDH17-induced autophagy, along with increased numbers of autophagic vacuoles and up-regulated autophagic proteins Atg-5, Atg-12 and LC3B II. Thus, PCDH17 acts as a tumour suppressor, exerting its anti-proliferative activity through inducing apoptosis and autophagy, and is frequently silenced in gastric and colorectal cancers. PCDH17 methylation is a tumour-specific event that could serve as an epigenetic biomarker for these tumours. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.	[Li, Lili; Rong, Rong; Su, Xianwei; Shu, Xingsheng; Tao, Qian] Chinese Univ Hong Kong, Dept Clin Oncol, Canc Epigenet Lab, State Key Lab Oncol S China,Sir YK Pao Ctr Canc, Shatin, Hong Kong, Peoples R China; [Li, Lili; Rong, Rong; Su, Xianwei; Shu, Xingsheng; Tao, Qian] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Shatin, Hong Kong, Peoples R China; [Sui, Xinbing; Huang, Xuefeng; He, Chao] Zhejiang Univ, Dept Colorectal Surg, Sir Run Run Shaw Hosp, Hangzhou 310003, Zhejiang, Peoples R China; [Hu, Xiaotong; Shi, Qinglan; Mo, Lijuan; Kuang, Yeye; He, Chao] Zhejiang Univ, Biomed Res Ctr, Sir Run Run Shaw Hosp, Hangzhou 310003, Zhejiang, Peoples R China; [Hu, Xiaotong; Shi, Qinglan; Mo, Lijuan; Kuang, Yeye; He, Chao] Zhejiang Univ, Key Lab Biotherapy Zhejiang Prov, Sir Run Run Shaw Hosp, Hangzhou 310003, Zhejiang, Peoples R China		Tao, Q (corresponding author), Chinese Univ Hong Kong, Ctr Canc, PWH, Rm 315, Shatin, Hong Kong, Peoples R China.	qtao@clo.cuhk.edu.hk; drhe_srrsh@sina.com	Hu, Xiao-tong/K-5820-2019; Tao, Qian/T-4743-2018; Li, Lili/Q-5750-2018	Tao, Qian/0000-0001-5383-4808; Li, Lili/0000-0002-0292-5889	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30770920, 81071651, 30928012]; Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [R2100213, 2010R50046, 2009C33142, Z2090056]; Program for Zhejiang Leading Team of ST innovation [2012R10046-03]; Hong Kong RGCHong Kong Research Grants Council [GRF 475009]; Group Research Scheme of the Chinese University of Hong Kong [3110085]	We thank Bert Vogelstein, Keith Robertson, Sun Young Rha, for some tumour cell lines. This study was supported by the National Natural Science Foundation of China (Grant Nos 30770920, 81071651 and 30928012), the Zhejiang Provincial Natural Science Foundation of China (Grant Nos R2100213, 2010R50046, 2009C33142 and Z2090056), the Program for Zhejiang Leading Team of S&T innovation (Grant No. 2012R10046-03) the Hong Kong RGC (Grant No. GRF 475009) and the Group Research Scheme of the Chinese University of Hong Kong (Grant No. 3110085).	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Pathol.	JAN	2013	229	1					62	73		10.1002/path.4093			12	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	057DM	WOS:000312542300007	22926751				2022-04-25	
J	Singh, AK; Verma, A; Singh, A; Arya, RK; Maheshwari, S; Chaturvedi, P; Nengroo, MA; Saini, KK; Vishwakarma, AL; Singh, K; Sarkar, J; Datta, D				Singh, Anup Kumar; Verma, Ayushi; Singh, Akhilesh; Arya, Rakesh Kumar; Maheshwari, Shrankhla; Chaturvedi, Priyank; Nengroo, Mushtaq Ahmad; Saini, Krishan Kumar; Vishwakarma, Achchhe Lal; Singh, Kavita; Sarkar, Jayanta; Datta, Dipak			Salinomycin inhibits epigenetic modulator EZH2 to enhance death receptors in colon cancer stem cells	EPIGENETICS			English	Article						EZH2; cancer stem cells; death receptors; salinomycin; apoptosis	SMALL-MOLECULE INHIBITOR; TRAIL RESISTANCE; BREAST-CANCER; TUMOR-GROWTH; APOPTOSIS; HETEROGENEITY; ACTIVATION; AUTOPHAGY; TARGET	Drug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumour cells is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotypes such as spheroid formationin-vitroand tumorigenic potentialin-vivoin colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug-resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.	[Singh, Anup Kumar; Verma, Ayushi; Singh, Akhilesh; Arya, Rakesh Kumar; Maheshwari, Shrankhla; Chaturvedi, Priyank; Nengroo, Mushtaq Ahmad; Saini, Krishan Kumar; Datta, Dipak] CSIR, Div Canc Biol, Cent Drug Res Inst CDRI, Lucknow, Uttar Pradesh, India; [Maheshwari, Shrankhla; Saini, Krishan Kumar; Datta, Dipak] Acad Sci & Innovat Res, New Delhi, India; [Vishwakarma, Achchhe Lal] CSIR, CDRI, SAIF, Lucknow, Uttar Pradesh, India; [Singh, Kavita] CSIR, CDRI, Electron Microscopy Unit, Lucknow, Uttar Pradesh, India; [Sarkar, Jayanta] CSIR, CDRI, Biochem Div, Lucknow, Uttar Pradesh, India; City Hope Comprehens Canc Ctr, Beckman Res Inst, Dept Canc Genet & Epigenet, Duarte, CA 91010 USA		Datta, D (corresponding author), CSIR, CDRI, Div Canc Biol, Lucknow 226031, Uttar Pradesh, India.	dipak.datta@cdri.res.in	Sarkar, Jayanta/C-3250-2009; Singh, Anup Kumar/T-9464-2019	Singh, Anup Kumar/0000-0001-5180-0727; Sarkar, Jayanta/0000-0002-9905-7722	Department of Biotechnology, Ministry of Science and Technology [BT/AIR0568/PACE-15/18]; DST-Science and Engineering Research Board [EMR/2016/006935]; ICMRIndian Council of Medical Research (ICMR) [2019-1350]	This work in part was supported by the Department of Biotechnology, Ministry of Science and Technology [BT/AIR0568/PACE-15/18]; DST-Science and Engineering Research Board [EMR/2016/006935] and ICMR [2019-1350].	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Wielenga MCB, 2015, CELL REP, V13, P489, DOI 10.1016/j.celrep.2015.09.016; Yang SZ, 2017, J BIOL CHEM, V292, P10390, DOI 10.1074/jbc.M117.786830; Yoshida T, 2001, FEBS LETT, V507, P381, DOI 10.1016/S0014-5793(01)02947-7; Yu J, 2010, ONCOGENE, V29, P5370, DOI 10.1038/onc.2010.269; Zhang YQ, 2008, MOL CANCER RES, V6, P1861, DOI 10.1158/1541-7786.MCR-08-0313; Zhi QM, 2011, BIOMED PHARMACOTHER, V65, P509, DOI 10.1016/j.biopha.2011.06.006	64	9	9	1	3	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	1559-2294	1559-2308		EPIGENETICS-US	Epigenetics	FEB 1	2021	16	2					144	161		10.1080/15592294.2020.1789270		JUL 2020	18	Biochemistry & Molecular Biology; Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Genetics & Heredity	QG3HT	WOS:000547834800001	32635858	Bronze, Green Published, Green Submitted			2022-04-25	
J	Lo Dico, A; Martelli, C; Diceglie, C; Lucignani, G; Ottobrini, L				Lo Dico, Alessia; Martelli, Cristina; Diceglie, Cecilia; Lucignani, Giovanni; Ottobrini, Luisa			Hypoxia-Inducible Factor-1 alpha Activity as a Switch for Glioblastoma Responsiveness to Temozolomide	FRONTIERS IN ONCOLOGY			English	Article						theranostic biomarker; hypoxia-inducible factor-1 alpha silencing; apoptosis; chaperone-mediated autophagy activity; temozolomide responsiveness	CHAPERONE-MEDIATED AUTOPHAGY; HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA HIF-1-ALPHA; IMAGING BIOMARKERS; MALIGNANT GLIOMAS; COLON-CANCER; STEM-CELLS; IN-VITRO; SENSITIVITY; INHIBITION; EXPRESSION	Rationale: The activity of the transcription factor, hypoxia-inducible factor (HIF)-1 alpha, is a common driver of a number of the pathways involved in the aggressiveness of glioblastomas (GBMs), and it has been suggested that the reduction in this activity observed, soon after the administration of temozolomide (TMZ), can be a biomarker of an early response in GBM models. As HIF-1 alpha is a tightly regulated protein, studying the processes involved in its downregulation could shed new light on the mechanisms underlying GBM sensitivity or resistance to TMZ. Methods: The effect of HIF-1 alpha silencing on cell responsiveness to TMZ was assessed in four genetically different human GBM cell lines by evaluating cell viability and apoptosis- related gene balance. LAMP-2A silencing was used to evaluate the contribution of chaperone-mediated autophagy (CMA) to the modulation of HIF-1 alpha activity in TMZ-sensitive and TMZ-resistant cells. Results: The results showed that HIF-1 alpha but not HIF-2 alpha activity is associated with GBM responsiveness to TMZ: its downregulation improves the response of TMZ-resistant cells, while blocking CMA-mediated HIF-1 alpha degradation induces resistance to TMZ in TMZ-sensitive cells. These findings are in line with the modulation of crucial apoptosis- related genes. Conclusion: Our results demonstrate the central role played by HIF-1 alpha activity in determining the sensitivity or resistance of GBMs to TMZ, and we suggest that CMA is the cellular mechanism responsible for modulating this activity after TMZ treatment.	[Lo Dico, Alessia; Ottobrini, Luisa] CNR, Inst Mol Bioimaging & Physiol IBFM, Milan, Italy; [Lo Dico, Alessia; Martelli, Cristina; Diceglie, Cecilia; Ottobrini, Luisa] Univ Milan, Dept Pathophysiol & Transplantat, Milan, Italy; [Lucignani, Giovanni] Univ Milan, Dept Hlth Sci, Milan, Italy; [Lucignani, Giovanni] San Paolo Hosp, Unit Nucl Med, Dept Diagnost Serv, Milan, Italy		Ottobrini, L (corresponding author), CNR, Inst Mol Bioimaging & Physiol IBFM, Milan, Italy.; Ottobrini, L (corresponding author), Univ Milan, Dept Pathophysiol & Transplantat, Milan, Italy.	luisa.ottobrini@unimi.it	Dico, Alessia Lo/AAK-3571-2020; Lucignani, Giovanni/C-6773-2008; lo dico, alessia/O-9721-2017	Lucignani, Giovanni/0000-0002-9674-8958; lo dico, alessia/0000-0002-8627-5050	 [GA305311]	The authors would like to thank Dr. G. Melillo for providing the U251-HRE cells and the HRE-luciferase reporter plasmid. This study was supported in part by the FP7-funded INSERT project (HEALTH-2012- INNOVATION-1, GA305311).	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Oncol.	JUL 2	2018	8								249	10.3389/fonc.2018.00249			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GL2QY	WOS:000436970000003	30013951	Green Published, gold			2022-04-25	
J	Saadat, YR; Khosroushahi, AY; Movassaghpour, AA; Talebi, M; Gargari, BP				Saadat, Yalda Rahbar; Khosroushahi, Ahmad Yari; Movassaghpour, Ali Akbar; Talebi, Mehdi; Gargari, Bahram Pourghassem			Modulatory role of exopolysaccharides of Kluyveromyces marxianus and Pichia kudriavzevii as probiotic yeasts from dairy products in human colon cancer cells	JOURNAL OF FUNCTIONAL FOODS			English	Article						Probiotic yeasts; Colon cancer; Apoptosis; Ferroptosis; Signaling pathways; Exopolysaccharides	APOPTOSIS; FERROPTOSIS; STRAINS; DEATH; BIOSYNTHESIS; AUTOPHAGY; CHEESE; LINES	Colorectal cancer (CRC) is a widespread and lethal cancer throughout the world. Nowadays there is considerable debate about the efficacy of conventional methods in CRC treatment. Though targeting vital molecular pathways, as well as induction of various forms of cell death by safe probiotic yeast components are regarded as potential therapeutic modalities against CRC. Hence, here we aimed to investigate the inhibitory role of the EPSs of Kluyveromyces marxianus and Pichia kudriavzevii on different colon cancer cell lines. In this regard, several cellular and molecular experiments were performed. Here, we found that both EPSs can induce apoptosis which were confirmed by DAPI and Annexin V/PI assays. Further, our data showed that the EPSs could not act via ferroptotic pathways, however, they could hinder the AKT-1, mTOR, and JAK-1 pathways, and induce apoptosis. Therefore, the probiotic yeast EPSs present beneficial effects and may provide as a novel molecular-targeted therapeutics for combating CRC.	[Saadat, Yalda Rahbar; Gargari, Bahram Pourghassem] Tabriz Univ Med Sci, Nutr Res Ctr, Tabriz, Iran; [Saadat, Yalda Rahbar] Tabriz Univ Med Sci, Student Res Comm, Tabriz, Iran; [Khosroushahi, Ahmad Yari] Tabriz Univ Med Sci, Drug Appl Res Ctr, Tabriz, Iran; [Khosroushahi, Ahmad Yari] Tabriz Univ Med Sci, Fac Adv Med Sci, Dept Med Nanotechnol, Tabriz, Iran; [Movassaghpour, Ali Akbar; Talebi, Mehdi] Tabriz Univ Med Sci, Hematol & Oncol Res Ctr, Tabriz, Iran; [Gargari, Bahram Pourghassem] Tabriz Univ Med Sci, Fac Nutr & Food Sci, Dept Biochem & Diet Therapy, Tabriz, Iran		Gargari, BP (corresponding author), Tabriz Univ Med Sci, Fac Nutr & Food Sci, Dept Biochem & Diet Therapy, Nutr Res Ctr, Tabriz, Iran.	pourghassemb@tbzmed.ac.ir	Rahbar Saadat, Yalda/O-8109-2017; Talebi, Mehdi/E-3808-2010	Rahbar Saadat, Yalda/0000-0002-3295-404X; Talebi, Mehdi/0000-0002-3633-2280	Nutrition Research Center, Tabriz University of Medical Sciences, Iran [1396.09.28, 5D.606013];  [97011018]	This project is part of a Ph.D. thesis (grant No. 1396.09.28, 5D.606013) funded by Nutrition Research Center, Tabriz University of Medical Sciences, Iran and Iran National Science Foundation (INSF) (grant No.: 97011018).	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JAN	2020	64								103675	10.1016/j.jff.2019.103675			9	Food Science & Technology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology; Nutrition & Dietetics	KE3WY	WOS:000508491000069		gold			2022-04-25	
J	Islam, F; Gopalan, V; Lam, AKY				Islam, Farhadul; Gopalan, Vinod; Lam, Alfred King-yin			RETREG1 (FAM134B): A new player in human diseases: 15 years after the discovery in cancer	JOURNAL OF CELLULAR PHYSIOLOGY			English	Review						cancer; endoplasmic reticulum; FAM134B; JK1; neuronal disorder; RETREG1	ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; SQUAMOUS-CELL CARCINOMA; AUTONOMIC NEUROPATHY; COLORECTAL-CANCER; COLON-CANCER; CLINICOPATHOLOGICAL SIGNIFICANCE; 3-DIMENSIONAL ARCHITECTURE; SELECTIVE AUTOPHAGY; MUTATIONS	FAM134B (family with sequence similarity 134, member B)/RETREG1 and its functional roles are relatively new in human diseases. This review aimed to summarize various functions of FAM134B since our first discovery of the gene in 2001. The protein encoded by FAM134B is a reticulophagy receptor that regulates turnover of the endoplasmic reticulum (ER) by selective phagocytosis. Absence or non-functional expression of FAM134B protein impairs ER-turnover and thereby is involved in the pathogenesis of some human diseases. FAM134B inhibition contributes to impair proteostasis in the ER due to the accumulation of misfolded or aggregated proteins, which in turn leads to compromised neuronal survival and progressive neuronal degenerative diseases. Mutations in FAM134B associated with hereditary sensory and autonomic neuropathy type IIB (HSAN IIB). Selective cleavage of FAM134B by Dengue, Zika, and West Nile virus encoded protease NS2B3 leads to the increased production of infection units, whereas upregulation of FAM134B inhibits viral replication. In cancer, FAM134B acts as a tumor suppressor and inhibit cancer growth both in-vitro and in-vivo. Pharmacological upregulation of FAM134B resulted in reduced cancer cell growth and proliferation. In addition, FAM134B mutations are common in patients with colorectal adenocarcinoma, and oesophageal squamous cell carcinoma. These mutations and expression changes of FAM134B were associated with the biological aggressiveness of these cancers. FAM134B also plays a role in allergic rhinitis, vascular dementia, and identification of stem cells. Taken together, information available in the literature suggests that FAM134B plays critical roles in human diseases, by interacting with different biological and chemical mediators, which are primarily regulated by ER turnover.	[Islam, Farhadul; Gopalan, Vinod; Lam, Alfred King-yin] Griffith Univ, Sch Med, Canc Mol Pathol, Gold Coast, Qld, Australia; [Islam, Farhadul; Gopalan, Vinod; Lam, Alfred King-yin] Griffith Univ, Griffith Hlth Inst, Gold Coast, Qld, Australia; [Islam, Farhadul] Rajshahi Univ, Dept Biochem & Mol Biol, Rajshahi, Bangladesh		Lam, AKY (corresponding author), Griffith Med Sch, Pathol, Gold Coast Campus, Gold Coast, Qld 4222, Australia.	a.lam@griffith.edu.au	Lam, Alfred/C-1652-2008; Islam, Farhadul/R-5643-2017	Lam, Alfred/0000-0003-2771-564X; Islam, Farhadul/0000-0001-5262-4702	Griffith UniversityGriffith University; Menzies Health Institute Queensland	Griffith University; Menzies Health Institute Queensland	Bernales S, 2006, PLOS BIOL, V4, P2311, DOI 10.1371/journal.pbio.0040423; Borgese N, 2006, CURR OPIN CELL BIOL, V18, P358, DOI 10.1016/j.ceb.2006.06.008; Chiramel AI, 2016, J INFECT DIS, V214, pS319, DOI 10.1093/infdis/jiw270; Croce CM, 2008, NEW ENGL J MED, V358, P502, DOI 10.1056/NEJMra072367; Cybulsky AV, 2017, NAT REV NEPHROL, V13, P681, DOI 10.1038/nrneph.2017.129; 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; Hamasaki M, 2005, TRAFFIC, V6, P56, DOI 10.1111/j.1600-0854.2004.00245.x; Haque MH, 2016, SCI REP-UK, V6, DOI 10.1038/srep29173; Houlden H, 2004, CURR OPIN NEUROL, V17, P569, DOI 10.1097/00019052-200410000-00007; 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; Junjhon J, 2014, J VIROL, V88, P4687, DOI 10.1128/JVI.00118-14; 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; Kaser A, 2008, CELL, V134, P743, DOI 10.1016/j.cell.2008.07.021; Khaminets A, 2015, NATURE, V522, P354, DOI 10.1038/nature14498; Klionsky DJ, 2008, AUTOPHAGY, V4, P740, DOI 10.4161/auto.6398; Knudson AG, 2001, NAT REV CANCER, V1, P157, DOI 10.1038/35101031; Kobayashi S, 2015, BIOL PHARM BULL, V38, P1098, DOI 10.1248/bpb.b15-00096; Kong M, 2011, PSYCHIAT GENET, V21, P37, DOI 10.1097/YPG.0b013e3283413496; Kurth I., 2015, GENEREVIEWS, P1993; 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; Lennemann NJ, 2017, AUTOPHAGY, V13, P322, DOI 10.1080/15548627.2016.1265192; Lin JH, 2008, ANNU REV PATHOL-MECH, V3, P399, DOI 10.1146/annurev.pathmechdis.3.121806.151434; Lipatova Z, 2015, PLOS GENET, V11, DOI 10.1371/journal.pgen.1005390; Melchiotti R, 2014, BMC MED GENET, V15, DOI 10.1186/1471-2350-15-73; Mizushima N, 2011, CELL, V147, P728, DOI 10.1016/j.cell.2011.10.026; Murphy SM, 2012, J NEUROL NEUROSUR PS, V83, P119, DOI 10.1136/jnnp.2010.228965; Phillips MJ, 2016, NAT REV MOL CELL BIO, V17, P69, DOI 10.1038/nrm.2015.8; Rao RV, 2006, CELL DEATH DIFFER, V13, P415, DOI 10.1038/sj.cdd.4401761; Riviere JB, 2011, AM J HUM GENET, V89, P219, DOI 10.1016/j.ajhg.2011.06.013; Rubinsztein DC, 2015, NATURE, V522, P291, DOI 10.1038/nature14532; Scheubert L, 2011, DNA RES, V18, P233, DOI 10.1093/dnares/dsr016; Schneider-Brachert W, 2004, IMMUNITY, V21, P415, DOI 10.1016/j.immuni.2004.08.017; Schuchman EH, 2010, FEBS LETT, V584, P1895, DOI 10.1016/j.febslet.2009.11.083; Schuck S, 2009, J CELL BIOL, V187, P525, DOI 10.1083/jcb.200907074; Schwarz DS, 2016, CELL MOL LIFE SCI, V73, P79, DOI 10.1007/s00018-015-2052-6; Song S., 2017, J CELLULAR PHYSL; Tang JCO, 2001, CLIN CANCER RES, V7, P1539; Tang WK, 2007, INT J MOL MED, V19, P915; Walter P, 2011, SCIENCE, V334, P1081, DOI 10.1126/science.1209038; Welsch S, 2009, CELL HOST MICROBE, V5, P365, DOI 10.1016/j.chom.2009.03.007; Westaway EG, 1997, J VIROL, V71, P6650, DOI 10.1128/JVI.71.9.6650-6661.1997; Yadav Raj Kumar, 2014, J Cancer Prev, V19, P75, DOI 10.15430/JCP.2014.19.2.75; Yorimitsu T, 2007, TRENDS CELL BIOL, V17, P279, DOI 10.1016/j.tcb.2007.04.005	50	30	31	1	205	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0021-9541	1097-4652		J CELL PHYSIOL	J. Cell. Physiol.	JUN	2018	233	6					4479	4489		10.1002/jcp.26384			11	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	FX6JP	WOS:000426190900009	29226326	Green Published			2022-04-25	
J	Ding, ZY; Chen, QB; Xiong, B; Cun, YL; Wang, HB; Xu, MY				Ding, Zheyu; Chen, Qingbo; Xiong, Bin; Cun, Yingli; Wang, Hongbo; Xu, Mingyao			Angustifoline inhibits human colon cancer cell growth by inducing autophagy along with mitochondrial-mediated apoptosis, suppression of cell invasion and migration and stimulating G2/M cell cycle arrest	JOURNAL OF BUON			English	Article						angustifoline; autophagy; cell migration; colon cancer; flow cytometry		Purpose: The prime objective of the present study was to investigate the anticancer properties of angustifoline against COLO-205 human colon cancer cells. Its effects on cell autophagy, apoptosis, cell invasion and cell migration, and cell cycle arrest were also evaluated in the current study. Methods: WST-1 assay was used to study cytotoxic effects of the compound on the cell viability. Effects on apoptosis and cell cycle arrest were evaluated by flow cytometry. In vitro wound healing assay and matrigel assay were carried out to study the effects of angustifoline on cell migration and cell invasion respectively. To confirm autophagy, we evaluated the expression of several autophagy-associated proteins using Western blot assay along with transmission electron microscopy (TEM). Results: The findings indicated that angustifoline induced dose- and time-dependent cytotoxicity in COLO-205 human colon cancer cells along with inhibiting cancer cell colony formation. Angustifoline-treated cells exhibited cell shrinkage along with distortion of the normal cell morphology. Angustifoline-treated cells were also arrested in the G2/M phase of the cell cycle, showing strong dose-dependence. The compound also led to inhibition of cell migration and cell invasion. The results showed that treatment of these cells led to generation of autophagic cell vesicles. Furthermore, it was observed that the expression of Beclin-1 and LC3-II proteins was significantly upregulated in the angustifoline-administered COLO-205 cells. Conclusions: In brief, the present study hints towards the potent anticancer potential of the natural product angustifoline against COLO-205 human colon cancer cells with in depth mechanistic studies.	[Ding, Zheyu; Chen, Qingbo; Wang, Hongbo; Xu, Mingyao] Hubei Canc Hosp, Dept Endoscopy, Wuhan 430079, Hubei, Peoples R China; [Ding, Zheyu] Colorectal Canc Clin Res Ctr Hubei Prov, Colorectal Canc Clin Res Ctr Wuhan, Wuhan 430079, Hubei, Peoples R China; [Xiong, Bin] Wuhan Univ, Dept Gastrointestinal Surg, Zhongnan Hosp, Wuhan 430079, Hubei, Peoples R China; [Cun, Yingli] Yunnan Canc Hosp, Dept Abdominal Surg, Kunming 650118, Yunnan, Peoples R China		Chen, QB (corresponding author), Hubei Canc Hosp, Dept Endoscopy, Wuhan 430079, Hubei, Peoples R China.	CovinVichto@yahoo.com					Abdel-Rahman WM, 2017, CURR MOL MED, V17, P34, DOI 10.2174/1566524017666170220094705; Alam M.M., 2017, CATHARANTHUS ROSEUS, P277; Almosnid NM, 2018, J ETHNOPHARMACOL, V211, P224, DOI 10.1016/j.jep.2017.09.032; Butler MS, 2014, NAT PROD REP, V31, P1612, DOI 10.1039/c4np00064a; Che T, 2018, MOLECULES, V23, DOI 10.3390/molecules23020493; Focaccetti C, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0115686; He MM, 2015, RSC ADV, V5, P16562, DOI 10.1039/c4ra14666b; Iqbal J, 2017, ASIAN PAC J TROP BIO, V5, P97; Llosa NJ, 2015, CANCER DISCOV, V5, P43, DOI 10.1158/2159-8290.CD-14-0863; O'Brien CA, 2007, NATURE, V445, P106, DOI 10.1038/nature05372; Patridge E, 2016, DRUG DISCOV TODAY, V21, P204, DOI 10.1016/j.drudis.2015.01.009; Pietkiewicz S, 2015, J IMMUNOL METHODS, V423, P99, DOI 10.1016/j.jim.2015.04.025; Roleira FMF, 2015, FOOD CHEM, V183, P235, DOI 10.1016/j.foodchem.2015.03.039; Twilley D, 2018, NATURAL PRODUCTS DRU, V5, P139; Yan L, 2015, ONCOGENE, V34, P3076, DOI 10.1038/onc.2014.236	15	0	0	0	4	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	JAN-FEB	2019	24	1					236	241					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	HK7XI	WOS:000458202600032	30941961				2022-04-25	
J	Lu, XH; Fu, HJ; Chen, R; Wang, Y; Zhan, YY; Song, G; Hu, TH; Xia, C; Tian, XM; Zhang, B				Lu, Xiaohong; Fu, Haijing; Chen, Rui; Wang, Yue; Zhan, Yanyan; Song, Gang; Hu, Tianhui; Xia, Chun; Tian, Xuemei; Zhang, Bing			Phosphoinositide specific phospholipase C gamma 1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro	INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES			English	Article						PLC gamma 1 inhibition; autophagic cell death (ACD); lung adenocarcinoma A549 cells; A549 xenograft nude mice	PROTEIN-KINASE B; SIGNALING PATHWAY; C-ALPHA; CANCER; ERK; ACTIVATION; EXPRESSION; APOPTOSIS; TARGET; GROWTH	Our previous studies indicated that phosphoinositide specific phospholipase C gamma 1 (PLC gamma 1) was involved in autophagy induction in colon and hepatic carcinoma cells. However, whether and how PLC gamma 1 regulation in human lung adenocarcinoma is linked to autophagy remains unclear. Here, we assessed the protein expression of PLC gamma 1 in human lung adenocarcinoma tissue using immunohistochemistry assay and the relationship between PLCG1 and autophagy in The Cancer Genome Atlas Network (TCGA) using Spearman correlation analysis and GSEA software. Furthermore, the interaction between PLC gamma 1 and autophagy-related signal molecules was investigated in human lung adenocarcinoma A549 cells treated with different inhibitors or transduction with lentivirus-mediated PLC gamma 1 gene short-hairpin RNA (shRNA) vectors using MTT, clonogenicity, Transwell migration, RT-PCR, Caspase-3, mitochondrial transmembrane potential, and western blotting assays, as well as transmission electron microscope technique. Additionally, the effect of shRNA/PLC gamma 1 alone or combined with autophagic activator Lithium Chloride (LiCl) on tumor growth and metastasis was measured using immunohistochemistry and assays in A549 xenograft nude mouse model. The results showed that increased PLC gamma 1 expression occurred frequently in human lung adenocarcinoma tissue with higher grades of T in TNM staging classification. PLC gamma 1 significantly enriched in autophagic process and regulation, which negatively regulating autophagy was enriched in higher expression of PLC gamma 1 PLC gamma 1 inhibition partially reduced cell proliferation and migration of A549 cells, with an increased autophagic flux involving alterations of AMPK alpha, mTOR, and ERK levels. However, PLC gamma 1 inhibition-driven autophagy led to cell death without depending on Caspase-3 and RIP]. Additionally, the abrogation of PLC gamma 1 signaling by shRNA and combination with autophagic activator LiCl could efficaciously suppress tumor growth and metastasis in A549 xenograft nude mice, in combination with a decrease in P62 level. These findings collectively suggest that reduction of cell proliferation and migration by PLC gamma 1 inhibition could be partially attributed to PLC gamma 1 inhibition-driven autophagic cell death (ACD). It highlights the potential role of a combination between targeting PLC gamma 1 and autophagy pathway in anti-tumor therapy, which may be an efficacious new strategy to overcome the autophagy addition of tumor and acquired resistance to current therapy.	[Lu, Xiaohong; Fu, Haijing; Chen, Rui; Zhan, Yanyan; Song, Gang; Hu, Tianhui; Zhang, Bing] Xiamen Univ, Canc Res Ctr, Sch Med, Fujian 361102, Peoples R China; [Wang, Yue; Xia, Chun] Xiamen Univ, Zhongshan Hosp, Xiamen 361004, Fujian, Peoples R China; [Tian, Xuemei] South China Normal Univ, Sch Life Sci, Guangzhou 510631, Guangdong, Peoples R China		Zhang, B (corresponding author), Xiamen Univ, Canc Res Ctr, Sch Med, Fujian 361102, Peoples R China.; Tian, XM (corresponding author), South China Normal Univ, Sch Life Sci, Guangzhou 510631, Guangdong, Peoples R China.	tianxuemei@m.scnu.edu.cn; cristal66@xmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81772533,81972091]	This study was funded by National Natural Science Foundation of China (No. 81772533,81972091). We would like to thank MS Jiqian Xia for statistical data analytics support.	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Z., 2016, COMPUTER MEASUREMENT, V6, P1; Zhuang LH, 2014, FOLIA HISTOCHEM CYTO, V52, P178, DOI 10.5603/FHC.2014.0021	51	5	5	2	8	IVYSPRING INT PUBL	LAKE HAVEN	PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA	1449-2288			INT J BIOL SCI	Int. J. Biol. Sci.		2020	16	8					1427	1440		10.7150/ijbs.42962			14	Biochemistry & Molecular Biology; Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics	KT5KW	WOS:000519054300011	32210730	Green Published, gold			2022-04-25	
J	Thorburn, A; Thamm, DH; Gustafson, DL				Thorburn, Andrew; Thamm, Douglas H.; Gustafson, Daniel L.			Autophagy and Cancer Therapy	MOLECULAR PHARMACOLOGY			English	Review							HISTONE DEACETYLASE INHIBITORS; CHEMOTHERAPY-INDUCED APOPTOSIS; ENDOPLASMIC-RETICULUM STRESS; INDUCED CELL-DEATH; TARGETING AUTOPHAGY; COLON-CANCER; INDUCED CYTOTOXICITY; MYELOMA CELLS; HMGB1 RELEASE; TUMOR-CELLS	Autophagy is the process by which cellular material is delivered to lysosomes for degradation and recycling. There are three different types of autophagy, but macroautophagy, which involves the formation of double membrane vesicles that engulf proteins and organelles that fuse with lysosomes, is by far the most studied and is thought to have important context-dependent roles in cancer development, progression, and treatment. The roles of autophagy in cancer treatment are complicated by two important discoveries over the past few years. First, most (perhaps all) anticancer drugs, as well as ionizing radiation, affect autophagy. In most, but not all cases, these treatments increase autophagy in tumor cells. Second, autophagy affects the ability of tumor cells to die after drug treatment, but the effect of autophagy may be to promote or inhibit cell death, depending on context. Here we discuss recent research related to autophagy and cancer therapy with a focus on how these processes may be manipulated to improve cancer therapy.	[Thorburn, Andrew] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA; [Thamm, Douglas H.; Gustafson, Daniel L.] Colorado State Univ, Flint Anim Canc Ctr, Dept Clin Sci, Ft Collins, CO 80523 USA		Thorburn, A (corresponding author), Univ Colorado, Sch Med, Dept Pharmacol, Anschutz Med Campus, Aurora, CO 80045 USA.	Andrew.Thorburn@ucdenver.edu	Thamm, Douglas/AAG-3672-2020; Thamm, Douglas H/I-5976-2013	Thamm, Douglas H/0000-0002-8914-7767	National Institutes of Health National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01-CA111421, R01-CA150925, P30-CA046934]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA046934, R01CA150925, R01CA111421] Funding Source: NIH RePORTER	This work was supported by grants from the National Institutes of Health National Cancer Institute [Grants R01-CA111421, R01-CA150925, and P30-CA046934].	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Pharmacol.	JUN	2014	85	6					830	838		10.1124/mol.114.091850			9	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	AH3QR	WOS:000336040400001	24574520	Green Published	Y	N	2022-04-25	
J	Azwar, S; Seow, HF; Abdullah, M; Jabar, MF; Mohtarrudin, N				Azwar, Shamin; Seow, Heng Fong; Abdullah, Maha; Jabar, Mohd Faisal; Mohtarrudin, Norhafizah			Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment	BIOLOGY-BASEL			English	Review						5-fluorouracil; 5-FU; chemotherapy drug resistance; colon cancer; thymidylate synthase; thymidine phosphorylase; dihydropyrimidine dehydrogenase; methylenetetrahydrofolate reductase; overcoming chemotherapy drug resistance	HUMAN COLORECTAL-CANCER; LONG NONCODING RNAS; DIHYDROPYRIMIDINE DEHYDROGENASE; THYMIDINE PHOSPHORYLASE; STEM-CELLS; THYMIDYLATE SYNTHASE; DRUG-RESISTANCE; 5-FU RESISTANCE; ADJUVANT CHEMOTHERAPY; ACQUIRED-RESISTANCE	Simple Summary Acquired resistance to chemotherapy by cancer cells is the predominant factor in chemotherapy failure, which ultimately leads to disease progression and death. Recent studies have presented compelling evidence of the various mechanisms and pathways through which cancer cells have developed resistance to drugs. This review summarises the mechanisms pertaining to 5-FU resistance and discusses ongoing efforts to prevent chemotherapy resistance in cancer cells and to re-sensitise them to cancer drugs. 5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient's overall survival.	[Azwar, Shamin; Seow, Heng Fong; Abdullah, Maha; Mohtarrudin, Norhafizah] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Pathol, Serdang 43400, Malaysia; [Jabar, Mohd Faisal] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Surg, Serdang 43400, Malaysia		Mohtarrudin, N (corresponding author), Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Pathol, Serdang 43400, Malaysia.	shamin.azwar@gmail.com; shf@upm.edu.my; maha@upm.edu.my; faisal@upm.edu.my; norhafizahm@upm.edu.my					Aggarwal V, 2019, BIOMOLECULES, V9, DOI 10.3390/biom9110735; Akasaka T, 2015, INT J ONCOL, V46, P63, DOI 10.3892/ijo.2014.2693; Al-Obeed O, 2020, CANCER CELL INT, V20, DOI 10.1186/s12935-020-01206-x; Alnuqaydan AM, 2020, AM J CANCER RES, V10, P799; Amstutz U, 2018, CLIN PHARMACOL THER, V103, P210, DOI 10.1002/cpt.911; An J, 2016, J MICROBIOL BIOTECHN, V26, P1490, DOI 10.4014/jmb.1605.05024; Andreucci E, 2019, J ENZYM INHIB MED CH, V34, P117, DOI 10.1080/14756366.2018.1532419; Angius A, 2019, INT J MED SCI, V16, P1480, DOI 10.7150/ijms.35269; 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J	Dai, S; Yang, S; Hu, X; Sun, W; Tawa, G; Zhu, WG; Schimmer, AD; He, C; Fang, BL; Zhu, HB; Zheng, W				Dai, Sheng; Yang, Shu; Hu, Xin; Sun, Wei; Tawa, Gregory; Zhu, Wenge; Schimmer, Aaron D.; He, Chao; Fang, Bingliang; Zhu, Hongbo; Zheng, Wei			17-Hydroxy Wortmannin Restores TRAIL's Response by Ameliorating Increased Beclin 1 Level and Autophagy Function in TRAIL-Resistant Colon Cancer Cells	MOLECULAR CANCER THERAPEUTICS			English	Article							ANTITUMOR-ACTIVITY; DOWN-REGULATION; TUMOR-CELL; APOPTOSIS; CASPASE-8; DEATH; EXPRESSION; INHIBITOR; MECHANISM; GENE	Targeting of extrinsic apoptosis pathway by TNF-related apoptosis-inducing ligand (TRAIL) is an attractive approach for cancer therapy. However, two TRAIL drug candidates failed in clinical trials due to lack of efficacy. We identified 17-hydroxy wortmannin (17-HW) in a drug repurposing screen that resensitized TRAIL'S response in the resistant colon cancer cells. The deficiency of caspase-8 in drug-resistant cells along with defects in apoptotic cell death was corrected by 17-HW, an inhibitor of PIK3C3-bedin 1 (BECN1) complex and autophagy activity. Further study found that BECN1 significantly increased in the TRAIL-resistant cells, resulting in increased autophagosome formation and enhanced autophagy flux. The extracellular domain (ECD) of BECN1 directly bound to the caspase-8 catalytic subunit (p10), leading to sequestration of caspase-8 in the autophagosome and its subsequent degradation. Inhibition of BECN1 restored the caspase-8 level and TRAIL's apoptotic response in the resistant colon cancer cells. An analysis of 120 colon cancer patient tissues revealed a correlation of a subgroup of patients (30.8%, 37/120) who have high BECN1 level and low caspase-8 level with a poor survival rate, Our study demonstrates that the increased BECN1 accompanied by enhanced autophagy activity is responsible for the TRAIL resistance, and a combination of TRAIL with a PIK3C3-BECN1 inhibitor is a promising therapeutic approach for the treatment of colon cancer.	[Dai, Sheng; He, Chao; Zhu, Hongbo] Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Dai, Sheng; Yang, Shu; Hu, Xin; Sun, Wei; Tawa, Gregory; Zheng, Wei] NCATS, NIH, 9800 Med Ctr Dr,MSC 3375, Bethesda, MD 20892 USA; [Zhu, Wenge] George Washington Univ, Med Sch, Dept Biochem & Mol Med, Washington, DC USA; [Schimmer, Aaron D.] Princess Margaret Canc Ctr, Toronto, ON, Canada; [Fang, Bingliang] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA		Dai, S (corresponding author), Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Hangzhou, Zhejiang, Peoples R China.; Dai, S; Zheng, W (corresponding author), NCATS, NIH, 9800 Med Ctr Dr,MSC 3375, Bethesda, MD 20892 USA.; Zhu, HB (corresponding author), Sir Run Run Shaw Hosp, Div Colorectal Surg, 3rd East Oingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.	daimd@zju.edu.cn; ykzhb@zju.edu.cn; wzheng@mail.nih.gov	dai, sheng/AGQ-0059-2022	Yang, Shu/0000-0001-8909-1962; Schimmer, Aaron/0000-0003-4023-3899; dai, sheng/0000-0002-5387-8517	Intramural Research Programs of the National Center for Advancing Translational Sciences, NIH; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81703076]; NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [ZIATR000018] Funding Source: NIH RePORTER	The authors thank the compound management group at NCATS, NIH for their professional support, and Dr. DeeAnn Visk, a medical writer and editor, for editing the manuscript. This work was supported by the Intramural Research Programs of the National Center for Advancing Translational Sciences, NIH (to W. Zheng), and a grant 81703076 from the National Natural Science Foundation of China (to D. Sheng).	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Cancer Ther.	JUL	2019	18	7					1265	1277		10.1158/1535-7163.MCT-18-1241			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	IG1FL	WOS:000473535800008	31092562	Green Accepted			2022-04-25	
J	Wong, ASL; Cheung, ZH; Ip, NY				Wong, Alan S. L.; Cheung, Zelda H.; Ip, Nancy Y.			Molecular machinery of macroautophagy and its deregulation in diseases	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE			English	Review						Autophagy; Autophagosome; Cdk5; Endophilin B1; Post-translational modification; Neurodegenerative disorder	INTERACTING FACTOR-I; CELL-DEATH; ALPHA-SYNUCLEIN; BECLIN 1; REGULATES AUTOPHAGY; AXONAL-TRANSPORT; COLON-CANCER; PINK1/PARKIN-MEDIATED MITOPHAGY; DECREASED EXPRESSION; PROTEIN AGGREGATION	Macroautophagy maintains cellular homeostasis through targeting cytoplasmic contents and organelles into autophagosomes for degradation. This process begins with the assembly of protein complexes on isolation membrane to initiate the formation of autophagosome, followed by its nucleation, elongation and maturation. Fusion of autophagosomes with lysosomes then leads to degradation of the cargo. In the past decade, significant advances have been made on the identification of molecular players that are implicated in various stages of macroautophagy. Post-translational modifications of macroautophagy regulators have also been demonstrated to be critical for the selective targeting of cytoplasmic contents into autophagosomes. In addition, recent demonstration of distinct macroautophagy regulators has led to the identification of different subtypes of macroautophagy. Since deregulation of macroautophagy is implicated in diseases including neurodegenerative disorders, cancers and inflammatory disorders, understanding the molecular machinery of macroautophagy is crucial for elucidating the mechanisms by which macroautophagy is deregulated in these diseases, thereby revealing new potential therapeutic targets and strategies. Here we summarize current knowledge on the regulation of mammalian macroautophagy machineries and their disease-associated deregulation. (C) 2011 Elsevier B.V. All rights reserved.	[Wong, Alan S. L.; Cheung, Zelda H.; Ip, Nancy Y.] Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Div Life Sci, Mol Neurosci Ctr, Kowloon, Hong Kong, Peoples R China		Ip, NY (corresponding author), Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Div Life Sci, Mol Neurosci Ctr, Kowloon, Hong Kong, Peoples R China.	boip@ust.hk	Cheung, Zelda Hiu Yee/C-1402-2012	Wong, Alan S.L./0000-0003-1790-3233; Ip, Nancy Yuk-Yu/0000-0002-2763-8907	Research Grants Council of Hong KongHong Kong Research Grants Council [HKUST 661007, 661109, 660309, 660210, 6/CRF/08]; University Grants Committee [AoE/B-15/01]; Hong Kong Jockey Club; Croucher Foundation	We apologize to authors whose work could not be discussed or cited due to space limitations. This work was supported in part by the Research Grants Council of Hong Kong (HKUST 661007, 661109, 660309, 660210, and 6/CRF/08), the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01) and the Hong Kong Jockey Club. N.Y.I. and Z.H.C were recipients of the Croucher Foundation Senior Research Fellow and Croucher Foundation Fellow respectively.	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Biophys. Acta-Mol. Basis Dis.	NOV	2011	1812	11					1490	1497		10.1016/j.bbadis.2011.07.005			8	Biochemistry & Molecular Biology; Biophysics; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics; Cell Biology	847DR	WOS:000296952600016	21787863	Bronze			2022-04-25	
J	Bednarczyk, M; Fatyga, E; Dziegielewska-Gesiak, S; Waniczek, D; Grabarek, B; Zmarzly, N; Janikowska, G; Muc-Wierzgon, M				Bednarczyk, Martyna; Fatyga, Edyta; Dziegielewska-Gesiak, Sylwia; Waniczek, Dariusz; Grabarek, Beniamin; Zmarzly, Nikola; Janikowska, Grazyna; Muc-Wierzgon, Malgorzata			The Expression Patterns of BECN1, LAMP2, and PINK1 Genes in Colorectal Cancer Are Potentially Regulated by Micrornas and CpG Islands: An In Silico Study	JOURNAL OF CLINICAL MEDICINE			English	Article						autophagy; colorectal cancer; expression genes; microRNAs (miRNAs); CpG islands	CHAPERONE-MEDIATED AUTOPHAGY; DNA METHYLATION; PROGNOSIS; DEGRADATION; MECHANISMS; SURVIVAL; GROWTH; MIRNA	Background: Autophagy plays a dual role of tumor suppression and tumor promotion in colorectal cancer. The study aimed to find those microRNAs (miRNAs) important in BECN1, LAMP2, and PINK1 regulation and to determine the possible role of the epigenetic changes in examined colorectal cancer using an in silico approach. Methods: A total of 44 pairs of surgically removed tumors at clinical stages I-IV and healthy samples (marginal tissues) from patients' guts were analyzed. Analysis of the obtained results was conducted using the PL-Grid Infrastructure and Statistica 12.0 program. The miRNAs and CpG islands were estimated using the microrna.org database and MethPrimer program. Results: The autophagy-related genes were shown to be able to be regulated by miRNAs (BECN1-49 mRNA, LAMP2-62 mRNA, PINK1-6 mRNA). It was observed that promotion regions containing at least one CpG region were present in the sequence of each gene. Conclusions: The in silico analysis performed allowed us to determine the possible role of epigenetic mechanisms of regulation gene expression, which may be an interesting therapeutic target in the treatment of colorectal cancer.	[Bednarczyk, Martyna; Fatyga, Edyta; Dziegielewska-Gesiak, Sylwia; Muc-Wierzgon, Malgorzata] Med Univ Silesia, Dept Internal Med, PL-40055 Katowice, Poland; [Waniczek, Dariusz] Med Univ Silesia, SHS Katowice, Chair Gen Colorectal & Polytrauma Surg, Dept Propedeut Surg, PL-40055 Katowice, Poland; [Grabarek, Beniamin; Zmarzly, Nikola] Univ Technol Katowice, Fac Med Zabrze, Dept Histol Cytophysiol & Embryol, PL-40055 Katowice, Poland; [Janikowska, Grazyna] Med Univ Silesia, Dept Analyt Chem, PL-40055 Katowice, Poland		Muc-Wierzgon, M (corresponding author), Med Univ Silesia, Dept Internal Med, PL-40055 Katowice, Poland.	martyna.bednarczyk@outlook.com; efatyga@sum.edu.pl; sgesiak@sum.edu.pl; dwaniczek@sum.edu.pl; bgrabarek7@gmail.com; nikola.zmarzly@gmail.com; grazynajanikowska@wp.pl; mwierzgon@sum.edu.pl	grabarek, beniamin/V-3630-2019	grabarek, beniamin/0000-0003-1633-7145; Muc-Wierzgon, Malgorzata/0000-0001-6562-7072; Janikowska, Grazyna/0000-0002-2839-174X; Bednarczyk, Martyna/0000-0001-8360-9126; Fatyga, Edyta/0000-0003-0389-206X; Zmarzly, Nikola/0000-0002-7833-6167; Waniczek, Dariusz/0000-0002-0410-8604; Dziegielewska-Gesiak, Sylwia/0000-0003-1019-5959	Medical University of Silesia Agreement [KNW-1-072/K/9/K]	Supported by grants from Medical University of Silesia Agreement (no. KNW-1-072/K/9/K).	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Clin. Med.	DEC	2020	9	12							4020	10.3390/jcm9124020			10	Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	General & Internal Medicine	PJ9SC	WOS:000602096600001	33322704	gold, Green Published			2022-04-25	
J	Zhao, YT; Shi, L; Hu, CL; Sang, SM				Zhao, Yantao; Shi, Lei; Hu, Changling; Sang, Shengmin			Wheat Bran for Colon Cancer Prevention: The Synergy between Phytochemical Alkylresorcinol C21 and Intestinal Microbial Metabolite Butyrate	JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY			English	Article						colorectal cancer; wheat bran; alkylresorcinols; butyrate; synergy	CHAIN FATTY-ACIDS; ENDOPLASMIC-RETICULUM STRESS; DIETARY FIBER INTAKE; COLORECTAL-CANCER; CELL-GROWTH; APOPTOSIS; AUTOPHAGY; NUTRIENTS; PATHWAY; ADENOMA	There is convincing evidence that consuming whole grains (WGs) may decrease the risk of colorectal cancer (CRC). Wheat bran (WB) is a rich source of dietary fiber and phytochemicals with health-promoting properties. However, the active components especially the interaction between different components in WG wheat have not been fully explored. Here, we investigated whether one of the major WB phytochemicals, alkylresorcinol (AR) C21, and the major active intestinal microbial metabolite of fiber, butyrate, could synergistically suppress human colon cancer cells. Our results demonstrated for the first time that the combination of C21 and butyrate synergistically inhibited the growth of human colon cancer cells and induced apoptosis. Further mechanistic studies demonstrated that the cotreatment of C21 and butyrate induced significant upregulations in cleaved Poly(ADP-ribose) polymerase (PARP), cleaved caspase 3, p53 upregulated modulator of apoptosis (PUMA), cytochrome C, lipid-conjugated membrane-bound form of microtubule-associated protein 1A/1B-light chain 3 (LC3-II), and C/EBP homologous protein (CHOP) expressions, indicating the synergistic anticancer effects of C21 and butyrate were associated with induction of apoptosis, autophagy, and ER stress pathways. Notably, the C21 concentrations in the large intestinal tract of mice treated with human relevant doses of C21, were from 0.86 to 1.78 mu mol/g, suggesting the C21 doses used in vitro may be achievable after daily WG wheat intake. These results provide novel insights into the dietary prevention of CRC regarding the potential interaction of bioactive WG wheat phytochemicals and the microbial metabolites of fiber.	[Zhao, Yantao; Shi, Lei; Hu, Changling; Sang, Shengmin] North Carolina Agr & Tech State Univ, Ctr Excellence Postharvest Technol, Lab Funct Foods & Human Hlth, North Carolina Res Campus,500 Laureate Way, Kannapolis, NC 28081 USA; [Shi, Lei] Ningxia Med Univ, Gen Hosp, Dept Colorectal Surg, Yinchuan 750004, Peoples R China		Sang, SM (corresponding author), North Carolina Agr & Tech State Univ, Ctr Excellence Postharvest Technol, Lab Funct Foods & Human Hlth, North Carolina Res Campus,500 Laureate Way, Kannapolis, NC 28081 USA.	ssang@ncat.edu		Sang, Shengmin/0000-0002-5005-3616	United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) R01 grant [2018-67001-28265]	This work was supported by funding from The United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) R01 grant 2018-67001-28265 to S.S.	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Agric. Food Chem.	NOV 20	2019	67	46					12761	12769		10.1021/acs.jafc.9b05666			9	Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Agriculture; Chemistry; Food Science & Technology	JR6OX	WOS:000499743400017	31675233				2022-04-25	
J	Zhao, YL; Fan, DM; Ru, BB; Cheng, KW; Hu, ST; Zhang, JW; Li, ETS; Wang, MF				Zhao, Yueliang; Fan, Daming; Ru, Beibei; Cheng, Ka-Wing; Hu, Shuting; Zhang, Jiangwen; Li, Edmund T. S.; Wang, Mingfu			6-C-(E-phenylethenyl)naringenin induces cell growth inhibition and cytoprotective autophagy in colon cancer cells	EUROPEAN JOURNAL OF CANCER			English	Article						6-CEPN; Anticancer; Colon cancer; RAS	RAS; DEATH; MODULATION; SIGNATURE; APOPTOSIS; PATHWAYS; PROTEIN	6-C-(E-phenylethenyl) naringenin (6-CEPN) is a small molecule found in naringenin fortified fried beef. It has been shown to suppress colon cancer cell proliferation, but the underlying mechanisms are not fully understood. Here we demonstrate that 6-CEPN suppresses tumour cell proliferation through cell cycle arrest in G(1) phase, induces necrotic cell death and autophagy in colon cancer cells. Blockade of autophagy by knockdown of the essential autophagy proteins, Atg7 or beclin-1, resulted in aggravated cell death in response to 6-CEPN treatment. In addition, genome-wide transcriptome expression profiling by RNA-sequencing revealed that 6-CEPN-mediated gene expression pattern was extremely similar to the transcriptome response induced by a RAS inhibitor salirasib (farnesylthiosalicylic acid [FTS; salirasib]). Subsequent molecular biological and biochemical experiments demonstrated that 6-CEPN indeed strongly inhibited RAS activation, leading to the inhibition of the downstream effector pathways c-Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase kinase and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin. More importantly, our computational molecular docking data showed that 6-CEPN could bind to the active site of isoprenylcysteine carboxyl methyltransferase (Icmt), a critical enzyme for the activation of RAS. Icmt activity assay showed that 6-CEPN inhibited its activity significantly. Knockdown of Icmt bysiRNA attenuated 6-CEPN-mediated autophagy and cell death. The present study demonstrates that 6-CEPN induces cell growth inhibition and cytoprotective autophagy in colon cancer cells, at least in part, though inhibition of the Icmt/RAS signalling pathways. (C) 2016 Elsevier Ltd. All rights reserved.	[Zhao, Yueliang; Fan, Daming; Ru, Beibei; Hu, Shuting; Zhang, Jiangwen; Li, Edmund T. S.; Wang, Mingfu] Univ Hong Kong, Sch Biol Sci, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China; [Cheng, Ka-Wing] Peking Univ, Coll Engn, Beijing, 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	Ru, Beibei/F-3830-2011; Zhang, Jiangwen/A-7654-2013; Cheng, Ka Wing/V-9433-2019; Wang, Mingfu/D-3136-2009; Wang, Mingfu/AAT-3292-2021	Zhang, Jiangwen/0000-0002-2911-8446; Wang, Mingfu/0000-0003-1469-3963; Cheng, Ka Wing/0000-0002-1201-312X; Fan, Daming/0000-0002-4907-9034			Baines AT, 2011, FUTURE MED CHEM, V3, P1787, DOI [10.4155/fmc.11.121, 10.4155/FMC.11.121]; Bharate SB, 2012, CURR MED CHEM, V19, P2273; Blum R, 2005, DRUG RESIST UPDATE, V8, P369, DOI 10.1016/j.drup.2005.11.002; Blum R, 2007, CANCER RES, V67, P3320, DOI 10.1158/0008-5472.CAN-06-4287; Bournet B, 2016, EUR J CANCER, V54, P75, DOI 10.1016/j.ejca.2015.11.012; Carew JS, 2007, AUTOPHAGY, V3, P464, DOI 10.4161/auto.4311; Cavaliere V, 2014, EUR J CANCER, V50, P3243, DOI 10.1016/j.ejca.2014.09.012; Chapnick DA, 2011, CELL BIOSCI, V1, DOI 10.1186/2045-3701-1-42; Cheng K.Y., 2009, THESIS; Cheng KW, 2008, CHEM RES TOXICOL, V21, P2026, DOI 10.1021/tx800220h; Coffelt SB, 2015, NATURE, V522, P345, DOI 10.1038/nature14282; Downward J, 2003, NAT REV CANCER, V3, P11, DOI 10.1038/nrc969; Gao JH, 2009, AM J TRANSL RES, V1, P312; Hashimoto I, 2008, EUR J CANCER, V44, P1022, DOI 10.1016/j.ejca.2008.02.043; Hoyer-Hansen M, 2008, AUTOPHAGY, V4, P574, DOI 10.4161/auto.5921; Kanaan Z, 2012, ANN SURG, V256, P544, DOI 10.1097/SLA.0b013e318265bd6f; Kondo Y, 2006, AUTOPHAGY, V2, P85, DOI 10.4161/auto.2.2.2463; Kramer K, 2003, MOL BIOL CELL, V14, P848, DOI 10.1091/mbc.E02-07-0390; Law CW, 2014, GENOME BIOL, V15, DOI 10.1186/gb-2014-15-2-r29; Liao Y, 2014, BIOINFORMATICS, V30, P923, DOI 10.1093/bioinformatics/btt656; Liao Y, 2013, NUCLEIC ACIDS RES, V41, DOI 10.1093/nar/gkt214; Morishima N, 1999, GENES CELLS, V4, P401, DOI 10.1046/j.1365-2443.1999.00270.x; Ritchie ME, 2015, NUCLEIC ACIDS RES, V43, DOI 10.1093/nar/gkv007; Roberts PJ, 2007, ONCOGENE, V26, P3291, DOI 10.1038/sj.onc.1210422; Salyan MEK, 2006, ANAL BIOCHEM, V349, P112, DOI 10.1016/j.ab.2005.10.040; Sawyers CL, 2003, CANCER CELL, V4, P343, DOI 10.1016/S1535-6108(03)00275-7; Schmukler E, 2014, ONCOTARGET, V5, P577, DOI 10.18632/oncotarget.1775; Schmukler E, 2013, ONCOTARGET, V4, P145; Schreck R, 2006, INT J CANCER, V119, P2261, DOI 10.1002/ijc.22144; Shi W, 2015, NAT IMMUNOL, V16, P663, DOI 10.1038/ni.3154; Spiegel J, 2014, NAT CHEM BIOL, V10, P613, DOI 10.1038/nchembio.1560; Wang M, 2010, ONCOGENE, V29, P4959, DOI 10.1038/onc.2010.247; Wang M, 2008, J BIOL CHEM, V283, P18678, DOI 10.1074/jbc.M801855200; Wu WKK, 2010, AUTOPHAGY, V6, P228, DOI 10.4161/auto.6.2.11042; Yaari S, 2005, CLIN CANCER RES, V11, P4321, DOI 10.1158/1078-0432.CCR-04-2071; Zhang N, 2010, AUTOPHAGY, V6, P1157, DOI 10.4161/auto.6.8.13614; Zundelevich A, 2007, MOL CANCER THER, V6, P1765, DOI 10.1158/1535-7163.MCT-06-0706	37	24	24	1	31	ELSEVIER SCI LTD	OXFORD	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND	0959-8049	1879-0852		EUR J CANCER	Eur. J. Cancer	NOV	2016	68						38	50		10.1016/j.ejca.2016.09.001			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EC0SS	WOS:000387811600005	27710830				2022-04-25	
J	Jo, YK; Kim, SC; Park, IJ; Park, SJ; Jin, DH; Hong, SW; Cho, DH; Kim, JC				Jo, Yoon Kyung; Kim, Seung Cheol; Park, In Ja; Park, So Jung; Jin, Dong-Hoon; Hong, Seung-Woo; Cho, Dong-Hyung; Kim, Jin Cheon			Increased Expression of ATG10 in Colorectal Cancer Is Associated with Lymphovascular Invasion and Lymph Node Metastasis	PLOS ONE			English	Article							UBIQUITIN-CONJUGATING ENZYME; METABOLIC STRESS; GASTRIC-CANCER; BREAST-CANCER; CELL-SURVIVAL; RECTAL-CANCER; AUTOPHAGY; TUMORIGENESIS; MACROAUTOPHAGY; DISEASE	Background: Autophagy has paradoxical and complex functions in cancer development, and autophagy-related genes (ATG) are key regulators in autophagy. Until now, more than 30 different ATG proteins have been identified in yeast, and their mammalian counterparts also have been reported. Although the roles of a few ATG proteins in cancer have been characterized, the role of ATG10 is almost completely unknown. Methodology/Principal Findings: To investigate the clinicopathological role of ATG10 in colorectal cancer, we analyzed ATG10 expression in colorectal cancer tissues and cell lines. Protein expression analysis showed that ATG10 is highly increased in colorectal cancer (tissue - 18/37 cases, 48%; cell line - 8/12 cell lines, 66%). Immunohistochemical analysis with clinicopathological features indicated a strong association of the up-regulation of ATG10 with tumor lymph node metastasis (p = 0.005) and invasion (p<0.001). Moreover, both 5-year disease free survival and overall survival rates of patients bearing tumors that did not express ATG10 were significantly higher than those of patients bearing ATG10-expressing tumors (p = 0.012). Conclusion/Significance: Increased expression of ATG10 in colorectal cancer is associated with lymphovascular invasion and lymph node metastasis indicating that ATG10 may be a potential prognostic maker in colorectal cancer.	[Jo, Yoon Kyung; Park, So Jung; Cho, Dong-Hyung] Kyung Hee Univ, Grad Sch EW Med Sci, Gyeonggi Do, South Korea; [Jo, Yoon Kyung; Kim, Seung Cheol; Jin, Dong-Hoon; Hong, Seung-Woo; Kim, Jin Cheon] Asan Med Ctr, Inst Innovat Canc Res, Seoul, South Korea; [Kim, Seung Cheol; Park, In Ja; Kim, Jin Cheon] Univ Ulsan, Dept Surg, Coll Med, Seoul, South Korea; [Jin, Dong-Hoon; Hong, Seung-Woo] Univ Ulsan, Dept Oncol, Coll Med, Seoul, South Korea		Cho, DH (corresponding author), Kyung Hee Univ, Grad Sch EW Med Sci, Gyeonggi Do, South Korea.	dhcho@khu.ac.kr; jckim@amc.seoul.kr	Park, In Ja/U-2371-2019	Park, In Ja/0000-0001-5355-3969	Center for Development and Commercialization of Anti-Cancer Therapeutics; Korean Health 21 RD Project [A062254, A102059]; Ministry of Health, Welfare and Family Affairs, KoreaMinistry of Health & Welfare, Republic of Korea; Asan Institute for Life Sciences [2011-069]; Basic Science Research Program (the National Research Foundation, Korea) [2010-0009164]	This work was supported by the Center for Development and Commercialization of Anti-Cancer Therapeutics and the Korean Health 21 R&D Project (A062254 and A102059, Ministry of Health, Welfare and Family Affairs, Korea), the Asan Institute for Life Sciences (2011-069), and the Basic Science Research Program (2010-0009164, the National Research Foundation, 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	Kim, SY; Yi, HK; Yun, BS; Lee, DY; Hwang, PH; Park, HR; Kim, MS				Kim, Sun-Young; Yi, Ho-Keun; Yun, Bong-Sik; Lee, Dae-Yeol; Hwang, Pyung Han; Park, Hae-Ryong; Kim, Min Sun			The extract of the immature fruit of Poncirus trifoliata induces apoptosis in colorectal cancer cells via mitochondrial autophagy	FOOD SCIENCE AND HUMAN WELLNESS			English	Article						Anticancer; Autophagy; Apoptosis; Mitochondria; Poncirus trifoliata	GROWTH-INHIBITION; SIGNALING PATHWAY; IN-VITRO; PROLIFERATION; CYTOTOXICITY; MACHINERY; CT26	The immature fruits of Poncirus trifoliate are used as a medicine for the treatment of gastrointestinal disorders, inflammation, and allergies in East Asia. However, their effect on colon cancer cells remains unclear. We investigated the effect of the immature fruit of P. trifoliate extract on colorectal adenocarcinoma. The extract of the immature fruit of P. trifoliata inhibited the proliferation of CT-26 cells compared with untreated cells and it induced autophagy and apoptosis through the protein kinase B/mammalian target of rapamycin and 5'-AMP-activated protein kinase pathways. The number of autophagic vacuoles and autophage markers increased in response to the extract. At later time-points, apoptosis increased dose/time-dependently. In CT-26 cells pre-treated a pan-caspase inhibitor prior to P. trifoliata immature fruit extract treatment, we did not find any change in pro-caspase 3 and pro-PARP levels. Additionally, in cells pre-treated autphage inhibitor, SQSTM1/p62 and LC3AB, pro-caspase 3 and pro-PARP levels did not change. Our results indicate the molecular mechanisms that the extract of the immature fruit of P. trifoliata induces apoptosis in colorectal carcinoma cells by inducing mitochondrial autophagy. In this study, we provided a draft for further investigate the use of MEPT for colorectal cancer inhibition. (c) 2020 "Society information". Production and hosting by Elsevier B.V. on behalf of KeAiCommunications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).	[Kim, Sun-Young; Lee, Dae-Yeol; Hwang, Pyung Han; Kim, Min Sun] Jeonbuk Natl Univ, Jeonbuk Natl Univ Hosp, Biomed Res Inst, Res Inst Clin Med, Jeonju 54907, South Korea; [Yi, Ho-Keun] Jeonbuk Natl Univ, Sch Dent, Inst Oral Biosci, Dept Oral Biochem, Jeonju 54907, South Korea; [Yun, Bong-Sik] Jeonbuk Natl Univ, Div Biotechnol, Iksan Si 54596, South Korea; [Yun, Bong-Sik] Jeonbuk Natl Univ, Adv Inst Environm & Biosci, Iksan Si 54596, South Korea; [Lee, Dae-Yeol; Hwang, Pyung Han; Kim, Min Sun] Jeonbuk Natl Univ, Dept Pediat, Med Sch, Jeonju 54907, South Korea; [Park, Hae-Ryong] Kyungnam Univ, Dept Food Sci & Biotechnol, Changwon Si 51767, South Korea		Kim, MS (corresponding author), Jeonbuk Natl Univ Hosp, Dept Pediat, 20 Baekje Daero, Jeonju Si 54907, Jeollabuk Do, South Korea.	children@jbnu.ac.kr	Kim, Minsun/ACB-3423-2022		Fund of Biomedical Research Institute, Jeonbuk National University Hospital	This work was supported by Fund of Biomedical Research Institute, Jeonbuk National University Hospital.	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Human Wellness	SEP	2020	9	3					237	244		10.1016/j.fshw.2020.05.001			8	Food Science & Technology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology; Nutrition & Dietetics	NX8KT	WOS:000575953600004		gold			2022-04-25	
J	Lv, L; Liu, HG; Dong, SY; Yang, F; Wang, QX; Guo, GL; Pan, YF; Zhang, XH				Lv, Lin; Liu, Hai-Guang; Dong, Si-Yang; Yang, Fan; Wang, Qing-Xuan; Guo, Gui-Long; Pan, Yi-Fei; Zhang, Xiao-Hua			Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells	TUMOR BIOLOGY			English	Article						CD44v6; Colorectal cancer; Chemoresistance; Autophagy	COLORECTAL-CANCER; DRUG-RESISTANCE; NEOADJUVANT CHEMOTHERAPY; PROTEIN EXPRESSION; PROGNOSTIC IMPACT; STEM-CELLS; VARIANT 6; BECLIN 1; 5-FLUOROURACIL; METASTASIS	The CD44 isoform containing variant exon v6 (CD44v6) plays an important role in the progression, metastasis, and prognosis of colorectal cancer (CRC). Recently, it was found that CD44v6 is involved in acquired drug resistance. This study aimed to investigate the molecular mechanism of CD44v6 in the resistance of CRC cells to chemotherapy. A stable CD44v6 overexpression model in SW480 cells was established via lentiviral transduction. The chemosensitivity of cells to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) was determined by cell counting kit (CCK)-8, lactate dehydrogenase (LDH) release, and colony formation assays. Immunohistochemical staining of CD44v6 was performed in human CRC tissues. The key components in cell apoptosis, drug efflux and metabolism, mismatch repair, autophagy, epithelial-mesenchymal transition (EMT), and the PI3K-Akt and MAPK-Ras-Erk1/2 pathways were assessed using flow cytometry, quantitative real-time polymerase chain reaction (PCR), and western blot assays. The CD44v6 overexpression cells showed a higher viability, a lower LDH release rate, and an increased clonogenicity than the control cells under drug treatment. Moreover, overexpression of CD44v6 resulted in enhanced autophagy flux, EMT, and phosphorylation of Akt and Erk in the presence of drugs. Furthermore, high CD44v6 expression in the primary tumor was closely associated with an early recurrence in CRC patients who underwent curative surgery and adjuvant chemotherapy. In conclusion, overexpression of CD44v6 contributes to chemoresistance in SW480 cells under cytotoxic stress via the modulation of autophagy, EMT, and activation of the PI3K-Akt and MAPK-Ras-Erk pathways.	[Lv, Lin; Liu, Hai-Guang; Dong, Si-Yang; Yang, Fan; Wang, Qing-Xuan; Guo, Gui-Long; Pan, Yi-Fei; Zhang, Xiao-Hua] Wenzhou Med Univ, Dept Oncol, Affiliated Hosp 1, Wenzhou 325000, Peoples R China		Zhang, XH (corresponding author), Wenzhou Med Univ, Dept Oncol, Affiliated Hosp 1, Wenzhou 325000, Peoples R China.	zhangxhoncology@163.com	Pan, Yi/AAJ-2341-2021		Science Foundation from the Health Bureau of Wenzhou City of Zhejiang, China [Y20140713]; First Affiliated Hospital of Wenzhou Medical University [FHY2014013]	This work was supported by the Science Foundation from the Health Bureau of Wenzhou City of Zhejiang, China (Y20140713) and by the Incubation Program from The First Affiliated Hospital of Wenzhou Medical University (FHY2014013).	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JUL	2016	37	7					8811	8824		10.1007/s13277-015-4755-6			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	DU4HU	WOS:000382174500032	26747179				2022-04-25	
J	Yu, HL; Huang, Y; Ge, YM; Hong, XP; Lin, X; Tang, KX; Wang, Q; Yang, Y; Sun, WM; Huang, YQ; Luo, H				Yu, Hailing; Huang, Yin; Ge, Yanming; Hong, Xiaopeng; Lin, Xi; Tang, Kexin; Wang, Qiang; Yang, Yang; Sun, Weiming; Huang, Yongquan; Luo, Hui			Selenite-induced ROS/AMPK/FoxO3a/GABARAPL-1 signaling pathway modulates autophagy that antagonize apoptosis in colorectal cancer cells	DISCOVER ONCOLOGY			English	Article						AMPK; Apoptosis; Autophagy; FoxO3a; Selenite	SWITCHES AUTOPHAGY; MEDIATED CLEAVAGE; AMPK; DEGRADATION; INHIBITION; ACTIVATION; AMBRA1; FLUX	Previous studies have shown that selenium possessed chemotherapeutic effect against multiple malignant cancers, inducing diverse stress responses including apoptosis and autophagy. Selenite was previously shown to induce apoptosis and autophagy in colorectal cancer cells. However, the relationship between selenite-induced apoptosis and autophagy was not fully understood. Our results revealed a pro-survival role of selenite-induced autophagy against apoptosis in colorectal cancer cells. Real-time PCR array of autophagy-related genes showed that GABARAPL-1 was significantly upregulated in colorectal cancer cells, which was confirmed by western blot and immunofluorescence results. Knockdown of GABARAPL-1 significantly inhibited selenite-induced autophagy and enhanced apoptosis. Furthermore, we found that selenite-induced upregulation of GABARAPL-1 was caused by upregulated p-AMPK and FoxO3a level. Their interaction was correlated with involved in regulation of GABARAPL-1. We observed that activation and inhibition of AMPK influenced both autophagy and apoptosis level via FoxO3a/ GABARAPL-1 signaling, implying the pro-survival role of autophagy against apoptosis. Importantly, we corroborated these findings in a colorectal cancer xenograft animal model with immunohistochemistry and western blot results. Collectively, these results show that sodium selenite could induce ROS/AMPK/FoxO3a/GABARAPL-1-mediated autophagy and downregulate apoptosis in both colorectal cancer cells and colon xenograft model. These findings help to explore sodium selenite as a potential anti-cancer drug in clinical practices.	[Yu, Hailing; Lin, Xi; Tang, Kexin; Sun, Weiming; Luo, Hui] Sun Yat Sen Univ, Affiliated Hosp 5, Guangdong Prov Key Lab Biomed Imaging, 52 Meihua Dong Rd, Zhuhai, Guangdong, Peoples R China; [Yu, Hailing; Lin, Xi; Tang, Kexin; Sun, Weiming; Luo, Hui] Sun Yat Sen Univ, Affiliated Hosp 5, Guangdong Prov Engn Res Ctr Mol Imaging, 52 Meihua Dong Rd, Zhuhai, Guangdong, Peoples R China; [Wang, Qiang] Chongqing Jiaotong Univ, Green Aerotech Res Inst, Chongqing, Peoples R China; [Huang, Yin] Sun Yat Sen Univ, Affiliated Hosp 5, Dept Cardiol, Zhuhai, Guangdong, Peoples R China; [Ge, Yanming] Sun Yat Sen Univ, Affiliated Hosp 5, Dept Pharm, Zhuhai, Guangdong, Peoples R China; [Hong, Xiaopeng] Sun Yat Sen Univ, Affiliated Hosp 5, Dept Hepatobiliary Surg, Zhuhai, Guangdong, Peoples R China; [Yang, Yang] Peking Union Med Coll, Inst Basic Med Sci, Beijing, Peoples R China; [Huang, Yongquan] Sun Yat Sen Univ, Affiliated Hosp 5, Dept Ultrasound, 52 Meihua Dong Rd, Zhuhai, Guangdong, Peoples R China		Luo, H (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 5, Guangdong Prov Key Lab Biomed Imaging, 52 Meihua Dong Rd, Zhuhai, Guangdong, Peoples R China.; Luo, H (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 5, Guangdong Prov Engn Res Ctr Mol Imaging, 52 Meihua Dong Rd, Zhuhai, Guangdong, Peoples R China.; Huang, YQ (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 5, Dept Ultrasound, 52 Meihua Dong Rd, Zhuhai, Guangdong, Peoples R China.	huangyq39@mail.sysu.edu.cn; luoh53@mail.sysu.edu.cn			Guangdong Basic and Applied Basic Research Foundation [2015A030310479, 2020A1515011001]; Guangdong Basic and Applied Basic Research Fund Regional Joint Fund-Youth Fund Project [2019A1515110457]	This work was supported by the Guangdong Basic and Applied Basic Research Foundation (2015A030310479 and 2020A1515011001), the Guangdong Basic and Applied Basic Research Fund Regional Joint Fund-Youth Fund Project (2019A1515110457).	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Oncol.	SEP 24	2021	12	1							35	10.1007/s12672-021-00427-4			12	Oncology; Endocrinology & Metabolism	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Endocrinology & Metabolism	UU6ZX	WOS:000698946700001	35201430	gold, Green Published			2022-04-25	
J	Hu, FQ; Li, G; Huang, CS; Hou, ZL; Yang, X; Luo, XL; Feng, YD; Wang, GH; Hu, JB; Cao, ZX				Hu, Fuqing; Li, Geng; Huang, Changsheng; Hou, Zhenlin; Yang, Xi; Luo, Xuelai; Feng, Yongdong; Wang, Guihua; Hu, Junbo; Cao, Zhixin			The autophagy-independent role of BECN1 in colorectal cancer metastasis through regulating STAT3 signaling pathway activation	CELL DEATH & DISEASE			English	Article							BECLIN 1; BREAST-CANCER; CELL-SURVIVAL; PROMOTES; TUMORIGENESIS; EXPRESSION; PHOSPHORYLATION; INHIBITION; PHENOTYPE; GROWTH	BECN1 is a critical regulator of autophagy, which plays important roles in tumor formation and metastasis. However, the autophagy-independent role of BECN1 and the clinical prediction value of BECN1 still need to be explored. Here, we observed significantly lower expression of BECN1 in colorectal cancers (CRCs) compared with adjacent normal colon tissue, and downregulation of BECN1 was positively related to poor prognosis in CRC patients. In addition, we found that knockdown of BECN1 markedly promoted CRC cell motility and invasion. Bioinformatics gene set enrichment analysis (GSEA) revealed that low levels of BECN1 were significantly correlated with the STAT3 signaling pathway in CRC. Consistently, knockdown of BECN1 increased the phosphorylation of STAT3 and activated the STAT3 signaling pathway in CRC cells. Furthermore, we demonstrated that STAT3 was involved in the CRC metastasis mediated by knockdown of BECN1 in vitro and in vivo. Mechanistically, knockdown of BECN1 promoted the phosphorylation of STAT3 via regulation of the interaction between STAT and JAK2 but did not inhibit autophagy. Our study revealed that BECN1 served as a negative regulator of CRC metastasis by regulating STAT3 signaling pathway activation in an autophagy-independent manner. The BECN1/JAK2/STAT3 signaling pathway can be used as a potential therapeutic target for metastatic CRC.	[Hu, Fuqing; Li, Geng; Huang, Changsheng; Hou, Zhenlin; Yang, Xi; Luo, Xuelai; Feng, Yongdong; Wang, Guihua; Hu, Junbo; Cao, Zhixin] Huazhong Univ Sci & Technol, Dept Gastrointestinal Surg Ctr, Tongji Med Coll, Tongji Hosp, Wuhan 430030, Hubei, Peoples R China		Hu, JB; Cao, ZX (corresponding author), Huazhong Univ Sci & Technol, Dept Gastrointestinal Surg Ctr, Tongji Med Coll, Tongji Hosp, Wuhan 430030, Hubei, Peoples R China.	jbhu@tjh.tjmu.edu.cn; zxcao@tjh.tjmu.edu.cn			NSFCNational Natural Science Foundation of China (NSFC) [81572725, 81802426, 81874186, 81570525]; `973' programNational Basic Research Program of China [2015CB553903-1]	We are grateful to the members of Guihua Wang's lab and Junbo Hu's lab for their critical input and suggestions. This work is supported by NSFC (No. 81572725, No. 81802426, No. 81874186, and No. 81570525) and the `973' program (No. 2015CB553903-1).	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MAY 1	2020	11	5							304	10.1038/s41419-020-2467-3			13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	LL1IP	WOS:000531309100002	32358527	Green Published, gold			2022-04-25	
J	Baliou, S; Goulielmaki, M; Ioannou, P; Cheimonidi, C; Trougakos, IP; Nagl, M; Kyriakopoulos, AM; Zoumpourlis, V				Baliou, Stella; Goulielmaki, Maria; Ioannou, Petros; Cheimonidi, Christina; Trougakos, Ioannis P.; Nagl, Markus; Kyriakopoulos, Anthony M.; Zoumpourlis, Vassilis			Bromamine T (BAT) Exerts Stronger Anti-Cancer Properties than Taurine (Tau)	CANCERS			English	Article						bromamine T; taurine; colon cancer; breast cancer		Simple Summary Taurine (Tau) has been shown to inhibit cancer growth. However, the mechanisms that underlie the growth-inhibitory effects of Tau remain obscure in both colon and breast cancer. In parallel, N-bromotaurine (TauNHBr) and a stable active bromine molecule, bromamine T (BAT), appear to exert strong anti-inflammatory effects. To our knowledge, this is the first study that evaluates the anti-cancer effects of BAT and its underlying mechanisms. To gain a comprehensive picture of the cytotoxic effect of BAT on colon and breast cancer, we compared its effect with that of Tau. Our data support that BAT exerts a superior anti-cancer effect than Tau, through the induction of cell death, probably due to the activation of distinct mitogen-activated protein kinase (MAPK) family members. Interestingly, BAT inhibits colon carcinogenesis in vivo to a greater extent than Tau. Our data significantly add to the use of BAT as a novel therapeutic modality in colon and breast cancer. Background: Taurine (Tau) ameliorates cancer pathogenesis. Researchers have focused on the functional properties of bromamine T (BAT), a stable active bromine molecule. Both N-bromotaurine (TauNHBr) and BAT exert potent anti-inflammatory properties, but the landscape remains obscure concerning the anti-cancer effect of BAT. Methods: We used Crystal Violet, colony formation, flow cytometry and Western blot experiments to evaluate the effect of BAT and Tau on the apoptosis and autophagy of cancer cells. Xenograft experiments were used to determine the in vivo cytotoxicity of either agent. Results: We demonstrated that both BAT and Tau inhibited the growth of human colon, breast, cervical and skin cancer cell lines. Among them, BAT exerted the greatest cytotoxic effect on both RKO and MDA-MB-468 cells. In particular, BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK1/2), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK1/2), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. In contrast, Tau exerted its cytotoxic effect by upregulating JNK1/2 forms, thus triggering mitochondrial apoptosis in RKO cells. Accordingly, colon cancer growth was impaired in vivo. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities.	[Baliou, Stella; Goulielmaki, Maria; Zoumpourlis, Vassilis] Natl Hellen Res Fdn, Inst Chem Biol, Biomed Applicat Unit, 48 Vas Constantinou Ave, Athens 11635, Greece; [Ioannou, Petros] Univ Hosp Heraklion, Dept Internal Med & Infect Dis, Iraklion 71110, Crete, Greece; [Cheimonidi, Christina; Trougakos, Ioannis P.] Natl & Kapodistrian Univ Athens, Fac Biol, Dept Cell Biol & Biophys, Athens 15784, Greece; [Nagl, Markus] Med Univ Innsbruck, Inst Hyg & Med Microbiol, Dept Hyg Microbiol & Publ Hlth, A-6020 Innsbruck, Austria; [Kyriakopoulos, Anthony M.] Nasco AD Biotechnol Lab, Dept Res & Dev, 11 Sachtouri Str, Piraeus 18536, Greece		Zoumpourlis, V (corresponding author), Natl Hellen Res Fdn, Inst Chem Biol, Biomed Applicat Unit, 48 Vas Constantinou Ave, Athens 11635, Greece.	smpaliou@eie.gr; mgoulielmaki@eie.gr; p.ioannou@med.uoc.gr; chrischeim@biol.uoa.gr; itrougakos@biol.uoa.gr; m.nagl@i-med.ac.at; antkyriak@gmail.com; vzub@eie.gr	; Trougakos, Ioannis/R-6149-2018	Ioannou, Petros/0000-0003-1082-5674; Nagl, Markus/0000-0002-1225-9349; Trougakos, Ioannis/0000-0002-6179-2772	I.K.Y. State Scholarship Foundation for S. Baliou's Ph.D. studies [2018-050-0502-13155]	This research was supported by I.K.Y. State Scholarship Foundation for S. Baliou's Ph.D. studies. The IKY code is 2018-050-0502-13155.	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J	Kim, YJ; Kang, KS; Choi, KC; Ko, H				Kim, Young-Joo; Kang, Ki Sung; Choi, Kyung-Chul; Ko, Hyeonseok			Cardamonin induces autophagy and an antiproliferative effect through JNK activation in human colorectal carcinoma HCT116 cells	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS			English	Article						Cardamonin; Autophagy; Antiproliferation; Colorectal carcinoma; p53; c-Jun N-terminal kinase (JNK)	MEDIATED UP-REGULATION; INDUCED APOPTOSIS; DOWN-REGULATION; DEATH; INHIBITION; INDUCTION; EXPRESSION; SURVIVAL; MTOR	Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) is derived from Alpinia katsumadai Hayata (Zingiberaceae), a plant that has been used in Traditional Chinese Medicine for thousands of years. Several anticancer agents have been reported to induce autophagy, which either protects cells or further sensitizes cells to drug treatment. However, the possible autophagic and antiproliferative effects of cardamonin on the human colorectal carcinoma HCT116 cell line are unclear. In the present study, experiments were conducted to determine the effects of cardamonin on cell proliferation, cell cycle distribution, and stimulation of autophagy in cultures of the HCT116 cell line. The results showed that cardamonin inhibited cell proliferation, induced G2/M phase cell cycle arrest, and enhanced autophagy in HCT116 cells. We found evidence that cardamonin-induced autophagic and antiproliferative effects are regulated by the tumor protein p53. We also found that the enhanced activation of c-Jun N-terminal kinase (JNK) by cardamonin was partially regulated by p53 and was critical for cardamonin-induced autophagic and antiproliferative effects in HCT116 cells. These findings suggest that cardamonin or other anticancer agents that increase p53/JNK-dependent stimulation of autophagy could be used to effectively treat patients with colorectal carcinoma. (C) 2015 Elsevier Ltd. All rights reserved.	[Kim, Young-Joo] Korea Inst Sci & Technol, Nat Prod Res Ctr, Kangnung, Gangwon Do, South Korea; [Kang, Ki Sung] Gachon Univ, Coll Korean Med, Songnam, South Korea; [Choi, Kyung-Chul] Univ Ulsan, Coll Med, Dept Biomed Sci, Seoul, South Korea; [Choi, Kyung-Chul] Univ Ulsan, Coll Med, Dept Pharmacol, Seoul, South Korea; [Ko, Hyeonseok] Dankook Univ, Coll Med, Mol Oncol Lab, Cheil Gen Hosp, Seoul, South Korea; [Ko, Hyeonseok] Dankook Univ, Coll Med, Womens Healthcare Ctr, Seoul, South Korea; [Choi, Kyung-Chul] Univ Ulsan, Coll Med, CDRC, Seoul, South Korea		Ko, H (corresponding author), Dankook Univ, Coll Med, Mol Oncol Lab, Cheil Gen Hosp, Seoul, South Korea.	drug9054@naver.com			Korea Institute of Science and Technology institutional program [2Z04381]; Basic Science Research Programs through the National Research Foundation of Korea - Ministry of Education, Science and Technology [NRF-2012R1A1A4A01014504]	This work was supported by the Korea Institute of Science and Technology institutional program (2Z04381) and Basic Science Research Programs through the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology (NRF-2012R1A1A4A01014504).	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Med. Chem. Lett.	JUN 15	2015	25	12					2559	2564		10.1016/j.bmcl.2015.04.054			6	Chemistry, Medicinal; Chemistry, Organic	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Chemistry	CJ0EL	WOS:000355147300022	25959811				2022-04-25	
J	Dutta, D; Chakraborty, B; Sarkar, A; Chowdhury, C; Das, P				Dutta, Debasmita; Chakraborty, Biswajit; Sarkar, Ankita; Chowdhury, Chinmay; Das, Padma			A potent betulinic acid analogue ascertains an antagonistic mechanism between autophagy and proteasomal degradation pathway in HT-29 cells	BMC CANCER			English	Article						Apoptosis; Autophagy; Betulinic acid analogue; Proteasomal pathway	CANCER-CELLS; PROTEIN; DEATH; APOPTOSIS; EXPRESSION; CLEARANCE; CROSSTALK; UBIQUITIN; COMPOUND; SURVIVAL	Background: Betulinic acid (BA), a member of pentacyclic triterpenes has shown important biological activities like anti-bacterial, anti-malarial, anti-inflammatory and most interestingly anticancer property. To overcome its poor aqueous solubility and low bioavailability, structural modifications of its functional groups are made to generate novel lead(s) having better efficacy and less toxicity than the parent compound. BA analogue, 2c was found most potent inhibitor of colon cancer cell line, HT-29 cells with IC50 value 14.9 mu M which is significantly lower than standard drug 5-fluorouracil as well as parent compound, Betulinic acid. We have studied another mode of PCD, autophagy which is one of the important constituent of cellular catabolic system as well as we also studied proteasomal degradation pathway to investigate whole catabolic pathway after exploration of 2c on HT-29 cells. Methods: Mechanism of autophagic cell death was studied using fluorescent dye like acridine orange (AO) and monodansylcadaverin (MDC) staining by using fluorescence microscopy. Various autophagic protein expression levels were determined by Western Blotting, qRT-PCR and Immunostaining. Confocal Laser Scanning Microscopy (CLSM) was used to study the colocalization of various autophagic proteins. These were accompanied by formation of autophagic vacuoles as revealed by FACS and transmission electron microscopy (TEM). Proteasomal degradation pathway was studied by proteasome-Glo (TM) assay systems using luminometer. Results: The formation of autophagic vacuoles in HT-29 cells after 2c treatment was determined by fluorescence staining - confirming the occurrence of autophagy. In addition, 2c was found to alter expression levels of different autophagic proteins like Beclin-1, Atg 5, Atg 7, Atg 5-Atg 12, LC3B and autophagic adapter protein, p62. Furthermore we found the formation of autophagolysosome by colocalization of LAMP 1 with LC3B, LC3B with Lysosome, p62 with lysosome. Finally, as proteasomal degradation pathway downregulated after 2c treatment colocalization of ubiquitin with lysosome and LC3B with p62 was studied to confirm that protein degradation in autophagy induced HT-29 cells follows autolysosomal pathway. Conclusions: In summary, betulinic acid analogue, 2c was able to induce autophagy in HT-29 cells and as proteasomal degradation pathway downregulated after 2c treatment so protein degradation in autophagy induced HT-29 cells follows autolysosomal pathway.	[Dutta, Debasmita; Sarkar, Ankita; Das, Padma] Indian Inst Chem Biol, CSIR, Canc Biol & Inflammatory Disorder Div, Kolkata 700032, India; [Chakraborty, Biswajit; Chowdhury, Chinmay] Indian Inst Chem Biol, CSIR, Organ & Med Chem Div, Kolkata 700032, India		Das, P (corresponding author), Indian Inst Chem Biol, CSIR, Canc Biol & Inflammatory Disorder Div, 4 Raja SC Mullick Rd, Kolkata 700032, India.	padmadas2005@yahoo.co.in		Dutta, Debasmita/0000-0003-0235-4649	CSIR-Indian Institute of Chemical Biology through CSIR-Network Project TREAT [BSC-0116]	This research work is financially supported by CSIR-Indian Institute of Chemical Biology through CSIR-Network Project TREAT (BSC-0116).	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J	Qiao, PF; Yao, L; Zeng, ZL				Qiao, Peng-Fei; Yao, Lei; Zeng, Zhao-Lin			Catalpol-mediated microRNA-34a suppresses autophagy and malignancy by regulating SIRT1 in colorectal cancer	ONCOLOGY REPORTS			English	Article						colorectal cancer; catalpol; autophagy; miR-34a; SIRT1	FACILITATES APOPTOSIS; INHIBITS MIGRATION; COLON-CANCER; KAPPA-B; CELLS; PROLIFERATION; INFLAMMATION; EXPRESSION; REPRESSION; RESISTANCE	Colorectal cancer (CRC) is one of the most common digestive tract tumors worldwide. Catalpol exerts inhibitory effects on the progression of several cancer types by regulating microRNAs (miRs). However, the precise role and carcinostatic mechanism of catalpol on CRC cells are poorly understood which limits the application of catalpol treatment. In the present study, miR-34a and sirtuin 1 (SIRT1) expression levels were detected in CRC tissues and CRC cell lines by RT-qPCR. Computational software analysis, luciferase assays and western blotting were used to demonstrate the downstream target of miR-34a in CRC cells. Effects of catalpol on cell viability, apoptosis, autophagic flux and the miR-34a/SIRT1 axis in the CRC cells were assessed by CCK-8 assay, flow cytometry, electron microscopy and western blotting, respectively. Whether the miR-34a/SIRT1 axis participated in catalpol-mediated autophagy and apoptosis was investigated. The effects of catalpol on the miR-34a/SIRT1 axis and malignant behavior were evaluated in a rat model of azoxymethane (AOM)-induced CRC. It was revealed that miR-34a expression levels were significantly decreased while SIRT1 was overexpressed in most of the CRC tissues and all the CRC cell lines. Clinically, a low level of miR-34a was correlated with poor clinicopathological characteristics in CRC patients. Catalpol reduced cell viability, suppressed autophagy, promoted apoptosis, and regulated the expression of SIRT1 by inducing miR-34a in vitro and in vivo. The autophagy-inhibiting effect of catalpol may be a mechanism to promote apoptosis of CRC cells. miR-34a mimic transfection resulted in autophagy-suppressive activity similar to that of catalpol, while the miR-34a inhibitor attenuated the antiautophagic effects of catalpol. In conclusion, miR-34a is involved in regulating catalpol-mediated autophagy and malignant behavior by directly inhibiting SIRT1 in CRC.	[Qiao, Peng-Fei; Yao, Lei; Zeng, Zhao-Lin] Harbin Med Univ, Dept Gen Surg, Affiliated Hosp 2, Harbin 150086, Heilongjiang, Peoples R China		Yao, L (corresponding author), Harbin Med Univ, Dept Gen Surg, Affiliated Hosp 2, Harbin 150086, Heilongjiang, Peoples R China.	oppoigod@sina.com			Heilongjiang Postdoctoral Funds for Scientific Research Initiation [LBH-Q17129]; Science Foundation of the Health Commission of Heilongjiang Province [2018346]	The present study was supported by Heilongjiang Postdoctoral Funds for Scientific Research Initiation (LBH-Q17129) and the Science Foundation of the Health Commission of Heilongjiang Province (2018346).	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Rep.	APR	2020	43	4					1053	1066		10.3892/or.2020.7494			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	LA1ZN	WOS:000523753100003	32323786	Green Published, hybrid			2022-04-25	
J	Liu, Y; Zhang, Y; Zou, JL; Yan, LX; Yu, XF; Lu, P; Wu, XN; Li, QZ; Gu, R; Zhu, DL				Liu, Ying; Zhang, Yan; Zou, Jilong; Yan, Lixin; Yu, Xiufeng; Lu, Peng; Wu, Xiaonneng; Li, Qiaozhi; Gu, Rui; Zhu, Daling			Andrographolide Induces Autophagic Cell Death and Inhibits Invasion and Metastasis of Human Osteosarcoma Cells in An Autophagy-Dependent Manner	CELLULAR PHYSIOLOGY AND BIOCHEMISTRY			English	Article						Andrographolide; Autophagy; Apoptosis; Epithelial-mesenchymal transition; Osteosarcoma	EPITHELIAL-MESENCHYMAL TRANSITION; COLON-CANCER CELLS; NF-KAPPA-B; SIGNALING PATHWAY; CYCLE ARREST; LUNG-CANCER; IN-VITRO; SILICA NANOPARTICLES; SINGLE-INSTITUTION; DOWN-REGULATION	Background/Aims: Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue. Although treatment effectiveness has improved, the OS survival rate has fluctuated in recent years. Andrographolide (AG) has been reported to have antitumor activity against a variety of tumors. Our aim was to investigate the effects and potential mechanisms of AG in human osteosarcoma. Methods: Cell viability and morphological changes were assessed by MTT and live/dead assays. Apoptosis was detected using Annexin V-FITC/PI double staining, DAPI, and caspase-3 assays. Autophagy was detected with mRFP-GFP-LC3 adenovirus transfection and western blot. Cell migration and invasion were detected by wound healing assay and Transwell (R) experiments. Results: AG dose-dependently reduced the viability of osteosarcoma cells. No increase in apoptosis was detected in AG-treated human OS MG63 and U-2OS cells, and the pan-caspase inhibitor z-VAD did not attenuate AG-induced cell death. However, AG induced autophagy by suppressing PI3K/Akt/mTOR and enhancing JNK signaling pathways. 3-MA and Beclin-1 siRNA could reverse the cytotoxic effects of AG. In addition, AG inhibited the invasion and metastasis of OS, and this effect could be reversed with Beclin-1 siRNA. Conclusion: AG inhibits viability and induces autophagic death in OS cells. AG-induced autophagy inhibits the invasion and metastasis of OS. (C) 2017 The Author(s) Published by S. Karger AG, Basel	[Liu, Ying; Yan, Lixin; Yu, Xiufeng; Gu, Rui; Zhu, Daling] Harbin Med Univ, Key Lab Heilongjiang Prov, Dept Biopharmaceut, Harbin, Heilongjiang, Peoples R China; [Liu, Ying; Yan, Lixin; Yu, Xiufeng; Gu, Rui; Zhu, Daling] Harbin Med Univ, Dept Biopharmaceut Sci, Daqing, Heilongjiang, Peoples R China; [Zhang, Yan; Zou, Jilong] Harbin Med Univ, Affiliated Hosp 1, Dept Orthopaed, Harbin, Heilongjiang, Peoples R China; [Yu, Xiufeng] Harbin Med Univ Daqing, Coll Med Lab Sci & Technol, Daqing, Heilongjiang, Peoples R China; [Lu, Peng] Baoquanling Cent Hosp, Dept Orthopaed, Baoquanling, Heilongjiang, Peoples R China; [Wu, Xiaonneng] Mudanjiang Med Univ, Affiliated Hosp 2, Dept Pharm, Mudanjiang, Heilongjiang, Peoples R China; [Li, Qiaozhi] Harbin Med Univ, Coll Pharm, Dept Pharmaceut Anal & Analyt Chem, Harbin, Heilongjiang, Peoples R China		Zhu, DL (corresponding author), Harbin Med Univ, Coll Pharm, Dept Biopharmaceut Sci, Xinyang Rd, Daqing, Heilongjiang, Peoples R China.	dalingz@yahoo.com		daling, Zhu/0000-0001-9763-9772; 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Zhao F, 2008, J ASIAN NAT PROD RES, V10, P473, DOI 10.1080/10286020801948599; Zhou J, 2010, BIOCHEM PHARMACOL, V79, P1242, DOI 10.1016/j.bcp.2009.12.014; Zuo DQ, 2017, J CELL MOL MED, V21, P208, DOI 10.1111/jcmm.12957	55	15	15	2	7	KARGER	BASEL	ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND	1015-8987	1421-9778		CELL PHYSIOL BIOCHEM	Cell. Physiol. Biochem.		2017	44	4					1396	1410		10.1159/000485536			15	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	FQ8KW	WOS:000418612700012	29197865	gold			2022-04-25	
J	Mouratidis, PXE; Rivens, I; ter Haar, G				Mouratidis, Petros X. E.; Rivens, Ian; ter Haar, Gail			A study of thermal dose-induced autophagy, apoptosis and necroptosis in colon cancer cells	INTERNATIONAL JOURNAL OF HYPERTHERMIA			English	Article						Apoptosis; autophagy; high intensity focused ultrasound; necroptosis; thermal dose	INTENSITY FOCUSED ULTRASOUND; HOMOLOGOUS RECOMBINATION; THERAPEUTIC APPLICATIONS; PROSTATE-CANCER; HYPERTHERMIA; NECROSIS; AGGREGATION; INHIBITION; MECHANISMS; PATHWAYS	Purpose: The pleiotropic effects of heat on cancer cells have been well documented. The biological effects seen depend on the temperature applied, and the heating duration. In this study we investigate the cytotoxic effects of heat on colon cancer cells and determine how different cell death processes such as autophagy, apoptosis and necroptosis play a role in cell response. Materials and methods: The thermal dose concept was used to provide a parameter that will allow comparison of different thermal treatments. Two human colon cancer cell lines, HCT116 and HT29, were subjected to ablative temperatures using a polymerase chain reaction thermal cycler. Temperature was recorded using thermocouples. Cell viability was assessed using the MTT assay. Induction of apoptosis was estimated using an enzyme-linked immunosorbent assay that detects cleaved cytoplasmic nucleosomes. Protein regulation was determined using immunoblotting. The percentage of cells undergoing apoptosis and autophagy was determined with annexin V/propidium iodide staining and a cationic amphiphilic tracer using fluorescence-activated cell sorting analysis. Results: Exposure of colon cancer cells to ablative thermal doses results in decreased cell viability. The cytotoxic effect of heat is associated with induction of apoptosis and autophagy, the amount depending on both the thermal dose applied and on the time elapsed after treatment. Autophagy induction is mainly seen in live cells. RIPK3 protein levels are increased after exposure of cells to heat. A necroptosis inhibitor does not affect cell viability. Conclusions: Autophagy, apoptosis and necroptosis are associated with the response of these cancer cell lines to supra-normal temperatures.	[Mouratidis, Petros X. E.; Rivens, Ian; ter Haar, Gail] Royal Marsden Hosp, Joint Dept Phys, Div Radiotherapy & Imaging, Inst Canc Res, London SW3 6JJ, England		Mouratidis, PXE (corresponding author), Royal Marsden Hosp, Joint Dept Phys, Div Radiotherapy & Imaging, Inst Canc Res London, Downs Rd, Sutton SM2 5NG, Surrey, England.	petros.mouratidis@icr.ac.uk		ter Haar, Gail/0000-0001-8909-0775	European Association of National Metrology Institutes (EURAMET); EUEuropean Commission [HLT03-REG2, HLT03 DUTy]; EPSRCUK Research & Innovation (UKRI)Engineering & Physical Sciences Research Council (EPSRC) [EP/F029217/1, EP/H046526/1] Funding Source: UKRI; Cancer Research UKCancer Research UK [16464] Funding Source: researchfish; Engineering and Physical Sciences Research CouncilUK Research & Innovation (UKRI)Engineering & Physical Sciences Research Council (EPSRC) [EP/H046526/1, EP/F029217/1] Funding Source: researchfish	This study was funded by the European Association of National Metrology Institutes (EURAMET) and the EU (Grant No.: HLT03-REG2; HLT03 DUTy). The authors alone are responsible for the content and writing of the paper.	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J. Hyperthermia	AUG	2015	31	5					476	488		10.3109/02656736.2015.1029995			13	Oncology; Radiology, Nuclear Medicine & Medical Imaging	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Radiology, Nuclear Medicine & Medical Imaging	CP6LA	WOS:000359997500004	25974074				2022-04-25	
J	Huang, X; Wang, XN; Yuan, XD; Wu, WY; Lobie, PE; Wu, ZS				Huang, Xing; Wang, Xiao-nan; Yuan, Xiao-dong; Wu, Wen-yong; Lobie, Peter E.; Wu, Zhengsheng			XIAP facilitates breast and colon carcinoma growth via promotion of p62 depletion through ubiquitination-dependent proteasomal degradation	ONCOGENE			English	Article							APOPTOSIS PROTEINS; SIGNALING ADAPTER; AUTOPHAGY; CANCER; INHIBITOR; TUMORIGENESIS; BECLIN-1	X-linked inhibitor of apoptosis protein (XIAP) possesses a critical role in promotion of cell survival and maintenance of cellular homeostasis. In cancer, elevated XIAP expression has been associated with malignancy, poor prognosis, and treatment resistance. However, the underlying mechanisms of these effects remain unclear. XIAP has previously been proposed to promote tumor growth through suppression of autophagy. In this study, we examined the expression of XIAP and p62, two critical mediators of autophagy, in breast and colon cancer. We observed a negative correlation between XIAP and p62 expression in normal and cancer tissues of breast and colon, and that the ratio of XIAP and p62 expression determines the cancer phenotype. In vitro, we observed that XIAP interacted with p62 and also that XIAP depletion resulted in increased expression of p62. XIAP functioned as an ubiquitination E3 ligase towards p62 and suppressed p62 expression through ubiquitin-proteasomal degradation. Furthermore, XIAP enhanced cancer cell proliferation, viability, and colony formation in vitro via suppression of p62. In addition, we demonstrated that XIAP-enhanced tumor growth is dependent on depletion of p62 in vivo. Herein, we have therefore delineated a novel mechanism by which XIAP contributes to development and progression of breast and colon carcinoma.	[Huang, Xing] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Key Lab Precis Diag & Treatment Hepatobiliary & P, Hangzhou 310003, Zhejiang, Peoples R China; [Wang, Xiao-nan; Yuan, Xiao-dong; Wu, Zhengsheng] Anhui Med Univ, Dept Pathol, Hefei 230032, Anhui, Peoples R China; [Huang, Xing] Southeast Univ, Inst Life Sci, Key Lab Dev Genes & Human Dis, Nanjing 210096, Jiangsu, Peoples R China; [Wu, Wen-yong] Anhui Med Univ, Dept Gen Surg, Affiliated Hosp 1, Hefei 230032, Anhui, Peoples R China; [Lobie, Peter E.] Tsinghua Univ, Tsinghua Berkeley Shenzhen Inst, Shenzhen, Guangdong, Peoples R China		Huang, X (corresponding author), Zhejiang Univ, Sch Med, Affiliated Hosp 1, Key Lab Precis Diag & Treatment Hepatobiliary & P, Hangzhou 310003, Zhejiang, Peoples R China.; Wu, ZS (corresponding author), Anhui Med Univ, Dept Pathol, Hefei 230032, Anhui, Peoples R China.; Huang, X (corresponding author), Southeast Univ, Inst Life Sci, Key Lab Dev Genes & Human Dis, Nanjing 210096, Jiangsu, Peoples R China.	dr.huangxing@foxmail.com; woozson@yahoo.com	黄, 星/AAB-2241-2019	黄, 星/0000-0002-8886-2777; Wu, Zhengsheng/0000-0002-6616-2745	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81502975, 81472493, 81572305]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2016T90413, 2015M581693]; Jiangsu Planned Projects for Postdoctoral Research Funds [1501002A]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [2242016R20027, 2242016K41045]; Anhui provincial academic and technical leader reserve candidate [2016H074]; Key Program of Outstanding Young Talents in Higher Education Institutions of Anhui [gxyqZD2016046]; Shenzhen Development and Reform Commission Subject Construction Project [[2017]1434]	We deeply thank Dr. Bert Vogelstein (Johns Hopkins University) for XIAP<SUP>-/-</SUP> HCT116 and XIAP<SUP>-/-</SUP> DLD1 cell lines, Dr. Noboru Mizushima (The University of Tokyo) for Atg5<SUP>-/-</SUP> MEF cell lines, and Dr. Tao Zhu (University of Science & Technology of China) for breast cell lines. Especially, the author Xing Huang would like to express deepest thanks to Dr. Mian Wu (University of Science & Technology of China) for the technological training and ideological inspiration in his lab. This work was supported by grants from National Natural Science Foundation of China (81502975, 81472493, and 81572305), and China Postdoctoral Science Foundation (2016T90413 and 2015M581693). The research was funded in part by Jiangsu Planned Projects for Postdoctoral Research Funds (1501002A), Fundamental Research Funds for the Central Universities (2242016R20027 and 2242016K41045), Anhui provincial academic and technical leader reserve candidate (#2016H074), Key Program of Outstanding Young Talents in Higher Education Institutions of Anhui (#gxyqZD2016046) and the Shenzhen Development and Reform Commission Subject Construction Project ([2017]1434).	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J	Su, CC				Su, Chin-Cheng			Tanshinone IIA potentiates the efficacy of 5-FU in Colo205 colon cancer cells in vivo through downregulation of P-gp and LC3-II	EXPERIMENTAL AND THERAPEUTIC MEDICINE			English	Article						tanshinone IIA; 5-fluorouracil; Colo205; P-glycoprotein; microtubule-associated protein light chain 3 II; in vivo	INHIBITION; EXTRACT; AUTOPHAGY; DANSHEN; VITRO; ACID	Traditional Chinese herbal medicines are widely accepted as an option for the treatment of colorectal cancers. Danshen (Salviae miltiorrhizae Radix) is widely prescribed in traditional Chinese medicine for cardiovascular diseases. Tanshinone IIA (Tan-HA) is extracted from Danshen. Our previous studies have shown that Tan-IIA induces apoptosis in Colo205 human colon cancer cells in vitro and in vivo. In the present study, we investigated the efficacy of Tan-IIA and 5-fluorouracil (5-FU) in a Colo205 cell xenograft model. For in vivo studies, SCID mice were engrafted with Colo205 cells and from day 10 onwards were randomly divided into 3 groups and treated with 5-FU plus Tan-IIA, 5-FU plus corn oil, and the vehicle alone. At the end of a 4-week dosing schedule, the SCID mice were sacrificed and xenograft tumors were dissected for protein western blot analysis. Our results showed that the Colo205 xenograft model co-treated with Tan-IIA plus 5-FU caused a reduction in the xenograft tumor volumes and decreased P-glycoprotein (P-gp) and microtubule-associated protein light chain 3 (LC3)-II expression compared to 5-FU alone. Based on these observations, it may be possible to develop Tan-HA plus 5-FU as therapeutic agents for human colon cancer.	[Su, Chin-Cheng] Changhua Christian Hosp, Dept Surg, Changhua 50006, Changhua, Taiwan; [Su, Chin-Cheng] China Med Univ, Sch Chinese Med, Coll Chinese Med, Taichung 40402, Taiwan; [Su, Chin-Cheng] Mingdao Univ, Changhua 52345, Taiwan		Su, CC (corresponding author), Changhua Christian Hosp, Dept Surg, 135 Nan Hsiao St, Changhua 50006, Changhua, Taiwan.	succ.maeva@msa.hinet.net			Committee on Chinese Medicine and Pharmacy, Department of Health, Executive Yuan, Taiwan, R.O.C. [CCMP97-RD-041]	This study was supported by a grant (CCMP97-RD-041) from the Committee on Chinese Medicine and Pharmacy, Department of Health, Executive Yuan, Taiwan, R.O.C.	Albertsson P, 2009, ACTA ONCOL, V48, P418, DOI 10.1080/02841860802409512; Boon H, 2004, EXPERT OPIN PHARMACO, V5, P2485, DOI 10.1517/14656566.5.12.2485; BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3; Chang PN, 2006, J PHARMACOL SCI, V101, P245, DOI 10.1254/jphs.FPJ05034X; Chau I, 2005, ANN ONCOL, V16, P549, DOI 10.1093/annonc/mdi116; Chen AJ, 2004, J SEP SCI, V27, P569, DOI 10.1002/jssc.200301710; Chen HC, 2004, FOOD CHEM TOXICOL, V42, P1251, DOI 10.1016/j.fct.2004.03.002; Department of Health Executive Yuan Taipei Taiwan R.O.C, 2008, STAT CAUS DEATH, P33; Eskelinen EL, 2002, TRAFFIC, V3, P878, DOI 10.1034/j.1600-0854.2002.31204.x; Fang YJ, 2009, INT J COLORECTAL DIS, V24, P875, DOI 10.1007/s00384-009-0725-z; Fish JM, 2006, CIRCULATION, V113, P1393, DOI 10.1161/CIRCULATIONAHA.105.601690; Gottesman MM, 1996, CURR OPIN GENET DEV, V6, P610, DOI 10.1016/S0959-437X(96)80091-8; He D, 2009, BMC CANCER, V9, DOI 10.1186/1471-2407-9-343; Jang SI, 2006, EUR J PHARMACOL, V542, P1, DOI 10.1016/j.ejphar.2006.04.044; Jemal A, 2004, CA-CANCER J CLIN, V54, P8, DOI 10.3322/canjclin.54.1.8; Kirkegaard K, 2004, NAT REV MICROBIOL, V2, P301, DOI 10.1038/nrmicro865; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Li W, 2007, J IMMUNOL, V178, P3856, DOI 10.4049/jimmunol.178.6.3856; Lin R, 2006, J ETHNOPHARMACOL, V108, P217, DOI 10.1016/j.jep.2006.05.004; LUM BL, 1993, PHARMACOTHERAPY, V13, P88; Su CC, 2008, PLANTA MED, V74, P1357, DOI 10.1055/s-2008-1081299; Su CC, 2008, INT J MOL MED, V22, P357, DOI 10.3892/ijmm_00000030; Verhoef Marja J, 2005, Integr Cancer Ther, V4, P274, DOI 10.1177/1534735405282361; Voboril R, 2004, J SURG RES, V120, P178, DOI 10.1016/j.jss.2003.11.023; Wang AM, 2003, ANTIMICROB AGENTS CH, V47, P1836, DOI 10.1128/AAC.47.6.1836-1841.2003; Wei SC, 2004, J BIOMED SCI, V11, P260, DOI 10.1159/000076038; Xu WL, 2009, NUTRITION, V25, P555, DOI 10.1016/j.nut.2008.10.019; Zhou LM, 2005, J CLIN PHARMACOL, V45, P1345, DOI 10.1177/0091270005282630	28	31	36	1	18	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-0981	1792-1015		EXP THER MED	Exp. Ther. Med.	MAR	2012	3	3					555	559		10.3892/etm.2011.441			5	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	893FF	WOS:000300340300033	22969929	Bronze, Green Published			2022-04-25	
J	Qureshi, AA; Zuvanich, EG; Khan, DA; Mushtaq, S; Silswal, N; Qureshi, N				Qureshi, Asaf A.; Zuvanich, Eleanor G.; Khan, Dilshad A.; Mushtaq, Shahida; Silswal, Neerupma; Qureshi, Nilofer			Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs	LIPIDS IN HEALTH AND DISEASE			English	Article						Potent anticancer compounds; Several cancer cell lines (Hela; Liver; Pancreas; Prostate; Breast; Lung; Melanoma; B-lymphocytes; T-cells; Inflammatory biomarkers	PALM OIL; LIPID-PEROXIDATION; PROTEIN OXIDATION; TOCOTRIENOLS; AUTOPHAGY; PHARMACOKINETICS; IDENTIFICATION; APOPTOSIS; GENES	Background: Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs. Methods: The anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of delta-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-alpha using total RNAs derived from plasmas of hepatitis C patients was investigated. Results: Our data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, delta-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% - 87%) with doses of 2.5-20 mu M, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, d-tocotrienol, and quercetin were 70% - 92%. However, thiostrepton, dexamethasone, 2-methoxyestradiol, delta-tocotrienol, quercetin, and quinine sulphate were effective in pancreatic, prostate, breast, lungs, melanoma, B-lymphocytes, and T-cells (Jurkat: 40% to 95%) compared to respective controls. In lung cancer cells, these compounds were effective between 5 and 40 mu M. The IC50 values of anti-proliferation properties of thiostrepton in most of these cell lines were between doses of 2.5-5 mu M, dexamethasone 2.5-20 mu M, 2-methoxyestradiol 2.5-10 mu M, delta-tocotrienol 2.5-20 mu M, quercetin 10-40 mu M, and (-) Corey lactone 40-80 mu M. In hepatitis C patients, delta-tocotrienol treatment resulted in significant decrease in the expression of pro-inflammatory cytokines. Conclusions: These data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, delta-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, B-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.	[Qureshi, Asaf A.; Zuvanich, Eleanor G.; Silswal, Neerupma; Qureshi, Nilofer] Univ Missouri Kansas City, Sch Med, Dept Basic Med Sci, 2411 Holmes St, Kansas City, MO 64108 USA; [Khan, Dilshad A.; Mushtaq, Shahida] Armed Forces Inst Pathol, Dept Chem Pathol & Endocrinol, Rawalpindi 64000, Pakistan; [Khan, Dilshad A.; Mushtaq, Shahida] Natl Univ Med Sci, Rawalpindi 64000, Pakistan; [Qureshi, Nilofer] Univ Missouri Kansas City, Sch Pharm, Pharmacol & Toxicol, 2464 Charlotte St, Kansas City, MO 64108 USA		Qureshi, AA (corresponding author), Univ Missouri Kansas City, Sch Med, Dept Basic Med Sci, 2411 Holmes St, Kansas City, MO 64108 USA.	qureshia@umkc.edu		Silswal, Neerupma/0000-0001-7151-2378	Advanced Medical Research, Madison, Wisconsin; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RO1 GM50870, 3RO1 GM631S1, 5RO1 GM10263]; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM050870] Funding Source: NIH RePORTER	The study supported in part by Advanced Medical Research, Madison, Wisconsin and NIH funds RO1 GM50870, 3RO1 GM631S1, and 5RO1 GM10263.	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APR 2	2018	17								62	10.1186/s12944-018-0697-5			26	Biochemistry & Molecular Biology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Nutrition & Dietetics	GB2QG	WOS:000428898600001	29606130	gold, Green Published			2022-04-25	
J	Kawakita, H; Tsuchida, A; Miyazawa, K; Naito, M; Shigoka, M; Kyo, B; Enomoto, M; Wada, T; Katsumata, K; Ohyashiki, K; Itoh, M; Tomoda, A; Aoki, T				Kawakita, Hideaki; Tsuchida, Akihiko; Miyazawa, Keisuke; Naito, Munekazu; Shigoka, Masatoshi; Kyo, Bunso; Enomoto, Masanobu; Wada, Tatehiko; Katsumata, Kenji; Ohyashiki, Kazuma; Itoh, Masahiro; Tomoda, Akio; Aoki, Tatsuya			Growth inhibitory effects of vitamin K2 on colon cancer cell lines via different types of cell death including autophagy and apoptosis	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE			English	Article						colon cancer; vitamin K2; chemoprevention; autophagy; apoptosis	HEPATOCELLULAR-CARCINOMA; LEUKEMIA-CELLS; LUNG-CANCER; INDUCTION; THERAPY; LC3	Vitamin K2 (menaquinone-4: MK4) has been reported to inhibit cell growth and induce apoptosis in various tumor cells. We examined the effects of MK4 using three types of colon cancer cell lines: PMCO1, COLO201, and DLD-1. Exposure to MK4 was at concentrations from 5 to 50 mu M, growth inhibitory effects were observed dose-dependently in COLO201 and PMCO1, whereas the growth inhibition observed in DLD-1 was minimal. Comparison of COLO201 and PMCO1 cells exhibiting distinct growth inhibitory effects showed that cell death via apoptosis accompanied by activation of caspase-3 was induced in PMCO1, while apoptosis was not induced in COLO201. On the contrary, immunoblot assay using an anti-LC3B antibody showed autophagy induction by addition of MK4 and incubation in all three types of colon cancer cell lines. Addition of 3-methyladenine (3-MA) attenuated the growth inhibitory effect of MK4 in COLO201, whereas no influence of 3-MA was noted in PCMO1. Electron microscopy images of COLO201 showed that addition of MK4 induced an increased number of cytoplasmic autophagosomes and autolysosomes as well as morphological changes including scantiness of cytoplasm accompanied by loss of cell organelles, nuclear shrinkage, and fragmentation of cytoplasmic membrane in some cells, indicating the induction of cell death via autophagy not accompanied by the formation of apoptotic bodies in COLO201 cells. These results suggested that the response to MK4 and the way of induction of cell death vary in different colon cancer cell lines.	[Tsuchida, Akihiko] Tokyo Med Univ, Dept Surg 3, Shinjuku Ku, Tokyo 1600023, Japan; [Miyazawa, Keisuke; Tomoda, Akio] Tokyo Med Univ, Dept Biochem, Tokyo 1600023, Japan; [Naito, Munekazu; Itoh, Masahiro] Tokyo Med Univ, Dept Anat, Tokyo 1600023, Japan; [Ohyashiki, Kazuma] Tokyo Med Univ, Dept Internal Med 1, Tokyo 1600023, Japan		Tsuchida, A (corresponding author), Tokyo Med Univ, Dept Surg 3, Shinjuku Ku, 6-7-1 Nishi Shinjuku, Tokyo 1600023, Japan.	akihikot@tokyo-med.ac.jp		Kawakita (he bei), Hideaki (ying ming)/0000-0001-9654-1407	Ministry of Health, Labor and Welfare of JapanMinistry of Health, Labour and Welfare, Japan	This study was supported by the 'Third-Term Comprehensive Control Research for Cancer' conducted by the Ministry of Health, Labor and Welfare of Japan. The authors are indebted to Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript, and would like to thank Ms. Ayako Hirota and Ms. Minako Suzuki for their expert technical assistance. We also thank Dr Tomohisa Yokoyama of M.D. Anderson Cancer Center, University of Texas for the kind gift of anti-LC3B Ab, and Eisai Co. for providing	Aoki H, 2007, MOL PHARMACOL, V72, P29, DOI 10.1124/mol.106.033167; Bampton ETW, 2005, AUTOPHAGY, V1, P23, DOI 10.4161/auto.1.1.1495; Enomoto M, 2007, INT J MOL MED, V20, P801; Green DR, 1998, SCIENCE, V281, P1309, DOI 10.1126/science.281.5381.1309; Habu D, 2004, JAMA-J AM MED ASSOC, V292, P358, DOI 10.1001/jama.292.3.358; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kanzawa T, 2003, CANCER RES, V63, P2103; 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; Lamson Davis W, 2003, Altern Med Rev, V8, P303; 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; Miyazawa K, 2000, LEUKEMIA, V14, P1156, DOI 10.1038/sj.leu.2401790; Miyazawa K, 2001, LEUKEMIA, V15, P1111, DOI 10.1038/sj.leu.2402155; Mizushima N, 2002, CELL STRUCT FUNCT, V27, P421, DOI 10.1247/csf.27.421; MIZUSHIMA N, 2007, AUTOPHAGY, V3, pE1; Mizuta T, 2006, CANCER, V106, P867, DOI 10.1002/cncr.21667; Ogawa M, 2007, INT J ONCOL, V31, P323; Paglin S, 2001, CANCER RES, V61, P439; SELGEN PO, 1982, P NATL ACAD SCI USA, V79, P1889; Shao YF, 2004, P NATL ACAD SCI USA, V101, P18030, DOI 10.1073/pnas.0408345102; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Tanida I, 2005, AUTOPHAGY, V1, P84, DOI 10.4161/auto.1.2.1697; Tokita H, 2006, INT J MOL MED, V17, P235; Tsujimoto Y, 2005, CELL DEATH DIFFER, V12, P1528, DOI 10.1038/sj.cdd.4401777; Yaguchi M, 1999, LEUKEMIA, V13, P144, DOI 10.1038/sj.leu.2401232; Yokoyama T, 2005, INT J ONCOL, V26, P33; Yokoyama T, 2008, AUTOPHAGY, V4, P629, DOI 10.4161/auto.5941; Yoshida T, 2003, INT J ONCOL, V23, P627	30	18	19	1	4	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1107-3756	1791-244X		INT J MOL MED	Int. J. Mol. Med.	JUN	2009	23	6					709	716		10.3892/ijmm_00000184			8	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	448GV	WOS:000266252000002	19424596	Bronze			2022-04-25	
J	Park, GB; Jeong, JY; Kim, D				Park, Ga Bin; Jeong, Jee-Yeong; Kim, Daejin			Ampelopsin-induced reactive oxygen species enhance the apoptosis of colon cancer cells by activating endoplasmic reticulum stress-mediated AMPK/MAPK/XAF1 signaling	ONCOLOGY LETTERS			English	Article						ampelopsin; reactive oxygen species; ER stress; 5 ' adenosine monophosphate-activated protein kinase; colon cancer	PROTEIN-KINASE; FACTOR-1 XAF1; TUMOR-CELLS; AMPK; GROWTH; PATHWAY; INHIBITION; EXPRESSION; CARCINOMA; AUTOPHAGY	Ampelopsin (Amp) is bioactive natural product and exerts anti-cancer effects against several cancer types. The present study investigated the anti-colon cancer activity of Amp and explored its mechanism of action. The treatment of colon cancer cells with Amp resulted in the dose-and time-dependent induction of apoptosis via the activation of endoplasmic reticulum (ER) stress, 5' adenosine monophosphate-activated protein kinase (AMPK), and c-Jun N-terminal protein kinase (JNK)/p38 mitogen-activated protein kinases (MAPKs). Salubrinal, an ER stress inhibitor, prevented the upregulation of ER stress-associated proteins, including phosphorylated protein kinase RNA-like ER kinase, phosphorylated eukaryotic translation initiation factor 2 alpha, glucose-regulated protein 78, and CCAAT/enhancer-binding protein homologous protein, as well as suppressing AMPK activation and the MAPK signaling pathway. Knockdown of AMPK by RNA interference failed to block ER stress. Additionally, SP600125 (a JNK inhibitor) and SB203580 (a p38-MAPK inhibitor) effectively inhibited apoptosis and attenuated the expression of X-linked IAP-associated factor 1 (XAF1) and apoptotic Bcl-2 family proteins (BCL2 antagonist/killer 1 and BCL2-associated X protein) in Amp-treated colon cancer cells. Furthermore, reactive oxygen species (ROS)-mediated ER stress/AMPK apoptotic signaling pathway in Amp-treated colon cancer cells were markedly inhibited by treatment with N-acetyl-L-cysteine, a ROS scavenger. These results demonstrate that treatment with Amp induces the apoptotic death of colon cancer cells through ER stress-initiated AMPK/MAPK/XAF1 signaling. These results also provide experimental information for developing Amp as therapeutic drug against colon cancer.	[Park, Ga Bin; Jeong, Jee-Yeong] Kosin Univ, Coll Med, Dept Biochem, 262 Gamcheon Ro, Busan 49267, South Korea; [Kim, Daejin] Inje Univ, Coll Med, Dept Anat, 75 Bokji Ro, Busan 47392, South Korea		Jeong, JY (corresponding author), Kosin Univ, Coll Med, Dept Biochem, 262 Gamcheon Ro, Busan 49267, South Korea.; Kim, D (corresponding author), Inje Univ, Coll Med, Dept Anat, 75 Bokji Ro, Busan 47392, South Korea.	jyjeong@kosin.ac.kr; kimdj@inje.ac.kr			Basic Science Research Program of the Ministry of Education [NRF-2015R1D1A1A01056672]; Ministry of Science, ICT and Future Planning through the National Research Foundation of the Republic of Korea [NRF-2015R1C1A2A01053732]	The present study was supported by the Basic Science Research Program of the Ministry of Education (grant no. NRF-2015R1D1A1A01056672) and the Ministry of Science, ICT and Future Planning (grant no. NRF-2015R1C1A2A01053732) through the National Research Foundation of the Republic of Korea.	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Lett.	DEC	2017	14	6					7947	7956		10.3892/ol.2017.7255			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FP0LV	WOS:000417293400224	29250183	Green Published, gold			2022-04-25	
J	Zhu, H; Zhao, N; Jiang, MZ				Zhu, Hao; Zhao, Na; Jiang, Maozhu			Isovitexin attenuates tumor growth in human colon cancer cells through the modulation of apoptosis and epithelial-mesenchymal transition via PI3K/Akt/mTOR signaling pathway	BIOCHEMISTRY AND CELL BIOLOGY			English	Article						colon cancer cells; cell proliferation; cell apoptosis; epithelial-mesenchymal transition (EMT); tumor-bearing mice	QUALITY-OF-LIFE; AUTOPHAGY; TARGETS; VITEXIN; BCL-2; BAX	Isovitexin, a biologically active flavone C-glycosylated derivative, has a variety of biological activities. We aimed to identify the effect of isovitexin (Isov) on colon cancer. Human colonic epithelial cells (HCECs) and cancer cells were treated with Isov and Cell Counting Kit-8 (CCK8) was used to detect cell proliferation and calculate the half-inhibitory concentration (IC50). The biological activity of cancer cells was assessed. The tumor size and volume were recorded. Protein expression levels were analyzed by western blotting. Isov inhibited cancer cell proliferation but had little cytotoxicity on HCECs. Isov significantly attenuated cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and induced cell apoptosis., This trend was blocked by insulin-like growth factor-1 (IGF-1) treatment. The expression levels of phosphorylated phosphatidylinositol 3-kinasep (p-PI3K), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and B cell lymphoma-2 (Bcl-2) decreased when treated with Isov, while the levels of Bcl2-associated X (Bax) and caspase-3 significantly increased. After Isov treatment, the tumor volume and weight were decreased, and the levels of p-PI3K, p-Akt, p-mTOR, and Bcl-2 significantly decreased in tumor tissues. Our findings demonstrated that Isov inhibited cancer cell migration, invasion, and EMT. Isov may be a new potential treatment for colon cancer.	[Zhu, Hao; Zhao, Na] Yantaishan Hosp, Dept Gastroenterol, Yantai 264003, Shandong, Peoples R China; [Jiang, Maozhu] Yantaishan Hosp, Dept Radiotherapy, Yantai 264003, Shandong, Peoples R China		Zhu, H (corresponding author), Yantaishan Hosp, Dept Gastroenterol, Yantai 264003, Shandong, Peoples R China.	zhuhao0729@163.com					Allemani C, 2018, LANCET, V391, P1023, DOI 10.1016/S0140-6736(17)33326-3; Banik K, 2019, PHARMACOL RES, V144, P192, DOI 10.1016/j.phrs.2019.04.004; Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI 10.3322/caac.21492; Chatterjee A, 2015, CELL SIGNAL, V27, P189, DOI 10.1016/j.cellsig.2014.11.023; Choi JS, 2014, FOOD CHEM TOXICOL, V64, P27, DOI 10.1016/j.fct.2013.11.020; Costa RLB, 2018, BREAST CANCER RES TR, V169, P397, DOI 10.1007/s10549-018-4697-y; da Silva ICV, 2018, ANTI-CANCER AGENT ME, V18, P1405, DOI 10.2174/1871520618666180315090949; Dlugosz PJ, 2006, EMBO J, V25, P2287, DOI 10.1038/sj.emboj.7601126; Findlay VJ, 2014, CANCER GENE THER, V21, P181, DOI 10.1038/cgt.2014.15; Fu XH, 2019, INT J CANCER, V144, P2109, DOI 10.1002/ijc.31973; Ganesan K, 2017, ANN NY ACAD SCI, V1401, P102, DOI 10.1111/nyas.13446; Gao JY, 2011, TOXICOL APPL PHARM, V254, P221, DOI 10.1016/j.taap.2011.03.016; Hanafi MMM, 2017, FRONT PHARMACOL, V8, DOI 10.3389/fphar.2017.00895; He M, 2016, FITOTERAPIA, V115, P74, DOI 10.1016/j.fitote.2016.09.011; Lee JH, 2019, PHARMACOL RES, V150, DOI 10.1016/j.phrs.2019.104504; Li CY, 2019, EUR J PHARMACOL, V858, DOI 10.1016/j.ejphar.2019.172463; Liang X, 2019, CANCER MANAG RES, V11, P8923, DOI 10.2147/CMAR.S222708; Lin CM, 2005, PLANTA MED, V71, P748, DOI 10.1055/s-2005-871287; Lv SX, 2018, BIOCHEM BIOPH RES CO, V496, P1047, DOI 10.1016/j.bbrc.2018.01.111; MCDERMOTT FT, 1981, BRIT J SURG, V68, P846, DOI 10.1002/bjs.1800681206; Mu D, 2018, J MICROBIOL BIOTECHN, V28, P1426, DOI 10.4014/jmb.1802.02014; Narayanankutty A, 2019, CURR DRUG TARGETS, V20, P1217, DOI 10.2174/1389450120666190618123846; Phipps E, 2008, J EVAL CLIN PRACT, V14, P254, DOI 10.1111/j.1365-2753.2007.00842.x; Rademaker G, 2019, ONCOGENESIS, V8, DOI 10.1038/s41389-019-0130-6; Sun V, 2012, EUR J ONCOL NURS, V16, P276, DOI 10.1016/j.ejon.2011.06.011; Sun X, 2019, CANCER PREV RES, V12, P653, DOI 10.1158/1940-6207.CAPR-19-0134; Wei R, 2019, J EXP CLIN CANC RES, V38, DOI 10.1186/s13046-019-1043-0; Yan S, 2019, ANN TRANSL MED, V7, DOI 10.21037/atm.2019.07.26; Zhang J, 2011, PHARMACOGN MAG, V7, P35, DOI 10.4103/0973-1296.75899; Zhu ML, 2020, BMC COMPLEMENT MED, V20, DOI 10.1186/s12906-020-02965-w	30	0	0	1	1	CANADIAN SCIENCE PUBLISHING	OTTAWA	65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA	0829-8211	1208-6002		BIOCHEM CELL BIOL	Biochem. Cell Biol.	DEC	2021	99	6					741	749		10.1139/bcb-2021-0045			9	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	XD3TW	WOS:000722636000009	34219464	Green Accepted			2022-04-25	
J	Guo, YB; Ye, Q; Deng, P; Cao, YN; He, DH; Zhou, ZH; Wang, C; Zaytseva, YY; Schwartz, CE; Lee, EY; Evers, BM; Morris, AJ; Liu, SD; She, QB				Guo, Yubin; Ye, Qing; Deng, Pan; Cao, Yanan; He, Daheng; Zhou, Zhaohe; Wang, Chi; Zaytseva, Yekaterina Y.; Schwartz, Charles E.; Lee, Eun Y.; Evers, B. Mark; Morris, Andrew J.; Liu, Side; She, Qing-Bai			Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression	NATURE COMMUNICATIONS			English	Article							C-MYC; DIFLUOROMETHYLORNITHINE DFMO; HUMAN-COLON; POLYAMINES; GENE; DEFICIENCY; AUTOPHAGY; MICE; TRANSCRIPTION; SENSITIVITY	Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis and causes tumor regression, but these effects are profoundly attenuated by silencing Bim. These findings uncover a key survival signal in CRC through convergent repression of Bim expression by distinct SMS- and MYC-mediated signaling pathways. Thus, combined inhibition of SMS and MYC signaling may be an effective therapy for CRC. Polyamine metabolism is frequently dysregulated in cancers. Here, the authors show that a polyamine biosynthetic enzyme, spermine synthase, is overexpressed in colorectal cancers and cooperates with MYC to prevent cancer cell apoptosis by repression of proapoptotic protein, Bim.	[Guo, Yubin; Liu, Side] Southern Med Univ, Nanfang Hosp, Dept Gastroenterol, Guangdong Prov Key Lab Gastroenterol, Guangzhou 510515, Peoples R China; [Guo, Yubin; Ye, Qing; Cao, Yanan; He, Daheng; Zhou, Zhaohe; Wang, Chi; Zaytseva, Yekaterina Y.; Lee, Eun Y.; Evers, B. Mark; She, Qing-Bai] Univ Kentucky, Coll Med, Markey Canc Ctr, Lexington, KY 40506 USA; [Ye, Qing; Cao, Yanan; She, Qing-Bai] Univ Kentucky, Coll Med, Dept Pharmacol & Nutr Sci, Lexington, KY 40506 USA; [Deng, Pan] Univ Kentucky, Superfund Res Ctr, Lexington, KY 40536 USA; [Wang, Chi] Univ Kentucky, Coll Publ Hlth, Dept Biostat, Lexington, KY 40506 USA; [Zaytseva, Yekaterina Y.] Univ Kentucky, Coll Med, Dept Toxicol & Canc Biol, Lexington, KY 40506 USA; [Schwartz, Charles E.] Greenwood Genet Ctr, Greenwood, SC 29646 USA; [Lee, Eun Y.] Univ Kentucky, Coll Med, Dept Pathol & Lab Med, Lexington, KY 40506 USA; [Evers, B. Mark] Univ Kentucky, Coll Med, Dept Surg, Lexington, KY 40506 USA; [Morris, Andrew J.] Univ Kentucky, Coll Med, Div Cardiovasc Med, Lexington, KY 40506 USA; [Morris, Andrew J.] Univ Kentucky, Coll Med, Gill Heart Inst, Lexington, KY 40506 USA; [Morris, Andrew J.] Lexington Vet Affairs Med Ctr, Lexington, KY 40506 USA		Liu, SD (corresponding author), Southern Med Univ, Nanfang Hosp, Dept Gastroenterol, Guangdong Prov Key Lab Gastroenterol, Guangzhou 510515, Peoples R China.; She, QB (corresponding author), Univ Kentucky, Coll Med, Markey Canc Ctr, Lexington, KY 40506 USA.; She, QB (corresponding author), Univ Kentucky, Coll Med, Dept Pharmacol & Nutr Sci, Lexington, KY 40506 USA.	liuside@163.com; qing-bai.she@uky.edu	He, Daheng/AAR-1813-2021; Cao, Yanan/AAF-7356-2021	Deng, Pan/0000-0003-2974-7389; She, Qing-Bai/0000-0002-7207-0599	NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA203257]; University of Kentucky [CCTS UL1TR001998]; NIH/NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [P30GM127211]; South Carolina Department of Disabilities and Special Needs; University of Kentucky Markey Cancer Center [P30CA177558, CCSG P30CA177558]	We thank the Markey Cancer Center's Research Communication Office for assistance with manuscript preparation. This work was supported by NCI grant R01CA203257, Start-Up funds (Q.-B.S.), pilot grants (Q.-B.S.) from CCSG P30CA177558 (University of Kentucky Markey Cancer Center) and CCTS UL1TR001998 (University of Kentucky), NIH/NIGMS grant P30GM127211 (A.J.M.), and a grant from the South Carolina Department of Disabilities and Special Needs (C.E.S.). This work was also supported in part by the Biospecimen Procurement and Translational Pathology, Cancer Research Informatics, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558).	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Commun.	JUN 26	2020	11	1								10.1038/s41467-020-17067-x			16	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	ME9AS	WOS:000544947000003	32591507	Green Published, gold			2022-04-25	
J	Zhao, Z; Feng, L; Wang, JQ; Cheng, DS; Liu, M; Ling, MR; Xu, WP; Sun, KY				Zhao, Zhen; Feng, Li; Wang, Jiqin; Cheng, Deshan; Liu, Mei; Ling, Meirong; Xu, Weiping; Sun, Keyu			NPC-26 kills human colorectal cancer cells via activating AMPK signaling	ONCOTARGET			English	Article						NPC-26; colorectal cancer; AMP-activated protein kinase (AMPK); mitochondrion; cell death	PROTEIN-KINASE AMPK; INDUCED GROWTH-INHIBITION; COLON-CANCER; INDUCED APOPTOSIS; CYCLOSPORINE-A; IN-VITRO; METABOLISM; AUTOPHAGY; SURVIVAL; CONTRIBUTES	NPC-26 is novel mitochondrion-interfering compound. The current study tested its potential effect against colorectal cancer (CRC) cells. We demonstrated that NPC-26 induced potent anti-proliferative and cytotoxic activities against CRC cell lines (HCT116, DLD-1 and HT-29). Activation of AMP-activated protein kinase (AMPK) signaling mediated NPC-26-induced CRC cell death. AMPKa1 shRNA knockdown or dominant negative mutation abolished NPC-26-induced AMPK activation and subsequent CRC cell death. NPC-26 disrupted mitochondrial function, causing mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) production. ROS scavengers (NAC or MnTBAP) and mPTP blockers (cyclosporin A or sanglifehrin A) blocked NPC-26-induced AMPK activation and attenuated CRC cell death. Significantly, intraperitoneal injection of NPC-26 potently inhibited HCT-116 tumor growth in severe combined immuno-deficient (SCID) mice. Yet, its anti-tumor activity was significantly weakened against AMPKa1-silenced HCT-116 tumors. Together, we conclude that NPC-26 kills CRC cells possibly via activating AMPK signaling.	[Zhao, Zhen] Fudan Univ, Minhang Hosp, Clin Lab, Shanghai, Peoples R China; [Feng, Li] Fudan Univ, Minhang Hosp, Dept Gastroenterol, Shanghai, Peoples R China; [Wang, Jiqin; Cheng, Deshan; Liu, Mei; Ling, Meirong; Sun, Keyu] Fudan Univ, Minhang Hosp, Emergency Dept, Shanghai, Peoples R China; [Xu, Weiping] Shanghai Univ Med Hlth Sci, Shanghai, Peoples R China		Sun, KY (corresponding author), Fudan Univ, Minhang Hosp, Emergency Dept, Shanghai, Peoples R China.; Xu, WP (corresponding author), Shanghai Univ Med Hlth Sci, Shanghai, Peoples R China.	weipingxulunwen@163.com; sunkeyulunwen@163.com			Shanghai medical key subject construction project [ZK2015B15]; Shanghai weak discipline construction plan [2016ZB0202]; Shanghai Minhang District science and technology research plan [2015MHZ039]	This work is supported by Shanghai medical key subject construction project (ZK2015B15), Shanghai weak discipline construction plan (2016ZB0202) and Shanghai Minhang District science and technology research plan (2015MHZ039). The funders have no role in design, in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.	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J	Wang, L; Yao, L; Li, XY; Chen, J; Lou, CH; Wang, YQ				Wang, Lu; Yao, Li; Li, Xiaoyu; Chen, Juan; Lou, Chenghua; Wang, Yiqi			Stephanthraniline A suppresses proliferation of HCT116 human colon cancer cells through induction of caspase-dependent apoptosis, dysregulation of mitochondrial function, cell cycle arrest and regulation of Akt/p38 signaling pathways	JOURNAL OF TOXICOLOGICAL SCIENCES			English	Article						C-21 steroidal aglycone; Apoptosis; Cell cycle arrest; Colon cancer	P38 MAPK; COLORECTAL-CANCER; IN-VITRO; INHIBITION; GLYCOSIDES; AUTOPHAGY; PI3K/AKT; KINASES	Stephanthraniline A (STA) is a C-21 steroidal aglycone isolated from the stem of Stephanotis mucronata (Blanco) Merr. that exerts growth inhibition in human colon cancer cells. However, the intracellular molecular mechanisms whereby this occurs have not been well characterized. In this study, we found that STA significantly inhibits the growth of HCT116 colon cancer cells in a time- and concentration-dependent manner. The inhibitory effect of STA on cell growth was related to the induction of apoptosis. Activated caspase-3, caspase-8 and caspase-9, along with a decreased Bcl-2/Bcl-x ratio and loss of mitochondria! membrane potential (Delta psi(m)), were observed in response to STA treatment. Furthermore, treatment of HCT116 cells with STA resulted in G0/G1 phase cell cycle arrest accompanied by decreased mRNA levels of cyclin-dependent kinase 4 (CDK4), p21 and c-myc. Additionally, the inhibition of Akt signaling and activation of p38 signaling were observed after treatment with STA in HCT116 cells. These findings indicate that STA inhibits HCT116 cell growth by promoting apoptosis, the dysregulation of mitochondrial function, and cell cycle arrest.	[Wang, Lu; Yao, Li; Lou, Chenghua; Wang, Yiqi] Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Zhejiang, Peoples R China; [Li, Xiaoyu] Zhejiang Acad Med Sci, Inst Mat Med, Hangzhou 310013, Zhejiang, Peoples R China; [Chen, Juan] Zhejiang Chinese Med Univ, Sch Basic Med Sci, Hangzhou 310053, Zhejiang, Peoples R China		Lou, CH; Wang, YQ (corresponding author), Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Zhejiang, Peoples R China.; Li, XY (corresponding author), Zhejiang Acad Med Sci, Inst Mat Med, Hangzhou 310013, Zhejiang, Peoples R China.	775423305@qq.com; lou.chenghua@hotmail.com; wangyiqi2011@126.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81603363, 81803806]	This work was financially supported by the National Natural Science Foundation of China (grant number #81603363, #81803806).	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Toxicol. Sci.		2019	44	7-9					523	533		10.2131/jts.44.523			11	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	KM6MM	WOS:000514252200008	31378763	gold			2022-04-25	
J	Li, BX; Li, CY; Peng, RQ; Wu, XJ; Wang, HY; Wan, DS; Zhu, XF; Zhang, XS				Li, Bao-Xiu; Li, Chun-Yan; Peng, Rui-Qing; Wu, Xiao-Jun; Wang, Hai-Ying; Wan, De-Sen; Zhu, Xiao-Feng; Zhang, Xiao-Shi			The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers	AUTOPHAGY			English	Article						beclin 1; prognosis; colon cancer; tumor suppressor gene; immunohistochemistry	MESSENGER-RNA EXPRESSION; AUTOPHAGY; GENE; PROTEIN	Beclin 1 is a key modulator bridging autophagy, apoptosis and differentiation. This study investigated the expression of beclin 1 in human colon cancers and its association with clinicopathological characteristics. A total of 115 cases of cancer tissues with intact follow-up data were obtained from colon cancer patients with stage IIIB. The expression of beclin 1 in cancer nest and adjacent normal tissue was examined with immunohistochemistry. The results showed the immunostaining of beclin 1 was distributed in plasma-membrane, cytoplasm and nucleus in tumor cells, which occurred in 98 cases (85.2%) of the 115 patients. No or modest beclin I expression was observed in adjacent noncancerous tissues. The higher level of beclin 1 expression strongly associated with longer survival. Both univariate analysis and multivariate analysis showed that the beclin I expression and invasive depth of primary mass (T stage) were independent prognostic factors. Additionally, there was no significant correlation of beclin 1 expression with clinicopathological characteristics, such as sex, age, site of primary mass, pathological classification, grade and invasive depth with the nonparametric correlation Kendall's tau-b test.	[Li, Bao-Xiu; Li, Chun-Yan; Peng, Rui-Qing; Wu, Xiao-Jun; Wang, Hai-Ying; Wan, De-Sen; Zhu, Xiao-Feng; Zhang, Xiao-Shi] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol S China, Guangzhou 510060, Guangdong, Peoples R China; [Li, Bao-Xiu; Li, Chun-Yan; Peng, Rui-Qing; Wang, Hai-Ying; Zhang, Xiao-Shi] Sun Yat Sen Univ, Ctr Canc, Biotherapy Ctr, Guangzhou 510060, Guangdong, Peoples R China; [Wu, Xiao-Jun; Wan, De-Sen] Sun Yat Sen Univ, Ctr Canc, Dept Abdominal Oncol, Guangzhou 510060, Guangdong, Peoples R China; [Zhu, Xiao-Feng] Sun Yat Sen Univ, Ctr Canc, Dept Expt Res, Guangzhou 510060, Guangdong, Peoples R China		Zhang, XS (corresponding author), Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol S China, 651 Dongfeng Rd E, Guangzhou 510060, Guangdong, Peoples R China.	zxs617@hotmail.com			Nature Science Foundation [05001693]; Bureau of Health Foundation of Guangdong Province, China [B2007071]	This study was supported by Nature Science Foundation (05001693) and Bureau of Health Foundation of Guangdong Province, China (B2007071).	Ahn CH, 2007, APMIS, V115, P1344, DOI 10.1111/j.1600-0463.2007.00858.x; Chen M, 2008, AUTOPHAGY, V4, P926, DOI 10.4161/auto.6716; Daniel F, 2007, CANCER INVEST, V25, P226, DOI 10.1080/07357900701206323; Erlich S, 2007, AUTOPHAGY, V3, P561, DOI 10.4161/auto.4713; Huerta S, 2008, EXPERT REV MOL DIAGN, V8, P277, DOI 10.1586/14737159.8.3.277; Jemal A, 2008, CA-CANCER J CLIN, V58, P71, DOI 10.3322/CA.2007.0010; Jin SK, 2007, AUTOPHAGY, V3, P28, DOI 10.4161/auto.3269; Karantza-Wadsworth V, 2007, AUTOPHAGY, V3, P610, DOI 10.4161/auto.4867; Koneri K, 2007, ANTICANCER RES, V27, P1453; Lee JW, 2007, APMIS, V115, P750, DOI 10.1111/j.1600-0463.2007.apm_640.x; 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; Liu CP, 2008, CHINESE J STRUC CHEM, V27, P25; Mathew R, 2007, GENE DEV, V21, P1367, DOI 10.1101/gad.1545107; Meyerhardt JA, 2005, NEW ENGL J MED, V352, P476, DOI 10.1056/NEJMra040958; Miracco C, 2007, INT J ONCOL, V30, P429; Sato K, 2007, CANCER RES, V67, P9677, DOI 10.1158/0008-5472.CAN-07-1462; Shen Y, 2008, AUTOPHAGY, V4, P1067, DOI 10.4161/auto.6827; Xu Y, 2008, AUTOPHAGY, V4, P110, DOI 10.4161/auto.5225; Zhang HF, 2008, J BIOL CHEM, V283, P10892, DOI 10.1074/jbc.M800102200; Zhang NH, 2008, CELL CYCLE, V7, P925, DOI 10.4161/cc.7.7.5621	21	123	126	0	12	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	1554-8627	1554-8635		AUTOPHAGY	Autophagy	APR 1	2009	5	3					303	306		10.4161/auto.5.3.7491			4	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	439KP	WOS:000265626300004	19066461	Bronze			2022-04-25	
J	Mosca, L; Pagano, M; Borzacchiello, L; Mele, L; Russo, A; Russo, G; Cacciapuoti, G; Porcelli, M				Mosca, Laura; Pagano, Martina; Borzacchiello, Luigi; Mele, Luigi; Russo, Annapina; Russo, Giulia; Cacciapuoti, Giovanna; Porcelli, Marina			S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-kappa B Activation	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						S-Adenosylmethionine; colorectal cancer; 5-Fluorouracil; multidrug resistance; P-glycoprotein; combination therapy	METHYL DONOR; COLON-CANCER; NATURAL COMPOUNDS; METHYLTHIOADENOSINE; APOPTOSIS; AUTOPHAGY; THERAPY	Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116(p53+/+) and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-kappa B, the activated form of NF-kappa B, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-kappa B signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.	[Mosca, Laura; Pagano, Martina; Borzacchiello, Luigi; Cacciapuoti, Giovanna; Porcelli, Marina] Univ Campania Luigi Vanvitelli, Dept Precis Med, Via Luigi De Crecchio 7, I-80138 Naples, Italy; [Pagano, Martina; Russo, Annapina; Russo, Giulia] Univ Naples Federico II, Dept Pharm, Via Domenico Montesano 49, I-80131 Naples, Italy; [Mele, Luigi] Univ Campania Luigi Vanvitelli, Dept Expt Med, Via Luciano Armanni 5, I-80138 Naples, Italy		Cacciapuoti, G; Porcelli, M (corresponding author), Univ Campania Luigi Vanvitelli, Dept Precis Med, Via Luigi De Crecchio 7, I-80138 Naples, Italy.	laura.mosca@unicampania.it; martina.pagano@unicampania.it; luigi.borzacchiello@unicampania.it; luigi.mele@unicampania.it; annapina.russo@unina.it; giulia.russo@unina.it; giovanna.cacciapuoti@unicampania.it; marina.porcelli@unicampania.it			Intradepartmental Projects, Department of Precision Medicine, Universita della Campania "Luigi Vanvitelli"; Regione Campania-POR Campania FESR 2014/2020 "Combattere la resistenza tumorale: piattaforma integrata multidisciplinare 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); Programme Valere 2019 (Progetto competitive intra/Ateneo "GO MAGIC" Universita della Campania "Luigi Vanvitelli")	The work was partially supported by Programme Valere 2019 (Progetto competitive intra/Ateneo "GO MAGIC" Universita della Campania "Luigi Vanvitelli") and by Intradepartmental Projects, Department of Precision Medicine, Universita della Campania "Luigi Vanvitelli", and by a grant from Regione Campania-POR Campania FESR 2014/2020 "Combattere la resistenza tumorale: piattaforma integrata multidisciplinare per un approccio tecnologico innovativo alle oncoterapie-Campania Oncoterapie" Project N. B61G18000470007 (A.R.); Fondo di ricerca di base FFABR-2017 (A.R. and G.R.); Ministero della Universita e della Ricerca (MIUR).	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J. Mol. Sci.	SEP	2021	22	17							9286	10.3390/ijms22179286			17	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	UO0BW	WOS:000694371000001	34502219	Green Published, gold			2022-04-25	
J	Garcia-Princival, IMR; Princival, JL; da Silva, ED; Lima, SMD; Carregosa, JC; Wisniewski, A; de Lucena, CCO; Halwass, F; Franca, JAA; Ferreira, LFGR; Hernandes, MZ; Saraiva, KLA; Peixoto, CA; Baratte, B; Robert, T; Bach, S; Gomes, DC; Paiva, PMG; Marchand, P; Rodrigues, MD; da Silva, TG				Rodini Garcia-Princival, Iza Mirela; Princival, Jefferson Luiz; da Silva, Emmanuel Dias; de Arruda Lima, Sandrine Maria; Carregosa, Jhonattas Carvalho; Wisniewski Jr, Alberto; Oliveira de Lucena, Caio Cezar; Halwass, Fernando; Alves Franca, Jose Adonias; Gomes Rebello Ferreira, Luiz Felipe; Hernandes, Marcelo Zaldini; Alcantara Saraiva, Karina Lidianne; Peixoto, Christina Alves; Baratte, Blandine; Robert, Thomas; Bach, Stephane; Gomes, Dayene Correia; Guedes Paiva, Patricia Maria; Marchand, Pascal; Rodrigues, Maria Desterro; da Silva, Teresinha Goncalves			Streptomyces hygroscopicus UFPEDA 3370: A valuable source of the potent cytotoxic agent nigericin and its evaluation against human colorectal cancer cells	CHEMICO-BIOLOGICAL INTERACTIONS			English	Article						Autophagy; Natural products; Nigericin; Protein kinases; Apoptosis	LUNG-CARCINOMA; JANUS KINASE; AUTOPHAGY; APOPTOSIS; ANTITUMOR; INHIBITION; CROSSTALK; GSK3-BETA; SURVIVAL; TARGETS	Streptomyces hygroscopicus UFPEDA 3370 was fermented in submerged cultivation and the biomass extract was partitioned, obtaining a fraction purified named EB1. After purification of EB1 fraction, nigericin free acid was obtained and identified. Nigericin presented cytotoxic activity against several cancer cell lines, being most active against HL-60 (human leukemia) and HCT-116 (human colon carcinoma) cell lines, presenting IC50 and (IS) values: 0.0014 mu M, (30.0) and 0.0138 mu M (3.0), respectively. On HCT-116, nigericin caused apoptosis and autophagy. In this study, nigericin was also screened both in vitro and in silico against a panel of cancer-related kinases. Nigericin was able to inhibit both JAK3 and GSK-3 beta kinases in vitro and its binding affinities were mapped through the intermolecular interactions with each target in silico.	[Rodini Garcia-Princival, Iza Mirela; de Arruda Lima, Sandrine Maria; Oliveira de Lucena, Caio Cezar; Rodrigues, Maria Desterro; da Silva, Teresinha Goncalves] Univ Fed Pernambuco, Dept Antibiot, Rua Prof Moraes Rego 1235, BR-50670901 Recife, PE, Brazil; [Princival, Jefferson Luiz; da Silva, Emmanuel Dias; Halwass, Fernando; Alves Franca, Jose Adonias] Univ Fed Pernambuco, Dept Quim Fundamental, Av Jornalista Anibal Fernandes S-N, BR-50740560 Recife, PE, Brazil; [Carregosa, Jhonattas Carvalho; Wisniewski Jr, Alberto] Univ Fed Sergipe, Dept Quim, Av Marechal Rondon S-N, BR-49100000 Aracaju, Sergipe, Brazil; [Gomes Rebello Ferreira, Luiz Felipe; Hernandes, Marcelo Zaldini] Univ Fed Pernambuco, Dept Ciencias Farmaceut, Lab Quim Teor Med LQTM, Av Prof Artur de Sa,Cidade Univ, BR-50740521 Recife, PE, Brazil; [Alcantara Saraiva, Karina Lidianne; Peixoto, Christina Alves] Fundacao Oswaldo Cruz FIOCRUZ, Lab Ultraestrutura Inst Aggeu Magalhaes IAM, Recife, PE, Brazil; [Peixoto, Christina Alves] Fundacao Oswaldo Cruz, Inst Ciencias & Tecnol Neuroimunomodulacao INCT N, Inst Oswaldo Cruz, Rio De Janeiro, RJ, Brazil; [Baratte, Blandine; Robert, Thomas; Bach, Stephane] Sorbonne Univ, Stn Biol Roscoff, Integrat Biol Marine Models Lab LBI2M, CNRS,UMR8227, F-29680 Roscoff, France; [Baratte, Blandine; Robert, Thomas; Bach, Stephane] Sorbonne Univ, CNRS, FR2424,Stn Biol, Kinase Inhibitor Specialized Screening Facil KISS, F-29688 Roscoff, France; [Gomes, Dayene Correia; Guedes Paiva, Patricia Maria] Univ Fed Pernambuco, Dept Bioquim, Rua Prof Moraes Rego SN, BR-50670420 Recife, PE, Brazil; [Marchand, Pascal] Univ Nantes, Cibles & Medicaments Infect & Canc, IICiMed, EA 1155, F-44000 Nantes, France		da Silva, TG (corresponding author), Univ Fed Pernambuco, Dept Antibiot, Rua Prof Moraes Rego 1235, BR-50670901 Recife, PE, Brazil.	baratte@sd-roscoff.fr; bach@sb-roscoff.fr; teresinha.goncalces@pq.cnpq.br	Wisniewski, Alberto/AAB-9263-2021; Paiva, Patricia Maria Guedes/S-4038-2019; Wisniewski, Alberto/E-9639-2014; da Silva, Emmanuel Dias/ABA-8679-2020; Gonçalves-Silva, TERESINHA/ABE-4945-2021	Wisniewski, Alberto/0000-0001-6815-0265; Paiva, Patricia Maria Guedes/0000-0003-3467-708X; Wisniewski, Alberto/0000-0001-6815-0265; da Silva, Emmanuel Dias/0000-0002-9678-7164; Carregosa, Jhonattas/0000-0002-9789-4551	CNPqConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ); FACEPEFundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE); CAPES/COFECUB programCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); FACEPEFundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE) [BFP-0109-4.03/19]	The authors thank CNPq, FACEPE and CAPES/COFECUB program for Financial support. The authors are also grateful to Central Analitica DQF from Federal University of Pernambuco (UFPE) for the infra structure and Center of Multi-users Chemistry Laboratory (CLQM) from Federal University of Sergipe (UFS) for the UHRMS facility, and Max Planck Institute for Biophysical Chemistry for the NMR spectra. The author Luiz F. G. R. Ferreira would like to thank the postdoctoral grant (BFP-0109-4.03/19) from FACEPE. The authors also thank the Canceropole Grand-Ouest (axis: Marine drugs, metabolism and cancer), GIS IBiSA (Infrastructures en Biologie Sante et Agronomie, France) and Biogenouest (Western France life science and environment core facility network) for supporting KISSf screening facility (Roscoff, France).	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Interact.	JAN 5	2021	333								109316	10.1016/j.cbi.2020.109316			11	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	PI1BB	WOS:000600832900006	33285127				2022-04-25	
J	Ljujic, M; Mijatovic, S; Bulatovic, MZ; Mojic, M; Maksimovic-Ivanic, D; Radojkovic, D; Topic, A				Ljujic, M.; Mijatovic, S.; Bulatovic, M. Z.; Mojic, M.; Maksimovic-Ivanic, D.; Radojkovic, D.; Topic, A.			ALPHA-1 Antitrypsin Affects U0126-Induced Cytotoxicity in Colon Cancer Cell Line (HCT116)	MOLECULAR BIOLOGY			English	Article						alpha-1 antitrypsin; apoptosis; autophagy; colon cancer cell line (HCT116)	PROGNOSTIC-SIGNIFICANCE; AUTOPHAGY; INHIBITOR; MALIGNANCY; LUNG	Alpha-1-antitrypsin (AAT), an acute phase protein, is the principal circulatory anti-protease. This multifunctional protein is encoded by the SERPINA1 gene. Although AAT was recognised as a potential tumour marker, its role in cancer biology remains unknown. Given that it has been demonstrated that AAT has an anti-apoptotic property against non-malignant cells, we aimed to investigate whether AAT affects apoptosis in a colon cancer cell line (HCT116). The presence of AAT in the HCT116 cell culture antagonized cytotoxicity of blockers of MEK1/2, PI3K/Akt pathways as well as NF-kappa B. The dominantly recovered cell viability was observed in the co-treatment with MEK1/2 inhibitor U0126. In addition, it was revealed that AAT almost completely abolished U0126-induced apoptosis through maintenance of the autophagy process. Our study revealed for the first time that the observed cyto-protection triggered by AAT was accompanied by sustained autophagy which opposed apoptosis. These results may contribute to understanding of the role of AAT in cancer development and evaluation of efficacy of cancer therapy.	[Ljujic, M.; Radojkovic, D.] Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade, Serbia; [Mijatovic, S.; Bulatovic, M. Z.; Mojic, M.; Maksimovic-Ivanic, D.] Univ Belgrade, Inst Biol Res Sinisa Stankovic, Belgrade, Serbia; [Topic, A.] Univ Belgrade, Fac Pharm, Inst Med Biochem, Belgrade, Serbia		Topic, A (corresponding author), Univ Belgrade, Fac Pharm, Inst Med Biochem, Belgrade, Serbia.	aleksandra.topic1@gmail.com		Ljujic, Mila/0000-0003-4428-2938	Serbian Ministry of Education and ScienceMinistry of Education, Science & Technological Development, Serbia [173013, 173008]	This work was supported by the Serbian Ministry of Education and Science (grant nos. 173013 and 173008).	Bujanda L, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0051810; Cheong H, 2015, ARCH PHARM RES, V38, P358, DOI 10.1007/s12272-015-0562-2; de Sa SV, 2007, CLIN CANCER RES, V13, P5322, DOI 10.1158/1078-0432.CCR-06-1477; HIGASHIYAMA M, 1992, BRIT J CANCER, V65, P300, DOI 10.1038/bjc.1992.60; Hsu PI, 2010, CANCER EPIDEM BIOMAR, V19, P405, DOI 10.1158/1055-9965.EPI-09-0609; Janciauskiene SM, 2011, RESP MED, V105, P1129, DOI 10.1016/j.rmed.2011.02.002; KARASHIMA S, 1990, INT J CANCER, V45, P244, DOI 10.1002/ijc.2910450207; Keppler D, 1996, BIOL CHEM H-S, V377, P301, DOI 10.1515/bchm3.1996.377.5.301; Kwon CH, 2014, BRIT J CANCER, V111, P1993, DOI 10.1038/bjc.2014.490; Li Y, 2011, J THORAC ONCOL, V6, P291, DOI 10.1097/JTO.0b013e31820213fb; Lockett AD, 2012, MOL MED, V18, P445, DOI 10.2119/molmed.2011.00207; Perez-Holanda S, 2014, BMC CANCER, V14, DOI 10.1186/1471-2407-14-355; Petrache I, 2006, AM J PATHOL, V169, P1155, DOI 10.2353/ajpath.2006.060058; Rosenfeldt MT, 2011, CARCINOGENESIS, V32, P955, DOI 10.1093/carcin/bgr031; Yang ZNJ, 2011, MOL CANCER THER, V10, P1533, DOI 10.1158/1535-7163.MCT-11-0047	15	1	1	3	5	MAIK NAUKA/INTERPERIODICA/SPRINGER	NEW YORK	233 SPRING ST, NEW YORK, NY 10013-1578 USA	0026-8933	1608-3245		MOL BIOL+	Mol. Biol.	JAN	2016	50	1					153	156		10.1134/S002689331601012X			4	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	DO9XB	WOS:000378140200018					2022-04-25	
J	Xu, CY; Zhang, WL; Liu, SQ; Wu, WH; Qin, MB; Huang, J				Xu, Chunyan; Zhang, Wenlu; Liu, Shiquan; Wu, Wenhong; Qin, Mengbin; Huang, Jiean			Activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer cells	ONCOLOGY LETTERS			English	Article						autophagy; sphingosine kinase 1; phosphate-extracellular signal-regulated kinase; colon cancer	SIGNALING PATHWAY; PROLIFERATION; MIGRATION; METASTASIS; EXPRESSION; SURVIVAL; INVASION	Sphingosine kinase 1 (SphK1) is a master kinase that catalyzes the synthesis of sphingosine 1 phosphate and participates in the regulation of cell proliferation and autophagy. The present study aimed to assess the effects of the activation of the SphK1/extracellular signal-regulated kinase (ERK)/phosphorylated (p-) ERK pathway in the regulation of autophagy in colon cancer (HT-29) cells. Inverted fluorescence microscopy was used to detect the expression of green fluorescent protein (GFP) in the SphK1-overexpressing HT-29 cells [SphK1(+)-HT-29] and the negative control HT-29 cells (NC-HT-29). Western blotting was used to detect the protein expression levels of SphK1, ERK1/2, p-ERK1/2, as well as those of the autophagy-associated markers LC3A, ATG5, and ULK1. Protein localization and expression of the LC3A antibody were detected by immunofluorescence. The results demonstrated that GFP was similarly expressed in SphK1(+)-HT-29 and NC-HT-29 cells. However, significantly increased SphK1 mRNA and protein expression levels were detected in SphK1(+)-HT-29 cells compared with in NC-HT-29 cells, which resulted in upregulated ERK/p-ERK. Furthermore, the protein expression levels of the three autophagy-associated markers increased. LC3A protein was localized in the cytoplasm of SphK1(+)-HT-29 cells, indicating autophagy. In summary, the findings of the present study suggested that activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer HT-29 cells.	[Xu, Chunyan; Liu, Shiquan; Wu, Wenhong; Qin, Mengbin; Huang, Jiean] Guangxi Med Univ, Dept Gastroenterol, Affiliated Hosp 2, 166 Daxuedong Rd, Nanning 530007, Guangxi, Peoples R China; [Zhang, Wenlu] Guangxi Med Univ, Dept Resp Med, Affiliated Hosp 1, Nanning 530021, Guangxi, Peoples R China		Liu, SQ; Huang, J (corresponding author), Guangxi Med Univ, Dept Gastroenterol, Affiliated Hosp 2, 166 Daxuedong Rd, Nanning 530007, Guangxi, Peoples R China.	poempower@163.com; 1404991727@qq.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81460380, g81260365]; Guangxi Graduate Education [YCBZ2017035, YCSW2017100]	This work was supported by grants from the National Natural Science Foundation of China (grant nos. 81460380 and g81260365) and the Innovation Project of Guangxi Graduate Education (grant nos. YCBZ2017035 and YCSW2017100).	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Lett.	JUN	2018	15	6					9719	9724		10.3892/ol.2018.8588			6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GJ3BK	WOS:000435149700197	29928348	Green Published, gold, Green Submitted			2022-04-25	
J	Blondy, S; David, V; Verdier, M; Mathonnet, M; Perraud, A; Christou, N				Blondy, Sabrina; David, Valentin; Verdier, Mireille; Mathonnet, Muriel; Perraud, Aurelie; Christou, Niki			5-Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes	CANCER SCIENCE			English	Review						5-fluorouracil; colorectal cancer; resistance mechanism	SYNTHASE MESSENGER-RNA; CELL-LINES RESISTANT; COLON-CANCER; CONFERS RESISTANCE; APOPTOTIC PATHWAY; DRUG-RESISTANCE; DNA METHYLATION; TGF-BETA; EXPRESSION; PROMOTES	Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5-fluorouracil (5-FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5-FU resistance. Some are disease-specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5-FU. In this review, we construct a global outline of different mechanisms from disruption of 5-FU-metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial-mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.	[Blondy, Sabrina; David, Valentin; Verdier, Mireille; Mathonnet, Muriel; Perraud, Aurelie; Christou, Niki] CAPTuR Control Cell Activat Tumor Progress & Ther, Lab EA3842, Fac Med, Limoges, France; [David, Valentin] Univ Hosp Limoges, Dept Pharm, Limoges, France; [Mathonnet, Muriel; Perraud, Aurelie; Christou, Niki] Univ Hosp Limoges, Serv Chirurg Digest, Dept Digest Gen & Endocrine Surg, Limoges, France		Christou, N (corresponding author), CHU Limoges, Serv Chirurg Digest Gen & Endocrinienne, Limoges, France.	christou.niki19@gmail.com	Mathonnet, Muriel/ABD-3021-2020; DAVID, Valentin/P-4483-2019; DAVID, Valentin/O-5067-2018	Mathonnet, Muriel/0000-0002-9127-3068; DAVID, Valentin/0000-0002-2260-6690; DAVID, Valentin/0000-0002-2260-6690; VERDIER, Mireille/0000-0002-8162-4856; Perraud, Aurelie/0000-0001-7882-0613			Abiko K, 2015, BRIT J CANCER, V112, P1501, DOI 10.1038/bjc.2015.101; Ambriovic-Ristov A, 2006, CURR SIGNAL TRANSD T, V1, P227, DOI 10.2174/157436206777012048; Ambudkar SV, 2006, EUR J PHARM SCI, V27, P392, DOI 10.1016/j.ejps.2005.10.010; 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SEP	2020	111	9					3142	3154		10.1111/cas.14532		AUG 2020	13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	NI5TU	WOS:000558760900001	32536012	gold, Green Published			2022-04-25	
J	Hotta, M; Sakatani, T; Ishino, K; Wada, R; Kudo, M; Yokoyama, Y; Yamada, T; Yoshida, H; Naito, Z				Hotta, Masahiro; Sakatani, Takashi; Ishino, Kousuke; Wada, Ryuichi; Kudo, Mitsuhiro; Yokoyama, Yasuyuki; Yamada, Takeshi; Yoshida, Hiroshi; Naito, Zenya			Farnesoid X receptor induces cell death and sensitizes to TRAIL-induced inhibition of growth in colorectal cancer cells through the up-regulation of death receptor 5	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Colorectal cancer; Farnesoid X receptor; Proteomics; Death receptor 5; Autophagy; TRAIL	NUCLEAR RECEPTORS; EXPRESSION; CARCINOMA; AUTOPHAGY; DR5	Farnesoid X receptor (FXR) exhibits critical anti-cancer functions in several types of cancer, including colorectal cancer, in vitro and in vivo. However, the underlying mechanism remains unclear. We evaluated pharmacological activation of FXR with the synthetic agonist GW4064 using comprehensive proteomic analysis in colorectal cancer cell lines (HCT116, SW480, and DLD1). Among the commonly detected proteins in all three cell lines, death receptor 5 (DR5) was the most up-regulated protein, and key autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 alpha/beta (MLP3A/36) and p62 sequestosome-1 (SQSTM), were also differentially expressed. Western blot analysis showed that GW4064 stimulation induced activation of the extrinsic death signaling pathway in all cell lines and induced activation of the intrinsic death signaling pathway in DLD1 cells. Western blotting showed that DR5 up-regulation was associated with inhibition of autophagic activity. These results suggest that FXR activation induced DR5 up-regulation through inhibition of autophagic activity and the DR5-related death signaling pathway. In addition, DR5 selective ligand, also known as TRAIL, has been widely used for anti-cancer treatment in several clinical trials. Co-treatment of TRAIL with GW4064 synergistically inhibited colorectal cancer cell proliferation as compared with single treatments. To the best of our knowledge, our results provide novel insights into FXR function in cancer cell lines. These findings may contribute to a new therapeutic strategy for colorectal cancer. (C) 2019 Elsevier Inc. All rights reserved.	[Hotta, Masahiro; Sakatani, Takashi; Ishino, Kousuke; Wada, Ryuichi; Kudo, Mitsuhiro; Yokoyama, Yasuyuki; Naito, Zenya] Nippon Med Sch, Dept Integrated Diagnost Pathol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo, Japan; [Hotta, Masahiro; Yokoyama, Yasuyuki; Yamada, Takeshi; Yoshida, Hiroshi] Nippon Med Sch, Dept Gastrointestinal & HepatoBiliary Pancreat Su, Bunkyo Ku, 1-1-5 Sendagi, Tokyo, Japan; [Sakatani, Takashi] Nippon Med Coll Hosp, Dept Diagnost Pathol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan		Sakatani, T (corresponding author), Nippon Med Coll Hosp, Dept Diagnost Pathol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan.	takashi-sakatani@nms.ac.jp	Ishino, Kousuke/G-8473-2018	Ishino, Kousuke/0000-0002-6862-9898			Alves S, 2015, ONCOTARGET, V6, P30787, DOI 10.18632/oncotarget.5021; Chen L, 2016, CELL DEATH DIS, V7, DOI 10.1038/cddis.2016.234; de Miguel D, 2016, CELL DEATH DIFFER, V23, P733, DOI 10.1038/cdd.2015.174; Degirolamo C, 2011, TRENDS MOL MED, V17, P564, DOI 10.1016/j.molmed.2011.05.010; Dermadi D, 2017, CANCER RES, V77, P3352, DOI 10.1158/0008-5472.CAN-16-2860; Gadaleta RM, 2017, MOL ASPECTS MED, V56, P66, DOI 10.1016/j.mam.2017.04.002; Glab JA, 2017, CELL DEATH DIFFER, V24, P944, DOI 10.1038/cdd.2017.53; Goncharenko-Khaider N, 2010, ONCOGENE, V29, P5523, DOI 10.1038/onc.2010.288; Haimovici A, 2017, CELL DEATH DIFFER, V24, P866, DOI 10.1038/cdd.2017.40; Ishino K, 2018, BIOCHEM BIOPH RES CO, V501, P668, DOI 10.1016/j.bbrc.2018.05.041; Kanzaki A, 2016, INT J ONCOL, V48, P1007, DOI 10.3892/ijo.2016.3323; Klionsky DJ, 2016, AUTOPHAGY, V12, P1, DOI 10.1080/15548627.2015.1100356; Kondo R, 2019, INT J ONCOL, V54, P1409, DOI 10.3892/ijo.2019.4710; Lax S, 2012, INT J CANCER, V130, P2232, DOI 10.1002/ijc.26293; Lee JM, 2014, NATURE, V516, P112, DOI 10.1038/nature13961; Lee J, 2010, J BIOL CHEM, V285, P12604, DOI 10.1074/jbc.M109.094524; Lew JL, 2004, J BIOL CHEM, V279, P8856, DOI 10.1074/jbc.M306422200; Modica S, 2008, CANCER RES, V68, P9589, DOI 10.1158/0008-5472.CAN-08-1791; Ohno T, 2012, CANCER LETT, V323, P215, DOI 10.1016/j.canlet.2012.04.015; Park E.J., 2016, SCI REP, V6, P1; Perimenis P., 2016, BMC CANCER, V16, P1; Qiao X., 2018, CANCER COMMUN, V38, P1; Romagnolo DF, 2014, ADV NUTR, V5, P373, DOI 10.3945/an.114.005868; Seok S, 2014, NATURE, V516, P108, DOI 10.1038/nature13949; Xie G., 2015, J CANC METASTATSIS T, V2, P24; Xie Guofeng, 2016, J Cancer Metastasis Treat, V2, P195, DOI 10.20517/2394-4722.2016.05	26	4	4	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. Biophys. Res. Commun.	NOV 19	2019	519	4					824	831		10.1016/j.bbrc.2019.09.033			8	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	KB3OO	WOS:000506409400025	31561852				2022-04-25	
J	Vanderlaag, K; Su, YP; Frankel, AE; Burghardt, RC; Barhoumi, R; Chadalapaka, G; Jutooru, I; Safe, S				Vanderlaag, Kathy; Su, Yunpeng; Frankel, Arthur E.; Burghardt, Robert C.; Barhoumi, Rola; Chadalapaka, Gayathri; Jutooru, Indira; Safe, Stephen			1,1-Bis(3 '-indolyl)-1-(p-substituted phenyl) methanes induce autophagic cell death in estrogen receptor negative breast cancer	BMC CANCER			English	Article							PROSTATE-CANCER; 3,3'-DIINDOLYLMETHANE DIM; GROWTH-INHIBITION; CYCLE ARREST; GAMMA AGONISTS; UP-REGULATION; TUMOR-GROWTH; APOPTOSIS; ACTIVATION; COLON	Background: A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death. Methods: The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3). Results: The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF(3) exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC), a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased. Conclusion: The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy.	[Burghardt, Robert C.; Barhoumi, Rola] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA; [Vanderlaag, Kathy; Chadalapaka, Gayathri; Jutooru, Indira; Safe, Stephen] Texas A&M Univ, Dept Vet Physiol & Pharmacol, College Stn, TX 77843 USA; [Su, Yunpeng; Frankel, Arthur E.] Scott & White Mem Hosp & Clin, Canc Res Inst, Temple, TX 76502 USA; [Safe, Stephen] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX 77030 USA		Burghardt, RC (corresponding author), Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.	rburghardt@cvm.tamu.edu; ssafe@cvm.tamu.edu	Burghardt, Robert C./AAF-4847-2021	Burghardt, Robert C./0000-0003-1021-8444	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA108718]; Texas AgriLife Research; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA108718] Funding Source: NIH RePORTER	This work was supported by the National Institutes of Health (R01CA108718) and Texas AgriLife Research.	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J	Monti, E; Marras, E; Prini, P; Gariboldi, MB				Monti, Elena; Marras, Emanuela; Prini, Pamela; Gariboldi, Marzia Bruna			Luteolin impairs hypoxia adaptation and progression in human breast and colon cancer cells	EUROPEAN JOURNAL OF PHARMACOLOGY			English	Article						Luteolin; HIF-1; Cell death; CD44; CD47; Migration	INDUCIBLE FACTORS; POOR-PROGNOSIS; HIF-1-ALPHA; CYTOTOXICITY; APOPTOSIS; AUTOPHAGY; OVEREXPRESSION; HIF-2-ALPHA; MAINTENANCE; EXPRESSION	Hypoxia-inducible factors (HIFs) are the force which drives hypoxic cancer cells to a more aggressive and resistant phenotype in a number of solid tumors, including colorectal and breast cancer. Results from recent studies suggest a role for HIF-1 in immune evasion and cancer stem cell phenotype promotion, establishing HIF-1 as a potential therapeutic target. Thus, identifying new compounds that might inhibit HIF1 activity, or at least exert antiproliferative effects that are unaffected by HIF1-dependent adaptations, is an attractive goal for the management of hypoxic tumors. Here we show that the flavonoid luteolin exerts a significant cytotoxic effect on the colon cancer cell line HCT116 and the breast adenocarcinoma cell line MDA-MB231, by inducing both apoptotic and necrotic cell death, and that this effect is not impaired by HIF-1 activation. In these cells, luteolin also stimulates autophagy; however this seems to be part of a protective response, rather than contribute to the cytotoxic effect. Interestingly, luteolin induces a decrease in HIF-1 transcriptional activity. This is accompanied by a decrease in the levels of protein markers of stemness and invasion, and by a reduction of migratory capacity of the cells. Taken together, our results suggest that luteolin could be developed into a useful therapeutic agent aimed at hypoxic tumors.	[Monti, Elena; Marras, Emanuela; Prini, Pamela; Gariboldi, Marzia Bruna] Univ Insubria, Dept Biotechnol & Life Sci DBSV, Via JH Dunant 3, I-21100 Varese, VA, Italy		Gariboldi, MB (corresponding author), Univ Insubria, Dept Biotechnol & Life Sci DBSV, Via Manara 7, Busto Arsizio, VA, Italy.	marzia.gariboldi@uninsubria.it		gariboldi, marzia bruna/0000-0002-5683-0885	Universita degli Studi dell'Insubria, Fondi di Ateneo per la Ricerca	This study was supported by the Universita degli Studi dell'Insubria, Fondi di Ateneo per la Ricerca "FAR2016" and "FAR2017" (to EM and MBG). The funding agencies were not involved in the research plan and the interpretation of the data.	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J. Pharmacol.	AUG 15	2020	881								173210	10.1016/j.ejphar.2020.173210			9	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	NI9LX	WOS:000565668300009	32526242				2022-04-25	
J	Zhang, MY; Wang, LY; Zhao, S; Guo, XC; Xu, YQ; Zheng, ZH; Lu, H; Zheng, HC				Zhang, Mei-Ying; Wang, Li-Yuan; Zhao, Shuang; Guo, Xiao-Chong; Xu, Ying-Qi; Zheng, Zhi-Hong; Lu, Hang; Zheng, Hua-Chuan			Effects of Beclin 1 overexpression on aggressive phenotypes of colon cancer cells	ONCOLOGY LETTERS			English	Article						colon cancer; Beclin 1; aggressive phenotypes; autophagy; gene therapy	PROGNOSTIC-SIGNIFICANCE; PROTEIN EXPRESSION; POOR-PROGNOSIS; AUTOPHAGY; TUMOR; TUMORIGENESIS; CLEAVAGE; GROWTH; LC3	Beclin 1 is involved in autophagy, differentiation, apoptosis and cancer progression, and functions as a haploinsufficient tumor suppressor gene. The aim of the present study was to elucidate the function of Beclin 1 in colon cancer. A Beclin 1-expressing plasmid was transfected into HCT-15 and HCT-116 cells, and the phenotypes and associated molecules were determined. Beclin 1 transfectants were subcutaneously injected into nude mice to determine tumor growth, and proliferation and apoptosis levels using Ki-67 immunostaining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), respectively. Beclin 1 overexpression inhibited viability as determined using a Cell Counting Kit-8 assay, inhibited migration and invasion as determined using a wound healing assay or Transwell assay, and lamellipodia formation by filamentous actin staining, induced autophagy as determined using electron microscopy, and light chain 3B (LC-3B) expression, and apoptosis as determined using Annexin V staining in the two cell lines (P<0.05). Beclin 1 induced G(2) arrest of HCT-15 transfectants as determined using propidium iodide staining (P<0.05), whereas HCT-116 transfectants were arrested in G(1) phase (P<0.05). The two transfectants exhibited increased expression of c-Myc, cyclin D1, -catenin, insulin-response element 1 and 78 kDa glucose-regulated protein compared with the control and mock cells as determined using the reverse transcription-quantitative polymerase chain reaction (P<0.05). Beclin 1 overexpression upregulated LC-3B and cyclin-dependent kinase 4 expression, but downregulated cyclin E expression of the cancer cell lines as determined using western blot analysis (P<0.05). Beclin 1 expression in vivo significantly suppressed the proliferation of colon cancer cells in xenograft models via inducing apoptosis by TUNEL, and inhibiting proliferation by Ki-67 expression (P<0.05). Beclin 1 overexpression may reverse aggressive phenotypes and suppress colon cancer tumor growth, and be employed as a target molecule for gene therapy of patients with colon cancer.	[Zhang, Mei-Ying; Wang, Li-Yuan; Guo, Xiao-Chong; Xu, Ying-Qi; Zheng, Zhi-Hong] China Med Univ, Coll Basic Med, Lab Anim Ctr, Shenyang 110001, Liaoning, Peoples R China; [Zhao, Shuang; Zheng, Hua-Chuan] China Med Univ, Coll Basic Med, Dept Biochem & Mol Biol, 77 Puhe Rd, Shenyang 110001, Liaoning, Peoples R China; [Lu, Hang] Liaoning Med Univ, Dept Surg, Affiliated Hosp 1, Jinzhou 121001, Liaoning, Peoples R China		Zheng, HC (corresponding author), China Med Univ, Coll Basic Med, Dept Biochem & Mol Biol, 77 Puhe Rd, Shenyang 110001, Liaoning, Peoples R China.	zheng_huachuan@hotmail.com			Scientific Research Fund of Liaoning Provincial Education Department [LJQ2014093, L2014333]; Liaoning BaiQianWan Talents Program; Outstanding Scientific Fund of Shengjing Hospital; Award for Liaoning Distinguished Professors; Shenyang Science and Technology Grand [18-013-0-59]; National Natural Scientific Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472544, 81672700]	The present study was supported by A Project Supported by Scientific Research Fund of Liaoning Provincial Education Department (grant nos. LJQ2014093 and L2014333), Liaoning BaiQianWan Talents Program, Outstanding Scientific Fund of Shengjing Hospital, Award for Liaoning Distinguished Professors, Shenyang Science and Technology Grand (grant no. 18-013-0-59) and the National Natural Scientific Foundation of China (grant nos. 81472544 and 81672700).	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Lett.	FEB	2019	17	2					2441	2450		10.3892/ol.2018.9817			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	HM5YS	WOS:000459551800129	30675309	Green Published, gold			2022-04-25	
J	Tang, YX; Chen, K; Luan, XX; Zhang, JY; Liu, RR; Zheng, XX; Xie, SZ; Ke, HP; Zhang, XN; Chen, W				Tang, Yuexiao; Chen, Ke; Luan, Xiaorui; Zhang, Jinyan; Liu, Rongrong; Zheng, Xiaoxiao; Xie, Shangzhi; Ke, Haiping; Zhang, Xianning; Chen, Wei			Knockdown of eukaryotic translation initiation factor 5A2 enhances the therapeutic efficiency of doxorubicin in hepatocellular carcinoma cells by triggering lethal autophagy	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						hepatocellular carcinoma; doxorubicin; chemotherapy; autophagic cell death	EPITHELIAL-MESENCHYMAL TRANSITION; CANCER CELLS; COLORECTAL-CANCER; EIF5A2; CHEMORESISTANCE; RESISTANCE; CONTRIBUTES; INHIBITION; ACTIVATION; EXPRESSION	Hepatocellular carcinoma (HCC) is an invasive malignant neoplasm with a poor prognosis. The development of chemoresistance severely obstructs the chemotherapeutic efficiency of HCC treatment. Therefore, understanding the mechanisms of chemoresistance is important for improving the outcomes of patients with HCC. Eukaryotic translation initiation factor 5A2 (eIF5A2), which is considered to be an oncogene, has been reported to mediate chemoresistance in various types of cancer; however, its precise role in HCC remains unclear. Accumulating evidence has suggested that autophagy serves a dual role in cancer chemotherapy. The present study aimed to investigate the role of autophagy in eIF5A2-mediated doxorubicin resistance in HCC. High expression levels of eIF5A2 in human HCC tissues were observed by immunohistochemistry using a tissue microarray, which was consistent with the results of reverse transcription-quantitative PCR analysis in paired HCC and adjacent healthy tissues. HCC patient-derived tumor xenograft mouse model was used for the in vivo study, and knockdown of eIF5A2 effectively enhanced the efficacy of doxorubicin chemotherapy compared with that in the control group. Notably, eIF5A2 served as a repressor in regulating autophagy under chemotherapy. Silencing of eIF5A2 induced doxorubicin sensitivity in HCC cells by triggering lethal autophagy. In addition, 5-ethynyl-2 '-deoxyuridine, lactate dehydrogenase release assay and calcein-AM/PI staining were used to determine the enhanced autophagic cell death induced by the silencing of eIF5A2 under doxorubicin treatment. Suppression of autophagy attenuated the sensitivity of HCC cells to doxorubicin induced by eIF5A2 silencing. The results also demonstrated that knockdown of the Beclin 1 gene, which is an autophagy regulator, reversed the enhanced autophagic cell death and doxorubicin sensitivity induced by eIF5A2 silencing. Taken together, these results suggested eIF5A2 may mediate the chemoresistance of HCC cells by suppressing autophagic cell death under chemotherapy through a Beclin 1-dependent pathway, and that eIF5A2 may be a novel potential therapeutic target for HCC treatment.	[Tang, Yuexiao; Luan, Xiaorui; Zhang, Jinyan; Zhang, Xianning] Zhejiang Univ, Sch Med, Inst Cell Biol, Dept Genet,Zhejiang Prov Key Lab Genet & Dev Diso, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China; [Tang, Yuexiao; Luan, Xiaorui; Zhang, Jinyan; Zheng, Xiaoxiao; Xie, Shangzhi; Chen, Wei] Zhejiang Acad Tradit Chinese Med, Tongde Hosp Zhejiang Prov, Canc Inst Integrated Tradit Chinese & Western, Hangzhou 310012, Zhejiang, Peoples R China; [Chen, Ke] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Gen Surg, Hangzhou 310016, Zhejiang, Peoples R China; [Liu, Rongrong] Zhejiang Univ, Sch Med, Childrens Hosp, Div Hematol Oncol, Hangzhou 310003, Zhejiang, Peoples R China; [Ke, Haiping] Ningbo Coll Hlth Sci, Dept Biol, Ningbo 315100, Zhejiang, Peoples R China		Zhang, XN (corresponding author), Zhejiang Univ, Sch Med, Inst Cell Biol, Dept Genet,Zhejiang Prov Key Lab Genet & Dev Diso, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China.; Chen, W (corresponding author), Zhejiang Acad Tradit Chinese Med, Tongde Hosp Zhejiang Prov, Canc Inst Integrated Tradit Chinese & Western, Hangzhou 310012, Zhejiang, Peoples R China.	zhangxianning@zju.edu.cn; wei_chen@zju.edu.cn	Zhang, Xian-Ning/B-8412-2009		Zhejiang Provincial Ten Thousand Plan for Young Top Talents (2018); Innovative Talents Training Project of Zhejiang Health Bureau (2018); Key Project Co-constructed by the Zhejiang Province and Ministry [WKJ-ZJ-1916]; National High Technology Research and Development Program of ChinaNational High Technology Research and Development Program of China [SS2014AA020533]; Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LQ13H160006]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81302071, 81673809]	This study was supported by the Zhejiang Provincial Ten Thousand Plan for Young Top Talents (2018), the Innovative Talents Training Project of Zhejiang Health Bureau (2018), the Key Project Co-constructed by the Zhejiang Province and Ministry (grant no. WKJ-ZJ-1916), the National High Technology Research and Development Program of China (grant no. SS2014AA020533), the Zhejiang Provincial Natural Science Foundation of China (grant no. LQ13H160006) and the Natural Science Foundation of China (grant nos. 81302071 and 81673809).	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J. Oncol.	DEC	2020	57	6					1368	1380		10.3892/ijo.2020.5143			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	OY0UU	WOS:000593970700002	33174013	Green Published, hybrid			2022-04-25	
J	Luo, MY; Li, HX; Han, DH; Yang, KZ; Kang, L				Luo, Mengyu; Li, Hongxia; Han, Duhong; Yang, Kaizhen; Kang, Ling			Inhibition of autophagy enhances apoptosis induced by Ce6-photodynamic therapy in human colon cancer cells	PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY			English	Article						Photodynamic therapy; Chlorin E6; Colorectal cancer; Autophagy; Apoptosis	MEDIATED PHOTODYNAMIC THERAPY; CHLORIN E(6); RESISTANCE; PATHWAY; TARGET; MG-63	Objective: To evaluate the therapeutic effect of Chlorin e6 photodynamic therapy (Ce6-PDT) in human colorectal cancer cells and investigate the role of autophagy in Ce6-PDT. Methods: SW480 cells underwent Ce6-PDT with and without pretreatment with the autophagy inhibitor 3-methyladenine (3MA). Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was evaluated using an Annexin V assay, using a rhodamine 123 (RH123) assay to evaluate mitochondrial membrane potential (MMP), and by measuring Caspase-3 and Bcl-2 protein expression using western blotting. Autophagy was evaluated by directly visualizing acridine orange-stained acidic vesicular organelles (AVOs) using fluorescent microscopy and by measuring LC3I/IIand Atg5 expression using western blotting. Results: Ce6-PDT decreased SW480 viability in a dose-dependent manner. Ce6-PDT induced apoptosis in SW480 cells via the mitochondrial apoptosis pathway as indicated by decreased mitochondrial membrane potential, increased Annexin V staining, and increased Caspase-3 expression. Ce6-PDT was also shown to induce autophagy as demonstrated by increased acridine-orange stained AVOs as well as increased expression of the autophagyassociated proteins Atg5. Inhibition of autophagy with 3MA potentiated SW480 cell response to Ce6-PDT and increased the rate of apoptosis in the treated cells. Conclusions: Ce6-PDT induces autophagy and apoptosis of SW480 cells in a dose-dependent manner. Inhibition of autophagy increases the apoptosis induced by Ce6-PDT. Modulation of autophagy may be a potential therapeutic target for colon cancer cells treated with Ce6-PDT.	[Luo, Mengyu; Li, Hongxia; Han, Duhong; Kang, Ling] Xinjiang Med Univ, Coll Publ Hlth, 567 SHangde North Rd, Urumqi, Xinjiang, Peoples R China; [Yang, Kaizhen] First Peoples Hosp Urumqi, Urumqi, Xinjiang, Peoples R China		Kang, L (corresponding author), Xinjiang Med Univ, Coll Publ Hlth, 567 SHangde North Rd, Urumqi, Xinjiang, Peoples R China.	540802213@qq.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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Ther.	DEC	2021	36								102605	10.1016/j.pdpdt.2021.102605		NOV 2021	7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	WZ2CZ	WOS:000719780700005	34715368				2022-04-25	
J	Zhang, JB; Wang, JG; Xu, J; Lu, YQ; Jiang, JK; Wang, LM; Shen, HM; Xia, DJ				Zhang, Jianbin; Wang, Jigang; Xu, Jian; Lu, Yuanqiang; Jiang, Jiukun; Wang, Liming; Shen, Han-Ming; Xia, Dajing			Curcumin targets the TFEB-lysosome pathway for induction of autophagy	ONCOTARGET			English	Article						Curcumin; lysosome; mTOR; TFEB; autophagy	SIGNALING PATHWAYS; OXIDATIVE STRESS; CELL-DEATH; IN-VITRO; MTOR; SUPPRESSION; INHIBITION; ACTIVATION; MECHANISMS; AMPK	Curcumin is a hydrophobic polyphenol derived from the herb Curcumalonga and its wide spectrum of pharmacological activities has been widely studied. It has been reported that Curcumin can induce autophagy through inhibition of the Akt-mTOR pathway. However, the effect of Curcumin on lysosome remains largely elusive. In this study, we first found that Curcumin treatment enhances autophagic flux in both human colon cancer HCT116 cells and mouse embryonic fibroblasts (MEFs). Moreover, Curcumin treatment promotes lysosomal function, evidenced by the increased lysosomal acidification and enzyme activity. Second, Curcumin is capable of suppressing the mammalian target of rapamycin (mTOR). Interestingly, Curcumin fails to inhibit mTOR and to activate lysosomal function in Tsc2(-/-)MEFs with constitutive activation of mTOR, indicating that Curcumin-mediated lysosomal activation is achieved via suppression of mTOR. Third, Curcumin treatment activates transcription factor EB (TFEB), a key nuclear transcription factor in control of autophagy and lysosome biogenesis and function, based on the following observations: (i) Curcumin directly binds to TFEB, (ii) Curcumin promotes TFEB nuclear translocation; and (iii) Curcumin increases transcriptional activity of TFEB. Finally, inhibition of autophagy and lysosome leads to more cell death in Curcumin-treated HCT116 cells, suggesting that autophagy and lysosomal activation serves as a cell survival mechanism to protect against Curcumin-mediated cell death. Taken together, data from our study provide a novel insight into the regulatory mechanisms of Curcumin on autophagy and lysosome, which may facilitate the development of Curcumin as a potential cancer therapeutic agent.	[Zhang, Jianbin] Zhejiang Prov Peoples Hosp, Clin Res Inst, Hangzhou, Zhejiang, Peoples R China; [Zhang, Jianbin; Wang, Jigang; Wang, Liming; Shen, Han-Ming] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore, Singapore; [Zhang, Jianbin; Xu, Jian; Xia, Dajing] Zhejiang Univ, Inst Immunol, Sch Publ Hlth, Hangzhou, Zhejiang, Peoples R China; [Lu, Yuanqiang; Jiang, Jiukun] Zhejiang Univ, Coll Med, Affiliated Hosp 1, Hangzhou, Zhejiang, Peoples R China; [Shen, Han-Ming] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore, Singapore		Shen, HM (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore, Singapore.; Xia, DJ (corresponding author), Zhejiang Univ, Inst Immunol, Sch Publ Hlth, Hangzhou, Zhejiang, Peoples R China.; Shen, HM (corresponding author), Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore, Singapore.	phsshm@nus.edu.sg; dxia@zju.edu.cn	SHEN, Han-Ming/B-5942-2011; Wang, Liming/M-7381-2019	SHEN, Han-Ming/0000-0001-7369-5227; Wang, Liming/0000-0002-5444-2424	Singapore National Medical Research CouncilNational Medical Research Council, Singapore [NMRC/1260/2010, NMRC/CIRG/1373/2013]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31471297]	We would like to thank Dr A Ballabio for providing the pCMV-TFEB-3X Flag plasmid [28] and the TFEB luciferase vector, [51] Dr. Noboru Mizushima (Tokyo Medical and Dental University, Japan) for the MEFs with stable expression of GFP-LC3, and Dr. DJ Kwiatkowski (Harvard University, USA) for providing the pair of Tsc2<SUP>+/+</SUP> and Tsc2<SUP>-/-</SUP> MEFs. This work was supported by grants from Singapore National Medical Research Council (NMRC/1260/2010 and NMRC/CIRG/1373/2013) to HMS and by a grant from the National Natural Science Foundation of China (No. 31471297) to DX.	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J	Budisan, L; Gulei, D; Jurj, A; Braicu, C; Zanoaga, O; Cojocneanu, R; Pop, L; Raduly, L; Barbat, A; Moldovan, A; Moldovan, C; Tigu, AB; Ionescu, C; Atanasov, AG; Irimie, A; Berindan-Neagoe, I				Budisan, Liviuta; Gulei, Diana; Jurj, Ancuta; Braicu, Cornelia; Zanoaga, Oana; Cojocneanu, Roxana; Pop, Laura; Raduly, Lajos; Barbat, Alexandru; Moldovan, Alin; Moldovan, Cristian; Tigu, Adrian Bogdan; Ionescu, Calin; Atanasov, Atanas G.; Irimie, Alexandru; Berindan-Neagoe, Ioana			Inhibitory Effect of CAPE and Kaempferol in Colon Cancer Cell LinesPossible Implications in New Therapeutic Strategies	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						natural compounds; polyphenols; colon cancer; CAPE; Kaempferol; Morin	ACID PHENETHYL ESTER; LONG NONCODING RNAS; INDUCED APOPTOSIS; POLYPHENOLS; PROPOLIS; INVASION	Background: Phytochemicals are natural compounds synthesized as secondary metabolites in plants and represent an important source of molecules with therapeutic applications. Attention is accorded to their potential in anti-cancer therapies as single agents or adjuvant treatment. Herby, we evaluated the in vitro effects of a panel of natural compounds with focus on caffeic acid phenethyl ester (CAPE) and Kaempferol for the treatment of human colon cancer. Methods: We exposed two human colon cancer cell lines, RKO and HCT-116, followed by functional examination of cell viability, cell proliferation and invasion, cell cycle, apoptosis, and autophagy. Modifications in gene expression were investigated through microarray and detection of existing mutations and finding of new ones was done with the help of Next Generation Sequencing (NGS). Results: Both CAPE and Kaempferol inhibit cell proliferation, motility and invasion, and stimulate apoptosis and autophagy, concomitant with modifications in coding and noncoding genes' expression. Moreover, there are pathogenic mutations that are no longer found upon treatment with CAPE and Kaempferol. Conclusions: Our findings indicate that CAPE and Kaempferol have the ability to negatively influence the development and advancement of colon cancer in vitro by specifically altering the cells at the molecular level; this activity can be exploited in possible adjuvant therapies once the optimal dose concentration with minimal side effects but with cancer inhibitory activity is set in vivo.	[Budisan, Liviuta; Jurj, Ancuta; Braicu, Cornelia; Zanoaga, Oana; Cojocneanu, Roxana; Pop, Laura; Raduly, Lajos; Barbat, Alexandru; Berindan-Neagoe, Ioana] Iuliu Hatieganu Univ Med & Pharm, Res Ctr Funct Genom Biomed & Translat Med, 23 Marinescu St, Cluj Napoca 400337, Romania; [Gulei, Diana; Moldovan, Alin; Moldovan, Cristian; Tigu, Adrian Bogdan; Berindan-Neagoe, Ioana] Iuliu Hatieganu Univ Med & Pharm, MEDFUTURE Res Ctr Adv Med, 23 Marinescu St, Cluj Napoca 400337, Romania; [Ionescu, Calin] Municipal Hosp, Surg Dept 5, Cluj Napoca 400139, Romania; [Ionescu, Calin] Iuliu Hatieganu Univ Med & Pharm, Cluj Napoca 400000, Romania; [Atanasov, Atanas G.] Polish Acad Sci, Inst Genet & Anim Breeding, PL-05552 Jastrzebiec, Poland; [Atanasov, Atanas G.] Univ Vienna, Dept Pharmacognosy, Althanstr 14, A-1090 Vienna, Austria; [Irimie, Alexandru] Iuliu Hatieganu Univ Med & Pharm, Dept Oncol Surg & Gynecol Oncol 11, Cluj Napoca 400015, Romania; [Irimie, Alexandru] Oncol Inst Prof Dr Ion Chiricuta, Dept Surg, Cluj Napoca 400015, Romania; [Berindan-Neagoe, Ioana] Oncol Inst Prof Dr Ion Chiricuta, Dept Funct Genom & Expt Pathol, 34-36 Republ St, Cluj Napoca 400015, Romania		Berindan-Neagoe, I (corresponding author), Iuliu Hatieganu Univ Med & Pharm, Res Ctr Funct Genom Biomed & Translat Med, 23 Marinescu St, Cluj Napoca 400337, Romania.; Berindan-Neagoe, I (corresponding author), Iuliu Hatieganu Univ Med & Pharm, MEDFUTURE Res Ctr Adv Med, 23 Marinescu St, Cluj Napoca 400337, Romania.; Ionescu, C (corresponding author), Municipal Hosp, Surg Dept 5, Cluj Napoca 400139, Romania.; Ionescu, C (corresponding author), Iuliu Hatieganu Univ Med & Pharm, Cluj Napoca 400000, Romania.; Berindan-Neagoe, I (corresponding author), Oncol Inst Prof Dr Ion Chiricuta, Dept Funct Genom & Expt Pathol, 34-36 Republ St, Cluj Napoca 400015, Romania.	liviutabudisan@gmail.com; diana.c.gulei@gmail.com; ancajurj15@gmail.com; braicucornelia@yahoo.com; zanoaga.oana@gmail.com; cojocneanur@gmail.com; laura.ancuta.pop@gmail.com; raduly.lajos78@gmail.com; barbatalexandruteodor@gmail.com; alin.moldovan92@yahoo.ro; moldovan.cristian1994@gmail.com; adrianbogdantigu@gmail.com; calin.ionescu@umfcluj.ro; atanas.atanasov@univie.ac.at; a.irimie@umfcluj.ro; ioana.neagoe@umfcluj.ro	Gulei, Diana/U-2864-2017; Pop, Laura/AAY-8349-2020; Țigu, Adrian Bogdan/AAI-9446-2020; Berindan-Neagoe, Ioana/AAH-9854-2019; Atanasov, Atanas G./C-5535-2013	Gulei, Diana/0000-0002-3030-8626; Pop, Laura/0000-0002-5806-0220; Țigu, Adrian Bogdan/0000-0001-9397-0791; Atanasov, Atanas G./0000-0003-2545-0967; Moldovan, Cristian/0000-0003-2927-4622; Raduly, Lajos/0000-0002-3926-5423; Cojocneanu, Roxana-Maria/0000-0002-7450-9454; Moldovan, Alin/0000-0001-7159-6102	Project PNCDI III [29PFE/18.10.2018]; Competitivity Operational Program [35/01.09.2016, MySMIS 103375, 3860]; Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania [193/2014]; Non-invasive intelligent systems for colorectal cancer diagnosis and prognosis based on circulating microRNAs integrated in the clinical workflow-INTELCOR [PN-II-PT-PCCA-2013-4-1959]; project "MicroRNAs biomarkers of response to chemotherapy and overall survival in colon cancer"-Terry Fox Foundation	This research was funded by Project PNCDI III 2015-2020 entitled "Increasing the performance of scientific research and technology transfer in translational medicine through the formation of a new generation of young researchers"-ECHITAS, No. 29PFE/18.10.2018, Competitivity Operational Program, 2014-2020, entitled "Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance"-CANTEMIR, No. 35/01.09.2016, MySMIS 103375, PhD project Nr.3860 /Date 10.01.2014-"Control of apoptosis in cancer with natural phytochemical compounds. The role of microRNAs/siRNAs" funded by Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania, research grant No. 193/2014; PN-II-PT-PCCA-2013-4-1959 "Non-invasive intelligent systems for colorectal cancer diagnosis and prognosis based on circulating microRNAs integrated in the clinical workflow-INTELCOR" and project "MicroRNAs biomarkers of response to chemotherapy and overall survival in colon cancer"-Terry Fox Foundation.	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J. Mol. Sci.	MAR 1	2019	20	5							1199	10.3390/ijms20051199			19	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	HQ6QE	WOS:000462542300198	30857282	Green Published, Green Submitted, gold			2022-04-25	
J	Lai, MC; Chang, CM; Sun, HS				Lai, Ming-Chih; Chang, Chiao-May; Sun, H. Sunny			Hypoxia Induces Autophagy through Translational Up-Regulation of Lysosomal Proteins in Human Colon Cancer Cells	PLOS ONE			English	Article							MESSENGER-RNA TRANSLATION; INTERNAL RIBOSOME ENTRY; INDUCIBLE FACTOR-I; GENE-EXPRESSION; COLORECTAL TUMORIGENESIS; CYCLE ARREST; STRESS; MTOR; PHOSPHORYLATION; ANGIOGENESIS	Hypoxia occurs in a wide variety of physiological and pathological conditions, including tumorigenesis. Tumor cells have to adapt to hypoxia by altering their gene expression and protein synthesis. Here, we showed that hypoxia inhibits translation through activation of PERK and inactivation of mTOR in human colon cancer HCT116 cells. Prolonged hypoxia (1% O-2, 16 h) dramatically inhibits general translation in HCT116 cells, yet selected mRNAs remain efficiently translated under such a condition. Using microarray analysis of polysome-associated mRNAs, we identified a large number of hypoxia-regulated genes at the translational level. Efficiently translated mRNAs during hypoxia were validated by polysome profiling and quantitative real-time RT-PCR. Pathway enrichment analysis showed that many of the up-regulated genes are involved in lysosome, glycan and lipid metabolism, antigen presentation, cell adhesion, and remodeling of the extracellular matrix and cytoskeleton. The majority of down-regulated genes are involved in apoptosis, ubiquitin-mediated proteolysis, and oxidative phosphorylation. Further investigation showed that hypoxia induces lysosomal autophagy and mitochondrial dysfunction through translational regulation in HCT116 cells. The abundance of several translation factors and the mTOR kinase activity are involved in hypoxia-induced mitochondrial autophagy in HCT116 cells. Our studies highlight the importance of translational regulation for tumor cell adaptation to hypoxia.	[Lai, Ming-Chih] Chang Gung Univ, Dept Biomed Sci, Taoyuan, Taiwan; [Lai, Ming-Chih] Chang Gung Mem Hosp, Dept Obstet & Gynecol, Taoyuan, Taiwan; [Chang, Chiao-May; Sun, H. Sunny] Natl Cheng Kung Univ, Bioinformat Ctr, Tainan 701, Taiwan; [Sun, H. Sunny] Natl Cheng Kung Univ, Inst Mol Med, Tainan 701, Taiwan		Sun, HS (corresponding author), Chang Gung Univ, Dept Biomed Sci, Taoyuan, Taiwan.	mclai@mail.cgu.edu.tw; hssun@mail.ncku.edu.tw		Sun, Sunny/0000-0002-3661-4448; Hung, Li-Man/0000-0002-6032-7668	Ministry of Science and Technology, TaiwanMinistry of Science and Technology, Taiwan [NSC100-2320-B-006-021-MY3, NSC101-2627-B-006-005]; Chang Gung Memorial Hospital, TaiwanChang Gung Memorial Hospital [CMRPD3E0012]	This work was supported by grants from Ministry of Science and Technology, Taiwan (NSC100-2320-B-006-021-MY3 to MCL and NSC101-2627-B-006-005 to HSS) and Chang Gung Memorial Hospital, Taiwan (CMRPD3E0012). 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	Sun, WL; Lan, D; Gan, TQ; Cai, ZW				Sun, W. L.; Lan, D.; Gan, T. Q.; Cai, Z. W.			Autophagy facilitates multidrug resistance development through inhibition of apoptosis in breast cancer cells	NEOPLASMA			English	Article						autophagy; apoptosis; multidrug resistance; breast cancer; chemotherapy	COLON-CANCER; HEPATOCELLULAR-CARCINOMA; DEATH; 5-FLUOROURACIL; MACROAUTOPHAGY; CHEMOTHERAPY; CHLOROQUINE; INDUCTION	Acquired multidrug resistance (MDR) is the main mechanism of chemotherapeutic drugs resistance. Nevertheless, the mechanisms of MDR are complex and still not very clear. Recently, including our previous study, several studies have revealed that macroautophagy (here referred to as autophagy) induced by anti-cancer drugs in breast cancer cells may facilitate the development of resistance to epirubicin (EPI), paclitaxel (PTX), tamoxifen or herceptin. Whereas there are a few studies on the relationship between autophagy and MDR, especially the studies designed directly employing induced resistant breast cancer cells. Based on previous study, we explored the relationship between autophagy and MDR. The results showed that induced EPI-resistant MCF-7er and SK-BR-3er cells were simultaneously resistant to PTX and vinorelbine (NVB), which demonstrated that the cells obtained MDR phenotype. Furthermore, PTX and NVB could also induce autophagy in MCF-7er and SK-BR-3er cells, and the induced autophagy protected the cells from apoptosis, which facilitated the development of resistance to PTX and NVB. Thus, autophagy promoted the development of MDR in breast cancer cells through inhibition of apoptosis. In addition, we found that P-glycoprotein (Pgp) was overexpressed in MCF-7er and SK-Br-3er cells. And we preliminarily investigated the relationship between autophagy and P-glycoprotein (Pgp). The results showed that the expression of the protein did not obviously change despite the inhibition of autophagy. Therefore, the role of Pgp in the development of MDR might be independent of autophahy. Also this finding implies that autophagy might be a target to overcome MDR in breast cancer cells, and clinical use autophagy inhibitors might be one of the important strategies for overcoming MDR in breast cancer therapy.	[Sun, W. L.; Lan, D.; Gan, T. Q.; Cai, Z. W.] Guangxi Med Univ, Affiliated Hosp 1, Dept Internal Med Oncol, Nanning 530021, Guangxi, Peoples R China		Sun, WL (corresponding author), Guangxi Med Univ, Affiliated Hosp 1, Dept Internal Med Oncol, Nanning 530021, Guangxi, Peoples R China.	swl20022001@hotmail.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81360340]; Wu Jieping Medical Foundation clinical research special fund [320.6750.12689]	This study is supported by grants from the National Natural Science Foundation of China (grant number 81360340) and Wu Jieping Medical Foundation clinical research special fund (grant number 320.6750.12689). We thank Professor T. Yoshimori and Ms. H. Omori (Department of Cellular Regulation Research Institute for Microbial Diseases, Osaka University; Japan) for kindly providing the pEGFP-LC3 plasmid.	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J	Li, YL; Gu, FT; Lin, X				Li, Yongliang; Gu, Feiteng; Lin, Xi			The role of miR-141/Sirt1 in colon cancer	JOURNAL OF BUON			English	Article						colon cancer cells; miR-141; Sirt1; proliferation; apoptosis	INHIBITS IN-VITRO; MICRORNA EXPRESSION; CELL-MIGRATION; AUTOPHAGY; PROLIFERATION; INDUCTION; APOPTOSIS; SIRT1; TUMORIGENESIS; SURVIVAL	Purpose: To explore the effects of micro ribonucleic acid-141 (miR)-141 on the proliferation and apoptosis of colon cancer cells and its association with the sirtuin 1 (Sirt1) expression. Methods: The samples of stage I, II, III and IV colon cancer were obtained, and the miRNA expression levels was analyzed, with normal colon tissues as controls. The expression of miR-141 and miR-34 was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and the cell proliferation and apoptosis in each group were detected via cell counting kit-8 (CCK8) assay, respectively. Finally, the protein expressions of Sirt1, Caspase-3 and Caspase-8 were determined using Western blotting. Results: The expressions of miR-141 and miR-34 (miR-34 is mentioned in previous methods. Furthermore, we found the expression of miR-141 increasing with the progression of colon cancer, which was higher in stage III than in stage I-II and also higher in stage IV than in stage III. miR-34 was also highly expressed in stage IV colon cancer in our study were up-regulated in the progression of colon cancer. Overexpression of miR-141 could promote cell proliferation (p<0.05) and inhibit apoptosis (p<0.05), while inhibition on miR-141 expression could significantly weaken cell proliferation (p<0.05) and promote apoptosis (p<0.05). The results of luciferase reporter assay showed that miR-141 obviously inhibited Sirt1 (p<0.05). SRT2183 reduced cell proliferation (p<0.05) but up-regulated the protein expressions of Sirt1, Caspase-3 and Caspase-8 (p<0.05), while EX 527 had the opposite effects (p<0.05). Conclusions: MiR-141 may promote proliferation and reduce apoptosis of colon cancer cells via targeting Sirt1.	[Li, Yongliang; Gu, Feiteng; Lin, Xi] Putian Univ, Affiliated Hosp, Dept Gastrointestinal Surg 2, 999 Dongzhen East Rd, Putian 351100, Fujian, Peoples R China		Li, YL (corresponding author), Putian Univ, Affiliated Hosp, Dept Gastrointestinal Surg 2, 999 Dongzhen East Rd, Putian 351100, Fujian, Peoples R China.	lylfjpt@126.com					Bartel DP, 2004, NAT REV GENET, V5, P396, DOI 10.1038/nrg1328; Vega AB, 2013, ONCOL REP, V30, P320, DOI 10.3892/or.2013.2475; Chen H, 2019, J BUON, V24, P1470; Chen XP, 2019, J BUON, V24, P488; Cheng HY, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0017745; Cruz JPM, 2018, J BUON, V23, P568; Ding L, 2017, ONCOL LETT, V13, P1665, DOI 10.3892/ol.2017.5653; Ding Y, 2019, J BUON, V24, P1817; Esquela-Kerscher A, 2006, NAT REV CANCER, V6, P259, DOI 10.1038/nrc1840; Fu MF, 2006, MOL CELL BIOL, V26, P8122, DOI 10.1128/MCB.00289-06; Garzon R, 2006, TRENDS MOL MED, V12, P580, DOI 10.1016/j.molmed.2006.10.006; Garzon R, 2009, ANNU REV MED, V60, P167, DOI 10.1146/annurev.med.59.053006.104707; Ji H, 2019, J BUON, V24, P91; Kabra N, 2009, J BIOL CHEM, V284, P18210, DOI 10.1074/jbc.M109.000034; Kim Kwangmin, 2018, J BUON, V23, P11; Mou LJ, 2019, J BUON, V24, P1870; Pox CP, 2014, DIGESTION, V89, P274, DOI 10.1159/000363287; Sakin A, 2019, J BUON, V24, P1801; Slaby O, 2009, MOL CANCER, V8, DOI 10.1186/1476-4598-8-102; Wang D, 2019, J BUON, V24, P1824; Wang RH, 2008, CANCER CELL, V14, P312, DOI 10.1016/j.ccr.2008.09.001; Winter J, 2009, NAT CELL BIOL, V11, P228, DOI 10.1038/ncb0309-228; Xiong W, 2019, J BUON, V24, P1488; Yang LD, 2009, WORLD J SURG, V33, P638, DOI 10.1007/s00268-008-9865-5; Yang Y, 2017, CELL PHYSIOL BIOCHEM, V41, P310, DOI 10.1159/000456162; Yin ZH, 2019, J BUON, V24, P1464; Yue M, 2019, J BUON, V24, P1852; Zhang LM, 2010, CARCINOGENESIS, V31, P559, DOI 10.1093/carcin/bgp335	28	2	2	0	0	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	NOV-DEC	2020	25	6					2665	2671					7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	PY4JJ	WOS:000612011800019	33455111				2022-04-25	
J	Giatromanolaki, A; Koukourakis, MI; Harris, AL; Polychronidis, A; Gatter, KC; Sivridis, E				Giatromanolaki, Alexandra; Koukourakis, Michael I.; Harris, Adrian L.; Polychronidis, Alexandros; Gatter, Kevin C.; Sivridis, Efthimios			Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas	JOURNAL OF CLINICAL PATHOLOGY			English	Article							TUMOR ANGIOGENESIS; EXPRESSION; GROWTH; CANCER; ASSOCIATION; SURVIVAL; CELLS	Aims The microtubule-associated protein 1 light chain 3(LC3A) is an essential component of the autophagic vacuoles, forming a reliable marker of autophagic activity. In a previous study, the authors showed that LC3A immunohistochemistry renders three patterns of autophagic expression in breast carcinomas: diffuse cytoplasmic, perinuclear and 'stone-like' intracellular structures (SLS), each with a distinct prognostic relevance. Methods Tumour tissues from 155 patients with stage IIA-III colorectal adenocarcinomas, treated with surgery alone, were assessed immunohistochemically for LC3A. Median values were used as cut-off points to separate groups into low and high autophagic activity. Associations with prognosis and with lactate dehydrogenase-5 (LDH5) were sought. Results High SLS counts were associated with metastases and poor prognosis, while the prominence of the perinuclear pattern was linked to localised disease and good prognosis. The cytoplasmic pattern was irrelevant. Furthermore, patients with increased SLS numbers, but suppressed perinuclear expression, were associated with LDH5 overexpression and had an extremely poor prognosis (3-year survival 16.5%). The prognosis improved considerably when high SLS counts were accompanied by intense perinuclear expression (3-year survival 67%) and were optimal when SLS numbers dropped below median values, irrespective of perinuclear status (3-year survival 94-100%). Multivariate analysis showed that SLS and perinuclear patterns were independent predictors of death events. Conclusions Perinuclear LC3A accumulation in colorectal tumour cells is a marker of good prognosis, presumably reflecting a basal autophagic activity. An abnormal or excessive autophagic response, as indicated by increased numbers of SLS, is linked to metastasis and poor prognosis.	[Giatromanolaki, Alexandra; Sivridis, Efthimios] Democritus Univ Thrace, Dept Pathol, Alexandroupolis 68100, Greece; [Giatromanolaki, Alexandra; Koukourakis, Michael I.; Harris, Adrian L.; Polychronidis, Alexandros; Sivridis, Efthimios] Univ Gen Hosp Alexandroupolis, Alexandroupolis, Greece; [Koukourakis, Michael I.] Democritus Univ Thrace, Dept Radiotherapy Oncol, Alexandroupolis 68100, Greece; [Harris, Adrian L.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Mol Oncol Labs,Canc Res UK, Oxford OX3 9DU, England; [Harris, Adrian L.; Gatter, Kevin C.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England; [Harris, Adrian L.; Polychronidis, Alexandros] Democritus Univ Thrace, Dept Surg, Alexandroupolis 68100, Greece		Sivridis, E (corresponding author), Democritus Univ Thrace, Dept Pathol, POB 128, Alexandroupolis 68100, Greece.	esivrid@med.duth.gr	Harris, Adrian/ABA-3343-2020	Harris, Adrian/0000-0003-1376-8409			Chen JL, 2008, J BIOL CHEM, V283, P34432, DOI 10.1074/jbc.M804239200; Ding ZB, 2008, CANCER RES, V68, P9167, DOI 10.1158/0008-5472.CAN-08-1573; Eisenberg-Lerner A, 2009, APOPTOSIS, V14, P376, DOI 10.1007/s10495-008-0307-5; Fujii S, 2008, CANCER SCI, V99, P1813, DOI 10.1111/j.1349-7006.2008.00893.x; Giatromanolaki A, 2004, APMIS, V112, P431, DOI 10.1111/j.1600-0463.2004.apm11207-0804.x; Harris AL, 2002, NAT REV CANCER, V2, P38, DOI 10.1038/nrc704; He H, 2003, J BIOL CHEM, V278, P29278, DOI 10.1074/jbc.M303800200; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; 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 CY, 2008, NAT CELL BIOL, V10, P776, DOI 10.1038/ncb1740; Lomonaco SL, 2009, INT J CANCER, V125, P717, DOI 10.1002/ijc.24402; Miyata S, 2006, AM J PATHOL, V168, P386, DOI 10.2353/ajpath.2006.050137; NOVIKOFF AB, 1978, P NATL ACAD SCI USA, V75, P5039, DOI 10.1073/pnas.75.10.5039; Pirtoli L, 2009, AUTOPHAGY, V5, P930, DOI 10.4161/auto.5.7.9227; Samokhvalov V, 2008, AUTOPHAGY, V4, P1034, DOI 10.4161/auto.6994; Shintani T, 2004, SCIENCE, V306, P990, DOI 10.1126/science.1099993; Sivridis E, 2010, AM J PATHOL, V176, P2477, DOI 10.2353/ajpath.2010.090049; Vazquez-Martin A, 2009, PLOS ONE, V4, DOI 10.1371/journal.pone.0006251	19	78	82	0	3	B M J PUBLISHING GROUP	LONDON	BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND	0021-9746			J CLIN PATHOL	J. Clin. Pathol.	OCT	2010	63	10					867	872		10.1136/jcp.2010.079525			6	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	654KY	WOS:000282168400002	20876316	Green Submitted, Bronze			2022-04-25	
J	Xie, W; Zhang, L; Jiao, HF; Guan, L; Zha, JM; Li, XT; Wu, M; Wang, ZX; Han, JH; You, H				Xie, Wei; Zhang, Lei; Jiao, Haifeng; Guan, Li; Zha, Junmin; Li, Xiaotong; Wu, Mian; Wang, Zhanxiang; Han, Jiahuai; You, Han			Chaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA	AUTOPHAGY			English	Article						apoptosis; BBC3; chaperone-mediated autophagy; IKBKB; IKK; PUMA; TNF	NF-KAPPA-B; COLORECTAL-CANCER CELLS; ALPHA-INDUCED APOPTOSIS; ENDOPLASMIC-RETICULUM; SERUM STARVATION; PUMA; P53; ACTIVATION; RECEPTOR; DEGRADATION	Autophagy is a potentially inimical pathway and together with apoptosis, may be activated by similar stress stimuli that can lead to cell death. The molecular cues that dictate the cell fate choice between autophagy and apoptosis remain largely unknown. Here we report that the proapoptotic protein BBC3/PUMA (BCL2 binding component 3) is a bona fide substrate of chaperone-mediated autophagy (CMA). BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. Inhibition of CMA results in stabilization of BBC3, which in turn sensitizes tumor cells to undergo apoptosis. We further demonstrate that upon TNF (tumor necrosis factor) treatment, IKBKB/IKK(inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase )-mediated BBC3 Ser10 phosphorylation is crucial for BBC3 stabilization via blocking its degradation by CMA. Mechanistically, Ser10 phosphorylation facilitates BBC3 translocation from the cytosol to mitochondria. BBC3 stabilization resulting from either Ser10 phosphorylation or CMA inhibition potentiates TNF-induced apoptotic cell death. Our findings thus reveal that the selective degradation of BBC3 underlies the prosurvival role of CMA and define a previously unappreciated proapoptotic role of IKBKB that acts through phosphorylation-mediated stabilization of BBC3, thereby promoting TNF-triggered apoptosis.	[Xie, Wei; Zhang, Lei; Jiao, Haifeng; Guan, Li; Zha, Junmin; Li, Xiaotong; Han, Jiahuai; You, Han] Sch Life Sci, Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Signaling Network, Xiamen, Fujian, Peoples R China; [Wu, Mian] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei, Anhui, Peoples R China; [Wu, Mian] Univ Sci & Technol China, Sch Life Sci, Hefei, Anhui, Peoples R China; [Wang, Zhanxiang] Xiamen Univ, Affiliated Hosp 1, Dept Neurosurg, Xiamen, Fujian, Peoples R China		Wang, ZX (corresponding author), Xiamen Univ, Affiliated Hosp 1, Dept Neurosurg, Xiamen, Fujian, Peoples R China.	sjwkwzx@163.com; hyou@xmu.edu.cn	Han, J/G-4671-2010	Wu, Mian/0000-0002-2714-0500	National Basic Research Program of China 973 ProgramNational Basic Research Program of China [2015CB553802]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31300627]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [20720150066]; National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [J1310027]; Ministry of Education of China 111 Project [B06016]	This work is supported by National Basic Research Program of China 973 Program Grant 2015CB553802 (to H.Y.), National Natural Science Foundation of China Grant 31300627 (to L.Z.), Fundamental Research Funds for the Central Universities Grant 20720150066 (to H.Y.), by the National Science Foundation of China for Fostering Talents in Basic Research (Grant No. J1310027), and Ministry of Education of China 111 Project B06016.	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J	Shimozawa, M; Anzai, S; Satow, R; Fukami, K				Shimozawa, Makoto; Anzai, Sakiho; Satow, Reiko; Fukami, Kiyoko			Phospholipase C delta 1 negatively regulates autophagy in colorectal cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						PLC delta 1; Autophagy; KRAS; Colorectal cancer	CHEMOTHERAPY; INHIBITION; RESISTANCE; TARGET	Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Kirsten rat sarcoma viral oncogene homolog (KRAS) is frequently mutated in CRC, and KRAS mutations promote cell motility, growth, and survival. We previously revealed that the expression of phospholipase C (PLC) delta 1, one of the most basal PLCs, is down-regulated in colon adenocarcinoma, and that the KRAS signaling pathway suppresses PLC delta 1 expression. Although recent studies revealed that KRAS mutations activate autophagy in cancer cells, a relation between PLC delta 1 and autophagy remains unclear. Here, we found that PLC delta 1 overexpression suppresses the formation of autophagosomes, which are key structures of autophagy, whereas endogenous PLC delta 1 knockdown increases autophagosome formation in CRC cells. We also showed that PLC delta 1 overexpression promotes cell death under nutrient deprivation. Furthermore, PLC delta 1 overexpression suppresses the autophagy induced by the anti-cancer drug oxaliplatin and promotes cell death under oxaliplatin treatment. These data suggest that PLC delta 1 negatively regulates autophagy, and PLC delta 1 suppression contributes to the tolerance of CRC cells harboring KRAS mutations to nutrient deprivation and anti-cancer drug treatment. (C) 2017 Elsevier Inc. All rights reserved.	[Shimozawa, Makoto; Anzai, Sakiho; Satow, Reiko; Fukami, Kiyoko] Tokyo Univ Pharm & Life Sci, Lab Genome & Biosignals, Hachioji, Tokyo 1920392, Japan; [Satow, Reiko; Fukami, Kiyoko] Japan Agcy Med Res & Dev, AMED CREST, Chiyoda Ku, Tokyo 1000004, Japan		Fukami, K (corresponding author), Tokyo Univ Pharm & Life Sci, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan.	kfukami@toyaku.ac.jp		Satow, Reiko/0000-0002-6339-4268	Japan Society for the Promotion of Science KAKENHIMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) [26293071, 26860221]; MEXT-Supported Program for the Strategic Research Foundation at Private UniversitiesMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [17gm0710002h0405]; Ono Medical Research Foundation; 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) [17H04051] Funding Source: KAKEN	We thank Dr. Y. Nakamura and Dr. A. Yoneda for constructive suggestions. We also thank Y. Mihana for technical assistance. This work was supported by Grants-in-Aid for Scientific Research (Japan Society for the Promotion of Science KAKENHI Grant No. 26293071) and the MEXT-Supported Program (17gm0710002h0405) for the Strategic Research Foundation at Private Universities to K.F. and a Grant-in-Aid for Young Scientists (Japan Society for the Promotion of Science KAKENHI Grant No. 26860221) to R.S. This work was also supported by a Grant-in Aid from the Ono Medical Research Foundation.	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Biophys. Res. Commun.	JUL 8	2017	488	4					578	583		10.1016/j.bbrc.2017.05.098			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	EY4VB	WOS:000403974600002	28528980				2022-04-25	
J	Park, SH; Kim, JH; Chi, GY; Kim, GY; Chang, YC; Moon, SK; Nam, SW; Kim, WJ; Yoo, YH; Choi, YH				Park, Shin-Hyung; Kim, Jeong-Hwan; Chi, Gyoo Yong; Kim, Gi-Young; Chang, Young-Chae; Moon, Sung-Kwon; Nam, Soo-Wan; Kim, Wun-Jae; Yoo, Young Hyun; Choi, Yung Hyun			Induction of apoptosis and autophagy by sodium selenite in A549 human lung carcinoma cells through generation of reactive oxygen species	TOXICOLOGY LETTERS			English	Article						Sodium selenite; Apoptosis; Autophagy; ROS; Nrf2	COLON-CANCER CELLS; OXIDATIVE STRESS; MITOCHONDRIAL DAMAGE; SIGNALING PATHWAY; GENE-EXPRESSION; DNA-DAMAGE; DUAL ROLES; CROSS-TALK; NRF2; ACTIVATION	Selenium in the form of sodium selenite has been reported to exert anti-tumor effects in several cancer cell types by inducing autophagic cell death and apoptosis mediated by reactive oxygen species (ROS). However, the exact molecular pathways underlying these effects have not been fully established. The present study used A549 human lung carcinoma cells for further investigation of the anti-cancer mechanism of sodium selenite. We showed that sodium selenite modulated both the extrinsic and intrinsic apoptotic pathways, which were interconnected by Bid truncation. We used z-VAD-fmk, a pan-caspase inhibitor, to demonstrate that sodium selenite-induced apoptosis was dependent on the activation of caspases. Sodium selenite also increased autophagy, as indicated by an increase in microtubule-associated protein light chain-3 (LC3) puncta, accumulation of LC3II, and elevation of autophagic flux. Pretreatment with bafilomycin A1 enhanced sodium selenite-induced apoptosis, indicating that sodium selenite-induced autophagy functioned as a survival mechanism. Sodium selenite treatment also resulted in generation of ROS, which abrogated mitochondrial membrane potential (MMP) and regulated both apoptosis and autophagy. Phospho-nuclear factor erythroid 2-related factor 2 (p-Nrf2) showed a ROS-dependent translocation to the nucleus, which suggested that Nrf2 might increase cell survival by suppressing ROS accumulation and apoptosis mediated by oxidative stress. Sodium selenite treatment of A549 cells therefore appeared to trigger both apoptosis and cytoprotective autophagy, which were both mediated by ROS. The data suggest that regulation of ROS generation and autophagy can be a potential strategy for treating lung cancer that is resistant to pro-apoptotic therapeutics. (C) 2012 Elsevier Ireland Ltd. All rights reserved.	[Choi, Yung Hyun] Dong Eui Univ, Coll Oriental Med, Dept Biochem, Pusan 614052, South Korea; [Park, Shin-Hyung; Chi, Gyoo Yong] Dong Eui Univ, Coll Oriental Med, Dept Pathol, Pusan 614052, South Korea; [Park, Shin-Hyung; Chi, Gyoo Yong] Dong Eui Univ, Coll Oriental Med, Res Inst Oriental Med, Pusan 614052, South Korea; [Kim, Jeong-Hwan; Nam, Soo-Wan; Choi, Yung Hyun] Dong Eui Univ, Grad Sch, Dept Biomaterial Control, Program BK21, Pusan 614714, South Korea; [Kim, Gi-Young] Jeju Natl Univ, Dept Marine Life Sci, Immunobiol Lab, Cheju 690756, South Korea; [Chang, Young-Chae] Catholic Univ, Sch Med, Res Inst Biomed Engn, Taegu 705718, South Korea; [Chang, Young-Chae] Catholic Univ, Sch Med, Dept Med, Taegu 705718, South Korea; [Moon, Sung-Kwon] Chunju Natl Univ, Dept Biotechnol, Chungbuk 380702, South Korea; [Nam, Soo-Wan] Dong Eui Univ, Dept Biotechnol & Bioengn, Pusan 614714, South Korea; [Nam, Soo-Wan; Choi, Yung Hyun] Dong Eui Univ, Antiaging Res Ctr & Blue Bio Ind RIC, Pusan 614714, South Korea; [Kim, Wun-Jae] Chungbuk Natl Univ, Coll Med, Dept Urol, Cheongju 361763, South Korea; [Yoo, Young Hyun] Dong A Univ, Coll Med, Dept Anat & Cell Biol, Pusan 602714, South Korea; [Yoo, Young Hyun] Dong A Univ, Mitochondria Hub Regulat Ctr, Pusan 602714, South Korea		Choi, YH (corresponding author), Dong Eui Univ, Coll Oriental Med, Dept Biochem, Pusan 614052, South Korea.	yhyoo@dau.ac.kr; choiyh@deu.ac.kr	Park, Shin-Hyung/O-3803-2015		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 [2009-0093193, 2010-001730]	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 (2009-0093193 and 2010-001730).	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Lett.	AUG 3	2012	212	3					252	261		10.1016/j.toxlet.2012.06.007			10	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	990GN	WOS:000307619100003	22721804				2022-04-25	
J	Huang, SB; Sinicrope, FA				Huang, Shengbing; Sinicrope, Frank A.			Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells	AUTOPHAGY			English	Article						celecoxib; NSAID; ABT-737; Bcl-2; apoptosis; autophagy	BH3 MIMETIC ABT-737; ENDOPLASMIC-RETICULUM STRESS; DRUG-INDUCED APOPTOSIS; BCL-2 FAMILY-MEMBERS; SMALL-MOLECULE BCL-2; GROWTH IN-VIVO; CYCLOOXYGENASE-2 INHIBITOR; ENZYME-INHIBITORS; DEATH; PROTEINS	Apoptosis and autophagy have been shown to be negatively regulated by prosurvival Bcl-2 proteins. We determined whether the anticancer agent celecoxib, alone or combined with a small molecule Bcl-2/Bcl-x L antagonist (ABT-737), can induce autophagy in colon cancer cells. Furthermore, we determined whether inhibition of autophagy can drive colon cancer cells into apoptosis. Celecoxib was shown to induce apoptosis that was attenuated by ectopic Bcl-2 or Bax knockout. ABT-737 synergistically enhanced celecoxib-induced cytotoxicity that was primarily due to apoptosis as shown by caspase cleavage and Annexin V labeling that was attenuated by a pan caspase inhibitor (z-VAD-fmk). Celecoxib triggered conversion of the autophagosome-associated protein light chain 3 (LC3) from a cytosolic (LC3I) to a membrane-bound (LC3II) form, as shown by immunoblotting and a punctate fluorescence pattern of an ectopic GFP-LC3 protein. Celecoxib-induced conversion of LC3 was due to autophagy induction, as supported using the lysosome inhibitor, bafilomycin A1, which produced an accumulation of LC3II. ABT-737 enhanced celecoxib-induced LC3 conversion and p62/SQSTM1 degradation. Inhibition of autophagy was then studied in an effort to drive cells into apoptosis. 3-methyladenine (3-MA) blocked LC3 conversion, and 3-MA and wortmannin significantly enhanced apoptotic signaling in cells treated with celecoxib plus ABT-737. Furthermore, knockdown of Atg8/LC3B or Vps34 using siRNA attenuated p62 degradation and enhanced apoptotic signaling; Vps34 siRNA potentiated annexin V(+), PI-labeled cells induced by celecoxib + ABT-737. In conclusion, celecoxib induces apoptosis and autophagy that can both be potentiated by ABT-737. Inhibition of autophagy was shown to enhance apoptosis, suggesting a novel therapeutic strategy against colon cancer.	[Sinicrope, Frank A.] Mayo Clin, Fiterman Ctr Digest Dis, Div Oncol & Gastroenterol, Rochester, MN 55905 USA; Mayo Clin, Mayo Canc Ctr, Rochester, MN USA		Sinicrope, FA (corresponding author), Mayo Clin, Fiterman Ctr Digest Dis, Div Oncol & Gastroenterol, Rochester, MN 55905 USA.	sinicrope.frank@mayo.edu			Fraternal Order of Eagles Foundation; Fraternal Order of Eagles Foundation [CA113681]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA113681, K05CA142885] Funding Source: NIH RePORTER	Grant support: Supported in part by a Fraternal Order of Eagles Foundation Award and a National Cancer Institute R01 grant CA113681 [both to F. A. S.].	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J	Lai, K; Killingsworth, MC; Lee, CS				Lai, K.; Killingsworth, M. C.; Lee, C. S.			The significance of autophagy in colorectal cancer pathogenesis and implications for therapy	JOURNAL OF CLINICAL PATHOLOGY			English	Review							COLON-CANCER; CELL-DEATH; BECLIN 1; INHIBITION; CHLOROQUINE; APOPTOSIS; 5-FLUOROURACIL; LC3; DEGRADATION; EXPRESSION	Colorectal cancer (CRC) is one of the most common cancers in developed countries with poor survival outcome in advanced stages of the disease due to its resistance to chemotherapy and other forms of treatment. New and alternative approaches are needed to overcome the tumour cells' capacity for survival and to drive the tumour towards cell death. Autophagy is a mechanism involved in the elimination of damaged cellular components through lysosomal degradation and is capable of inducing programmed cell death. The process has recently gained much interest in understanding the pathogenesis of CRC and its potential for treatment of the disease due to its role in host protection and anticancer activity. This review describes and illustrates the fundamental mechanisms of autophagy, its importance as a prognostic marker and the current approaches to harness its protective and anticancer activity in CRC therapy.	[Lai, K.; Lee, C. S.] Ingham Inst Appl Med Res, Sydney, NSW, Australia; [Lai, K.; Killingsworth, M. C.; Lee, C. S.] Univ Western Sydney, Sch Med, Discipline Pathol, Liverpool, NSW 2170, Australia; [Lai, K.; Killingsworth, M. C.; Lee, C. S.] Univ Western Sydney, Sch Med, Mol Med Res Grp, Liverpool, NSW 2170, Australia; [Lai, K.] Univ Sydney, Dept Pathol, Sydney, NSW 2006, Australia; [Lai, K.; Killingsworth, M. C.] Liverpool Hosp, Electron Microscopy Lab, Sydney, NSW, Australia; [Lai, K.; Killingsworth, M. C.; Lee, C. S.] Liverpool Hosp, Dept Anat Pathol, Sydney, NSW, Australia; [Lee, C. S.] Univ Sydney, Bosch Inst, Dept Canc Pathol, Sydney, NSW 2006, Australia		Lai, K (corresponding author), Univ Western Sydney, Sch Med, Discipline Pathol, Bldg K,Coll St, Liverpool, NSW 2170, Australia.	ken.lai@uws.edu.au	Killingsworth, Murray/O-3736-2019; Killingsworth, Murray C/G-5908-2015	Killingsworth, Murray/0000-0002-6125-1183; Lee, C. Soon/0000-0003-1058-5826			Abdel-Aziz AK, 2014, CHEM-BIOL INTERACT, V217, P28, DOI 10.1016/j.cbi.2014.04.007; Amaravadi RK, 2011, CLIN CANCER RES, V17, P654, DOI 10.1158/1078-0432.CCR-10-2634; Chen J, 2002, CANCER J, V8, P154, DOI 10.1097/00130404-200203000-00009; Chen N, 2011, CANCER BIOL THER, V11, P157, DOI 10.4161/cbt.11.2.14622; Crighton D, 2006, CELL, V126, P121, DOI 10.1016/j.cell.2006.05.034; Giatromanolaki A, 2010, J CLIN PATHOL, V63, P867, DOI 10.1136/jcp.2010.079525; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Greene LM, 2013, INT J ONCOL, V43, P927, DOI 10.3892/ijo.2013.1989; Guo GF, 2011, WORLD J GASTROENTERO, V17, P4779, DOI 10.3748/wjg.v17.i43.4779; He G, 2014, TUMOR BIOL, V35, P1003, DOI 10.1007/s13277-013-1134-z; Hiratsuka T, 2013, ONCOL REP, V29, P2140, DOI 10.3892/or.2013.2394; Honscheid P, 2014, INT J RADIAT BIOL, V90, P628, DOI 10.3109/09553002.2014.907932; Huo HZ, 2014, BIOCHEM BIOPH RES CO, V443, P406, DOI 10.1016/j.bbrc.2013.11.099; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kaneko M, 2014, J CANCER RES CLIN, V140, P769, DOI 10.1007/s00432-014-1628-0; Kondo Y, 2006, AUTOPHAGY, V2, P85, DOI 10.4161/auto.2.2.2463; 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; Li BX, 2009, AUTOPHAGY, V5, P303, DOI 10.4161/auto.5.3.7491; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Loven D, 2013, DRUG DISCOV TODAY, V18, P193, DOI 10.1016/j.drudis.2012.07.015; MATHE G, 1989, BIOMED PHARMACOTHER, V43, P237, DOI 10.1016/0753-3322(89)90003-6; Mathew R, 2011, CURR OPIN GENET DEV, V21, P113, DOI 10.1016/j.gde.2010.12.008; McAfee Q, 2012, P NATL ACAD SCI USA, V109, P8253, DOI 10.1073/pnas.1118193109; Miao YF, 2010, HEPATO-GASTROENTEROL, V57, P257; Miki H, 2012, INT J ONCOL, V40, P1020, DOI 10.3892/ijo.2012.1325; Mizushima N, 2002, CELL STRUCT FUNCT, V27, P421, DOI 10.1247/csf.27.421; 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; Raina K, 2013, AUTOPHAGY, V9, P697, DOI 10.4161/auto.23960; Rosenfeld MR, 2010, J CLIN ONCOL, V28; Sasaki K, 2012, ANTI-CANCER DRUG, V23, P675, DOI 10.1097/CAD.0b013e328353f8c7; 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; Schneider JL, 2014, CURR OPIN GENET DEV, V26, P16, DOI 10.1016/j.gde.2014.04.003; 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; Selvakumaran M, 2013, CLIN CANCER RES, V19, P2995, DOI 10.1158/1078-0432.CCR-12-1542; Shi Y, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0051076; STEINMAN RM, 1983, J CELL BIOL, V96, P1, DOI 10.1083/jcb.96.1.1; Wang JR, 2008, AUTOPHAGY, V4, P947, DOI 10.4161/auto.6787; Wei MF, 2014, AUTOPHAGY, V10, P1179, DOI 10.4161/auto.28679; White E, 2010, CURR OPIN CELL BIOL, V22, P212, DOI 10.1016/j.ceb.2009.12.008; Xie CM, 2011, FREE RADICAL BIO MED, V51, P1365, DOI 10.1016/j.freeradbiomed.2011.06.016; Yamamoto A, 1998, CELL STRUCT FUNCT, V23, P33, DOI 10.1247/csf.23.33; Yuk JM, 2010, AUTOPHAGY, V6, P46, DOI 10.4161/auto.6.1.10325; Zhang JW, 2014, BIOCHEM PHARMACOL, V90, P265, DOI 10.1016/j.bcp.2014.05.009	48	29	31	0	18	BMJ PUBLISHING GROUP	LONDON	BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND	0021-9746	1472-4146		J CLIN PATHOL	J. Clin. Pathol.	OCT	2014	67	10					854	858		10.1136/jclinpath-2014-202529			5	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	AQ1UA	WOS:000342566000003	25055793				2022-04-25	
J	Lauzier, A; Normandeau-Guimond, J; Vaillancourt-Lavigueur, V; Boivin, V; Charbonneau, M; Rivard, N; Scott, MS; Dubois, CM; Jean, S				Lauzier, Annie; Normandeau-Guimond, Josiann; Vaillancourt-Lavigueur, Vanessa; Boivin, Vincent; Charbonneau, Martine; Rivard, Nathalie; Scott, Michelle S.; Dubois, Claire M.; Jean, Steve			Colorectal cancer cells respond differentially to autophagy inhibition in vivo	SCIENTIFIC REPORTS			English	Article							SPARE RESPIRATORY CAPACITY; BREAST-CANCER; GROWTH; PROGRESSION; EXPRESSION; MTORC1; TUMORS; PHOSPHORYLATION; METABOLISM; PHYSIOLOGY	Autophagy has both tumor-promoting and - suppressing effects in cancer, including colorectal cancer (CRC), with transformed cells often exhibiting high autophagic flux. In established tumors, autophagy inhibition can lead to opposite responses resulting in either tumor cell death or hyperproliferation. The functional mechanisms underlying these differences are poorly understood. The present study aimed to investigate the relationship between the autophagic capacities of CRC cells and their sensitivities to autophagy inhibition. All studied CRC cell lines showed high basal autophagic flux. However, only HCT116 and Caco-2/15 cells displayed regulated autophagic flux upon starvation. Knockdown of ATG5 (which disrupts autophagosome elongation) or RAB21 (which decreases autophagosome/lysosome fusion) had little effect on CRC cell proliferation in vitro. Nonetheless, inhibition of autophagy in vivo had a substantial cell line-dependent impact on tumor growth, with some cells displaying decreased (HCT116 and Caco-2/15) or increased (SW480 and LoVo) proliferation. RNA sequencing and Western blot analyses in hyperproliferative SW480 tumors revealed that the mTORC2 and AKT pathways were hyperactivated following autophagy impairment. Inhibition of either mTOR or AKT activities rescued the observed hyperproliferation in autophagy-inhibited SW480 and reduced tumor growth. These results highlight that autophagy inhibition can lead, in specific cellular contexts, to compensatory mechanisms promoting tumor growth.	[Lauzier, Annie; Normandeau-Guimond, Josiann; Vaillancourt-Lavigueur, Vanessa; Boivin, Vincent; Charbonneau, Martine; Rivard, Nathalie; Scott, Michelle S.; Dubois, Claire M.; Jean, Steve] Univ Sherbrooke, Fac Med & Sci Sante, 3201 Rue Jean Mignault, Sherbrooke, PQ J1E 4K8, Canada; [Lauzier, Annie; Normandeau-Guimond, Josiann; Vaillancourt-Lavigueur, Vanessa; Charbonneau, Martine; Rivard, Nathalie; Dubois, Claire M.; Jean, Steve] Univ Sherbrooke, Dept Anat & Cell Biol, 3201 Rue Jean Mignault, Sherbrooke, PQ J1E 4K8, Canada; [Boivin, Vincent; Scott, Michelle S.] Univ Sherbrooke, Dept Biochem, 3201 Rue Jean Mignault, Sherbrooke, PQ J1E 4K8, Canada		Jean, S (corresponding author), Univ Sherbrooke, Fac Med & Sci Sante, 3201 Rue Jean Mignault, Sherbrooke, PQ J1E 4K8, Canada.; Jean, S (corresponding author), Univ Sherbrooke, Dept Anat & Cell Biol, 3201 Rue Jean Mignault, Sherbrooke, PQ J1E 4K8, Canada.	steve.jean@usherbrooke.ca	Dubois, Claire M/K-1985-2013	Jean, Steve/0000-0001-6881-5781	Centre d'excellence en Recherche en Inflammation et Oncologie Digestive de l'Universite de Sherbrooke (CRIODUS); Cancer Research Society; Canadian Institutes of Health Research (CIHR)Canadian Institutes of Health Research (CIHR); Canada Research Chair in Colorectal Cancer [227765]; Research Chair from the Centre de recherche medicale de l'Universite de Sherbrooke (CRMUS); FRQS	We thank members of the laboratory for their helpful comments during the course of this work. We also thank Marie-Josee Boucher for helpful discussion through the progression of this work and Gaspard Reulet for help with RNASeq data handling. This research was supported by a seed grant from the Centre d'excellence en Recherche en Inflammation et Oncologie Digestive de l'Universite de Sherbrooke (CRIODUS), and operating grants from the Cancer Research Society and the Canadian Institutes of Health Research (CIHR) and by junior faculty salary awards from CIHR and Fonds de Recherche du Quebec en Sante (FRQS) to S.J. S.J., C.M.D., M.S.S. and N.R. are members of the FRQS-Funded Centre de Recherche du CHUS. N.R. is a recipient of a Canada Research Chair in Colorectal Cancer and Inflammatory Cell Signaling (227765). S.J. is a recipient of a Research Chair from the Centre de recherche medicale de l'Universite de Sherbrooke (CRMUS).	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Zhang XC, 2017, MOL CELL BIOL, V37, DOI 10.1128/MCB.00357-16	79	23	23	0	3	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	2045-2322			SCI REP-UK	Sci Rep	AUG 5	2019	9								11316	10.1038/s41598-019-47659-7			16	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	IN5VC	WOS:000478743700028	31383875	Green Published, gold			2022-04-25	
J	Yan, Z; Zhang, B; Huang, YY; Qiu, HJ; Chen, P; Guo, GF				Yan, Zheng; Zhang, Bei; Huang, Yuanyuan; Qiu, Huijuan; Chen, Ping; Guo, Gui-Fang			Involvement of autophagy inhibition in Brucea javanica oil emulsion-induced colon cancer cell death	ONCOLOGY LETTERS			English	Article						Brucea javanica oil emulsion; autophagy; apoptosis; colon cancer; light chain 3	ADVANCED SOLID TUMORS; PHASE-I TRIAL; NF-KAPPA-B; INDUCED APOPTOSIS; DOWN-REGULATION; INDUCTION; MTOR; HYDROXYCHLOROQUINE; DIFFERENTIATION; CHEMOTHERAPY	Brucea javanica oil emulsion (BJOE), the petroleum ether extract of B. javanica emulsified by phospholipid, is widely used in China as an anticancer agent. The extracts from B. javanica induce cancer cell death by various mechanisms; however, it is not known whether these mechanisms involve autophagy, which is an important process in cancer development and treatment. Thus, the current study. aimed to investigate whether BJOE modulates autophagy in HCT116 human colon cancer cells and whether modulation of autophagy is an anticancer mechanism of BJOE. Immunoblotting was employed to analyze the protein expression levels of microtubule-associated protein light-chain 3 (LC3), a specific protein marker of autophagy, in HCT116 cancer cells following exposure to BJOE. The apoptosis rate of the HCT116 cancer cells was detected by performing an Annexin V-fluorescein isothiocyanate/propidium iodide assay. According to the effect of BJOE administration on autophagy in the HCT116 cancer cells (induction or suppression), a functionally opposite agent (autophagy suppressor or inducer) was applied to counteract this effect, and the apoptosis rate of the cancer cells was detected again. The role of autophagy (pro-survival or pro-death) was demonstrated by comparing the rates of apoptotic cancer cells prior to and following the counteraction. The results revealed that BJOE suppressed the protein expression levels of LC3, including the LC3-I and LC3-II forms, and induced apoptosis in the HCT116 cancer cells with a high level of basal LC3. The apoptosis-inducing activity of BJOE was significantly attenuated when autophagy was induced by the administration of trehalose, an autophagy inducer. The data indicates that autophagy inhibition is involved in BJOE-induced cancer cell death, and that this inhibition may be a potential anticancer mechanism of BJOE.	[Yan, Zheng; Zhang, Bei; Huang, Yuanyuan; Qiu, Huijuan; Chen, Ping; Guo, Gui-Fang] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China; [Yan, Zheng] Sun Yat Sen Univ, Ctr Canc, Dept Med Oncol, Guangzhou 510060, Guangdong, Peoples R China; [Zhang, Bei; Huang, Yuanyuan; Qiu, Huijuan; Chen, Ping; Guo, Gui-Fang] Sun Yat Sen Univ, Ctr Canc, VIP Reg, Guangzhou 510060, Guangdong, Peoples R China		Guo, GF (corresponding author), Sun Yat Sen Univ, Ctr Canc, VIP Reg, 651 Dongfeng East Rd, Guangzhou 510060, Guangdong, Peoples R China.	sysucc@163.com	Yan, Zheng/AFD-5256-2022	Yan, Zheng/0000-0001-9324-2161; guo, gui fang/0000-0002-6283-7266	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81302141]; Administration of Traditional Chinese Medicine of Guangdong Province [20111169]; Science and Technology Planning Project of Guangdong Province [2010B031600317]; Fundamental Research Funds for the Sun Yat-sen University Young Teacher Training Project [12ykpy56]	The present study was supported by grants from the National Natural Science Foundation of China (no. 81302141), the Administration of Traditional Chinese Medicine of Guangdong Province (no. 20111169), the Science and Technology Planning Project of Guangdong Province (no. 2010B031600317) and the Fundamental Research Funds for the Sun Yat-sen University Young Teacher Training Project (no. 12ykpy56).	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Lett.	MAR	2015	9	3					1425	1431		10.3892/ol.2015.2875			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CD2OE	WOS:000350918100077	25663926	gold, Green Submitted, Green Published			2022-04-25	
J	Pettersen, K; Monsen, VT; Pettersen, CHH; Overland, HB; Pettersen, G; Samdal, H; Tesfahun, AN; Lundemo, AG; Bjorkoy, G; Schonberg, SA				Pettersen, Kristine; Monsen, Vivi Talstad; Pettersen, Caroline Hild Hakvag; Overland, Hilde Bremseth; Pettersen, Grete; Samdal, Helle; Tesfahun, Almaz Nigatu; Lundemo, Anne Goril; Bjorkoy, Geir; Schonberg, Svanhild A.			DHA-induced stress response in human colon cancer cells - Focus on oxidative stress and autophagy	FREE RADICAL BIOLOGY AND MEDICINE			English	Article						n 3 PUFA; DHA; Oxidative stress; Autophagy; NFE2L2; Colon cancer	TRANSCRIPTION FACTOR NRF2; ENDOPLASMIC-RETICULUM STRESS; POLYUNSATURATED FATTY-ACIDS; COLORECTAL-CANCER; SELECTIVE AUTOPHAGY; CALCIUM HOMEOSTASIS; QUALITY-CONTROL; ER STRESS; PATHWAY; SURVIVAL	Polyunsaturated fatty acids (PUFAs) are important constituents of the diet and health benefits of omega-3/n 3 PUFAs, especially eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) have been well documented in relation to several diseases. Increasing evidence suggests that n-3 PUFAs may have anticancer activity and improve the effect of conventional cancer therapy. The mechanisms behind these effects are still unclear and need to be elucidated. We have examined the DHA-induced stress response in two human colon cancer cell lines, SW620 and Caco-2. SW620 cells are growth-inhibited at early time points by DHA, while the growth of Caco-2 cells almost remains unaffected by the same treatment. Gene expression analysis of SW620 cells treated with DHA revealed changes at early time points; transcripts involved in oxidative stress and autophagy were among the first to be differentially expressed. We find that oxidative stress is induced in both cell lines, although at different time points and to different extent. DHA induced nuclear translocation of the oxidative stress sensor NFE2L2 in both cell lines, indicating an induction of an anti-oxidative response. However, vitamin E did not counteract ROS-production or the translocation of NFE2L2 to the nucleus. Neither vitamin E nor the antioxidants butylated hydoxyanisole (BHA) and butylated hydoxytoluene (BHT) did affect the growth inhibition in SW620 cells after DHA-treatment. Also, siRNA-mediated down-regulation of NFE2L2 did not sensitize SW620 and Caco-2 cells to DHA. These results indicate that oxidative stress response is not the cause of DHA-induced cytotoxicity in SW620 cells. Using biochemical and imaging based functional assays, we found a low basal level of autophagy and no increase in autophagic flux after adding DHA to the SW620 cells. However, Caco-2 cells displayed a higher level of autophagy, both in the absence and presence of DHA. Inhibition of autophagy by siRNA mediated knock down of ATG5 and ATG7 sensitized both SW620 and Caco-2 cells to DHA. Stimulation of autophagy by rapamycin in 5W620 and Caco-2 cells resulted in decreased DHA-sensitivity and inhibition of autophagy in Caco-2 cells by chloroquine resulted in increased DHA-sensitivity. These results suggest that autophagy is important for the DHA sensitivity of colon cancer cells and imply possible therapeutic effects of this fatty acid against cancer cells with low autophagy. (C)2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.	[Pettersen, Kristine; Monsen, Vivi Talstad; Pettersen, Caroline Hild Hakvag; Overland, Hilde Bremseth; Pettersen, Grete; Samdal, Helle; Tesfahun, Almaz Nigatu; Lundemo, Anne Goril; Schonberg, Svanhild A.] Norwegian Univ Sci & Technol, Dept Lab Med, Childrens & Womens Hlth, Fac Med,NTNU, N-7006 Trondheim, Norway; [Pettersen, Kristine; Bjorkoy, Geir] Univ Coll Sor Trondelag, Dept Technol, N-7006 Trondheim, Norway; [Overland, Hilde Bremseth] Cent Norway Reg Hlth Author, N-7055 Stjordal, Norway; [Pettersen, Kristine; Bjorkoy, Geir] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Ctr Mol Inflammat Res, N-7491 Trondheim, Norway		Schonberg, SA (corresponding author), Norwegian Univ Sci & Technol, Dept Lab Med, Childrens & Womens Hlth, Fac Med,NTNU, N-7006 Trondheim, Norway.	svanhild.schonberg@ntnu.no		Pettersen, Caroline/0000-0003-0658-0061; Pettersen, Kristine/0000-0002-6446-0984	Faculty of Medicine; NTNU; Norwegian Cancer SocietyNorwegian Cancer Society; Cancer Research Foundation at St. Olavs Hospital; Central Norway Regional Health Authority and The Research Council of Norway through "Smaforsk" grant	We thank Terje Johansen and Hans Krokan for discussions and comments. Gene expression profiling was performed at the Norwegian Microarray consortium (NMC) in Trondheim. We thank Cathrine Goberg Olsen for gene expression profiling, Turid Follestad for the statistical analysis, Lena Pape, Nina Beate Liabakk, Kamilla Zub and Ida Johansson for their experimental input. This work was supported by grants from The Faculty of Medicine, NTNU, the Norwegian Cancer Society, the Cancer Research Foundation at St. Olavs Hospital, the Central Norway Regional Health Authority and The Research Council of Norway through "Smaforsk" grant.	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Biol. Med.	JAN	2016	90						158	172		10.1016/j.freeradbiomed.2015.11.018			15	Biochemistry & Molecular Biology; Endocrinology & Metabolism	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Endocrinology & Metabolism	CZ9CY	WOS:000367396600015	26585906	Green Accepted, Green Published, hybrid			2022-04-25	
J	Zhang, ZY; Zhang, SF; Yang, JJ; Yi, PJ; Xu, PP; Yi, M; Peng, WJ				Zhang, Zheyu; Zhang, Sifang; Yang, Jingjing; Yi, Pengji; Xu, Panpan; Yi, Min; Peng, Weijun			Integrated transcriptomic and metabolomic analyses to characterize the anti-cancer effects of (-)-epigallocatechin-3-gallate in human colon cancer cells	TOXICOLOGY AND APPLIED PHARMACOLOGY			English	Article						EGCG; Colorectal cancer; Transcriptomic; Metabolomics; Glutathione metabolism; Glycerophospholipid metabolism	EPIGALLOCATECHIN GALLATE; PROLIFERATION; APOPTOSIS; GROWTH; EGCG; INHIBITION; AUTOPHAGY; PATHWAY	(-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive component in tea (Camellia sinensis) catechins, and exhibits potential antitumor activity against colorectal cancer (CRC). However, the underlying mechanisms are largely unclear. We investigated the effects of EGCG on activities of CRC cells and the exact molecular mechanism. We used human colon cancer cells (HT-29) and exposed them to EGCG at various concentrations. The MTT assay, flow cytometry, and TUNEL staining were used to study the underlying mechanisms of EGCG (proliferation, apoptosis, autophagy). Western blotting was used to measure expression of marker proteins of the cell cycle, apoptosis, and autophagy. Using a combined microarray-based transcriptomic and ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-QTOF/MS)-based metabolomic approach, we investigated the perturbed pathways induced by EGCG treatment at transcript and metabolite levels. Transcriptomic analyses showed that 486 genes were differentially expressed between untreated and EGCG-treated cells. Also, 88 differentially expressed metabolites were identified between untreated and EGCG-treated cells. The altered metabolites were involved in the metabolism of glutathione, glycerophospholipids, starch, sucrose, amino sugars, and nucleotide sugars. There was substantial agreement between the results of transcriptomics and metabolomics analyses. Our data indicate that the anticancer activity of EGCG against HT-29 cells is mediated by induction of cell-cycle arrest, apoptosis, and autophagy. EGCG modulates cancer-cell metabolic pathways. These results provide a platform for future molecular mechanistic studies of EGCG.	[Zhang, Zheyu; Zhang, Sifang; Yi, Pengji; Xu, Panpan; Yi, Min; Peng, Weijun] Cent South Univ, Xiangya Hosp 2, Dept Integrated Tradit Chinese & Western Med, 139 Middle Renmin Rd, Changsha 410011, Hunan, Peoples R China; [Zhang, Zheyu] Cent South Univ, Xiangya Hosp, Dept Gastroenterol, Changsha 410008, Hunan, Peoples R China; [Zhang, Zheyu] Guilin Med Univ, Dept Gastroenterol, Affiliated Hosp, Guilin 541001, Guangxi, Peoples R China; [Yang, Jingjing] Cent South Univ, Xiangya Hosp, Dept Integrated Tradit Chinese & Western Med, Changsha 410008, Hunan, Peoples R China		Yi, M; Peng, WJ (corresponding author), Cent South Univ, Xiangya Hosp 2, Dept Integrated Tradit Chinese & Western Med, 139 Middle Renmin Rd, Changsha 410011, Hunan, Peoples R China.	yimin66@csu.edu; pengweijun87@csu.edu.cn	Peng, Weijun/M-5131-2014	Peng, Weijun/0000-0002-4506-0942	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81273722, 81603670]; Hunan Provincial Natural Science Foundation of ChinaNatural Science Foundation of Hunan Province [2017JJ3459, 2018JJ2595]	This work was supported by the National Natural Science Foundation of China (81273722, 81603670) and the Hunan Provincial Natural Science Foundation of China (2017JJ3459, 2018JJ2595).	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Appl. Pharmacol.	AUG 15	2020	401								115100	10.1016/j.taap.2020.115100			13	Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Toxicology	MO4QK	WOS:000551512500013	32512070				2022-04-25	
J	Matarrese, P; Mattia, G; Pagano, MT; Pontecorvi, G; Ortona, E; Malorni, W; Care, A				Matarrese, Paola; Mattia, Gianfranco; Pagano, Maria Teresa; Pontecorvi, Giada; Ortona, Elena; Malorni, Walter; Care, Alessandra			The Sex-Related Interplay between TME and Cancer: On the Critical Role of Estrogen, MicroRNAs and Autophagy	CANCERS			English	Review						cancer; gender; sex; sex hormones; microRNA; autophagy; tumor microenvironment	CELL LUNG-CANCER; BETA ER-BETA; HUMAN OSTEOSARCOMA SAOS-2; RECEPTOR-BETA; COLORECTAL-CANCER; X-CHROMOSOME; CUTANEOUS MELANOMA; STEROID-HORMONES; XENO-CANNIBALISM; LYMPHOMA GROWTH	Simple Summary Autophagy is a complex cell process that allow the cell to survive in unfavorable conditions, e.g., in the lack of nutritional elements coming from the environment. Here we focused on the role played by autophagy in the crosstalk between the microenvironment surrounding the tumor and cancer cells. This environment is in fact known as pivotal in determining the growth or the inhibition of a tumor. Cancer progression and response to therapy significantly differ between women and men and the microenvironment, in particular sex hormones and microRNAs, appears a critical factor. Four representative types of cancer, i.e., colon cancer, melanoma, lymphoma, and lung cancer showing sex/gender specificities have been described herein. We underscore that the use of a "gender tailored" approach could provide a better comprehension of the cellular and molecular mechanisms of cancer growth control contributing to the development of novel therapeutic approaches towards an increasingly personalized medicine. The interplay between cancer cells and the tumor microenvironment (TME) has a fundamental role in tumor progression and response to therapy. The plethora of components constituting the TME, such as stroma, fibroblasts, endothelial and immune cells, as well as macromolecules, e.g., hormones and cytokines, and epigenetic factors, such as microRNAs, can modulate the survival or death of cancer cells. Actually, the TME can stimulate the genetically regulated programs that the cell puts in place under stress: apoptosis or, of interest here, autophagy. However, the implication of autophagy in tumor growth appears still undefined. Autophagy mainly represents a cyto-protective mechanism that allows cell survival but, in certain circumstances, also leads to the blocking of cell cycle progression, possibly leading to cell death. Since significant sex/gender differences in the incidence, progression and response to cancer therapy have been widely described in the literature, in this review, we analyzed the roles played by key components of the TME, e.g., estrogen and microRNAs, on autophagy regulation from a sex/gender-based perspective. We focused our attention on four paradigmatic and different forms of cancers-colon cancer, melanoma, lymphoma, and lung cancer-concluding that sex-specific differences may exert a significant impact on TME/cancer interaction and, thus, tumor growth.	[Matarrese, Paola; Mattia, Gianfranco; Pagano, Maria Teresa; Pontecorvi, Giada; Ortona, Elena; Care, Alessandra] Ist Super Sanita, Ctr Gender Specif Med, I-00161 Rome, Italy; [Malorni, Walter] Univ Roma Tor Vergata, Fac Farmacy, Dept Biol, I-00133 Rome, Italy; [Malorni, Walter] Univ Cattolica Sacro Cuore, Ctr Global Hlth, I-00168 Rome, Italy		Malorni, W (corresponding author), Univ Roma Tor Vergata, Fac Farmacy, Dept Biol, I-00133 Rome, Italy.; Malorni, W (corresponding author), Univ Cattolica Sacro Cuore, Ctr Global Hlth, I-00168 Rome, Italy.	paola.matarrese@iss.it; gianfranco.mattia@iss.it; mariateresa.pagano@guest.iss.it; giada.pontecorvi@iss.it; elena.ortona@iss.it; walter.malorni@unicatt.it; alessandra.care@iss.it	; Care, Alessandra/H-5090-2016	Pagano, Maria Teresa/0000-0002-9215-9187; matarrese, paola/0000-0001-5477-3752; Care, Alessandra/0000-0003-4106-3342			Abdrakhmanov A, 2019, BIOL CHEM, V400, P161, DOI 10.1515/hsz-2018-0210; Akkoc Y, 2021, FRONT ONCOL, V11, DOI 10.3389/fonc.2021.627023; 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J	Wang, JB; Ren, XR; Piao, HL; Zhao, SL; Osada, T; Premont, RT; Mook, RA; Morse, MA; Lyerly, HK; Chen, W				Wang, Jiangbo; Ren, Xiu-rong; Piao, Hailan; Zhao, Shengli; Osada, Takuya; Premont, Richard T.; Mook, Robert A., Jr.; Morse, Michael A.; Lyerly, Herbert Kim; Chen, Wei			Niclosamide-induced Wnt signaling inhibition in colorectal cancer is mediated by autophagy	BIOCHEMICAL JOURNAL			English	Article							POTENTIAL ROLE; COLON-CANCER; CELL-LINES; TARGET	The Wnt signaling pathway, known for regulating genes critical to normal embryonic development and tissue homeostasis, is dysregulated in many types of cancer. Previously, we identified that the anthelmintic drug niclosamide inhibited Wnt signaling by promoting internalization of Wnt receptor Frizzled 1 and degradation of Wnt signaling pathway proteins, Dishevelled 2 and beta-catenin, contributing to suppression of colorectal cancer growth in vitro and in vivo. Here, we provide evidence that niclosamide-mediated inhibition of Wnt signaling is mediated through autophagosomes induced by niclosamide. Specifically, niclosamide promotes the co-localization of Frizzled 1 or beta-catenin with LC3, an autophagosome marker. Niclosamide inhibition of Wnt signaling is attenuated in autophagosome-deficient ATG5(-/-) MEF cells or cells expressing shRNA targeting Beclin1, a critical constituent of autophagosome. Treatment with the autophagosome inhibitor 3MA blocks niclosamide-mediated Frizzled 1 degradation. The sensitivity of colorectal cancer cells to growth inhibition by niclosamide is correlated with autophagosome formation induced by niclosamide. Niclosamide inhibits mTORC1 and ULK1 activities and induces LC3B expression in niclosamide-sensitive cell lines, but not in the niclosamide-resistant cell lines tested. Interestingly, niclosamide is a less effective inhibitor of Wnt-responsive genes (beta-catenin, c-Myc, and Survivin) in the niclosamide-resistant cells than in the niclosamide-sensitive cells, suggesting that deficient autophagy induction by niclosamide compromises the effect of niclosamide on Wnt signaling. Our findings provide a mechanistic understanding of the role of autophagosomes in the inhibition of Wnt signaling by niclosamide and may provide biomarkers to assist selection of patients whose tumors are likely to respond to niclosamide.	[Wang, Jiangbo; Ren, Xiu-rong; Piao, Hailan; Zhao, Shengli; Premont, Richard T.; Mook, Robert A., Jr.; Chen, Wei] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA; [Osada, Takuya; Morse, Michael A.; Lyerly, Herbert Kim] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA		Wang, JB; Chen, W (corresponding author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA.	jiangbo.wang@duke.edu; w.chen@duke.edu	Lyerly, Herbert Kim/AAX-4925-2020	Lyerly, Herbert Kim/0000-0002-0063-4770; Chen, Wei/0000-0002-9934-4000	Clinical Oncology Research Center Development Grant [5K12-CA100639-08];  [5 R01 CA172570]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA172570] Funding Source: NIH RePORTER	This work was funded, in part, by 5 R01 CA172570 (W.C.) and Clinical Oncology Research Center Development Grant 5K12-CA100639-08 (R.A.M.).	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J.	FEB 14	2019	476		3				535	546		10.1042/BCJ20180385			12	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	HQ4OX	WOS:000462392000007	30635359	Green Accepted			2022-04-25	
J	Yang, YS; Wen, D; Zhao, XF				Yang, Yu-Shen; Wen, Dan; Zhao, Xue-Feng			Preventive and therapeutic effect of intraportal oridonin on BALb/c nude mice hemispleen model of colon cancer liver metastasis	TRANSLATIONAL CANCER RESEARCH			English	Article						BALb/c nude mice; colon cancer liver metastasis; hemispleen model; intraportal oridonin; prevention and treatment	ANTITUMOR-ACTIVITY; LUNG-CANCER; ANTICANCER; EXPRESSION; CISPLATIN; APOPTOSIS; AUTOPHAGY; PROTEIN; GROWTH	Background: This study is to investigate the preventive and therapeutic effect of intraportal oridonin on colorectal cancer liver metastasis (CRCLM). Methods: The inhibitory effect of oridonin on HT29 cells was determined by CCK-8 and MTT assays. The preventive and therapeutic effect of intraportal oridonin on CRCLM were investigated by establishing BALb/c nude mice hemispleen models of colon cancer liver metastasis. The microscopic characteristics of tumor tissues were observed by hematoxylin-eosin staining, immunohistochemistry and TUNEL staining. On the other hand, liver function enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), were detected to evaluate the hepatotoxicity of intraportal oridonin. The serum levels of tumor markers, including carcinoembryonic antigen (CEA) and a-fetoprotein (AFP), were used to investigate the intervention effect of intraportal oridonin on CRCLM. Results: Oridonin exerted an inhibitory effect on the proliferation of HT29 cells in vitro. Intraportal oridonin was found to effectively prevent the occurrence and formation of CRCLM, whilst intraportal oridonin can also exert a therapeutic effect on CRCLM. Additionally, liver enzymes testing indicated that intraportal oridonin possesses non-hepatotoxicity, instead can effectively alleviate liver injury caused by tumor. Furthermore, intraportal oridonin was also revealed to decrease the serum levels of AFP and CEA. Conclusions: Intraportal oridonin can effectively inhibit the formation of liver metastatic tumor and exert a certain degree of preventive and therapeutic effect on CRCLM. These findings indicate intraportal oridonin to be a promising anti-metastasis agent for CRCLM.	[Yang, Yu-Shen; Wen, Dan; Zhao, Xue-Feng] Dalian Univ, Affiliated Xinhua Hosp, Dept Gen Surg, 156 Wansui St, Dalian 116021, Liaoning, Peoples R China		Zhao, XF (corresponding author), Dalian Univ, Affiliated Xinhua Hosp, Dept Gen Surg, 156 Wansui St, Dalian 116021, Liaoning, Peoples R China.	zoserbong@163.com			Liaoning Provincial Natural Science Foundations of China [201602037]	This study was supported by Liaoning Provincial Natural Science Foundations of China (grant nos. 201602037).	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Cancer Res.	MAR	2021	10	3					1324	+		10.21037/tcr-20-3042			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	RF7LI	WOS:000635021300013	35116458	Green Published, gold			2022-04-25	
J	Dai, LZ; Chen, XL; Lu, XH; Wang, F; Zhan, YY; Song, G; Hu, TH; Xia, C; Zhang, B				Dai, Lianzhi; Chen, Xiaolei; Lu, Xiaohong; Wang, Fen; Zhan, Yanyan; Song, Gang; Hu, Tianhui; Xia, Chun; Zhang, Bing			Phosphoinositide-specific phospholipase C gamma 1 inhibition induces autophagy in human colon cancer and hepatocellular carcinoma cells	SCIENTIFIC REPORTS			English	Article							ACTIVATED PROTEIN-KINASE; FOCAL ADHESION KINASE; GASTRIC-CANCER; LUNG-CANCER; AMPK; PATHWAY; METASTASIS; TARGET; HOMEOSTASIS; MECHANISM	Phosphoinositide-specific phospholipase C (PLC)gamma 1 has been reported to be involved in cancer cell proliferation and metastasis. However, whether PLC gamma 1 modulates autophagy and the underlying mechanism remains unclear. Here, we investigated the relationship between PLC gamma 1 and autophagy in the human colon cancer cell line HCT116 and hepatocellular carcinoma cell line HepG2. The results indicated that PLC gamma 1 inhibition via lentivirus-mediated transduction with shRNA/PLC gamma 1 or transient transfection with pRK5-PLC gamma 1 (Y783A) vector increased LC3B-II levels and the number of autophagic vacuoles and decreased p62 levels. Addition of an autophagy inhibitor led to LC3B and p62 accumulation. Furthermore, AMPK activation promoted the autophagy induced by PLC gamma 1 inhibition by blocking the FAK/PLC gamma 1 axis. In addition, PLC gamma 1 inhibition either blocked the mTOR/ULK1 axis or enhanced dissociation of the Beclin1-IP3R-Bcl-2 complex to induce autophagy. Taken together, our findings revealed that PLC gamma 1 inhibition induced autophagy and the FAK/PLC gamma 1 axis is a potential downstream effector of the AMPK activation-dependent autophagy signalling cascade. Both blockade of the mTOR/ULK1 axis and dissociation of the Beclin1-IP3R-Bcl-2 complex contributed to the induction of autophagy by PLC gamma 1 inhibition. Consequently, these findings provide novel insight into autophagy regulation by PLC gamma 1 in colon cancer and hepatocellular carcinoma cells.	[Dai, Lianzhi; Lu, Xiaohong; Wang, Fen; Zhan, Yanyan; Song, Gang; Hu, Tianhui; Zhang, Bing] Xiamen Univ, Med Sch, Xiamen 361102, Fujian, Peoples R China; [Chen, Xiaolei; Xia, Chun] Xiamen Univ, Zhongshan Hosp, Xiamen 361004, Fujian, Peoples R China		Zhang, B (corresponding author), Xiamen Univ, Med Sch, Xiamen 361102, Fujian, Peoples R China.; Xia, C (corresponding author), Xiamen Univ, Zhongshan Hosp, Xiamen 361004, Fujian, Peoples R China.	chunxia@xmu.edu.cn; cristal66@xmu.edu.cn			National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81572189, 81572589, 81470793, 81472568]; Natural Science Foundation of Xiamen, China [3502Z20159014]	This study was supported by the National Science Foundation of China (No. 81572189, 81572589, 81470793, 81472568) and the Natural Science Foundation of Xiamen, China (No. 3502Z20159014).	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J	Zheng, YC; Zhu, GG				Zheng, Yingcheng; Zhu, Guoguo			HMGB1 suppresses colon carcinoma cell apoptosis triggered by co-culture with dendritic cells via an ER stress-associated autophagy pathway	MOLECULAR MEDICINE REPORTS			English	Article						HMGB1; dendritic cell; ER stress; autophagy; JNK	ENDOPLASMIC-RETICULUM STRESS; REGULATES AUTOPHAGY; IMMUNE-RESPONSES; CANCER; PROTEIN; INFLAMMATION; DISEASE; ESCAPE; TIM-3	High mobility group box protein 1 (HMGB1) is a versatile molecule that affects the immune system in various ways; however, its role in cancer immunity has not yet been completely elucidated. In the current study, bone marrow-derived dendritic cells from BALB/c mice and undifferentiated murine colon carcinoma CT26.WT cells were used as a cellular model to study the primary role of HMGB1 in colon cancer immunity. Annexin V and acridine orange/ethidium bromide staining was used to assess cellular apoptosis, Cell Counting kit 8 and lactate dehydrogenase assays were performed to evaluate cell viability and a monodansylcadaverine assay was used to detect autophagy. Western blot analysis was performed to detect the expression levels of proteins of interest. Endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase phosphorylation were also investigated in CT26.WT cells exposed to dendritic cells. The present results demonstrated that the CT26.WT cells underwent apoptotic cell death following co-culturing with dendritic cells. However, pretreatment with HMGB1 resulted in a significant increase in viability of the CT26.WT cells exposed to dendritic cells. Furthermore, HMGB1 promoted ER stress-induced autophagy through the activation of JNK, which inhibited the apoptosis triggered by the dendritic cells, suggesting that HMGB1 has a role in immune evasion by colon cancer cells.	[Zheng, Yingcheng] Wuhan Gen Hosp Guangzhou Command, Dept Infect Control, Wuhan 430070, Hubei, Peoples R China; [Zhu, Guoguo] Wuhan Gen Hosp Guangzhou Command, Dept Emergency & Crit Care Med, 627 Luoyu Rd, Wuhan 430070, Hubei, Peoples R China		Zhu, GG (corresponding author), Wuhan Gen Hosp Guangzhou Command, Dept Emergency & Crit Care Med, 627 Luoyu Rd, Wuhan 430070, Hubei, Peoples R China.	guoguoicetea@hotmail.com					Banchereau J, 1998, NATURE, V392, P245, DOI 10.1038/32588; Banchereau J, 2005, NAT REV IMMUNOL, V5, P296, DOI 10.1038/nri1592; Campana L, 2008, CURR OPIN IMMUNOL, V20, P518, DOI 10.1016/j.coi.2008.04.012; Chiba S, 2012, NAT IMMUNOL, V13, P832, DOI 10.1038/ni.2376; Engblom C, 2016, NAT REV CANCER, V16, P447, DOI 10.1038/nrc.2016.54; Hoyer-Hansen M, 2007, CELL DEATH DIFFER, V14, P1576, DOI 10.1038/sj.cdd.4402200; James BR, 2014, CANCER IMMUNOL IMMUN, V63, P685, DOI 10.1007/s00262-014-1548-5; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Kang R, 2010, AUTOPHAGY, V6, P1209, DOI 10.4161/auto.6.8.13651; Khong HT, 2002, NAT IMMUNOL, V3, P999, DOI 10.1038/ni1102-999; Kim R, 2007, IMMUNOLOGY, V121, P1, DOI 10.1111/j.1365-2567.2007.02587.x; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Kusume A, 2009, PATHOBIOLOGY, V76, P155, DOI 10.1159/000218331; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Li CY, 2006, J IMMUNOL, V177, P5163, DOI 10.4049/jimmunol.177.8.5163; Liu L, 2011, LEUKEMIA, V25, P23, DOI 10.1038/leu.2010.225; Lutz MB, 1999, J IMMUNOL METHODS, V223, P77, DOI 10.1016/S0022-1759(98)00204-X; Martinotti S, 2015, IMMUNOTARGETS THER, V4, P101, DOI 10.2147/ITT.S58064; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Ogata M, 2006, MOL CELL BIOL, V26, P9220, DOI 10.1128/MCB.01453-06; Oppenheim JJ, 2005, CURR OPIN IMMUNOL, V17, P359, DOI 10.1016/j.coi.2005.06.002; Scaffidi P, 2002, NATURE, V418, P191, DOI 10.1038/nature00858; Steinman RM, 2007, NATURE, V449, P419, DOI 10.1038/nature06175; Tang DL, 2012, NAT IMMUNOL, V13, P808, DOI 10.1038/ni.2396; Tang DL, 2010, J CELL BIOL, V190, P881, DOI 10.1083/jcb.200911078; Tang DL, 2010, BBA-GENE REGUL MECH, V1799, P131, DOI 10.1016/j.bbagrm.2009.11.014; White E, 2009, CLIN CANCER RES, V15, P5308, DOI 10.1158/1078-0432.CCR-07-5023	27	5	7	0	7	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1791-2997	1791-3004		MOL MED REP	Mol. Med. Rep.	FEB	2018	17	2					3123	3132		10.3892/mmr.2017.8202			10	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	FT5WP	WOS:000423224300133	29257231	Bronze			2022-04-25	
J	Sena, P; Mancini, S; Benincasa, M; Mariani, F; Palumbo, C; Roncucci, L				Sena, Paola; Mancini, Stefano; Benincasa, Marta; Mariani, Francesco; Palumbo, Carla; Roncucci, Luca			Metformin Induces Apoptosis and Alters Cellular Responses to Oxidative Stress in Ht29 Colon Cancer Cells: Preliminary Findings	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						colorectal cancer cells; metformin; apoptosis; oxidative stress	NF-KAPPA-B; COLORECTAL-CANCER; IN-VITRO; DIABETES-MELLITUS; DUAL ROLES; RISK; NRF2; AUTOPHAGY; GROWTH; VIVO	Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-B). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer.	[Sena, Paola; Benincasa, Marta; Palumbo, Carla] Univ Modena & Reggio Emilia, Sect Human Morphol, Dept Biomed Metab & Neurosci, Via Pozzo 71, I-41125 Modena, Italy; [Mancini, Stefano; Mariani, Francesco; Roncucci, Luca] Univ Modena & Reggio Emilia, Dept Diagnost & Clin Med & Publ Hlth, Via Pozzo 71, 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.	paola.sena@unimore.it; mancini77@cloud.com; marta.benincasa@unimore.it; francesco.mariani@unimore.it; carla.palumbo@unimore.it; luca.roncucci@unimore.it	Sena, Paola/G-9394-2016; Palumbo, Carla/V-5905-2019; Roncucci, Luca/L-1392-2016; Mancini, Stefano/B-1190-2016	Sena, Paola/0000-0003-4724-8786; Palumbo, Carla/0000-0003-0587-0112; Roncucci, Luca/0000-0002-0410-1760; Mancini, Stefano/0000-0002-7350-5603	Associazione per la Ricerca sui Tumori Intestinali (ARTI); Fondazione Cassa di Risparmio di Vignola	The study was supported by funds of the Associazione per la Ricerca sui Tumori Intestinali (ARTI) and Fondazione Cassa di Risparmio di Vignola. The authors wish to thank the Centro Interdipartimentale Grandi Strumenti (C.I.G.S.) of the University of Modena and Reggio Emilia, for software, instrument availability, and assistance.	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J. Mol. Sci.	MAY	2018	19	5							1478	10.3390/ijms19051478			16	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	GJ4BO	WOS:000435297000214	29772687	Green Published, gold, Green Submitted			2022-04-25	
J	Liu, Y; Zhang, B; Cao, WB; Wang, HY; Niu, L; Zhang, GZ				Liu, Yang; Zhang, Bo; Cao, Wen-Bin; Wang, Hai-Yan; Niu, Lei; Zhang, Guo-Zhi			Study on Clinical Significance of LncRNA EGOT Expression in Colon Cancer and Its Effect on Autophagy of Colon Cancer Cells	CANCER MANAGEMENT AND RESEARCH			English	Article						LncRNA EGOT; colon cancer; diagnosis; autophagy	PROGNOSIS; NCRNA	Background: Colon cancer (CC) is a common digestive tract tumor, and the increase of new and dead patients every year still puzzles clinical workers. LncRNA eosinophil granule ontogeny transcript (EGOT), as a newly discovered long-chain noncoding RNA (lncRNA), is differentially expressed in other tumors, but there are fewer studies of it in colon cancer. Methods: The relative expression and diagnostic value of EGOT in CC were detected and analyzed by starBase online website and qRT-PCR. The patients were followed-up for five years, and Cox regression was used to analyze the independent prognostic factors of CC. The effects of EGOT overexpression (pcDNA-RGOT) on CC cell function were detected by CCK-8, transwell and flow cytometry. WB was applied to detect autophagy. The influence of knocking out EGOT (sh-EGOT) on tumor growth was observed by tumor allogeneic inhibition. The microRNA (miR) and mRNA in the downstream of EGOT were predicted and the ceRNA network map was drawn. Results: The online database and qRT-PCR detection showed that EGOT was highly expression in patients with CC and had good diagnostic value. The five-year survival rate of patients with high expression of EGOT decreased. EGOT and TNM staging were independent prognostic factors of patients with CC. Functional analysis revealed that the growth and invasion abilities of cells increased, and the apoptosis rate decreased after overexpression. Upregulation of EGOT inhibited autophagy of CC cells and promoted cell growth. However, the tumor in nude mice was significantly lessened after knockout of EGOT. Bioinformatic analysis showed that microRNA-33a-5p and microRNA-33b-5p had targeted binding sites with EGOT. Conclusion: EGOT is highly expressed in CC and has high diagnostic value. In addition, inhibition of EGOT can promote autophagy of CC cells and inhibit cell growth and metastasis, which is expected to be a potential therapeutic index.	[Liu, Yang; Zhang, Bo; Cao, Wen-Bin; Zhang, Guo-Zhi] North China Univ Sci & Technol, Dept Gen Surg, Affiliated Hosp, Tangshan City 063000, Hebei, Peoples R China; [Wang, Hai-Yan] Chinese Peoples Liberat Army, Dept Oncol, Hosp 982, Joint Logist Support Force, Tangshan City 063000, Hebei, Peoples R China; [Niu, Lei] Tangshan Hong Ci Hosp Co Ltd, Dept Resp Med, Tangshan City 063000, Hebei, Peoples R China		Zhang, GZ (corresponding author), North China Univ Sci & Technol, Dept Gen Surg, Affiliated Hosp, Tangshan City 063000, Hebei, Peoples R China.	myfypwly@163.com					Arnold MW, 2018, SURG ONCOL CLIN N AM, V27, pXV, DOI 10.1016/j.soc.2017.11.012; Attallah AM, 2018, BRIT J BIOMED SCI, V75, P122, DOI 10.1080/09674845.2018.1456309; Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI 10.3322/caac.21492; Chao YJ, 2019, MED SCI MONITOR, V25, P6581, DOI 10.12659/MSM.915100; Clark JAM, 2020, ANIM MODEL EXP MED, V3, P103, DOI 10.1002/ame2.12111; Ferre F, 2016, BRIEF BIOINFORM, V17, P106, DOI 10.1093/bib/bbv031; Huang JZ, 2017, MOL CELL, V68, P171, DOI 10.1016/j.molcel.2017.09.015; Jin L, 2017, MOL MED REP, V16, P7072, DOI 10.3892/mmr.2017.7470; Kawasaki Y, 2019, EMBO REP, V20, DOI 10.15252/embr.201847052; Li JH, 2014, NUCLEIC ACIDS RES, V42, pD92, DOI 10.1093/nar/gkt1248; Liu CH, 2020, GENE, V729, DOI 10.1016/j.gene.2019.144317; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Loewen G, 2014, J HEMATOL ONCOL, V7, DOI 10.1186/s13045-014-0090-4; Loos F, 2019, CELL DEATH DIS, V10, DOI 10.1038/s41419-019-2011-5; Ni Y, 2020, BIOSCI REP, DOI [10.1042/BSR2019389330, DOI 10.1042/BSR2019389330]; Orangio GR, 2018, SURG ONCOL CLIN N AM, V27, P327, DOI 10.1016/j.soc.2017.11.007; Peng W, 2019, PATHOL ONCOL RES, V25, P883, DOI 10.1007/s12253-017-0367-3; Slaby O, 2016, ADV EXP MED BIOL, V937, P153, DOI 10.1007/978-3-319-42059-2_8; Wang JZ, 2019, MOL THER, V27, P1718, DOI 10.1016/j.ymthe.2019.09.001; Wang J, 2019, ONCOL LETT, V18, P1491, DOI 10.3892/ol.2019.10425; Weinberg BA, 2019, CURR ONCOL REP, V21, DOI 10.1007/s11912-019-0756-8; Wu Q, 2018, J CELL PHYSIOL, V233, P6750, DOI 10.1002/jcp.26383; Wu SM, 2019, ONCOTARGETS THER, V12, P11623, DOI 10.2147/OTT.S218308; Wu Y, 2017, EXP THER MED, V14, P3817, DOI 10.3892/etm.2017.4949; Xu J, 2018, ADV EXP MED BIOL, V1094, P77, DOI 10.1007/978-981-13-0719-5_8; Xu SP, 2015, TUMOR BIOL, V36, P9807, DOI 10.1007/s13277-015-3746-y; Xu SP, 2019, MOL CANCER, V18, DOI 10.1186/s12943-019-1017-z; Yang J, 2017, BIOSCI BIOTECH BIOCH, V81, P2301, DOI 10.1080/09168451.2017.1387048; ZHANG XP, 2019, INT J MOL SCI, V0020; Zhao Z, 2020, LIFE SCI, V254, DOI 10.1016/j.lfs.2019.116900; Zhou FR, 2019, ONCOTARGETS THER, V12, P5767, DOI 10.2147/OTT.S215419; Zhou R, 2019, CANCER IMMUNOL IMMUN, V68, P433, DOI 10.1007/s00262-018-2289-7	32	2	2	0	3	DOVE MEDICAL PRESS LTD	ALBANY	PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND	1179-1322			CANCER MANAG RES	Cancer Manag. Res.		2020	12						13501	13512		10.2147/CMAR.S285254			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	PN2BU	WOS:000604290800001	33408522	Green Published, gold			2022-04-25	
J	Costelli, P; De Stefanis, D; Reffo, P; Autelli, R; Bonelli, G; Baccino, FM				Costelli, Paola; De Stefanis, Daniela; Reffo, Patrizia; Autelli, Riccardo; Bonelli, Gabriella; Baccino, Francesco M.			Differential modulation of TNf alpha-induced cell death by 3-methyladenine, an autophagy inhibitor	LETTERS IN DRUG DESIGN & DISCOVERY			English	Article						apoptosis; autophagy; 3-methyladenine; TNF alpha	TUMOR-NECROSIS-FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS; ISOLATED RAT HEPATOCYTES; INDUCED APOPTOSIS; PROTEIN-DEGRADATION; FLOW-CYTOMETRY; CANCER-CELLS; SURVIVAL; ACTIVATION; MECHANISMS	Cell death by apoptosis is a fundamental mechanism for the maintenance of tissue homeostasis, activated to get rid of excess, damaged, or infected cells. It may be induced by several stimuli such as growth factor withdrawal, oxidative stress, drugs, or humoral mediators such as cytokines. The present study is focused on the cytotoxic activity of TNF alpha, a pleiotropic cytokine that promotes a variety of biological effects. TNF alpha cytotoxicity depends on the cell type and state. Although apoptosis (or type I cell death) has long been considered as the paradigm, various observations have stressed the possibility that TNF alpha-induced cell death may also develop with other features. Particularly interesting, in this regard, is the possibility that TNF alpha effects include stimulation of autophagy and/or induction of autophagic (type II) cell death. Aim of the present study has been to investigate if TNF alpha-induced death in cell types of different origin can be modulated by interference with the autophagic process. The work has been performed on U937 (lymphoid), HT-29 (colon carcinoma), L929 (fibrosarcoma) and HTC (hepatoma) cell lines. All of them undergo apoptosis or apoptosis-like death in response to TNF alpha alone (U937, L929), or combined with transcription or translation inhibitors (HT-29, HTC). However, when TNF alpha is coupled with 3-methyladenine, a well known inhibitor of the autophagic process, the various cell lines show different behaviors: HTC cells are partially protected from TNF alpha-induced death, whereas HT-29, L929 and U937 cells are sensitized, albeit to varying degrees, since the percentage of apoptotic cells is higher than in cultures exposed to the cytokine alone. These results show that 3-methyladenine can modulate TNF alpha-induced death both positively and negatively, depending on the cell type. Moreover, they are consistent with the view that modulation of autophagy can be relevant to the design of therapeutic strategies aimed to reduce excess apoptosis, such as that occurring in acute hepatitis, or to enhance cell death in pathologies characterized by defective apoptosis, such as cancer.	Univ Turin, Dipartimento Med & Oncol Sperimentale, I-10125 Turin, Italy		Costelli, P (corresponding author), Univ Turin, Dipartimento Med & Oncol Sperimentale, Corso Raffaello 30, I-10125 Turin, Italy.	paola.costelli@unito.it		Bonelli, Gabriella/0000-0002-5164-8902			Anthony RS, 1998, BONE MARROW TRANSPL, V21, P441, DOI 10.1038/sj.bmt.1701134; Autelli R, 2005, APOPTOSIS, V10, P777, DOI 10.1007/s10495-005-2944-2; BARBIERO G, 1995, EXP CELL RES, V217, P410, DOI 10.1006/excr.1995.1104; Bauvy C, 2001, EXP CELL RES, V268, P139, DOI 10.1006/excr.2001.5285; Blommaart EFC, 1997, EUR J BIOCHEM, V243, P240, DOI 10.1111/j.1432-1033.1997.0240a.x; Bonelli G, 1996, EXP CELL RES, V228, P292, DOI 10.1006/excr.1996.0329; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Bursch W, 2004, FEMS YEAST RES, V5, P101, DOI 10.1016/j.femsyr.2004.07.006; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; CHAZAUD B, 1994, EUR J CELL BIOL, V64, P15; Chi SJ, 1999, ONCOGENE, V18, P2281, DOI 10.1038/sj.onc.1202538; Choi EK, 2006, INT IMMUNOPHARMACOL, V6, P908, DOI 10.1016/j.intimp.2006.01.007; CLARKE PGH, 1990, ANAT EMBRYOL, V181, P195, DOI 10.1007/bf00174615; Dosenko V. 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Drug Des. Discov.	NOV	2006	3	9					662	667		10.2174/157018006778341156			6	Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	092SZ	WOS:000241118900010					2022-04-25	
J	Cheng, TC; Lai, CS; Chung, MC; Kalyanam, N; Majeed, M; Ho, CT; Ho, YS; Pan, MH				Cheng, Tzu-Chun; Lai, Ching-Shu; Chung, Min-Ching; Kalyanam, Nagabhushanam; Majeed, Muhammed; Ho, Chi-Tang; Ho, Yuan-Soon; Pan, Min-Hsiung			Potent Anti-Cancer Effect of 3 '-Hydroxypterostilbene in Human Colon Xenograft Tumors	PLOS ONE			English	Article							CELL-CYCLE ARREST; CARCINOMA CELLS; PTEROSTILBENE; CANCER; APOPTOSIS; AUTOPHAGY; PATHWAYS; AGENTS; CHEMOPREVENTION; INDUCTION	Here we report that 3'-hydroxypterostilbene (HPSB), a natural pterostilbene analogue, was more potent than pterostilbene against the growth of human cancer cells (COLO 205, HCT-116, and HT-29) with measured IC50 values of 9.0, 40.2, and 70.9 mu M, respectively. We found that HPSB effectively inhibited the growth of human colon cancer cells by inducing apoptosis and autophagy. Autophagy occurred at an early stage and was observed through the formation of acidic vesicular organelles and microtubule-associated protein 1 light chain 3-II production. At the molecular levels, the results from western blot analysis showed that HPSB significantly down-regulated phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signalings including decreased the phosphorylation of mammalian target of rapamycin (mTOR). Significant therapeutic effects were demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with HPSB (10 mg/kg i.p.). These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of cyclooxygenase-2 (COX-2), matrix metallopeptidase-9 (MMP-9), vascular endothelial growth factor (VEGF), and cyclin D1, as well as by the induction of apoptosis in colon tumors. Our findings suggest that HPSB could serve as a novel promising agent for colon cancer treatment.	[Cheng, Tzu-Chun; Ho, Yuan-Soon] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei, Taiwan; [Lai, Ching-Shu; Chung, Min-Ching; Pan, Min-Hsiung] Natl Taiwan Univ, Inst Food Sci & Technol, Taipei 10764, Taiwan; [Kalyanam, Nagabhushanam; Majeed, Muhammed] Sabinsa Corp, East Windsor, NJ USA; [Ho, Chi-Tang] Rutgers State Univ, Dept Food Sci, New Brunswick, NJ 08903 USA; [Ho, Yuan-Soon] Taipei Med Univ Hosp, Dept Lab Med, Taipei, Taiwan; [Ho, Yuan-Soon] Taipei Med Univ, Coll Med Sci & Technol, Sch Med Lab Sci & Biotechnol, Taipei, Taiwan; [Ho, Yuan-Soon] Taipei Med Univ, Ctr Comprehens Canc, Taipei, Taiwan; [Pan, Min-Hsiung] China Med Univ, China Med Univ Hosp, Dept Med Res, Taichung, Taiwan		Ho, YS (corresponding author), Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei, Taiwan.	hoyuansn@tmu.edu.tw; mhpan@ntu.edu.tw	Pan, Min-Hsiung/AAT-8865-2021	Pan, Min-Hsiung/0000-0002-5188-7030	National Science CouncilMinistry of Science and Technology, Taiwan [NSC 101-2628-B-022-001-MY4, 102-2628-B-002-053-MY3, NTU-103R7777]; Health and welfare surcharge of tobacco products [MOHW103-TD-B-111-01]	This study was supported by the National Science Council NSC 101-2628-B-022-001-MY4, 102-2628-B-002-053-MY3, and NTU-103R7777 (for Dr. Pan) and by the Health and welfare surcharge of tobacco products MOHW103-TD-B-111-01 (for Dr. Ho). Sabinsa Corporation provided support in the form of salaries for authors NK & MM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.	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J	Vessoni, AT; Filippi-Chiela, EC; Menck, CFM; Lenz, G				Vessoni, A. T.; Filippi-Chiela, E. C.; Menck, C. F. M.; Lenz, G.			Autophagy and genomic integrity	CELL DEATH AND DIFFERENTIATION			English	Review						autophagy; DNA repair; genomic integrity; oxidative stress	DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; BASE-EXCISION-REPAIR; REGULATES AUTOPHAGY; COLON-CANCER; PIECEMEAL MICROAUTOPHAGY; HISTONE-DEACETYLASES; SIGNALING PATHWAY; INDUCED APOPTOSIS; OXIDATIVE STRESS	DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.	[Vessoni, A. T.; Menck, C. F. M.] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, BR-05508900 Sao Paulo, Brazil; [Filippi-Chiela, E. C.; Lenz, G.] Univ Fed Rio Grande do Sul, Dept Biophys, Porto Alegre, RS, Brazil; [Filippi-Chiela, E. 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NOV	2013	20	11					1444	1454		10.1038/cdd.2013.103			11	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	233EL	WOS:000325548900005	23933813	Green Published			2022-04-25	
J	Deng, JY; Tian, AL; Pan, H; Sauvat, A; Leduc, M; Liu, P; Zhao, LW; Zhang, S; Chen, H; Taly, V; Laurent-Puig, P; Senovilla, L; Li, YQ; Kroemer, G; Kepp, O				Deng, Jiayin; Tian, Ai-Ling; Pan, Hui; Sauvat, Allan; Leduc, Marion; Liu, Peng; Zhao, Liwei; Zhang, Shuai; Chen, Hui; Taly, Valerie; Laurent-Puig, Pierre; Senovilla, Laura; Li, Yingqiu; Kroemer, Guido; Kepp, Oliver			Everolimus and plicamycin specifically target chemoresistant colorectal cancer cells of the CMS4 subtype	CELL DEATH & DISEASE			English	Article							CONSENSUS MOLECULAR SUBTYPES; PHASE-II; COLON-CANCER; IN-VITRO; BEVACIZUMAB; INHIBITOR; PROGNOSIS; APOPTOSIS; IMMUNE; TRIAL	Colorectal cancers (CRC) can be classified into four consensus molecular subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 that has the worst outcome. CMS4 CRC is notoriously resistant against therapeutic interventions, as demonstrated by preclinical studies and retrospective clinical observations. Here, we report the finding that two clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently target the prototypic CMS4 cell line MDST8. As compared to the prototypic CMS1 cell line LoVo, MDST8 cells treated with EVE or PLI demonstrated stronger cytostatic and cytotoxic effects, increased signs of apoptosis and autophagy, as well as a more pronounced inhibition of DNA-to-RNA transcription and RNA-to-protein translation. Moreover, nontoxic doses of EVE and PLI induced the shrinkage of MDST8 tumors in mice, yet had only minor tumor growth-reducing effects on LoVo tumors. Altogether, these results suggest that EVE and PLI should be evaluated for their clinical activity against CMS4 CRC.	[Deng, Jiayin; Li, Yingqiu] Sun Yat Sen Univ, Sch Life Sci, MOE Key Lab Gene Funct & Regulat, State Key Lab Biocontrol, Guangzhou, Peoples R China; [Deng, Jiayin; Tian, Ai-Ling; Pan, Hui; Chen, Hui] Univ Paris Sud, Paris Saclay, Fac Med, Le Kremlin Bicetre, France; [Deng, Jiayin; Tian, Ai-Ling; Pan, Hui; Sauvat, Allan; Leduc, Marion; Liu, Peng; Zhao, Liwei; Zhang, Shuai; Chen, Hui; Senovilla, Laura; Kroemer, Guido; Kepp, Oliver] Univ Paris Saclay, Gustave Roussy Canc Ctr, Metab & Cell Biol Platforms, Villejuif, France; [Deng, Jiayin; Tian, Ai-Ling; Pan, Hui; Sauvat, Allan; Leduc, Marion; Liu, Peng; Zhao, Liwei; Zhang, Shuai; Chen, Hui; Taly, Valerie; Laurent-Puig, Pierre; Senovilla, Laura; Kroemer, Guido; Kepp, Oliver] Sorbonne Univ, Univ Paris, Inserm U1138, Ctr Rech Cordeliers,Equipe Labellisee Ligue Contr, Paris, France; [Deng, Jiayin; Tian, Ai-Ling; Pan, Hui; Sauvat, Allan; Leduc, Marion; Liu, Peng; Zhao, Liwei; Zhang, Shuai; Chen, Hui; Taly, Valerie; Laurent-Puig, Pierre; Senovilla, Laura; Kroemer, Guido; Kepp, Oliver] Inst Univ France, CNRS SNC 5096, Paris, France; [Laurent-Puig, Pierre; Senovilla, Laura] Univ Valladolid, CSIC, Unidad Excelencia Inst Biol & Genet Mol IBGM, Valladolid, Spain; [Kroemer, Guido] Hop Europeen Georges Pompidou, AP HP, Inst Canc Paris Carpem, Pole Biol, Paris, France; [Kroemer, Guido] Chinese Acad Med Sci, Suzhou Inst Syst Med, Suzhou, Jiangsu, Peoples R China; [Kroemer, Guido] Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden		Li, YQ (corresponding author), Sun Yat Sen Univ, Sch Life Sci, MOE Key Lab Gene Funct & Regulat, State Key Lab Biocontrol, Guangzhou, Peoples R China.; Kroemer, G; Kepp, O (corresponding author), Univ Paris Saclay, Gustave Roussy Canc Ctr, Metab & Cell Biol Platforms, Villejuif, France.; Kroemer, G; Kepp, O (corresponding author), Sorbonne Univ, Univ Paris, Inserm U1138, Ctr Rech Cordeliers,Equipe Labellisee Ligue Contr, Paris, France.; Kroemer, G; Kepp, O (corresponding author), Inst Univ France, CNRS SNC 5096, Paris, France.; Kroemer, G (corresponding author), Hop Europeen Georges Pompidou, AP HP, Inst Canc Paris Carpem, Pole Biol, Paris, France.; Kroemer, G (corresponding author), Chinese Acad Med Sci, Suzhou Inst Syst Med, Suzhou, Jiangsu, Peoples R China.; Kroemer, G (corresponding author), Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.	lsslyq@mail.sysu.edu.cn; kroemer@orange.fr; captain.olsen@gmail.com	Kepp, Oliver/N-2763-2017; laurent-puig, pierre/B-2226-2013	Kepp, Oliver/0000-0002-6081-9558; laurent-puig, pierre/0000-0001-8475-5459; Senovilla, Laura/0000-0001-6887-2436; LIU, Peng/0000-0002-1682-9222	China Scholarship CouncilChina Scholarship Council; DIM ELICIT initiative of the Ile de France; Institut National du Cancer (INCa)Institut National du Cancer (INCA) France; Ligue contre le Cancer (equipes labellisees, Program "Equipe labelisee LIGUE'') [EL2016.LNCC (VT/PLP)]; Agence National de la Recherche (ANR)-Projets blancsFrench National Research Agency (ANR); ANR under the frame of E-Rare-2French National Research Agency (ANR); ERA-Net for Research on Rare Diseases; AMMICa [US23/CNRS UMS3655]; Association pour la recherche sur le cancer (ARC)Fondation ARC pour la Recherche sur le Cancer; Association "Le Cancer du Sein, Parlons-en!"; Canceropole Ile-de-France; Chancelerie des universites de Paris (Legs Poix); Fondation pour la Recherche Medicale (FRM)Fondation pour la Recherche Medicale; Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea; European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; INCaInstitut National du Cancer (INCA) France; Inserm (HTE); Institut Universitaire de France; LeDucq FoundationLeducq Foundation; LabEx Immuno-Oncology [ANR-18-IDEX-0001]; RHU Torino Lumiere; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); SIRIC Cancer Research and Personalized Medicine (CARPEM); Gustave Roussy; Universite Paris-Saclay; Plateforme Imagerie et Cytometrie (PFIC); UMS AMMICa INSERM [US23-CNRS 3655]	JD, A-LT, HP, SZ, and HC are supported by the China Scholarship Council. OK receives funding by the DIM ELICIT initiative of the Ile de France and Institut National du Cancer (INCa); GK, VT, and PLP are supported by the Ligue contre le Cancer (equipes labellisees, Program "Equipe labelisee LIGUE"; no. EL2016.LNCC (VT/PLP)); Agence National de la Recherche (ANR)-Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association "Le Cancer du Sein, Parlons-en!"; Canceropole Ile-de-France; Chancelerie des universites de Paris (Legs Poix), Fondation pour la Recherche Medicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; INCa; Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumiere; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). We are grateful to the support of the Gustave Roussy, Universite Paris-Saclay, Plateforme Imagerie et Cytometrie (PFIC), UMS AMMICa INSERM US23-CNRS 3655.	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OCT 21	2021	12	11							978	10.1038/s41419-021-04270-x			11	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	WK6GL	WOS:000709823000002	34675191	gold, Green Published			2022-04-25	
J	Ovadje, P; Ammar, S; Guerrero, JA; Arnason, JT; Pandey, S				Ovadje, Pamela; Ammar, Saleem; Guerrero, Jose-Antonio; Arnason, John Thor; Pandey, Siyaram			Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways	ONCOTARGET			English	Article						cancer; oxidative stress; phytochemical composition; gene expression; natural health product	NF-KAPPA-B; SELECTIVE INDUCTION; NATURAL-PRODUCTS; APOPTOSIS; AUTOPHAGY; LOCALIZATION; TARAXASTEROL; MITOCHONDRIA; CASPASE-8; DISEASE	Dandelion extracts have been studied extensively in recent years for its antidepressant and anti-inflammatory activity. Recent work from our lab, with in-vitro systems, shows the anti-cancer potential of an aqueous dandelion root extract (DRE) in several cancer cell models, with no toxicity to non-cancer cells. In this study, we examined the cancer cell-killing effectiveness of an aqueous DRE in colon cancer cell models. Aqueous DRE induced programmed cell death (PCD) selectively in >95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment. The anti-cancer efficacy of this extract was confirmed in in-vivo studies, as the oral administration of DRE retarded the growth of human colon xenograft models by more than 90%. We found the activation of multiple death pathways in cancer cells by DRE treatment, as revealed by gene expression analyses showing the expression of genes implicated in programmed cell death. Phytochemical analyses of the extract showed complex multi-component composition of the DRE, including some known bioactive phytochemicals such as alpha-amyrin, beta-amyrin, lupeol and taraxasterol. This suggested that this natural extract could engage and effectively target multiple vulnerabilities of cancer cells. Therefore, DRE could be a non-toxic and effective anti-cancer alternative, instrumental for reducing the occurrence of cancer cells drug-resistance.	[Ovadje, Pamela; Pandey, Siyaram] Univ Windsor, Dept Chem & Biochem, Windsor, ON, Canada; [Ammar, Saleem; Guerrero, Jose-Antonio; Arnason, John Thor] Univ Ottawa, Dept Biol, Ottawa, ON, Canada; [Guerrero, Jose-Antonio] Inst Ecol AC, Red Estudios Mol Avanzados, Xalapa, Veracruz, Mexico		Pandey, S (corresponding author), Univ Windsor, Dept Chem & Biochem, Windsor, ON, Canada.	spandey@uwindsor.ca	Pandey, Siyaram/AAI-5491-2020; Guerrero-Analco, José A./Q-6733-2018	Guerrero-Analco, José A./0000-0003-0998-757X	Donna Dave Couvillon; Pajama Angels, Late & John Hecht Foundation; Jesse & Julie Rasch Foundation	The authors would like to acknowledge funding/ support from the following individuals and agencies: Donna & Dave Couvillon, The Pajama Angels, Late & John Hecht Foundation, Jesse & Julie Rasch Foundation. The authors would also like to acknowledge the contribution of Dr. Andrew Brooke from the University of Guelph, for the toxicological analysis of dandelion root extract in mice models. The authors would like to acknowledge the efforts of Drs. Tirumalai and Sikorska in the complete editing and revamping of this manuscript.	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J	Olsen, BB; Svenstrup, TH; Guerra, B				Olsen, Birgitte B.; Svenstrup, Tina H.; Guerra, Barbara			Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						glioblastoma cells; autophagy; CK2; mammalian target of rapamycin; extracellular signaling-regulated protein kinase 1/2; reactive oxygen species	MALIGNANT GLIOMA-CELLS; COLON-CANCER CELLS; MAMMALIAN TARGET; RADIATION; APOPTOSIS; PHOSPHORYLATION; INHIBITION; THERAPY; PROLIFERATION; MATURATION	Glioblastoma multiforme is the most common primary brain tumor and one of the most aggressive types of cancer in adults. Survival signaling and apoptosis resistance are hallmarks of malignant glioma cells. However, recent studies have shown that other types of cell death such as autophagy can be induced in malignant glioma cells. This suggests that stimulation of this process may be explored in new therapeutic strategies against glioblastoma multiforme. Protein kinasc CK2 is a highly conserved and constitutively active enzyme that promotes numerous cellular processes such as survival, proliferation and differentiation. CK2 has been found elevated in several malignancies including brain tumors, and to confer resistance against chemotherapeutic agents and apoptotic stimuli. Recently, we have shown that the siRNA-mediated downregulation of CK2 leads to cell death in DNA-PK-proficient human glioblastoma cells. We show, here, that lack of CK2 results in significant induction of autophagic cell death in two human glioblastoma cell lines, M059K and T98G, as indicated by the positive staining of cells with the acidotropic dye acridine orange, and the specific recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosome membranes. Induction of autophagy is accompanied by CK2-dependent decreased phosphorylation of p70 ribosomal S6 and AKT kinases and significantly reduced expression levels of Raptor. In contrast, phosphorylation and activity levels of ERK1/2 are enhanced suggesting an inhibition of the PI3K/AKT/mTORC1 and activation of the ERK1/2 pathways. Furthermore, si RNA-mediated silencing of CK2 results in increased mitochondrial superoxide production in both glioblastoma cell lines. However, mitochondrial reactive oxygen species release correlates with induction of autophagy only in T98G cells. Taken together, our findings identify CK2 as a novel component of the autophagic machinery and underline the potential of its downregulation to kill glioblastoma cells by overcoming the resistance to multiple anticancer agents.	[Svenstrup, Tina H.; Guerra, Barbara] Univ So Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark; [Olsen, Birgitte B.] Odense Univ Hosp, Dept Nucl Med, DK-5000 Odense, Denmark		Guerra, B (corresponding author), Univ So Denmark, Dept Biochem & Mol Biol, Campusvej 55, DK-5230 Odense, Denmark.	bag@bmb.sdu.dk		Olsen, Birgitte Brinkmann/0000-0002-6130-0387; Guerra, Barbara/0000-0003-1136-2413	Danish Cancer SocietyDanish Cancer Society [DP08152]	This study was supported by a Grant from the Danish Cancer Society (DP08152) to BG.	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J	Qureshi-Baig, K; Kuhn, D; Viry, E; Pozdeev, VI; Schmitz, M; Rodriguez, F; Ullmann, P; Koncina, E; Nurmik, M; Frasquilho, S; Nazarov, PV; Zuegel, N; Boulmont, M; Karapetyan, Y; Antunes, L; Val, D; Mittelbronn, M; Janji, B; Haan, S; Letellier, E				Qureshi-Baig, Komal; Kuhn, Diana; Viry, Elodie; Pozdeev, Vitaly I.; Schmitz, Martine; Rodriguez, Fabien; Ullmann, Pit; Koncina, Eric; Nurmik, Martin; Frasquilho, Sonia; Nazarov, Petr V.; Zuegel, Nikolaus; Boulmont, Marc; Karapetyan, Yervand; Antunes, Laurent; Val, Daniel; Mittelbronn, Michel; Janji, Bassam; Haan, Serge; Letellier, Elisabeth			Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway	AUTOPHAGY			English	Article						Autophagy; colorectal cancer; cancer stem cell; ezrin; hypoxia; protein kinase C; self-renewal capacity; tumor-initiating cell	STEM-CELLS; TARGETING AUTOPHAGY; INDUCIBLE FACTORS; SELF-RENEWAL; SURVIVAL; EXPRESSION; BNIP3; BREAST; DEATH; SPECIFICATION	In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enrichedpatient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures. Gene expression data revealed macroautophagy/autophagy as one of the major pathways induced by hypoxia in TICs. Interestingly, hypoxia-induced autophagy was found to induce phosphorylation of EZR (ezrin) at Thr567 residue, which could be reversed by knocking down ATG5, BNIP3, BNIP3L, or BECN1. Furthermore, we identified PRKCA/PKC alpha as a potential kinase involved in hypoxia-induced autophagy-mediated TIC self-renewal. Genetic targeting of autophagy or pharmacological inhibition of PRKC/PKC and EZR resulted in decreased tumor-initiating potential of TICs. In addition, we observed significantly reduced in vivo tumor initiation and growth after a stable knockdown of ATG5. Analysis of human CRC samples showed that p-EZR is often present in TICs located in the hypoxic and autophagic regions of the tumor. Altogether, our results establish the hypoxia-autophagy-PKC-EZR signaling axis as a novel regulatory mechanism of TIC self-renewal and CRC progression. Autophagy inhibition might thus represent a promising therapeutic strategy for cancer patients.	[Qureshi-Baig, Komal; Kuhn, Diana; Viry, Elodie; Pozdeev, Vitaly I.; Schmitz, Martine; Rodriguez, Fabien; Ullmann, Pit; Koncina, Eric; Nurmik, Martin; Haan, Serge; Letellier, Elisabeth] Univ Luxembourg, Life Sci Res Unit, Mol Dis Mech Grp, Esch Sur Alzette, Luxembourg; [Viry, Elodie; Janji, Bassam] Luxembourg Inst Hlth, Lab Expt Canc Res, Strassen, Luxembourg; [Frasquilho, Sonia; Karapetyan, Yervand; Antunes, Laurent] Integrated Biobank Luxembourg, Dudelange, Luxembourg; [Nazarov, Petr V.] Luxembourg Inst Hlth, Proteome & Genome Res Unit, Strassen, Luxembourg; [Zuegel, Nikolaus; Boulmont, Marc] Ctr Hosp Emile Mayrisch, Dept Surg, Esch Sur Alzette, Luxembourg; [Antunes, Laurent; Val, Daniel; Mittelbronn, Michel] LNS, Dept Anat & Mol Pathol, Dudelange, Luxembourg; [Mittelbronn, Michel] Univ Luxembourg, LCSB, Esch Sur Alzette, Luxembourg; [Mittelbronn, Michel] LIH, NORLUX Neurooncol Lab, Strassen, Luxembourg; [Mittelbronn, Michel] Luxembourg Ctr Neuropathol LCNP, Dudelange, Luxembourg		Letellier, E (corresponding author), Univ Luxembourg, Life Sci Res Unit, 6 Ave Swing,Campus Belval, L-4367 Esch Sur Alzette, Luxembourg.	elisabeth.letellier@uni.lu	Pozdeev, Vitaly/AAA-4087-2020; , Karapetyan/AAN-1433-2020; Letellier, Elisabeth/I-9515-2016	Letellier, Elisabeth/0000-0001-8242-9393; Pozdeev, Vitaly/0000-0002-6526-9890; Nurmik, Martin/0000-0002-6350-0577; Mittelbronn, Michel/0000-0002-2998-052X; Nazarov, Petr/0000-0003-3443-0298; JANJI, Bassam/0000-0002-9763-0943	TELEVIE [28504270, R-AGR-3140, 7456517, R-AGR3377]; Fondation Cancer [F1R-LSC-PAU-13HY2C]; Janssen CilagJohnson & JohnsonJohnson & Johnson USAJanssen Biotech Inc; Fondation du Pelican de Mie and Pierre Hippert-Faber under Fondation de Luxembourg; CORELuxembourg National Research Fund [C16/BM/11282028]; POC grant [PoC18/12554295]; Fonds National de la Recherche (FNR) (AFR grant scheme); Fonds National de la Recherche (FNR) (PRIDE scheme)	This project was supported by the TELEVIE (28504270, R-AGR-3140) and Fondation Cancer (grant F1R-LSC-PAU-13HY2C) and Janssen Cilag. Dr. Komal Qureshi-Baig, Dr. Pit Ullmann and Martin Nurmik are supported by the Fonds National de la Recherche (FNR) (under the AFR grant scheme and PRIDE scheme) and by the Fondation du Pelican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg. EV is supported by a TELEVIE grant (7456517, R-AGR3377). EL is supported by a CORE (C16/BM/11282028) and a POC grant (PoC18/12554295). 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	Zhao, PF; Yin, WM; Wu, AH; Tang, YS; Wang, JY; Pan, ZZ; Lin, TT; Zhang, M; Chen, BF; Duan, YF; Huang, YZ				Zhao, Pengfei; Yin, Weimin; Wu, Aihua; Tang, Yisi; Wang, Jinyu; Pan, Zhenzhen; Lin, Tingting; Zhang, Meng; Chen, Binfan; Duan, Yifei; Huang, Yongzhuo			Dual-Targeting to Cancer Cells and M2 Macrophages via Biomimetic Delivery of Mannosylated Albumin Nanoparticles for Drug-Resistant Cancer Therapy	ADVANCED FUNCTIONAL MATERIALS			English	Article						albumin nanoparticles; combination therapy; mannose receptors; multidrug resistance; SPARC	TUMOR-ASSOCIATED MACROPHAGES; COLORECTAL-CANCER; SPARC EXPRESSION; PANCREATIC-CANCER; BOUND PACLITAXEL; NAB-PACLITAXEL; BREAST-CANCER; LUNG-CANCER; AUTOPHAGY; DISULFIRAM	Multidrug resistance (MDR) is an issue that is not only related to cancer cells but also associated with the tumor microenvironments. MDR involves the complicated cancer cellular events and the crosstalk between cancer cells and their surroundings. Ideally, an effective system against MDR cancer should take dual action on both cancer cells and tumor microenvironments. The authors find that both the drug-resistant colon cancer cells and the protumor M2 macrophages highly express two nutrient transporters, i.e., secreted protein acidic and rich in cysteine (SPARC) and mannose receptors (MR). By targeting SPARC and MR, a system can act on both cancer cells and M2 macrophages. Herein the authors develop a mannosylated albumin nanoparticles with coencapsulation of different drugs, i.e., disulfiram/copper complex (DSF/Cu) and regorafenib (Rego). The results show that combination therapy of DSF/Cu and Rego efficiently inhibits the growth of drug-resistant colon tumor, and the combination has not been reported yet for use in anticancer treatment. The system significantly improves the treatment outcomes in the animal model bearing drug-resistant tumors. The therapeutic mechanisms involve enhanced apoptosis, upregulation of intracellular ROS, anti-angiogenesis, and tumor-associated macrophage "re-education." This strategy is characterized by dual targeting to and the simultaneous action on cancer cells and M2 macrophages, with biomimetic codelivery of a novel drug combination.	[Zhao, Pengfei; Yin, Weimin; Duan, Yifei; Huang, Yongzhuo] Nanchang Univ, Coll Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China; [Zhao, Pengfei; Yin, Weimin; Wu, Aihua; Tang, Yisi; Wang, Jinyu; Pan, Zhenzhen; Lin, Tingting; Zhang, Meng; Chen, Binfan; Huang, Yongzhuo] Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China; [Wu, Aihua; Tang, Yisi] Guangzhou Univ Chinese Med, Trop Med Inst, 12 Jichang Rd, Guangzhou 501450, Guangdong, Peoples R China; [Pan, Zhenzhen] Guangxi Univ Chinese Med, Fac Pharm, 13 Wuhe Rd, Nanning 530200, Peoples R China; [Lin, Tingting] Binzhou Med Univ Hosp, Dept Pharm, 661 Huanghe Rd, Binzhou 256603, Peoples R China		Huang, YZ (corresponding author), Nanchang Univ, Coll Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China.; Huang, YZ (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China.	yzhuang@simm.ac.cn	Huang, Yongzhuo/A-4688-2013	Huang, Yongzhuo/0000-0001-7067-8915	National Basic Research Program of China (973 Program)National Basic Research Program of China [2014CB931900, 2013CB932503]; NSFC, ChinaNational Natural Science Foundation of China (NSFC) [81373357, 81422048, 81673382, 81521005]	The authors thank the National Basic Research Program of China (973 Program 2014CB931900, 2013CB932503) and NSFC, China (81373357, 81422048, 81673382, 81521005) for the support. The authors also thank National Center for Protein Science Shanghai, CAS, for the technical support at Electron Microscopy Facility.	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Funct. Mater.	NOV 24	2017	27	44							1700403	10.1002/adfm.201700403			15	Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Science & Technology - Other Topics; Materials Science; Physics	FN5GR	WOS:000416035400019					2022-04-25	
J	Wu, J; Zhang, DW; Li, J; Deng, X; Liang, GN; Long, Y; He, XM; Dai, TY; Ren, DL				Wu, Jian; Zhang, Dawei; Li, Jun; Deng, Xin; Liang, Guannan; Long, Yang; He, Xuemei; Dai, Tianyang; Ren, Delian			MACC1 induces autophagy to regulate proliferation, apoptosis, migration and invasion of squamous cell carcinoma	ONCOLOGY REPORTS			English	Article						metastasis-associated colon cancer-1; metastasis; autophagy; AMPK signaling; esophageal squamous cell carcinoma	METASTASIS; EXPRESSION; BECLIN-1; CANCER; PREDICTS; GENE; MET	Metastasis-associated colon cancer-1 (MACC1) plays an important role in cancer development, but the role and mechansim of MACC1 in squamous cell carcinoma (ESCC) remain unclear. In this study, we found that MACC1 expression was increased in ESCC, and correlated with lymph node metastasis. MACC1 knockdown suppresed ESCC cell proliferation, metastasis and enchanced cell apoptosis. Moreover, MACC1 knockdown inhibited ESCC cell autophagy, and 3-methyladenine was able to rescue MACC1-induced malignant phenotype of ESCC cells. Furthermore, MACC1 knockdown inactivated AMPK-ULK1 signaling pathway, and metformin could rescue MACC1-induced autophagy in ESCC cells. Collectively, this study found that upregulation of MACC1 in ESCC was associated with lymph node metastasis of patients, and MACC1 regulated ESCC cell proliferation, apoptosis, migration and invasion mainly through AMPK-ULK1 induced autophagy.	[Wu, Jian; Zhang, Dawei; Li, Jun; Liang, Guannan; Long, Yang; He, Xuemei; Dai, Tianyang] South West Med Univ, Affiliated Hosp, Dept Cardiothorac Surg, Luzhou, Sichuan, Peoples R China; [Ren, Delian] South West Med Univ, Basic Med Coll, Dept Immunol, Luzhou 646000, Sichuan, Peoples R China; [Deng, Xin] Southwest Med Univ, Drug Discovery Res Ctr, Luzhou, Sichuan, Peoples R China; [Deng, Xin] Southwest Med Univ, Sch Pharm, Dept Pharmacol, Lab Cardiovasc Pharmacol, Luzhou, Sichuan, Peoples R China		Ren, DL (corresponding author), South West Med Univ, Basic Med Coll, Dept Immunol, Luzhou 646000, Sichuan, Peoples R China.	rendelian0605@sina.com			Joint Fund of Technology Department, Sichuan Province [2014TSX-0102]; Youth Foundation of Affiliated Hospital of South West Medical University [16025]; Sichuan Science and Technology Plan projects [2016RZ0076]	The authors wish to thank Mr. Biao Zhou, and KaiMing He for assistance in obtaining patient tissue samples. This study was supported by The Joint Fund of Technology Department, Sichuan Province (2014TSX-0102), and by Youth Foundation of Affiliated Hospital of South West Medical University (16025), and by Sichuan Science and Technology Plan projects (no. 2016RZ0076).	Ahn JS, 2016, ONCOTARGET, V7, P79033, DOI 10.18632/oncotarget.12986; Carchman EH, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0164273; DeVorkin L, 2017, MOL CANCER RES, V15, P250, DOI 10.1158/1541-7786.MCR-16-0132; Guo WN, 2017, THERANOSTICS, V7, P2231, DOI 10.7150/thno.18835; He YJ, 2016, ONCOTARGET, V7, P54537, DOI 10.18632/oncotarget.10402; Hu D, 2017, ONCOTARGET, V8, P23841, DOI 10.18632/oncotarget.13318; Ilm K, 2016, ONCOTARGET, V7, P53443, DOI 10.18632/oncotarget.10803; Jia YL, 2016, CELL DEATH DIS, V7, DOI 10.1038/cddis.2016.247; Kim R, 2016, WORLD J GASTROENTERO, V22, P8389, DOI 10.3748/wjg.v22.i37.8389; Lee E, 2016, ONCOTARGET, V7, P67919, DOI 10.18632/oncotarget.12084; Li HY, 2015, ONCOL LETT, V9, P1989, DOI 10.3892/ol.2015.2984; Li JL, 2017, CANCER BIOMARK, V18, P11, DOI 10.3233/CBM-160667; Lu C, 2016, ONCOL REP, V35, P3559, DOI 10.3892/or.2016.4753; Mao Y, 2016, ONCOTARGET, V7, P51223, DOI 10.18632/oncotarget.9981; Qu JH, 2012, WORLD J GASTROENTERO, V18, P2995, DOI 10.3748/wjg.v18.i23.2995; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Sawada G, 2016, GASTROENTEROLOGY, V150, P1171, DOI 10.1053/j.gastro.2016.01.035; Shirahata A, 2010, ANTICANCER RES, V30, P2689; Stein U, 2009, CELL CYCLE, V8, P2467, DOI 10.4161/cc.8.15.9018; Stein U, 2009, NAT MED, V15, P59, DOI 10.1038/nm.1889; Sun LF, 2015, MOL MED REP, V12, P3423, DOI 10.3892/mmr.2015.3886; Tan WG, 2016, ONCOTARGET, V7, P84408, DOI 10.18632/oncotarget.12910; Wang HY, 2017, ONCOTARGET, V8, P7540, DOI 10.18632/oncotarget.13602; Weh KM, 2016, MOL CARCINOGEN, V55, P1876, DOI 10.1002/mc.22432; Xia JL, 2016, CANCER LETT, V381, P31, DOI 10.1016/j.canlet.2016.07.014; Xie C, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0064235; Yamada E, 2016, ONCOTARGET, V7, P74612, DOI 10.18632/oncotarget.11916; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100; Zhan L, 2016, ONCOTARGET, V7, P83476, DOI 10.18632/oncotarget.13080	29	14	16	1	10	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	OCT	2017	38	4					2369	2377		10.3892/or.2017.5889			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FI1JD	WOS:000411688200054	28791376	Bronze			2022-04-25	
J	Kaushal, JB; Bhatia, R; Kanchan, RK; Raut, P; Mallapragada, S; Ly, QP; Batra, SK; Rachagani, S				Kaushal, Jyoti B.; Bhatia, Rakesh; Kanchan, Ranjana K.; Raut, Pratima; Mallapragada, Surya; Ly, Quan P.; Batra, Surinder K.; Rachagani, Satyanarayana			Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3 beta	CANCERS			English	Article						niclosamide; pancreatic cancer; apoptosis; autophagy; Hh signaling; Gsk3 beta	GLYCOGEN-SYNTHASE KINASE-3; HUMAN COLON-CANCER; WNT/BETA-CATENIN; SIGNALING PATHWAY; CARCINOMA CELLS; IN-VITRO; AUTOPHAGY; HEDGEHOG; GROWTH; ACTIVATION	Simple Summary: The current obstacles for discovering new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the identification of new uses for approved or investigational drugs for new therapeutic purposes. Niclosamide (Nic) is a Food and Drug Administration (FDA)-approved anti-helminthic drug, reported to have anti-cancer effects, and is being assessed in various clinical trials. In the current study, we assessed the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. Our results revealed mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. This study provided a novel mechanistic insight for anti-cancer efficacy of Nic by increasing p-Gsk3 beta that modulates molecular signaling(s), including inhibition of hedgehog (Hh) signaling-mediated cellular proliferation and increased apoptosis through mTORC1-dependent autophagy may prove helpful for the development of novel PC therapies. Abstract: Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3 beta inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3 beta activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3 beta acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagymediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3 beta mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.	[Kaushal, Jyoti B.; Bhatia, Rakesh; Kanchan, Ranjana K.; Raut, Pratima; Batra, Surinder K.; Rachagani, Satyanarayana] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA; [Mallapragada, Surya] Iowa State Univ, Nanovaccine Inst, Dept Chem & Biol Engn, Ames, IA 50011 USA; [Ly, Quan P.] Univ Nebraska Med Ctr, Dept Surg Oncol, Omaha, NE 68198 USA; [Batra, Surinder K.] Univ Nebraska Med Ctr, Fred & Pamela Buffet Canc Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA		Rachagani, S (corresponding author), Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA.	jyoti.kaushal@unmc.edu; rocky.bhatia@unmc.edu; ranjana.kanchan@unmc.edu; pratima.raut@unmc.edu; suryakm@iastate.edu; qly@wnmc.edu; sbatra@unmc.edu; srachagani@unmc.edu	Kaushal, Jyoti Bala/AAR-4934-2021; Kanchan, Ranjana/AAD-6218-2022	Kaushal, Jyoti Bala/0000-0003-3185-4175; Batra, Surinder K./0000-0001-9470-9317	National Institutes of Health, National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01 CA247763, R21 CA238953, P01 CA217798, R01 CA 228524, R01 CA206444]	The authors and work in this manuscript are, in parts, supported by the National Institutes of Health, National Cancer Institute (R01 CA247763, R21 CA238953, P01 CA217798, R01 CA 228524, and R01 CA206444).	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J	Maximchik, P; Abdrakhmanov, A; Inozemtseva, E; Tyurin-Kuzmin, PA; Zhivotovsky, B; Gogvadze, V				Maximchik, Polina; Abdrakhmanov, Alibek; Inozemtseva, Evgeniya; Tyurin-Kuzmin, Pyotr A.; Zhivotovsky, Boris; Gogvadze, Vladimir			2-Deoxy-D-glucose has distinct and cell line-specific effects on the survival of different cancer cells upon antitumor drug treatment	FEBS JOURNAL			English	Article						apoptosis; cancer; ER stress; glycolysis; mitochondria	ENDOPLASMIC-RETICULUM STRESS; CISPLATIN-INDUCED APOPTOSIS; ER STRESS; AUTOPHAGY; INHIBITION; RADIOTHERAPY; GLYCOLYSIS; ACTIVATION; CHAPERONE; DEATH	The dependence of tumors on glycolysis for ATP generation offers a rationale for therapeutic strategies aimed at selective inhibition of the glycolytic pathway. Analysis of tumor cell responses to anticancer drugs revealed that inhibition of glycolysis by 2-deoxy-D-glucose (2-DG) generally augmented the apoptotic response; however, in HCT116 human colon carcinoma cells, apoptosis was suppressed. A comparison of neuroblastoma SK-N-BE(2) and HCT116 cells revealed, that in contrast to HCT116, in SK-N-BE(2) cells 2-DG alone was able to induce cell death. In SK-N-BE(2) cells the decrease in ATP levels upon treatment with 2-DG was more prominent because in HCT116 cells mitochondria compensated for the loss of ATP caused by glycolysis suppression. In both cells lines 2-DG triggered endoplasmic reticulum (ER) stress, assessed by the accumulation of the marker protein GRP78/BiP. Suppression of ER stress by mannose attenuated the 2-DG-induced apoptotic response in SK-N-BE(2) cells, implying that apoptosis in these cells is a consequence of ER stress induction. In HCT116 cells, ER stress stimulated autophagy, assessed by the accumulation of the lipidated form of LC3. The inhibitor of ER stress mannose attenuated autophagy and reversed 2-DG-mediated suppression of cisplatin-induced apoptosis. When autophagy in HCT116 cells was suppressed by bafilomycin, cisplatin-induced apoptosis was decreased. At the same time, stimulation of autophagy in SK-N-BE(2) cells suppressed cell death. Thus, successful treatment of tumors with conventionally used anticancer drugs should be combined with targeting metabolic pathways involved in the regulation of apoptosis, autophagy, and cellular bioenergetics.	[Maximchik, Polina; Abdrakhmanov, Alibek; Inozemtseva, Evgeniya; Tyurin-Kuzmin, Pyotr A.; Zhivotovsky, Boris; Gogvadze, Vladimir] Moscow MV Lomonosov State Univ, Fac Med, Moscow, Russia; [Zhivotovsky, Boris; Gogvadze, Vladimir] Karolinska Inst, Inst Environm Med, Div Toxicol, Box 210, SE-17177 Stockholm, Sweden		Gogvadze, V (corresponding author), Karolinska Inst, Inst Environm Med, Div Toxicol, Box 210, SE-17177 Stockholm, Sweden.	Vladimir.Gogvadze@ki.se	Tyurin-Kuzmin, Pyotr A./A-8193-2014; Gogvadze, Vladimir/A-4392-2014; Zhivotovsky, Boris/A-4346-2014	Tyurin-Kuzmin, Pyotr A./0000-0002-1901-1637; Abdrakhmanov, Alibek/0000-0002-5315-3479; Mickols, Evgeniya/0000-0002-4044-2669; Zhivotovsky, Boris/0000-0002-2238-3482	Russian Science FoundationRussian Science Foundation (RSF) [14-25-00056]; Stockholm [161292]; Swedish Cancer Societies [160733]; Swedish Childhood Cancer FoundationEuropean Commission [PR-2016-0090]; Russian Foundation for Basic ResearchRussian Foundation for Basic Research (RFBR) [18-04-00720, 18-315-00327]	This work was supported by a grant from the Russian Science Foundation (14-25-00056). The work in the authors' laboratories is supported by grants from the Stockholm (161292) and Swedish (160733) Cancer Societies, the Swedish Childhood Cancer Foundation (PR-2016-0090), and the Russian Foundation for Basic Research (18-04-00720 to VG and 18-315-00327 to PM). We thank Prof. Bert Vogelstein for HCT116 cells, Prof. Fazoil Ataullakhanov and Dr. Pyotr Makhov for plasmid containing LC3-GFP.	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DEC	2018	285	24					4590	4601		10.1111/febs.14687			12	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	HE6ZH	WOS:000453570200005	30375744	Bronze			2022-04-25	
J	Parks, M; Tillhon, M; Dona, F; Prosperi, E; Scovassi, AI				Parks, Michele; Tillhon, Micol; Dona, Francesca; Prosperi, Ennio; Scovassi, A. Ivana			2-Methoxyestradiol: New perspectives in colon carcinoma treatment	MOLECULAR AND CELLULAR ENDOCRINOLOGY			English	Article						Apoptosis; Autophagy; Cell cycle; Colon carcinoma cells; 2-Methoxyestradiol	ENDOGENOUS ESTROGEN METABOLITE; CELL-CYCLE PROGRESSION; IN-VITRO; SUPEROXIDE-DISMUTASE; ORAL 2-METHOXYESTRADIOL; INHIBITS ANGIOGENESIS; MAMMALIAN METABOLITE; APOPTOSIS INDUCTION; TUMOR-GROWTH; G2/M ARREST	Colon carcinoma represents a major problem in oncology, since this type of cancer responds poorly to conventional chemotherapy. Many groups are actively involved in the search of new experimental strategies to bypass this problem. We investigated the effects of 2-methoxyestradiol (2-ME), which derives from the NADPH-dependent cytochrome P450 metabolism of 17 beta-estradiol. This compound has raised much interest in the past few decades for its inhibitory effects on the growth of cancer cells of different origin: however, little is known about its use on colon carcinoma-derived cell lines. In the present study, we investigated the effects of 2-ME on cell proliferation and cell cycle of two human colon carcinoma cell lines, namely HCT116 and SW613-B3. Our results showed a net anti-proliferative effect of 2-ME on both cell lines, which is accompanied by cell cycle arrest; moreover, we demonstrated that 2-ME is able to induce apoptosis as well as autophagy. This body of evidence points out that 2-ME could be considered as a promising tool against colon carcinoma. (C) 2010 Elsevier Ireland Ltd. All rights reserved.	[Parks, Michele; Tillhon, Micol; Dona, Francesca; Prosperi, Ennio; Scovassi, A. Ivana] Ist Genet Mol CNR, I-27100 Pavia, Italy		Scovassi, AI (corresponding author), Ist Genet Mol CNR, Via Abbiategrasso 207, I-27100 Pavia, Italy.	scovassi@igm.cnr.it	Scovassi, Anna Ivana/F-2458-2010; Prosperi, Ennio/A-3439-2014; Tillhon, Micol/AAQ-6994-2020	Scovassi, Anna Ivana/0000-0003-3484-9881; Prosperi, Ennio/0000-0001-5391-5157; Parks, Michael/0000-0001-8240-0603	Regione Lombardia, ItalyRegione Lombardia [4328, 13810096]; AIRCFondazione AIRC per la ricerca sul cancro [5126]; Fondazione CariploFondazione Cariplo [2006-0734]	The work in the laboratory is supported by Regione Lombardia, Italy (Projects Metadistretti n. 4328 and ATP n. 13810096). MT is a PhD student from University of Pavia (Dottorato in Scienze genetiche e molecolari) supported by the AIRC grant 5126; FD is supported by Fondazione Cariplo (grant # 2006-0734). We are indebted to Prof. L. Moro (Universita Avogadro, Novara, Italy), and Dr. P. Lombardi (Naxospharma, Novate Milanese, Italy) for helpful discussion. We thank Dr. G. Mazzini and Dr. V. Giansanti (IGM-CNR, Pavia, Italy) for help in autophagy experiments. We kindly acknowledge the reviewers for stimulating us to improve the manuscript.	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Cell. Endocrinol.	JAN 1	2011	331	1					119	128		10.1016/j.mce.2010.08.017			10	Cell Biology; Endocrinology & Metabolism	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Endocrinology & Metabolism	692CT	WOS:000285129800014	20816916	Green Submitted			2022-04-25	
J	Nakamura, Y; Yogosawa, S; Izutani, Y; Watanabe, H; Otsuji, E; Sakai, T				Nakamura, Yoshitaka; Yogosawa, Shingo; Izutani, Yasuyuki; Watanabe, Hirotsuna; Otsuji, Eigo; Sakai, Tosiyuki			A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy	MOLECULAR CANCER			English	Article							MALIGNANT GLIOMA-CELLS; PROTEIN-DEGRADATION; SOY ISOFLAVONES; DOWN-REGULATION; INDOLE-3-CARBINOL; CARCINOGENESIS; PATHWAY; CHEMOPREVENTION; GROWTH; DEATH	Background: The chemopreventive effects of dietary phytochemicals on malignant tumors have been studied extensively because of a relative lack of toxicity. To achieve desirable effects, however, treatment with a single agent mostly requires high doses. Therefore, studies on effective combinations of phytochemicals at relatively low concentrations might contribute to chemopreventive strategies. Results: Here we found for the first time that co-treatment with I3C and genistein, derived from cruciferous vegetables and soy, respectively, synergistically suppressed the viability of human colon cancer HT-29 cells at concentrations at which each agent alone was ineffective. The suppression of cell viability was due to the induction of a caspase-dependent apoptosis. Moreover, the combination effectively inhibited phosphorylation of Akt followed by dephosphorylation of caspase-9 or down-regulation of XIAP and survivin, which contribute to the induction of apoptosis. In addition, the co-treatment also enhanced the induction of autophagy mediated by the dephosphorylation of mTOR, one of the downstream targets of Akt, whereas the maturation of autophagosomes was inhibited. These results give rise to the possibility that co-treatment with I3C and genistein induces apoptosis through the simultaneous inhibition of Akt activity and progression of the autophagic process. This possibility was examined using inhibitors of Akt combined with inhibitors of autophagy. The combination effectively induced apoptosis, whereas the Akt inhibitor alone did not. Conclusion: Although in vivo study is further required to evaluate physiological efficacies and toxicity of the combination treatment, our findings might provide a new insight into the development of novel combination therapies/chemoprevention against malignant tumors using dietary phytochemicals.	[Nakamura, Yoshitaka; Yogosawa, Shingo; Izutani, Yasuyuki; Watanabe, Hirotsuna; Sakai, Tosiyuki] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Mol Targeting Canc Prevent, Kamigyo Ku, Kyoto 6028566, Japan; [Nakamura, Yoshitaka; Otsuji, Eigo] Kyoto Prefectural Univ Med, Dept Surg, Div Digest Surg, Kamigyo Ku, Kyoto 6028566, Japan		Sakai, T (corresponding author), Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Mol Targeting Canc Prevent, Kamigyo Ku, Kyoto 6028566, Japan.	nakamura@koto.kpu-m.ac.jp; yogosawa@koto.kpu-m.ac.jp; izutani@koto.kpu-m.ac.jp; w-h123@koto.kpu-m.ac.jp; otsuji@koto.kpu-m.ac.jp; tsakai@koto.kpu-m.ac.jp			Japanese Ministry of Education, Culture, Sports, Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science	We would like to thank Dr. Yoshihide Tsujimoto and Dr. Yoshihiro Sowa for helpful comments on the manuscript. We are supported by a Grant-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and a Grant-in-aid for the Encouragement of Young Scientists from the Japan Society for the Promotion of Science.	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Cancer	NOV 12	2009	8								100	10.1186/1476-4598-8-100			15	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	526IQ	WOS:000272281900001	19909554	gold, Green Published			2022-04-25	
J	Mou, LJ; Liang, BY; Liu, GJ; Jiang, JJ; Liu, J; Zhou, B; Huang, JG; Zang, N; Liao, YY; Ye, L; Liang, H				Mou, Lianjun; Liang, Bingyu; Liu, Guanjun; Jiang, Junjun; Liu, Jie; Zhou, Bo; Huang, Jiegang; Zang, Ning; Liao, Yanyan; Ye, Li; Liang, Hao			Berbamine exerts anticancer effects on human colon cancer cells via induction of autophagy and apoptosis, inhibition of cell migration and MEK/ERK signalling pathway	JOURNAL OF BUON			English	Article						colon cancer; berbamine; autophagy; apoptosis; migration	PRODUCT-DERIVED COMPOUNDS; NATURAL-PRODUCTS; SYNTHETIC DERIVATIVES; DRUGS	Purpose: Berbamine is a plant-derived alkaloid with amazing and wide diversity of pharmacological properties which range from antimicrobial and anticancer. Nonetheless, the anticancer properties of Berbamine have not been thoroughly evaluated against colon cancer cells. This study was undertaken to evaluate the anticancer effects of Berbamine against the human colon cancer cell line HT-29. Methods: CCK-8 assay was used to determine the cell viability. DAPI and propidium iodide (PI) staining assays were used for the detection of apoptosis. Electron microscopy was used for the determination of autophagy. Wound healing assay was used to monitor cell migration. Protein expression was determined by western blotting. Results: The results showed that Berbamine caused a remarkable decrease in the HT-29 cell viability with an IC50 of 14 mu M, while the high IC50 of Berbamine against the normal CDD-18Co cells indicated low toxicity of this mol-ecule against the normal cells. DAPI and PI staining assays showed nuclear fragmentation, indicative of apoptosis in HT-29 cells. Berbamine also caused activation of caspase-3 and 9 and increased the Bax/Bcl-2 ratio. Electron microscopic analysis showed that Berbamine triggered the development of autophagic vesicles in the HT-29 cells which was concomitant with the increase in protein levels of LC3B-I, ATG-5, ATG-12 and Beclin-1. Wound healing assay showed that Berbamine decreased the migration potential of the HT29 and also blocked the MEK/ERK signalling pathway in colon cancer cells. Conclusion: Berbamine may prove an efficient lead molecule for the development of more potent anticancer agents through semi-synthetic approaches.	[Mou, Lianjun; Liang, Bingyu; Jiang, Junjun; Liu, Jie; Zhou, Bo; Huang, Jiegang; Zang, Ning; Liao, Yanyan; Ye, Li; Liang, Hao] Guangxi Med Univ, Sch Publ Hlth, Guangxi Key Lab AIDS Prevent & Treatment, 22 Shuangyong Rd, Nanning 530021, Peoples R China; [Mou, Lianjun; Liang, Bingyu; Jiang, Junjun; Liu, Jie; Zhou, Bo; Huang, Jiegang; Zang, Ning; Liao, Yanyan; Ye, Li; Liang, Hao] Guangxi Med Univ, Life Sci Inst, Guangxi Collaborat Innovat Ctr Biomed, Nanning 530021, Peoples R China; [Mou, Lianjun] Hainan Med Univ, Affiliated Hosp 1, Dept Pathol, Haikou 571101, Hainan, Peoples R China; [Liu, Guanjun] Zhengzhou Univ, Henan Prov Peoples Hosp, Peoples Hosp, Dept Oncol, Zhengzhou 450003, Henan, Peoples R China		Liang, H (corresponding author), Guangxi Med Univ, Sch Publ Hlth, Guangxi Key Lab AIDS Prevent & Treatment, 22 Shuangyong Rd, Nanning 530021, Peoples R China.; Liang, H (corresponding author), Guangxi Med Univ, Sch Publ Hlth, Guangxi Univ Key Lab Prevent & Control Highly Pre, Nanning 530021, Guangxi, Peoples R China.	hgotenl@yahoo.com					Arnold M, 2017, GUT, V66, P683, DOI 10.1136/gutjnl-2015-310912; Butler MS, 2008, NAT PROD REP, V25, P475, DOI 10.1039/b514294f; Butler MS, 2005, NAT PROD REP, V22, P162, DOI 10.1039/b402985m; Duan HY, 2010, CYTOTECHNOLOGY, V62, P341, DOI 10.1007/s10616-009-9240-x; Grynkiewicz G, 2008, PHARMACOL REP, V60, P439; Guinney J, 2015, NAT MED, V21, P1350, DOI 10.1038/nm.3967; LIU CX, 1991, PHYTOTHER RES, V5, P228, DOI 10.1002/ptr.2650050508; Meng Z, 2013, MOL CANCER THER; Montagut C, 2009, CANCER LETT, V283, P125, DOI 10.1016/j.canlet.2009.01.022; Nam S, 2012, MOL ONCOL, V6, P484, DOI 10.1016/j.molonc.2012.05.002; Newman DJ, 2007, J NAT PROD, V70, P461, DOI 10.1021/np068054v; POTTER JD, 1993, EPIDEMIOL REV, V15, P499, DOI 10.1093/oxfordjournals.epirev.a036132; Rahmatullah M, 2014, J PHARM PHARM SCI, V3, P95; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Tauriello DVF, 2018, NATURE, V554, P538, DOI 10.1038/nature25492; Wang Guan-yu, 2007, Journal of Zhejiang University-Science B, V8, P248, DOI 10.1631/jzus.2007.B0248; Wang GY, 2009, J ASIAN NAT PROD RES, V11, P219, DOI 10.1080/10286020802675076; Wang S, 2009, MOL CANCER, V8, DOI 10.1186/1476-4598-8-81; Xie JW, 2009, EUR J MED CHEM, V44, P3293, DOI 10.1016/j.ejmech.2009.02.018; Yang F, 2013, CANCER BIOL THER, V14, P1024, DOI 10.4161/cbt.26045; Yang FL, 2014, PLOS ONE, V9, DOI [10.1371/journal.pone.0076458, 10.1371/journal.pone.0100031]; Zhao XY, 2007, CHINESE MED J-PEKING, V120, P802, DOI 10.1097/00029330-200705010-00012	22	9	10	0	4	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	SEP-OCT	2019	24	5					1870	1875					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JU6CG	WOS:000501762000017	31786849				2022-04-25	
J	Varela-Lopez, A; Vera-Ramirez, L; Giampieri, F; Navarro-Hortal, MD; Forbes-Hernandez, TY; Battino, M; Quiles, JL				Varela-Lopez, Alfonso; Vera-Ramirez, Laura; Giampieri, Francesca; Navarro-Hortal, Maria D.; Forbes-Hernandez, Tamara Y.; Battino, Maurizio; Quiles, Jose L.			The central role of mitochondria in the relationship between dietary lipids and cancer progression	SEMINARS IN CANCER BIOLOGY			English	Article						Apoptosis; Autophagy; Bioenergetics; Lipogenesis; Redox biology	POLYUNSATURATED FATTY-ACIDS; INDUCED PANCREATIC-CANCER; CELLS IN-VITRO; BREAST-CANCER; COLON-CANCER; EICOSAPENTAENOIC ACID; COLORECTAL-CANCER; PROSTATE-CANCER; LUNG-CANCER; INDUCED APOPTOSIS	Evidence demonstrates the importance of lipid metabolism and signaling in cancer cell biology. De novo lipogenesis is an important source of lipids for cancer cells, but exogenous lipid uptake remains essential for many cancer cells. Dietary lipids can modify lipids present in tumor microenvironment affecting cancer cell metabolism. Clinical trials have shown that diets rich in polyunsaturated fatty acids (PUFA) can negatively affect tumor growth. However, certain n-6 PUFAs can also contribute to cancer progression. Identifying the molecular mechanisms through which lipids affect cancer progression will provide an opportunity for focused dietary interventions that could translate into the development of personalized diets for cancer control. However, the effective mechanisms of action of PUFAs have not been fully clarified yet. Mitochondria controls ATP generation, redox homeostasis, metabolic signaling, apoptotic pathways and many aspects of autophagy, and it has been recognized to play a key role in cancer. The purpose of this review is to summarize the current evidence linking dietary lipids effects on mitochondrial aspects with consequences for cancer progression and the molecular mechanisms that underlie this association.	[Varela-Lopez, Alfonso; Navarro-Hortal, Maria D.; Quiles, Jose L.] Univ Granada, Dept Physiol, Inst Nutr & Food Technol Jose Mataix Verdu, Biomed Res Ctr, Avda Conocimiento S-N, Granada 18100, Spain; [Vera-Ramirez, Laura] Pfizer Univ Granada & Andalusian Reg Govt, GENYO Ctr Genom & Oncol, Dept Genom Med, Granada, Spain; [Giampieri, Francesca; Battino, Maurizio] Univ Politecn Marche, Dept Clin Sci, I-60131 Ancona, Italy; [Giampieri, Francesca] King Abdulaziz Univ, Dept Biochem, Fac Sci, Jeddah, Saudi Arabia; [Forbes-Hernandez, Tamara Y.] CACTI Univ Vigo, CITACA, Dept Analyt & Food Chem, Nutr & Food Sci Grp, Vigo 36310, Spain; [Battino, Maurizio] Jiangsu Univ, Int Res Ctr Food Nutr & Safety, Zhenjiang 212013, Jiangsu, Peoples R China; [Quiles, Jose L.] Univ Europea Atlantico, Res Grp Food Nutr Biochem & Hlth, Santander, Spain		Quiles, JL (corresponding author), Univ Granada, Dept Physiol, Inst Nutr & Food Technol Jose Mataix Verdu, Biomed Res Ctr, Avda Conocimiento S-N, Granada 18100, Spain.	jlquiles@ugr.es	Varela-López, Alfonso/F-8055-2016; 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Cancer Biol.	AUG	2021	73				SI		86	100		10.1016/j.semcancer.2021.01.001		JUN 2021	15	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	SR7TI	WOS:000661248600008	33434641				2022-04-25	
J	Tian, X; Han, Z; Zhu, QX; Tan, J; Liu, WJ; Wang, YF; Chen, W; Zou, YL; Cai, YS; Huang, SS; Chen, AF; Zhan, T; Huang, M; Liu, M; Huang, XD				Tian, Xia; Han, Zheng; Zhu, Qingxi; Tan, Jie; Liu, Weijie; Wang, Yanfen; Chen, Wei; Zou, Yanli; Cai, Yishan; Huang, Shasha; Chen, Aifang; Zhan, Ting; Huang, Min; Liu, Meng; Huang, Xiaodong			Silencing of cadherin-17 enhances apoptosis and inhibits autophagy in colorectal cancer cells	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Cadherin-17; Apoptosis; Autophagy; Colorectal cancer; Rapamycin	LIVER-INTESTINE-CADHERIN; HEPATOCELLULAR-CARCINOMA; METASTASIS; EXPRESSION; MARKER; INTEGRIN; DISEASE; PROTEIN; GENE; LC3	Cadherin-17 (CDH17), a structurally unique member of the non-classical cadherin family, is associated with poor survival, cell proliferation, and metastasis in colorectal cancer. However, the role of CDH17 in the apoptosis and autophagy of colorectal cancer cells remains unclear. Here, we aimed to investigate the effect of CDH17 knockdown on autophagy and apoptosis in colorectal cancer cells. We inhibited CDH17 expression in KM12SM and KM12C colorectal cancer cells by RNA interference and found that silencing of CDH17 significantly inhibited cell viability and increased apoptosis in KM12SM and KM12C cells. In addition, silencing of CDH17 significantly increased the expression of cleaved caspase-3 and Bax and decreased the expression of Bcl-2. Concurrently, silencing of CDH17 significantly inhibited the conversion of LC3-I to LC3-II and decreased the formation of LC3(+) autophagic vacuoles and the accumulation of acidic vesicular organelles, indicating that autophagy was significantly inhibited in KM12SM and KM12C cells. Additionally, treatment with the autophagy-specific activator rapamycin attenuated apoptosis in CDH17-knockdown cells and as indicated by decreased caspase-3 activity, decreased expression of cleaved caspase-3 and Bax, and increased expression of Bcl-2. In conclusion, CDH17 silencing induced apoptosis and inhibited autophagy in KM12SM and KM12C cells, and this autophagy protected the cells from apoptotic cell death.	[Tian, Xia; Han, Zheng; Zhu, Qingxi; Tan, Jie; Liu, Weijie; Wang, Yanfen; Chen, Wei; Zou, Yanli; Cai, Yishan; Huang, Shasha; Chen, Aifang; Zhan, Ting; Huang, Min; Liu, Meng; Huang, Xiaodong] Wuhan Univ, Wuhan Hosp 3, Tongren Hosp, Dept Gastroenterol, 241 Pengliuyang Rd, Wuhan 430060, Hubei, Peoples R China		Liu, M; Huang, XD (corresponding author), Wuhan Univ, Wuhan Hosp 3, Tongren Hosp, Dept Gastroenterol, 241 Pengliuyang Rd, Wuhan 430060, Hubei, Peoples R China.	mengliu16@sina.com; xdhuang17@sina.com		Huang, Xiaodong/0000-0002-5815-7655	Wuhan Science and Technology Bureau of Applied Basic Research Projects [2015060101010064]; Hubei Province Natural Science Foundation of ChinaNatural Science Foundation of Hubei Province [2013CFB358]; Project of Health and Family Planning Commission of Wuhan Municipality [WX15C09, WX14C18]	This work was supported by Wuhan Science and Technology Bureau of Applied Basic Research Projects (2015060101010064), Hubei Province Natural Science Foundation of China (2013CFB358), and Project of Health and Family Planning Commission of Wuhan Municipality (WX15C09 and WX14C18).	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Pharmacother.	DEC	2018	108						331	337		10.1016/j.biopha.2018.09.020			7	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	HA2UZ	WOS:000450101800040	30227326	hybrid			2022-04-25	
J	Wang, L; Wang, Y; Lu, YY; Zhang, QY; Qu, XJ				Wang, Lu; Wang, Yan; Lu, Yuyin; Zhang, Qianyun; Qu, Xianjun			Heterozygous deletion of ATG5 in Apc(Min/+) mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma	CANCER BIOLOGY & THERAPY			English	Article						Apc Min; mouse; ATG5; colorectal cancer; heterozygous deletion; intestinal adenoma; IFN-; ATG5; autophagy related gene 5; CRC; colorectal cancer; IFN-; Interferon-gamma; 5-FU; 5-fluorouracil; Apc; adenomatous polyposis coli; siRNAs; small interfering RNAs; EGFR; epidermal growth factor receptor; Erk; extracellular signal-regulated kinase; LC3; microtubule-associated protein 1 light chain 3; PCNA; proliferating cell nuclear antigen	COLORECTAL-CANCER; ADJUVANT TREATMENT; BETA-CATENIN; COLON-CANCER; AUTOPHAGY; CELLS; APOPTOSIS; APC	Autophagy related gene 5 (ATG5) was lost in 23% of the patients with colorectal cancer (CRC) and the role of loss of ATG5 in the pathogenesis of CRC remains unclear. Knockdown of ATG5 in cancer cells enhances the antitumor efficacy of lots of chemotherapeutic agents. However, there is still no animal model to validate these in vitro observations in vivo. In this study, we found that heterozygous deletion of ATG5 in Apc(Min/+) mice increased the number and size of adenomas as compared with those in Apc(Min/+)ATG5(+/+) mice. To investigate whether ATG5 deficiency could sensitize tumors to chemotherapies, we compared the antitumor effects of Interferon-gamma (IFN-) between Apc(Min/+)ATG5(+/+) and Apc(Min/+)ATG5(+/-) mice, as IFN- is a potential tumor suppressor for CRC and has been used clinically as an efficient adjuvant to chemotherapy of cancer. We revealed that heterozygous deletion of ATG5 significantly enhanced the antitumor efficacy of IFN-. Early treatment of Apc(Min/+)ATG5(+/-) mice with IFN- decreased tumor incidence rate to 16.7% and reduced the number of adenomas by 95.5% and late treatment led to regression of tumor. Moreover, IFN- treatment did not cause any evident toxic reaction. Mechanistic analysis revealed that heterozygous deletion of ATG5 activated EGFR/ERK1/2 and Wnt/-catenin pathways in adenomas of Apc(Min/+) mice and enhanced the effects of IFN--dependent inhibition of these 2 pathways. Our results demonstrate that ATG5 plays important roles in intestinal tumor growth and combination of IFN- and ATG5 deficiency or ATG5-targeted inhibition is a promising strategy for prevention and treatment of CRC.	[Wang, Lu; Lu, Yuyin; Zhang, Qianyun; Qu, Xianjun] Shandong Univ, Sch Pharmaceut Sci, Dept Pharmacol, Jinan 250100, Shandong, Peoples R China; [Wang, Yan] Shandong Acad Med Sci, Inst Mat Med, Dept Pharmacol, Jinan, Shandong, Peoples R China		Qu, XJ (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Pharmacol, Jinan 250100, Shandong, Peoples R China.	qxj@sdu.edu.cn			Natural Science Foundation of China for Research Resources [91229113]	This research was made possible by the Grant 91229113 from Natural Science Foundation of China for Research Resources.	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Ther.	MAR	2015	16	3					383	391		10.1080/15384047.2014.1002331			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CF5OQ	WOS:000352607000005	25695667	Green Published, Bronze			2022-04-25	
J	Wang, XF; Zhang, C; Yan, XM; Lan, B; Wang, JY; Wei, CY; Cao, XX; Wang, RX; Yao, JH; Zhou, T; Zhou, M; Liu, QL; Jiang, B; Jiang, PF; Kesari, S; Lin, XJ; Guo, F				Wang, Xuefeng; Zhang, Chen; Yan, Xiangming; Lan, Bin; Wang, Jianyong; Wei, Chongyang; Cao, Xingxin; Wang, Renxiao; Yao, Jianhua; Zhou, Tao; Zhou, Mi; Liu, Qiaoling; Jiang, Biao; Jiang, Pengfei; Kesari, Santosh; Lin, Xinjian; Guo, Fang			A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria	CLINICAL CANCER RESEARCH			English	Article							CELL-DEATH; AUTOPHAGY; BCL-2; APOGOSSYPOL; GOSSYPOL; ABT-737; TARGET; MTOR; DIFFERENTIATION; MITOPHAGY	Purpose: Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing antiapoptotic proteins, have been shown to inhibit the growth of various human cancer cells in culture and xenograft models. Here, we evaluated the antitumor efficacy of a novel gossypol derivative and BH3 mimetic ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone) in colon cancer models. Several innovative combination strategies were also explored and elaborated. Experimental Design: Ch282-5 was synthesized by modifying the active aldehyde groups and R groups of gossypol according to a computer-aided drug design program. The stability of ch282-5 was examined by high-performance liquid chromatography, and cytotoxic effects of ch282-5 on colon cancer cells were assessed by MTS assay. Activation of mitochondrial apoptotic pathway by ch282-5 was evidenced with a series of molecular biology techniques. In vivo antitumor activity of ch282-5 and its combination with chloroquine, rapamycin, oxaliplatin, and ABT-263 was also evaluated in colon cancer xenograft models and experimental liver metastasis models. Results: Ch282-5 showed antiproliferative and pro-cell death activity against colon cancer cells both in vitro and in vivo, and the response to the drug correlated with inhibition of antiapoptotic Bcl-2 proteins, induction of mitochondria-dependent apoptotic pathway, and disruption of mitophagy and mTOR pathway. Ch282-5 also suppressed liver metastasis produced by intrasplenic injection of colon cancer cells. Furthermore, ch282-5 could potentiate the effectiveness of oxaliplatin and rescue ABT-263 efficacy by downregulation of Mcl-1 and elevation of platelet number. Conclusions: These findings provide a rational basis for clinical investigation of this highly promising BH3 mimetic in colon cancer. (C)2015 AACR.	[Wang, Xuefeng; Yan, Xiangming; Wang, Jianyong; Wei, Chongyang; Liu, Qiaoling; Guo, Fang] Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Adv Res Inst, Lab Tumor Targeted Therapy, 99 Haike Rd, Shanghai 201210, Peoples R China; [Wang, Xuefeng; Lan, Bin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai 201210, Peoples R China; [Wang, Xuefeng; Lan, Bin] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200030, Peoples R China; [Zhang, Chen; Cao, Xingxin; Wang, Renxiao; Yao, Jianhua; Zhou, Mi; Jiang, Biao] Univ Chinese Acad Sci, Shanghai Inst Organ Chem, CAS Key Lab Synthet Chem Nat Subst, Shanghai, Peoples R China; [Lan, Bin; Guo, Fang] Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Minist Educ, Key Lab Syst Biomed, Shanghai 200030, Peoples R China; [Zhou, Tao] Shanghai Univ, Acad Life Sci, Shanghai, Peoples R China; [Jiang, Pengfei; Kesari, Santosh; Lin, Xinjian] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA; [Jiang, Pengfei; Kesari, Santosh; Lin, Xinjian] Univ Calif San Diego, UC San Diego Moores Canc Ctr, La Jolla, CA 92093 USA		Guo, F (corresponding author), Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Adv Res Inst, Lab Tumor Targeted Therapy, 99 Haike Rd, Shanghai 201210, Peoples R China.; Lin, XJ (corresponding author), Univ Calif San Diego, UC San Diego Moores Canc Ctr, Dept Med, 3855 Hlth Sci Dr, La Jolla, CA 92093 USA.	xlin@ucsd.edu; guof@sari.ac.cn	Kesari, Santosh/E-8461-2013	wang, xuefeng/0000-0003-3613-6113	Shanghai Commission for Science and Technology [11DZ1910200]; National Basic Research ProgramNational Basic Research Program of China [2011CB510106]; National High Technology Research and Development Program of ChinaNational High Technology Research and Development Program of China [2013AA032201]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31171308, 81172208, 81472610]; Interdisciplinary Science & Youth Innovation Program of Shanghai Advanced Research Institute [2015Y52643232]	This work was supported by Shanghai Commission for Science and Technology (11DZ1910200), The National Basic Research Program (2011CB510106), The National High Technology Research and Development Program of China (2013AA032201), and The National Natural Science Foundation of China (31171308, 81172208, and 81472610) as well as a grant from Interdisciplinary Science & Youth Innovation Program of Shanghai Advanced Research Institute (2015Y52643232).	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Cancer Res.	MAR 15	2016	22	6					1445	1458		10.1158/1078-0432.CCR-15-0732			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	DI2WD	WOS:000373358900020	26515494	Bronze			2022-04-25	
J	Oh, BM; Lee, SJ; Cho, HJ; Park, YS; Kim, JT; Yoon, SR; Lee, SC; Lim, JS; Kim, BY; Choe, YK; Lee, HG				Oh, Byung Moo; Lee, Seon-Jin; Cho, Hee Jun; Park, Yun Sun; Kim, Jong-Tae; Yoon, Suk Ran; Lee, Sang Chul; Lim, Jong-Seok; Kim, Bo-Yeon; Choe, Yong-Kyung; Lee, Hee Gu			Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer	CELL DEATH & DISEASE			English	Article							DEUBIQUITINASE INHIBITOR; CYSTEINE PROTEINASES; IN-VITRO; APOPTOSIS; MECHANISMS; PROTEASES; GENERATION; PATHWAYS; SURVIVAL; NEURONS	Cystatin SN (CST1) is a specific inhibitor belonging to the cystatin superfamily that controls the proteolytic activities of cysteine proteases such as cathepsins. Our previous study showed that high CST1 expression enhances tumor metastasis and invasiveness in colorectal cancer. Recently, auranofin (AF), a gold(I)-containing thioredoxin reductase 1 (TrxR1) inhibitor, has been used clinically to treat rheumatoid arthritis. AF is a proteasome-associated deubiquitinase inhibitor and can act as an anti-tumor agent. In this study, we investigated whether CST1 expression induces autophagy and tumor cell survival. We also investigated the therapeutic effects of AF as an anti-tumor agent in colorectal cancer (CRC) cells. We found that CRC cells expressing high levels of CST1 undergo increased autophagy and exhibit chemotherapeutic resistance to AF-induced cell death, while those expressing low levels of CST1 are sensitive to AF. We also observed that knockdown of CST1 in high-CST1 CRC cells using CST1-specific small interfering RNAs attenuated autophagic activation and restored AF-induced cell mortality. Conversely, the overexpression of CST1 increased autophagy and viability in cells expressing low levels of CST1. Interestingly, high expression of CST1 attenuates AF-induced cell death by inhibiting intracellular reactive oxygen species (ROS) generation, as demonstrated by the fact that the blockage of ROS production reversed AF-induced cell death in CRC cells. In addition, upregulation of CST1 expression increased cellular glutathione reductase (GR) activity, reducing the cellular redox state and inducing autophagy in AF-treated CRC cells. These results suggest that high CST1 expression may be involved in autophagic induction and protects from AF-induced cell death by inhibition of ROS generation through the regulation of GR activity.	[Oh, Byung Moo; Lee, Seon-Jin; Cho, Hee Jun; Park, Yun Sun; Kim, Jong-Tae; Choe, Yong-Kyung; Lee, Hee Gu] Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, 125 Gwahak ro, Daejeon 34141, South Korea; [Oh, Byung Moo; Lee, Seon-Jin; Lee, Hee Gu] Univ Sci & Technol UST, Dept Biomol Sci, Daejeon, South Korea; [Lee, Sang Chul; Lim, Jong-Seok] Sookmyung Womens Univ, Dept Biol Sci, Seoul, South Korea; [Kim, Bo-Yeon] Korea Res Inst Biosci & Biotechnol, World Class Inst, Ochang, South Korea		Lee, HG (corresponding author), Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, 125 Gwahak ro, Daejeon 34141, South Korea.	hglee@kribb.re.kr	Lee, Seon-Jin/AAJ-8258-2020	Lee, Seon-Jin/0000-0001-7214-7536	National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [NRF- 2014R1A2A2A09052492]; Creative Allied Project and National Agenda Project through the National Research Council of Science and Technology	This work was supported by the National Research Foundation of Korea (NRF) grant by the Ministry of Science, ICT & Future Planning (NRF- 2014R1A2A2A09052492) and by the Creative Allied Project and National Agenda Project through the National Research Council of Science and Technology.	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MAR	2017	8								e2682	10.1038/cddis.2017.100			10	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	EP5VM	WOS:000397447100043	28300829	Green Published, gold			2022-04-25	
J	Cleven, AHG; Wouters, BG; Schutte, B; Spiertz, AJG; van Engeland, M; de Bruine, AP				Cleven, A. H. G.; Wouters, B. G.; Schutte, B.; Spiertz, A. J. G.; van Engeland, M.; de Bruine, A. P.			Poorer outcome in stromal HIF-2 alpha- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis	BRITISH JOURNAL OF CANCER			English	Article						colorectal cancer; hypoxia; TP53; BNIP3; outcome	HYPOXIA-INDUCIBLE FACTORS; METHYLATION-SPECIFIC PCR; CELL-DEATH; PROGNOSTIC VALUE; CANCER PATIENTS; UP-REGULATION; COLON-CANCER; K-RAS; P53; GENE	Stromal expression of hypoxia inducible factor 2 alpha (HIF-2 alpha) and carbonic anhydrase 9 (CA9) are associated with a poorer prognosis in colorectal cancer (CRC). Tumour cell death, regulated by a hypoxic stromal microenvironment, could be of importance in this respect. Therefore, we correlated apoptosis, TP53 mutational status and BNIP3 promoter hypermethylation of CRC cells with HIF-2 alpha- and CA9-related poor outcome. In a series of 195 CRCs, TP53 mutations in exons 5-8 were analysed by direct sequencing, and promoter hypermethylation of BNIP3 was determined by methylation-specific PCR. Expressions of HIF-2 alpha, CA9, p53, BNIP3 and M30 were analysed immunohistochemically. Poorer survival of HIF-2 alpha and CA9 stromal-positive CRCs was associated with wild-type TP53 ( P = 0.001 and P = 0.0391), but not with BNIP3 methylation. Furthermore, apoptotic levels were independent of the TP53 status, but lower in unmethylated BNIP3 CRCs ( P = 0.004). It appears that wild-type TP53 in CRC cells favours the progression of tumours expressing markers for hypoxia in their stroma, rather than in the epithelial compartment. Preserved BNIP3 function in CRC cells lowers apoptosis, and may thus be involved in alternative cell death pathways, such as autophagic cell death. However, BNIP3 silencing in tumour cells does not impact on hypoxia-driven poorer prognosis. These results suggest that the biology of CRC cells can be modified by alterations in the tumour microenvironment under conditions of tumour hypoxia.	[Cleven, A. H. G.; Spiertz, A. J. G.; van Engeland, M.; de Bruine, A. P.] Univ Hosp, Dept Pathol, GROW Sch Oncol & Dev Biol, NL-6202 AZ Maastricht, Netherlands; [Wouters, B. 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J. Cancer	AUG	2008	99	5					727	733		10.1038/sj.bjc.6604547			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	341NB	WOS:000258720100009	18728663	Green Published, hybrid			2022-04-25	
J	Yan, SY; Zhou, N; Zhang, DR; Zhang, KL; Zheng, WN; Bao, YH; Yang, WC				Yan, Siyuan; Zhou, Nan; Zhang, Deru; Zhang, Kaile; Zheng, Wenao; Bao, Yonghua; Yang, Wancai			PFKFB3 Inhibition Attenuates Oxaliplatin-Induced Autophagy and Enhances Its Cytotoxicity in Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						PFKFB3; Oxaliplatin; autophagy; colorectal cancer; proliferation	DOUBLE-EDGED-SWORD; COLORECTAL-CANCER; APOPTOSIS; GLYCOLYSIS; RESISTANCE; PHOSPHORYLATION; NORMALIZATION; STATISTICS; REDUCTION	6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), a glycolytic enzyme highly expressed in cancer cells, has been reported to participate in regulating metabolism, angiogenesis, and autophagy. Although anti-cancer drug oxaliplatin (Oxa) effectively inhibits cell proliferation and induces apoptosis, the growing resistance and side-effects make it urgent to improve the therapeutic strategy of Oxa. Although Oxa induces the autophagy process, the role of PFKFB3 in this process remains unknown. In addition, whether PFKFB3 affects the cytotoxicity of Oxa has not been investigated. Here, we show that Oxa-inhibited cell proliferation and migration concomitant with the induction of apoptosis and autophagy in SW480 cells. Both inhibition of autophagy by small molecule inhibitors and siRNA modification decreased the cell viability loss and apoptosis induced by Oxa. Utilizing quantitative PCR and immunoblotting, we observed that Oxa increased PFKFB3 expression in a time- and dose-dependent manner. Meanwhile, suppression of PFKFB3 attenuated both the basal and Oxa-induced autophagy, by monitoring the autophagic flux and phosphorylated-Ulk1, which play essential roles in autophagy initiation. Moreover, PFKFB3 inhibition further inhibited the cell proliferation/migration, and cell viability decreased by Oxa. Collectively, the presented data demonstrated that PFKFB3 inhibition attenuated Oxa-induced autophagy and enhanced its cytotoxicity in colorectal cancer cells.	[Yan, Siyuan; Zhou, Nan; Zhang, Deru; Zhang, Kaile; Zheng, Wenao; Bao, Yonghua; Yang, Wancai] Jining Med Univ, Key Lab Precis Oncol Shandong Higher Educ, Inst Precis Med, Jining 272067, Peoples R China; [Yang, Wancai] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA		Yan, SY; Yang, WC (corresponding author), Jining Med Univ, Key Lab Precis Oncol Shandong Higher Educ, Inst Precis Med, Jining 272067, Peoples R China.; Yang, WC (corresponding author), Univ Illinois, Dept Pathol, Chicago, IL 60612 USA.	yansy@mail.jnmc.edu.cn; zhounanzn720@163.com; zhangdr2613@163.com; zhangkaile1315@163.com; zwa2019med@163.com; baoyonghua2005@126.com; wyang06@uic.edu		Yang, Wancai/0000-0001-7437-9197	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31801169]; Teacher Research Support Foundation in Jining medical university [JYFC2018KJ065]; Faculty Start-up Funds of Jining Medical University	This work was supported by grants from the National Natural Science Foundation of China (31801169 to Yan S.), the Teacher Research Support Foundation in Jining medical university (JYFC2018KJ065 to Yan S.), and the Faculty Start-up Funds of Jining Medical University (to Yan S.).	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J. Mol. Sci.	NOV	2019	20	21							5415	10.3390/ijms20215415			15	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	JQ4VU	WOS:000498946100173	31671668	Green Published, gold			2022-04-25	
J	Lai, M; Amato, R; La Rocca, V; Bilgin, M; Freer, G; Spezia, P; Quaranta, P; Piomelli, D; Pistello, M				Lai, Michele; Amato, Rachele; La Rocca, Veronica; Bilgin, Mesut; Freer, Giulia; Spezia, Piergiorgio; Quaranta, Paola; Piomelli, Daniele; Pistello, Mauro			Acid ceramidase controls apoptosis and increases autophagy in human melanoma cells treated with doxorubicin	SCIENTIFIC REPORTS			English	Article							LONG-CHAIN CERAMIDES; COLON-CANCER CELLS; UP-REGULATION; SPHINGOSINE; INHIBITION; DEFICIENCY; TARGET; SPHINGOLIPIDS; MECHANISMS; EXPRESSION	Acid ceramidase (AC) is a lysosomal hydrolase encoded by the ASAH1 gene, which cleaves ceramides into sphingosine and fatty acid. AC is expressed at high levels in most human melanoma cell lines and may confer resistance against chemotherapeutic agents. One such agent, doxorubicin, was shown to increase ceramide levels in melanoma cells. Ceramides contribute to the regulation of autophagy and apoptosis. Here we investigated the impact of AC ablation via CRISPR-Cas9 gene editing on the response of A375 melanoma cells to doxorubicin. We found that doxorubicin activates the autophagic response in wild-type A375 cells, which effectively resist apoptotic cell death. In striking contrast, doxorubicin fails to stimulate autophagy in A375 AC-null cells, which rapidly undergo apoptosis when exposed to the drug. The present work highlights changes that affect melanoma cells during incubation with doxorubicin, in A375 melanoma cells lacking AC. We found that the remarkable reduction in recovery rate after doxorubicin treatment is strictly associated with the impairment of autophagy, that forces the AC-inhibited cells into apoptotic path.	[Lai, Michele; Freer, Giulia; Spezia, Piergiorgio; Quaranta, Paola; Pistello, Mauro] Univ Pisa, Retrovirus Ctr, Dept Translat Med & New Technol Med & Surg, Pisa, Italy; [Amato, Rachele; La Rocca, Veronica] Scuola St Anna Pisa, Inst Life Sci, Pisa, Italy; [Bilgin, Mesut] Danish Canc Soc Res Ctr, Ctr Autophagy Recycling & Dis, Cell Death & Metab Unit, Copenhagen, Denmark; [Piomelli, Daniele] Univ Calif Irvine, Anat & Neurobiol, Irvine, CA 92717 USA; [Pistello, Mauro] Pisa Univ Hosp, Virol Unit, Pisa, Italy		Lai, M (corresponding author), Univ Pisa, Retrovirus Ctr, Dept Translat Med & New Technol Med & Surg, Pisa, Italy.	michele.lai@unipi.it	Lai, Michele/AAO-3499-2021; Pistello, Mauro/AAD-4214-2022	Lai, Michele/0000-0001-7597-123X; 	"I-GENE, In-vivo Gene Editing by Nanotransducers", European call identifier H2020-FETOPEN-2018-2020 [862714]	This research was funded by "I-GENE, In-vivo Gene Editing by Nanotransducers", European call identifier H2020-FETOPEN-2018-2020, Proposal ID 862714.	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J	Feng, Y; Gao, SH; Gao, YJ; Wang, XF; Chen, Z				Feng, Ye; Gao, Shuohui; Gao, Yongjian; Wang, Xuefeng; Chen, Zhi			Anti-EGFR antibody sensitizes colorectal cancer stem-like cells to Fluorouracil-induced apoptosis by affecting autophagy	ONCOTARGET			English	Article						colorectal carcinoma (CRC); cancer stem cells (CSCs); CD133; CD44; EphB2	RECEPTOR MONOCLONAL-ANTIBODIES; RECTAL-CANCER; MARKERS CD133; SKIN-CANCER; CD44; EXPRESSION; DISEASE; CRC; 5-FLUOROURACIL; BIOMARKERS	Recent reports suggest that colorectal carcinoma (CRC) may be sustained by a small subpopulation of cells, termed cancer stem cells (CSCs), which have drug resistance properties as a key reason for chemotherapy failure. The epidermal growth factor receptor (EGFR) controls CRC initiation and progression. Monoclonal antibody against EGFR (cetuximab) has been used in treatment of several cancers. However, the effects of cetuximab on CSCs in the CRC chemotherapy remain unclear. Here, we studied the effects of cetuximab on the CSC-like cells in Fluorouracil (5-FU)-treated CRC cells. CSC-like cells were independently isolated from CRC cells using CD133, CD44 or EphB2-high as markers and confirmed by tumor sphere formation assay. We found that 5-FU increased the apoptotic death of CSC-like CRC cells. Co-application of cetuximab augmented the apoptotic death of CSC-like CRC cells by 5-FU, seemingly through inhibition of 5-FU-induced increases in cell autophagy in CSC-like CRC cells. Together, our data suggest that EGFR monoclonal antibody may sensitize CSC-like CRC cells to 5-FU-induced apoptosis by affecting autophagy.	[Feng, Ye; Gao, Shuohui; Gao, Yongjian; Wang, Xuefeng] Jilin Univ, China Japan Union Hosp, Dept Gastrointestinal Colorectal & Anal Surg, Changchun 130033, Peoples R China; [Chen, Zhi] Jilin Univ, Hosp 1, Dept Nephrol, Changchun 130021, Peoples R China		Chen, Z (corresponding author), Jilin Univ, Hosp 1, Dept Nephrol, Changchun 130021, Peoples R China.	Fengye0431@163.com			Jilin Province Natural Science Foundation of China [20160101115JC]; Provincal Funds for Health Service of Jilin	This study was supported by Jilin Province Natural Science Foundation of China 20160101115JC, and the Provincal Funds for Health Service of Jilin.	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J	Kwon, J; Lee, Y; Jeong, JH; Ryu, JH; Kim, KI				Kwon, Junhee; Lee, Yunkyeong; Jeong, Ji Hye; Ryu, Jae-Ha; Kim, Keun Il			Inhibition of autophagy sensitizes lignan-induced endoplasmic reticulum stress-mediated cell death	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						DFS; Autophagy; ER stress; AMPK signaling; TFEB; Cell death	ER STRESS; AMPK; COMPONENTS; ACTIVATION; PROTEIN; TFEB	Relationship between autophagy and endoplasmic reticulum (ER) stress and their application to treat cancer have been actively studied these days. Recently, a lignan [(-)-(2R, 3R)-1,4-O-diferuloylsecoisolariciresinol, DFS] from Alnus japonica has been found to reduce the viability of colon cancer cells. In this study, we have observed DFS-induced autophagy in a variety of cancer cell lines. In addition, DFS led to ER stress, based on the activation of unfolded protein response (UPR) transducers and an elevated expression of UPR target genes in prostate and colon cancer cells. Further investigation has shown that DFS triggered the activation of AMP-activated protein kinase (AMPK) signaling and nuclear translocation of transcription factor EB (TFEB). Furthermore, the cytotoxicity of DFS was potentiated by the co-treatment of autophagy inhibitor in these cancer cells. This study has provided a noble implication that the combination of DFS and autophagy inhibition exerts a synergistic effect in cancer treatment. (C) 2020 Elsevier Inc. All rights reserved.	[Kwon, Junhee; Lee, Yunkyeong; Kim, Keun Il] Sookmyung Womens Univ, Dept Biol Sci, Seoul 04310, South Korea; [Kwon, Junhee; Lee, Yunkyeong; Kim, Keun Il] Sookmyung Womens Univ, Cellular Heterogene Res Ctr, Seoul 04310, South Korea; [Kwon, Junhee; Lee, Yunkyeong; Kim, Keun Il] Sookmyung Womens Univ, Res Inst Womens Hlth, Seoul 04310, South Korea; [Jeong, Ji Hye; Ryu, Jae-Ha] Sookmyung Womens Univ, Res Ctr Cell Fate Control, Seoul 04310, South Korea; [Jeong, Ji Hye; Ryu, Jae-Ha] Sookmyung Womens Univ, Coll Pharm, Seoul 04310, South Korea		Kim, KI (corresponding author), Sookmyung Womens Univ, Dept Biol Sci, Seoul 04310, South Korea.; Ryu, JH (corresponding author), Sookmyung Womens Univ, Coll Pharm, Seoul 04310, South Korea.	ryuha@sookmyung.ac.kr; kikim@sookmyung.ac.kr	KIM, KEUN IL/D-2959-2011	Lee, Yunkyeong/0000-0001-9617-4520	National Research Foundation of Korea (NRF) - Korean Government (MSIP) [20110030074]	We thank Professor T. Yoshimori (Department of Genetics, Graduate School of Medicine, Osaka University, Japan) for kindly providing mRFP-GFP-LC3 expressing plasmid, and Atg5 wild-type and knockout mouse embryonic fibroblasts (MEFs). The present study was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (No. 20110030074).	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Biophys. Res. Commun.	MAY 28	2020	526	2					300	305		10.1016/j.bbrc.2020.03.081			6	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	LJ2XE	WOS:000530031800004	32209256				2022-04-25	
J	Gozuacik, D; Akkoc, Y; Ozturk, DG; Kocak, M; Agostinis, P				Gozuacik, Devrim; Akkoc, Yunus; Ozturk, Deniz Gulfem; Kocak, Muhammed; Agostinis, Patrizia			Autophagy-Regulating microRNAs and Cancer	FRONTIERS IN ONCOLOGY			English	Review						autophagy; microRNA; post-transcriptional control; cancer growth; metastasis; chemotherapy; radiotherapy; biomarker	CELL LUNG-CANCER; HEPATOCELLULAR-CARCINOMA CELLS; STARVATION-INDUCED AUTOPHAGY; CISPLATIN-INDUCED APOPTOSIS; DOWN-REGULATION CONTRIBUTES; HYPOXIA-INDUCED AUTOPHAGY; BREAST-CANCER; COLON-CANCER; SELECTIVE AUTOPHAGY; INHIBITS AUTOPHAGY	Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis. Consequently, abnormalities of autophagy are associated with a number of diseases, including Alzheimers's disease, Parkinson's disease, and cancer. According to the current view, autophagy seems to serve as a tumor suppressor in the early phases of cancer formation, yet in later phases, autophagy may support and/or facilitate tumor growth, spread, and contribute to treatment resistance. Therefore, autophagy is considered as a stage-dependent dual player in cancer. microRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level. miRNAs control several fundamental biological processes, and autophagy is no exception. Furthermore, accumulating data in the literature indicate that dysregulation of miRNA expression contribute to the mechanisms of cancer formation, invasion, metastasis, and affect responses to chemotherapy or radiotherapy. Therefore, considering the importance of autophagy for cancer biology, study of autophagy-regulating miRNA in cancer will allow a better understanding of malignancies and lead to the development of novel disease markers and therapeutic strategies. The potential to provide study of some of these cancer-related miRNAs were also implicated in autophagy regulation. In this review, we will focus on autophagy, miRNA, and cancer connection, and discuss its implications for cancer biology and cancer treatment.	[Gozuacik, Devrim; Akkoc, Yunus; Ozturk, Deniz Gulfem; Kocak, Muhammed; Agostinis, Patrizia] Sabanci Univ, Fac Engn & Nat Sci, Mol Biol Gent & Bioengn Program, Istanbul, Turkey; [Gozuacik, Devrim] Sabanci Univ, EFSUN, Istanbul, Turkey		Gozuacik, D (corresponding author), Sabanci Univ, Fac Engn & Nat Sci, Mol Biol Gent & Bioengn Program, Istanbul, Turkey.	dgozuacik@sabanciuniv.edu	Agostinis, Patrizia/ABI-1177-2020; Agostinis, Patrizia/AAO-2468-2020; AKKOC, Yunus/AAK-8853-2020; Devrim, Gozuacik/C-3330-2008; Öztürk, Deniz Gülfem/AAH-5404-2019	Agostinis, Patrizia/0000-0003-1314-2115; AKKOC, Yunus/0000-0001-5379-6151; Devrim, Gozuacik/0000-0001-7739-2346; Öztürk, Deniz Gülfem/0000-0002-2514-126X	European Union COST Action Transautophagy [CA15138]; Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114Z241, 114Z982]; TUBITAK-BIDEBTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)	This work was supported by the European Union COST Action Transautophagy (CA15138) and The Scientific and Technological Research Council of Turkey (TUBITAK) 1001 project numbers 114Z241 and 114Z982. YA is supported by a TUBITAK-BIDEB 2211 scholarship for Ph. D. studies.	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Oncol.	APR 18	2017	7								65	10.3389/fonc.2017.00065			22	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	ES2OY	WOS:000399369000002	28459042	Green Published, gold			2022-04-25	
J	Ratovitski, EA				Ratovitski, Edward A.			Tumor Protein (TP)-p53 Members as Regulators of Autophagy in Tumor Cells upon Marine Drug Exposure	MARINE DRUGS			English	Article						marine drugs; cancer; autophagy; p53 family members; transcription	BREAST-CANCER CELLS; TARGETING PATHWAYS; NATURAL-PRODUCTS; DNA-DAMAGE; P53 FAMILY; ANTICANCER; APOPTOSIS; DEATH; ACTIVATION; INDUCTION	Targeting autophagic pathways might play a critical role in designing novel chemotherapeutic approaches in the treatment of human cancers, and the prevention of tumor-derived chemoresistance. Marine compounds were found to decrease tumor cell growth in vitro and in vivo. Some of them were shown to induce autophagic flux in tumor cells. In this study, we observed that the selected marine life-derived compounds (Chromomycin A2, Psammaplin A, and Ilimaquinone) induce expression of several autophagic signaling intermediates in human squamous cell carcinoma, glioblastoma, and colorectal carcinoma cells in vitro through a transcriptional regulation by tumor protein (TP)-p53 family members. These conclusions were supported by specific qPCR expression analysis, luciferase reporter promoter assay, and chromatin immunoprecipitation of promoter sequences bound to the TP53 family proteins, and silencing of the TP53 members in tumor cells.	[Ratovitski, Edward A.] Johns Hopkins Univ, Sch Med, Head & Neck Canc Res Div, Baltimore, MD 21231 USA		Ratovitski, EA (corresponding author), Johns Hopkins Univ, Sch Med, Head & Neck Canc Res Div, Baltimore, MD 21231 USA.	eratovi1@jhmi.edu	Dyshlovoy, Sergey A./B-3586-2013	Dyshlovoy, Sergey A./0000-0002-7155-9245	Flight Attendant Research Institutions grant [082469]	This study was supported in part by the Flight Attendant Research Institutions grant (#082469). E.A.R. is a Distinguished Professor of the Prometeo Project of the Secretariat for Higher Education, Science, Technology, and Innovation (SENESCYT) of the Republic of Ecuador.	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Drugs	AUG	2016	14	8							154	10.3390/md14080154			19	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	DV9TI	WOS:000383284700006	27537898	Green Published, gold, Green Submitted			2022-04-25	
J	Chen, GY; Chen, CL; Tuan, HY; Yuan, PX; Li, KC; Yang, HJ; Hu, YC				Chen, Guan-Yu; Chen, Chiu-Ling; Tuan, Hsing-Yu; Yuan, Pei-Xiang; Li, Kuei-Chang; Yang, Hong-Jie; Hu, Yu-Chen			Graphene Oxide Triggers Toll-Like Receptors/Autophagy Responses In Vitro and Inhibits Tumor Growth In Vivo	ADVANCED HEALTHCARE MATERIALS			English	Article						graphene oxide; nanomaterials; autophagy; toll-like receptors; cancer therapy	PLURIPOTENT STEM-CELLS; BECLIN 1; TLR4-INDUCED AUTOPHAGY; SIGNALING PATHWAYS; INNATE IMMUNITY; CANCER-THERAPY; MACROPHAGES; ACTIVATION; RECEPTORS; NANOPARTICLES	Graphene oxide (GO) is a nanomaterial with burgeoning bioapplications, while autophagy is implicated in cancer therapy. Although induction of autophagy by nanomaterials is reported, the underlying signaling mechanism in cancer cells and how this implicates the potential of GO in cancer therapy remain obscure. Here, it is shown that GO itself can induce the toll-like receptors (TLRs) responses and autophagy in cancer cells and confer antitumor effects in mice. GO can be phagocytosed by CT26 colon cancer cells, simultaneously triggering autophagy as well as TLR-4 and TLR-9 signaling cascades. By dissecting the crosstalk between the TLRs and autophagy pathways, it is uncovered that the GO-activated autophagy is regulated through the myeloid differentiation primary response gene 88 (MyD88)- and TNF receptor-associated factor 6 (TRAF6)-associated TLR-4/9 signaling pathways. Injection of GO alone into immunocompetent mice bearing the CT26 colon tumors not only suppresses the tumor progression but also enhances cell death, autophagy, and immune responses within the tumor bed. These data altogether implicate the potential of GO as an effective nanomaterial for autophagy induction and cancer therapy.	[Chen, Guan-Yu; Chen, Chiu-Ling; Tuan, Hsing-Yu; Yuan, Pei-Xiang; Li, Kuei-Chang; Yang, Hong-Jie; Hu, Yu-Chen] Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu 300, Taiwan		Hu, YC (corresponding author), Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu 300, Taiwan.	ychu@mx.nthu.edu.tw		Tuan, Hsing-Yu/0000-0003-2819-2270	National Tsing Hua University (Toward World-Class University Project) [102N2051E1]; National Tsing Hua University (NTHU-CGMH Joint Research Program) [102N2766E1]; National Science Council, TaiwanMinistry of Science and Technology, Taiwan [NSC 99-2221-E-007-025-MY3, 101-2628-E-007-009-MY3, 101-2923-E-007-002-MY3]	The authors acknowledge the financial support from the National Tsing Hua University (Toward World-Class University Project 102N2051E1 and NTHU-CGMH Joint Research Program 102N2766E1) and National Science Council, Taiwan (NSC 99-2221-E-007-025-MY3, 101-2628-E-007-009-MY3, and 101-2923-E-007-002-MY3). The authors also thank C.-S. Chiang and J-.C. Wu for providing cancer cells and Y.-C. Chao for TEM experiment.	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Healthc. Mater.	SEP	2014	3	9					1486	1495		10.1002/adhm.201300591			10	Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials	Science Citation Index Expanded (SCI-EXPANDED)	Engineering; Science & Technology - Other Topics; Materials Science	AP2MY	WOS:000341907800018	24652749				2022-04-25	
J	Saiprasad, G; Chitra, P; Manikandan, R; Sudhandiran, G				Saiprasad, Gowrikumar; Chitra, Palanivel; Manikandan, Ramar; Sudhandiran, Ganapasam			Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated phosphoinositide-3-kinase/Akt/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis	EUROPEAN JOURNAL OF CANCER			English	Article						Colon cancer; Apoptosis; PI3K; Autophagy; mTOR; GSK-3 beta; Aurora-A	COLORECTAL-CANCER; CELL-SURVIVAL; ACTIVATION; PATHWAYS; CYCLE; P21; P53	Abnormalities in the homeostasis mechanisms involved in cell survival and apoptosis are contributing factors for colon carcinogenesis. Interventions of these mechanisms by pharmacologically safer agents gain predominance in colon cancer prevention. We previously reported the chemopreventive efficacy of hesperidin against colon carcinogenesis. In the present study, we aimed at investigating the potential of hesperidin over the abrogated Aurora-A coupled pro-survival phosphoinositide-3-kinase (PI3K)/Akt signalling cascades. Further, the role of hesperidin over apoptosis and mammalian target of rapamycin (mTOR) mediated autophagic responses were studied. Azoxymethane (AOM) induced mouse model of colon carcinogenesis was involved in this study. Hesperidin treatment was provided either in initiation/post-initiation mode respectively. Hesperidin significantly altered AOM mediated anti-apoptotic scenario by modulating Bax/Bcl-2 ratio together with enhanced cytochromec release and caspase-3, 9 activations. In addition, hesperidin enhanced p53-p21 axis with concomitant decrease in cell cycle regulator. Hesperidin treatment caused significant up-regulation of tumour suppressor phosphatase and tensin homologue (PTEN) with a reduction in the expression of AOM mediated p-PI3K and p-Akt. Additionally, hesperidin administration exhibited inhibition against p-mTOR expression which in turn led to stimulation of autophagic markers Beclin-1 and LC3-II. Aurora-A an upstream regulator of PI3K/Akt pathway was significantly inhibited by hesperidin. Furthermore, hesperidin administration restored glycogen synthase kinase-3 beta (GSK-3 beta) activity which in turn prevented the accumulation of oncoproteins beta-catenin, c-jun and c-myc. Taken together, hesperidin supplementation initiated apoptosis via targeted inhibition of constitutively activated Aurora-A mediated PI3K/Akt/GSK-3 beta and mTOR pathways coupled with autophagic stimulation against AOM induced colon carcinogenesis. (C) 2014 Elsevier Ltd. All rights reserved.	[Saiprasad, Gowrikumar; Chitra, Palanivel; Sudhandiran, Ganapasam] Univ Madras, Dept Biochem, Cell Biol Lab, Madras 600025, Tamil Nadu, India; [Manikandan, Ramar] Univ Madras, Dept Zool, Madras 600025, Tamil Nadu, India		Sudhandiran, G (corresponding author), Univ Madras, Dept Biochem, Cell Biol Lab, Guindy Campus, Madras 600025, Tamil Nadu, India.	sudhandiran@yahoo.com	Gowrikumar, Saiprasad/AAG-9611-2019; Sudhandiran, G/AAG-9967-2019; Ganapasam, Sudhandiran/AAD-4264-2021	Sudhandiran, G/0000-0003-0066-7801; 	University Grants Commission (UGC), New Delhi - IndiaUniversity Grants Commission, India	The first author G. Saiprasad thanks the University Grants Commission (UGC), New Delhi - India for the financial assistant in the form of UGC meritorious research fellowship.	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J. Cancer	SEP	2014	50	14					2489	2507		10.1016/j.ejca.2014.06.013			19	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AO6GU	WOS:000341449200013	25047426				2022-04-25	
J	Di Conza, G; Cafarello, ST; Loroch, S; Mennerich, D; Deschoemaeker, S; Di Matteo, M; Ehling, M; Gevaert, K; Prenen, H; Zahedi, RP; Sickmann, A; Kietzmann, T; Moretti, F; Mazzone, M				Di Conza, Giusy; Cafarello, Sarah Trusso; Loroch, Stefan; Mennerich, Daniela; Deschoemaeker, Sofie; Di Matteo, Mario; Ehling, Manuel; Gevaert, Kris; Prenen, Hans; Zahedi, Rene Peiman; Sickmann, Albert; Kietzmann, Thomas; Moretti, Fabiola; Mazzone, Massimiliano			The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1 alpha Levels and Colorectal Cancer Cell Survival under Hypoxia	CELL REPORTS			English	Article							PROLYL HYDROXYLASES; INDUCIBLE FACTOR; MAMMALIAN TARGET; AUTOPHAGY; HIF; INHIBITION; EXPRESSION; REDD1; DEGRADATION; PROTEIN	Oxygen-dependent HIF1 alpha hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1 alpha partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125(S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1 alpha. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55 alpha, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1a accumulation. These events promote autophagy- mediated cell survival in colorectal cancer (CRC) cells. B55 alpha knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55 alpha, and HIF1 alpha but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth.	[Di Conza, Giusy; Cafarello, Sarah Trusso; Deschoemaeker, Sofie; Di Matteo, Mario; Ehling, Manuel; Mazzone, Massimiliano] VIB, Ctr Canc Biol, Lab Tumor Inflammat & Angiogenesis, B-3000 Leuven, Belgium; [Di Conza, Giusy; Cafarello, Sarah Trusso; Deschoemaeker, Sofie; Di Matteo, Mario; Ehling, Manuel; Mazzone, Massimiliano] Katholieke Univ Leuven, Ctr Canc Biol, Dept Oncol, Lab Tumor Inflammat & Angiogenesis, B-3000 Leuven, Belgium; [Loroch, Stefan; Zahedi, Rene Peiman; Sickmann, Albert] ISAS eV, Leibniz Inst Analyt Wissensch, D-44227 Dortmund, Germany; [Mennerich, Daniela; Kietzmann, Thomas] Univ Oulu, Fac Biochem & Mol Med, SF-90220 Oulu, Finland; [Mennerich, Daniela; Kietzmann, Thomas] Univ Oulu, Bioctr Oulu, SF-90220 Oulu, Finland; [Gevaert, Kris] VIB, Dept Med Prot Res, B-9000 Ghent, Belgium; [Gevaert, Kris] Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium; [Prenen, Hans] Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Oncol, Digest Oncol Unit, B-3000 Leuven, Belgium; [Sickmann, Albert] Univ Aberdeen, Coll Phys Sci, Dept Chem, Aberdeen AB24 3UE, Scotland; [Sickmann, Albert] Ruhr Univ Bochum, Med Proteom Ctr, D-44801 Bochum, Germany; [Moretti, Fabiola] Natl Res Council Italy, Inst Cell Biol & Neurobiol, I-00143 Rome, Italy		Mazzone, M (corresponding author), VIB, Ctr Canc Biol, Lab Tumor Inflammat & Angiogenesis, B-3000 Leuven, Belgium.; Mazzone, M (corresponding author), Katholieke Univ Leuven, Ctr Canc Biol, Dept Oncol, Lab Tumor Inflammat & Angiogenesis, B-3000 Leuven, Belgium.	massimiliano.mazzone@vib-kuleuven.be	Deschoemaeker, Sofie/AAF-8321-2020; Moretti, Fabiola/I-5647-2013; Deschoemaeker, Sofie/AAE-1359-2022; Gevaert, Kris/D-6489-2017; Di Conza, Giusy/AAU-9661-2020; Sickmann, Albert/A-1010-2011; Zahedi, René/A-9148-2012; Gevaert, Kris/AAE-4212-2019	Deschoemaeker, Sofie/0000-0001-5449-282X; Moretti, Fabiola/0000-0002-2691-1254; Gevaert, Kris/0000-0002-4237-0283; Sickmann, Albert/0000-0002-2388-5265; Zahedi, René/0000-0002-4960-5460; Gevaert, Kris/0000-0002-4237-0283; Di Matteo, Mario/0000-0001-7811-7450; Di Conza, Giusy/0000-0003-1353-5867; Prenen, Hans/0000-0001-8802-7352; Loroch, Stefan/0000-0002-7758-0301	ERANET [G0D8115N]; FWOFWO [1505611N00]; FWO- Marie Curie fellowship [1211413N]; DFGGerman Research Foundation (DFG)European Commission [EH 472/ 1- 1]; EVDS [419.052.173]; OxyMO [308459]	supported by grants from ERANET (OxyUC, G0D8115N), FWO (1505611N00), Stichting Tegen Kanker (2010- 169), Bundesministerium fur Bildung und Forschung, and the Ministerium fur ur Innovation, Wissenschaft und Forschung des Landes Nordrhein- Westfalen. G. D. C. is supported by a Pegasus FWO-Marie Curie fellowship (1211413N), M. E. by DFG (EH 472/1-1), and S. D. by VLK (EVDS and 419.052.173). M. M. received an ERC starting grant (OxyMO, 308459).	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J	Sui, XB; Kong, N; Wang, X; Fang, Y; Hu, XT; Xu, YH; Chen, W; Wang, KF; Li, D; Jin, W; Lou, F; Zheng, Y; Hu, H; Gong, L; Zhou, XY; Pan, HM; Han, WD				Sui, Xinbing; Kong, Na; Wang, Xian; Fang, Yong; Hu, Xiaotong; Xu, Yinghua; Chen, Wei; Wang, Kaifeng; Li, Da; Jin, Wei; Lou, Fang; Zheng, Yu; Hu, Hong; Gong, Liu; Zhou, Xiaoyun; Pan, Hongming; Han, Weidong			JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy	SCIENTIFIC REPORTS			English	Article							INDUCED APOPTOSIS; THERAPEUTIC TARGET; ACTIVATION; INDUCTION; DRUG; PHOSPHORYLATION; CHEMOTHERAPY; CHLOROQUINE; PROTEIN; KINASE	Deficiency or mutation in the p53 tumor suppressor gene commonly occurs in human cancer and can contribute to disease progression and chemotherapy resistance. Currently, although the pro-survival or pro-death effect of autophagy remains a controversial issue, increasing data seem to support the idea that autophagy facilitates cancer cell resistance to chemotherapy treatment. Here we report that 5-FU treatment causes aberrant autophagosome accumulation in HCT116 p53(-/-) 2 and HT- 29 cancer cells. Specific inhibition of autophagy by 3-MA, CQ or small interfering RNA treatment targeting Atg5 or Beclin 1 can potentiate the re-sensitization of these resistant cancer cells to 5-FU. In further analysis, we show that JNK activation and phosphorylation of Bcl-2 are key determinants in 5-FU-induced autophagy. Inhibition of JNK by the compound SP600125 or JNK siRNA suppressed autophagy and phosphorylation of c-Jun and Bcl-2 but increased 5-FU-induced apoptosis in both HCT116 p53(-/-) 2 and HT29 cells. Taken together, our results suggest that JNK activation confers 5-FU resistance in HCT116 p53(-/-) 2 and HT29 cells by promoting autophagy as a pro-survival effect, likely via inducing Bcl-2 phosphorylation. These results provide a promising strategy to improve the efficacy of 5-FU-based chemotherapy for colorectal cancer patients harboring a p53 gene mutation.	[Sui, Xinbing; Kong, Na; Wang, Xian; Fang, Yong; Xu, Yinghua; Chen, Wei; Wang, Kaifeng; Li, Da; Jin, Wei; Lou, Fang; Zheng, Yu; Hu, Hong; Gong, Liu; Zhou, Xiaoyun; Pan, Hongming; Han, Weidong] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Med Oncol, Hangzhou 310003, Zhejiang, Peoples R China; [Sui, Xinbing; Kong, Na; Wang, Xian; Hu, Xiaotong; Pan, Hongming; Han, Weidong] Biomed Res Ctr, Hangzhou 310016, Zhejiang, Peoples R China; [Sui, Xinbing; Kong, Na; Wang, Xian; Hu, Xiaotong; Pan, Hongming; Han, Weidong] Key Lab Biotherapy Zhejiang Prov, Hangzhou 310016, Zhejiang, Peoples R China		Pan, HM (corresponding author), Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Med Oncol, Hangzhou 310003, Zhejiang, Peoples R China.	drpanhm@aliyun.com; weidong2011@163.com	Hu, Xiao-tong/K-5820-2019		National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81301891, 81272593, 81071651, 81071963]; Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LQ13H160008, LQ13H160009]	We thank Mian Wu for providing HCT116 p5<SUP>3+/+</SUP>, HCT116 p53<SUP>-/-</SUP> cell lines. This study is supported by grants from National Natural Science Foundation of China (grant No. 81301891, 81272593, 81071651 and 81071963) and Zhejiang Provincial Natural Science Foundation of China (grant No. LQ13H160008 and LQ13H160009).	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J	Li, H; Wang, P; Sun, QH; Ding, WX; Yin, XM; Sobol, RW; Stolz, DB; Yu, J; Zhang, L				Li, Hua; Wang, Peng; Sun, Quanhong; Ding, Wen-Xing; Yin, Xiao-Ming; Sobol, Robert W.; Stolz, Donna B.; Yu, Jian; Zhang, Lin			Following Cytochrome c Release, Autophagy Is Inhibited during Chemotherapy-Induced Apoptosis by Caspase 8-Mediated Cleavage of Beclin 1	CANCER RESEARCH			English	Article							CELL-DEATH; MEDIATED CLEAVAGE; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; BH3-ONLY PROTEIN; PUMA; MITOCHONDRIA; TUMORIGENESIS; SURVIVAL; GENE	Autophagy is an evolutionarily conserved stress response mechanism that often occurs in apoptosis-defective cancer cells and can protect against cell death. In this study, we investigated how apoptosis and autophagy affect each other in cancer cells in response to chemotherapeutic treatment. We found that specific ablation of the proapoptotic function of cytochrome c, a key regulator of mitochondria-mediated apoptosis, enhanced autophagy following chemotherapeutic treatment. Induction of autophagy required Beclin 1 and was associated with blockage of Beclin 1 cleavage by caspase 8 at two sites. To investigate the role of Beclin 1 cleavage in the suppression of autophagy and cell survival, a caspase-resistant mutant of Beclin 1 was knocked into HCT116 colon cancer cells. Beclin 1 mutant knockin resulted in markedly increased autophagy and improved long-term cell survival after chemotherapeutic treatment but without affecting apoptosis and caspase activation. Furthermore, Beclin 1 mutant tumors were significantly less responsive to chemotherapeutic treatment than were wild-type tumors. These results show that chemotherapy-induced apoptosis inhibits autophagy at the execution stage subsequent to cytochrome c release through caspase 8-mediated cleavage of Beclin 1. If apoptosis fails to execute, autophagy is unleashed due to lack of Beclin 1 cleavage by caspases and can contribute to cancer cell survival and therapeutic resistance. Therefore, Beclin 1 may be a useful target for inhibiting autophagy to sensitize chemotherapy. Cancer Res; 71(10); 3625-34. (C) 2011 AACR.	[Li, Hua; Wang, Peng; Sobol, Robert W.; Zhang, Lin] Univ Pittsburgh, Univ Pittsburgh Canc Inst, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA; [Sun, Quanhong; Ding, Wen-Xing; Yin, Xiao-Ming; Yu, Jian] Univ Pittsburgh, Univ Pittsburgh Canc Inst, Dept Pathol, Pittsburgh, PA USA; [Stolz, Donna B.] Univ Pittsburgh, Univ Pittsburgh Canc Inst, Dept Cell Biol & Physiol, Pittsburgh, PA USA; [Sobol, Robert W.] Univ Pittsburgh, Univ Pittsburgh Canc Inst, Dept Human Genet, Pittsburgh, PA USA		Zhang, L (corresponding author), Hillman Canc Ctr, UPCI Res Pavil, Room 2-42A,5117 Ctr Ave, Pittsburgh, PA 15213 USA.	zhanglx@upmc.edu	Yu, Jian/A-8301-2009; LI, HUA/I-9569-2014; Zhang, Lin/A-7389-2009; Li, Hua/C-3126-2013; Sobol, Robert W./E-4125-2013	Yu, Jian/0000-0002-4021-1000; Zhang, Lin/0000-0003-0018-3903; Sobol, Robert W./0000-0001-7385-3563	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA106348, CA121105, CA129829, U01DK085570, CA132385, GM087798, CA148629]; American Cancer SocietyAmerican Cancer Society [RSG-07-156-01-CNE, RSG-10-124-10-CCE]; American Lung Association/CHEST Foundation; UPCI Cancer Center [CA047904]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA047904, R01CA148629, R01CA129829, R01CA121105, R01CA106348, P20CA132385] 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) [U01DK085570] 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) [R44GM087798, R43GM087798] Funding Source: NIH RePORTER	This work is supported by NIH grants CA106348, CA121105, American Cancer Society grant RSG-07-156-01-CNE, and the American Lung Association/CHEST Foundation (L. Zhang), NIH grants CA129829, U01DK085570, and American Cancer Society grant RSG-10-124-10-CCE (J. Yu), NIH grants CA132385, GM087798, and CA148629 (R.W. Sobol), and the UPCI Cancer Center Support grant (CA047904).	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MAY 15	2011	71	10					3625	3634		10.1158/0008-5472.CAN-10-4475			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	764EH	WOS:000290610900020	21444671	Green Accepted, Bronze			2022-04-25	
J	Giatromanolaki, A; Koukourakis, MI; Koutsopoulos, AV; Harris, AL; Gatter, KC; Sivridis, E				Giatromanolaki, A.; Koukourakis, M. I.; Koutsopoulos, A. V.; Harris, A. L.; Gatter, K. C.; Sivridis, E.			Autophagy and hypoxia in colonic adenomas related to aggressive features	COLORECTAL DISEASE			English	Article						Autophagy; colon cancer; adenoma; hypoxia	COLORECTAL-CANCER; CARCINOMA SEQUENCE; PROGNOSTIC RELEVANCE; BECLIN 1; EXPRESSION; PATTERNS; ADENOCARCINOMAS; CARCINOGENESIS; PROGRESSION; NEOPLASIA	Aim The study investigated whether autophagic activity and hypoxia parallel the adenomacarcinoma sequence. Method The study comprised 120 tubular adenomas with high-grade dysplasia, including 22 with questionable evidence of invasion, 37 with definite stromal invasion and 29 with severely dysplastic adenoma, 10 traditional serrated adenomas and 22 classical tubular adenomas lacking aggressive features. The samples were stained immunohistochemically for autophagy (LC3A and Beclin-1) and hypoxia-inducible factor1-alpha (HIF1) markers. Results LC3A was detected as diffuse cytoplasmic staining and as dense stone-like structures (SLS) within cytoplasmic vacuoles. Beclin-1 reactivity was purely cytoplasmic, whereas that of HIF1 was both cytoplasmic and nuclear. SLS counts in noninvasive, nontransformed areas of tubular adenomas were consistently low (median SLS=0.5; 200x magnification), whereas a progressive increase was noted from areas of equivocal invasion (median SLS=1.3; 200x magnification) and intramucosal carcinoma (median SLS=1.4; 200x magnification) to unequivocal invasive foci (median SLS=2.1; 200x magnification) (P<0.0001). A similar association was shown for Beclin-1 and HIF1 expression (P<0.05). Traditional serrated adenomas yielded low SLS counts and weak HIF1 reactivity, but high cytoplasmic LC3A and Beclin-1 expression (P<0.01). Conclusion A hypoxia-driven autophagy in adenomatous polyps, when particularly intense and localized, is commonly associated with early invasion or severely dysplastic adenoma.	[Giatromanolaki, A.; Koutsopoulos, A. V.; Sivridis, E.] Democritus Univ Thrace, Sch Med, Dept Pathol, Alexandroupolis 68100, Greece; [Giatromanolaki, A.; Koukourakis, M. I.; Koutsopoulos, A. V.; Sivridis, E.] Univ Gen Hosp Alexandroupolis, Alexandroupolis 68100, Greece; [Koukourakis, M. I.] Democritus Univ Thrace, Sch Med, Dept Radiotherapy Oncol, Alexandroupolis 68100, Greece; [Harris, A. L.] Univ Oxford, Canc Res UK, Mol Oncol Labs, Weatherall Inst Mol Med, Oxford, England; [Gatter, K. C.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England		Giatromanolaki, A (corresponding author), Democritus Univ Thrace, Sch Med, POB 12, Alexandroupolis 68100, Greece.	agiatrom@med.duth.gr	Koutsopoulos, Anastasios/AAO-9498-2020; Harris, Adrian/ABA-3343-2020	Koutsopoulos, Anastasios/0000-0002-8430-7565; Harris, Adrian/0000-0003-1376-8409	Tumour and Angiogenesis Research Group; NIHR Oxford Biomedical Research CentreNational Institute for Health Research (NIHR); Cancer Research UKCancer Research UK [11359] Funding Source: researchfish; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0611-10163] Funding Source: researchfish	We thank Mrs Kyriaki Devetzi and Mrs Giannoula Kirmizi for excellent technical assistance. The study was financially supported by the Tumour and Angiogenesis Research Group and the NIHR Oxford Biomedical Research Centre.	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MAY	2013	15	5					E223	E230		10.1111/codi.12147			8	Gastroenterology & Hepatology; Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology; Surgery	137LC	WOS:000318436400003	23351172				2022-04-25	
J	Jin, HR; Zhao, J; Zhang, Z; Liao, Y; Wang, CZ; Huang, WH; Li, SP; He, TC; Yuan, CS; Du, W				Jin, H. R.; Zhao, J.; Zhang, Z.; Liao, Y.; Wang, C-Z; Huang, W-H; Li, S-P; He, T-C; Yuan, C-S; Du, W.			The antitumor natural compound falcarindiol promotes cancer cell death by inducing endoplasmic reticulum stress	CELL DEATH & DISEASE			English	Article						ER stress; falcarindiol; apoptosis; unfolded protein response; proteasome	UNFOLDED PROTEIN RESPONSE; CHEMOTHERAPY-INDUCED NAUSEA; MULTIPLE-MYELOMA; CONSTITUENTS; INHIBITION; APOPTOSIS; AUTOPHAGY; TARGET; IDENTIFICATION; GRP78/BIP	Falcarindiol (FAD) is a natural polyyne with various beneficial biological activities. We show here that FAD preferentially kills colon cancer cells but not normal colon epithelial cells. Furthermore, FAD inhibits tumor growth in a xenograft tumor model and exhibits strong synergistic killing of cancer cells with 5-fluorouracil, an approved cancer chemotherapeutic drug. We demonstrate that FAD-induced cell death is mediated by induction of endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Decreasing the level of ER stress, either by overexpressing the ER chaperone protein glucose-regulated protein 78 (GRP78) or by knockout of components of the UPR pathway, reduces FAD-induced apoptosis. In contrast, increasing the level of ER stress by knocking down GRP78 potentiates FAD-induced apoptosis. Finally, FAD-induced ER stress and apoptosis is correlated with the accumulation of ubiquitinated proteins, suggesting that FAD functions at least in part by interfering with proteasome function, leading to the accumulation of unfolded protein and induction of ER stress. Consistent with this, inhibition of protein synthesis by cycloheximide significantly decreases the accumulation of ubiquitinated proteins and blocks FAD-induced ER stress and cell death. Taken together, our study shows that FAD is a potential new anticancer agent that exerts its activity through inducing ER stress and apoptosis. Cell Death and Disease (2012) 3, e376; doi: 10.1038/cddis.2012.122; published online 23 August 2012	[Jin, H. R.; Zhao, J.; Liao, Y.; Du, W.] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA; [Zhang, Z.; Wang, C-Z; Yuan, C-S] Univ Chicago, Tang Ctr Herbal Med Res, Chicago, IL 60637 USA; [Zhang, Z.; Wang, C-Z; Yuan, C-S] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA; [Huang, W-H; Li, S-P] Univ Macau, State Key Lab Qual Res Chinese Med, Taipa, Peoples R China; [Huang, W-H; Li, S-P] Univ Macau, Inst Chinese Med Sci, Taipa, Peoples R China; [He, T-C] Univ Chicago, Dept Surg, Chicago, IL 60637 USA		Du, W (corresponding author), Univ Chicago, Ben May Dept Canc Res, 929 E 57th St, Chicago, IL 60637 USA.	wei@uchicago.edu	Liao, Yang/M-6300-2013; Wang, Chong-Zhi/B-8337-2014	Wang, Chong-Zhi/0000-0002-0950-2109; Huang, Wei-Hua/0000-0003-4167-8304; Li, SP/0000-0003-4255-6229	University of Macau [NIH/NCCAM AT004418, NIH GM074197, NIH/NCI CA149275, DOD W81XWH-10-1-0077, UL015A]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA149275] Funding Source: NIH RePORTER; NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Complementary & Alternative Medicine [P01AT004418] 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) [R01GM074197] Funding Source: NIH RePORTER	We thank Drs David Ron and Laurie Glimcher for the PERK<SUP>-/-</SUP> and XBP1<SUP>-/-</SUP> MEFs, Dr. Jianjun Chen for the RAJI, MonoMac6, and KOPN-1 cells, Dr. Jinhua Xu for the MCF10A cells, Dr. Geoffrey Greene for the MDA-MB231 and MCF7 cells. We also thank Dr. Gopal Thinakaran and Gabe Gordon for reading the manuscript. This work was supported in part by the following grants: NIH/NCCAM AT004418, NIH GM074197, NIH/NCI CA149275, DOD W81XWH-10-1-0077, and UL015A from the University of Macau.	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AUG	2012	3								e376	10.1038/cddis.2012.122			9	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	002SC	WOS:000308553800017	22914324	Green Published, gold			2022-04-25	
J	Maillet, A; Yadav, S; Loo, YL; Sachaphibulkij, K; Pervaiz, S				Maillet, A.; Yadav, S.; Loo, Y. L.; Sachaphibulkij, K.; Pervaiz, S.			A novel Osmium-based compound targets the mitochondria and triggers ROS-dependent apoptosis in colon carcinoma	CELL DEATH & DISEASE			English	Article						cancer therapy; novel compound; mitochondria; ROS	DRUG-INDUCED APOPTOSIS; CELL-DEATH; HYDROGEN-PEROXIDE; TUMOR-CELLS; CANCER-CELLS; ARENE COMPLEXES; JNK ACTIVATION; AUTOPHAGY; PATHWAY; ACIDIFICATION	Engagement of the mitochondrial-death amplification pathway is an essential component in chemotherapeutic execution of cancer cells. Therefore, identification of mitochondria-targeting agents has become an attractive avenue for novel drug discovery. Here, we report the anticancer activity of a novel Osmium-based organometallic compound (hereafter named Os) on different colorectal carcinoma cell lines. HCT116 cell line was highly sensitive to Os and displayed characteristic features of autophagy and apoptosis; however, inhibition of autophagy did not rescue cell death unlike the pan-caspase inhibitor z-VAD-fmk. Furthermore, Os significantly altered mitochondrial morphology, disrupted electron transport flux, decreased mitochondrial transmembrane potential and ATP levels, and triggered a significant increase in reactive oxygen species (ROS) production. Interestingly, the sensitivity of cell lines to Os was linked to its ability to induce mitochondrial ROS production (HCT116 and RKO) as HT29 and SW620 cell lines that failed to show an increase in ROS were resistant to the death-inducing activity of Os. Finally, intra-peritoneal injections of Os significantly inhibited tumor formation in a murine model of HCT116 carcinogenesis, and pretreatment with Os significantly enhanced tumor cell sensitivity to cisplatin and doxorubicin. These data highlight the mitochondria-targeting activity of this novel compound with potent anticancer effect in vitro and in vivo, which could have potential implications for strategic therapeutic drug design.	[Maillet, A.; Yadav, S.; Loo, Y. L.; Sachaphibulkij, K.; Pervaiz, S.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Apoptosis & Canc Biol Lab,ROS, 2 Med Dr,Bldg MD9 01-05, Singapore 117597, Singapore; [Pervaiz, S.] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117597, Singapore; [Pervaiz, S.] Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore, Singapore; [Pervaiz, S.] Singapore MIT Alliance, Singapore, Singapore		Pervaiz, S (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Apoptosis & Canc Biol Lab,ROS, 2 Med Dr,Bldg MD9 01-05, Singapore 117597, Singapore.	phssp@nus.edu.sg	Pervaiz, Shazib/C-4188-2015		National Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC); Biomedical Research Council of SingaporeAgency for Science Technology & Research (ASTAR); Experimental Therapeutics Program of the Cancer Science Institute, National University of Singapore, Singapore; National Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC); Biomedical Research Council of SingaporeAgency for Science Technology & Research (ASTAR); Experimental Therapeutics Program of the Cancer Science Institute, National University of Singapore, Singapore	S.P. is supported by grants from the National Medical Research Council and the Biomedical Research Council of Singapore, and the Experimental Therapeutics Program of the Cancer Science Institute, National University of Singapore, Singapore.	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JUN	2013	4								e653	10.1038/cddis.2013.185			10	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	173WE	WOS:000321111700004	23744353	Green Published, gold			2022-04-25	
J	Park, BS; Choi, NE; Lee, JH; Kang, HM; Yu, SB; Kim, HJ; Kang, HK; Kim, IR				Park, Bong-Soo; Choi, Nak-Eun; Lee, Ji Hye; Kang, Hae-Mi; Yu, Su-Bin; Kim, Hye-Jin; Kang, Hyun-Kyung; Kim, In-Ryoung			Crosstalk between Fisetin-induced Apoptosis and Autophagy in Human Oral Squamous Cell Carcinoma	JOURNAL OF CANCER			English	Article						fisetin; oral squamous cell carcinoma; apoptosis; autophagy	DIETARY FLAVONOID FISETIN; MALIGNANT GLIOMA-CELLS; COLON-CANCER CELLS; INHIBITION; INDUCTION; PATHWAYS; DEATH; ACTIVATION; BCL-2; MACROAUTOPHAGY	Fisetin (3,3-,4-,7-tetrahydroxyflavone), a naturally occurring flavonoid, has antioxidant, anti-inflammatory, and anticancer effects. Oral squamous cell carcinoma (OSCC) has a 5-year survival rate lower than that of most other carcinomas, and can create functional and aesthetic problems for the patient. New therapies for OSCC are necessary, and treatment using plant-derived natural substances has recently become a trend. It has been suggested that autophagy may play an important role in cancer therapy. Several studies demonstrated that autophagy inhibition enhances apoptotic cell death. Therefore, autophagy inhibition might be a promising therapeutic method against OSCC. Our results showed that fisetin induced apoptotic cell death in human tongue squamous cell line Ca9-22 could be enhanced by inhibition of autophagy. Thus, autophagy process in fisetin treated OSCC might presumed to play a role of pro-survival. The combination of fisetin and an effective autophagy inhibitor could be a potentially adjuvant and useful treatment for oral cancer.	[Park, Bong-Soo; Choi, Nak-Eun; Kang, Hae-Mi; Yu, Su-Bin; Kim, In-Ryoung] Pusan Natl Univ, Sch Dent, Dept Oral Anat, Busandaehak Ro 49, Yangsan Si 50612, Gyeongsangnam D, South Korea; [Lee, Ji Hye] Pusan Natl Univ, Sch Dent, Dept Oral Pathol, Busandaehak Ro 49, Yangsan Si 50612, Gyeongsangnam D, South Korea; [Park, Bong-Soo; Lee, Ji Hye; Kang, Hae-Mi] Pusan Natl Univ, Sch Dent, BK21 PLUS Project, Busandaehak Ro 49, Yangsan Si 50612, Gyeongsangnam D, South Korea; [Park, Bong-Soo; Lee, Ji Hye; Kim, In-Ryoung] Pusan Natl Univ, Inst Translat Dent Sci, Busandaehak Ro 49, Yangsan Si 50612, Gyeongsangnam D, South Korea; [Kim, Hye-Jin] Dong Eui Univ, Dept Dent Hyg, Gaya 1 Dong, Busan 47230, South Korea; [Kang, Hyun-Kyung] Silla Univ, Dept Dent Hyg, 140 Baekyang Daero 700 Beon Gil, Busan 46958, South Korea		Kim, IR (corresponding author), Pusan Natl Univ, Sch Dent, Dept Oral Anat, Busandaehak Ro 49, Yangsan Si 50612, Gyeongsangnam D, South Korea.	biowool@pusan.ac.kr			National Research Foundation of Korea (NRF) - Korea governmentNational Research Foundation of Korea [NRF-2017R1C1B5018034]	This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No. NRF-2017R1C1B5018034).	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Cancer		2019	10	1					138	146		10.7150/jca.28500			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	HE3PM	WOS:000453270100016	30662534	gold, Green Submitted, Green Published			2022-04-25	
J	Zhang, K; Zhou, XT; Wang, JQ; Zhou, YJ; Qi, WC; Chen, HH; Nie, SP; Xie, MY				Zhang, Ke; Zhou, Xingtao; Wang, Junqiao; Zhou, Yujia; Qi, Wucheng; Chen, Haihong; Nie, Shaoping; Xie, Mingyong			Dendrobium officinale polysaccharide triggers mitochondrial disorder to induce colon cancer cell death via ROS-AMPK-autophagy pathway	CARBOHYDRATE POLYMERS			English	Article						Dendrobium officinale polysaccharide; ROS; AMPK; Autophagy; Mitochondrial dysfunction; ATP	GROWTH	The homeostasis between mitochondrial function and autophagy is crucial to the physiological activity of cancer cells, and its mechanism is conducive to the development of anti-tumor drugs. Here, we aimed to explore the effect and mechanism of Dendrobium officinale polysaccharide (DOP) on colon cancer cell line CT26. Our data showed that DOP significantly inhibited the proliferation of CT26 cells and elevated autophagy level. Moreover, DOP disrupted mitochondrial function through increasing reactive oxygen species (ROS) and reducing mitochondrial membrane potential (MMP), thereby impairing ATP biosynthesis, which activated AMPK/mTOR autophagy signaling. Intriguingly, the further experiments demonstrated that DOP-induced cytotoxicity, excessive autophagy and mitochondrial dysfunction were reversed after CT26 cells pretreated with antioxidant (Nacetyl-L-cysteine). Herein, these findings implied that DOP-induced mitochondrial dysfunction and cytotoxic autophagy repressed the propagation of CT26 cells via ROS-ATP-AMPK signaling, providing a new opinion for the study of antineoplastic drugs.	[Zhang, Ke; Zhou, Xingtao; Wang, Junqiao; Zhou, Yujia; Qi, Wucheng; Chen, Haihong; 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		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.	zhouxingtao@ncu.edu.cn; myxie@ncu.edu.cn	周, 兴涛/F-2927-2019	周, 兴涛/0000-0002-1902-9677; Nie, Shao-Ping/0000-0002-2412-4679	Chinese Academy of Food Science and Technology-Jiangzhong Gastrointestinal Health Special Fund [201905]; National Key Research and Development Program of China [2017YFC1600405]; Jiangxi Province Science and technology plan project [20192AEI91004, 20194AFD44002]; Project of State Key Laboratory of food science and technology [SKLF-ZZA-201911]	The financial support from Chinese Academy of Food Science and TechnologyJiangzhong Gastrointestinal Health Special Fund (201905) , National Key Research and Development Program of China (2017YFC1600405) , Jiangxi Province Science and technology plan project (20192AEI91004; 20194AFD44002) and Project of State Key Laboratory of food science and technology (SKLF-ZZA-201911) were gratefully acknowledged.	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J	Honeggar, M; Beck, R; Moos, PJ				Honeggar, Matthew; Beck, Robert; Moos, Philip J.			Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity	TOXICOLOGY AND APPLIED PHARMACOLOGY			English	Article						Methylseleninic acid; Thioredoxin reductase; Selenium; Apoptosis	HUMAN PROSTATE-CANCER; PREVENTION TRIAL SELECT; SELENIUM SUPPLEMENTATION; COLORECTAL-CANCER; MAMMALIAN THIOREDOXIN; SERUM SELENIUM; VITAMIN-E; IN-VIVO; DEFICIENCY; ACID	The relationship between selenium and cancer is complex because individuals with low serum selenium levels benefit from selenium supplementation, but those with high serum selenium levels are at increased risk for other diseases. This suggests that the use of selenocompounds might be limited to particular circumstances, such as adjuvant therapy. A contributor to this dichotomy may be the activity of certain selenium containing enzymes like the cytosolic thioredoxin reductase (TR1). We evaluated the cellular response to select selenocompounds that have anticancer activity when TR1 was attenuated by siRNA in RKO colon cancer cells. Methylseleninic acid (MSA). which is a substrate for TR1, enhanced cytotoxicity to colon cancer cells when TR1 was attenuated. MSA induced stress in the endoplasmic reticulum, as measured by GRP78 protein levels. However, this pathway did not appear to account for the change in cytotoxicity when TR1 was attenuated. Instead, knockdown of the cytosolic TR plus incubation with MSA increased autophagy, as measured by LOB cleavage, and apoptosis, as measured by Annexin V and mitochondrial dysfunction. Therefore, the use of selenocompounds with anticancer activity, like MSA, might be utilized most effectively with agents that targets TR1 in chemotherapeutic applications. (C) 2009 Elsevier Inc. All rights reserved.	[Honeggar, Matthew; Beck, Robert; Moos, Philip J.] Univ Utah, Dept Pharmacol & Toxicol, LS Skaggs Pharm, Salt Lake City, UT 84112 USA		Moos, PJ (corresponding author), Univ Utah, Dept Pharmacol & Toxicol, LS Skaggs Pharm, Rm 201,30 S 2000 E, Salt Lake City, UT 84112 USA.	philip.moos@utah.edu		Moos, Philip/0000-0002-8223-442X	USPHSUnited States Department of Health & Human ServicesUnited States Public Health Service [CA115616];  [P30 CA042014]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA042014, R01CA115616] Funding Source: NIH RePORTER	This project was supported by a USPHS Grants CA115616 (PJM) We also acknowledge the use of core facilities supported by P30 CA042014 awarded to the Huntsman Cancer Institute.	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Appl. Pharmacol.	DEC 15	2009	241	3					348	355		10.1016/j.taap.2009.09.010			8	Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Toxicology	520JX	WOS:000271841400012	19782697	Green Accepted			2022-04-25	
J	Cheng, CY; Lin, YH; Su, CC				Cheng, Chun-Yuan; Lin, Yi-Hsiang; Su, Chin-Cheng			Sann-Joong-Kuey-Jian-Tang increases the protein expression of microtubule-associated protein II light chain 3 in human colon cancer colo 205 cells	MOLECULAR MEDICINE REPORTS			English	Article						Sann-Joong-Kuey-Jian-Tang; microtubule-associated protein II light chain 3; colo 205 cells; autophagy	AUTOPHAGY	Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicine, has been prescribed as complementary medication for colon cancer in Taiwan. However, its molecular mechanisms are not yet understood. In the present study. we investigated the effects of SJKJT oil human colon cancer colo 205 cells ill vitro. The cytotoxicity of SJKJT in colo 205 cells was evaluated using the MTT assay, and the protein expression of microtubule-associated protein 11 light chain 3 (MAP-LC3-II) was measured using Western blot analysis. The results showed that SJKJT inhibited the survival rates of colo 205 cells in a time- and dose-dependent manner, with all IC50 concentration at 24 h of 590.34 mu g/ml. In addition, SJKJT up-regulated the protein expression of MAP-LC3-II in colo 205 cells. These findings indicate that one of the molecular mechanisms by which SJKJT inhibits the proliferation of colo 205 cells ill vitro may be through the induction of the autophagic pathway. SJKJT may therefore have therapeutic potential for the treatment of human colon cancer.	[Su, Chin-Cheng] Buddhist Tzu Chi Gen Hosp, Div Gen Surg, Hualien 970, Taiwan; [Lin, Yi-Hsiang; Su, Chin-Cheng] Tzu Chi Univ, Inst Pharmacol & Toxicol, Hualien, Taiwan; [Cheng, Chun-Yuan] Changhua Christian Hosp, Changhua 500, Taiwan; [Cheng, Chun-Yuan] Chung Shan Med Univ, Inst Med, Taichung 40201, Taiwan		Su, CC (corresponding author), Buddhist Tzu Chi Gen Hosp, Div Gen Surg, 707 Sec 3,Chung Yang Rd, Hualien 970, Taiwan.	succ.maeva@msa.hinet.net			Research Section of Buddhist Tzu Chi General Hospital, Hualien, Taiwan [TCRD97-05]; Chen-Han Foundation for Education	This study was supported by grant no. TCRD97-05 from the Research Section of Buddhist Tzu Chi General Hospital, Hualien, Taiwan. This Study was supported in part by the Chen-Han Foundation for Education.	CLARKE PGH, 1990, ANAT EMBRYOL, V181, P195, DOI 10.1007/bf00174615; Department of Health Executive Yuan Taipei Taiwan R.O.C, 2008, STAT CAUS DEATH, P33; Eskelinen EL, 2002, TRAFFIC, V3, P878, DOI 10.1034/j.1600-0854.2002.31204.x; Eskelinen EL, 2002, MOL BIOL CELL, V13, P3355, DOI 10.1091/mbc.E02-02-0114; Hsu YL, 2006, BIOL PHARM BULL, V29, P2388, DOI 10.1248/bpb.29.2388; Jemal A, 2004, CA-CANCER J CLIN, V54, P8, DOI 10.3322/canjclin.54.1.8; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kirkegaard K, 2004, NAT REV MICROBIOL, V2, P301, DOI 10.1038/nrmicro865; Moretti L, 2007, DRUG RESIST UPDATE, V10, P135, DOI 10.1016/j.drup.2007.05.001; Rauh Rolf, 2007, Chin Med, V2, P8; Su CC, 2008, INT J MOL MED, V22, P357, DOI 10.3892/ijmm_00000030; Wei SC, 2004, J BIOMED SCI, V11, P260, DOI 10.1159/000076038; YA K, 2006, AUTOPHAGY, V2, P85; YANG CH, 1994, ADV SPACE RES-SERIES, V14, P115, DOI 10.1016/0273-1177(94)90459-6; Yang YP, 2005, ACTA PHARMACOL SIN, V26, P1421, DOI 10.1111/j.1745-7254.2005.00235.x	15	6	6	0	4	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1791-2997	1791-3004		MOL MED REP	Mol. Med. Rep.	SEP-OCT	2009	2	5					707	711		10.3892/mmr_00000160			5	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	481TU	WOS:000268835600004	21475889	Bronze			2022-04-25	
J	Delou, JMA; Biasoli, D; Borges, HL				Delou, Joao M. A.; Biasoli, Deborah; Borges, Helena L.			The Complex Link between Apoptosis and Autophagy: a Promising New Role for RB	ANAIS DA ACADEMIA BRASILEIRA DE CIENCIAS			English	Article						retinoblastoma; neoplasm; autophagy; cell death; antineoplastic agents	PROGRAMMED CELL-DEATH; BCL-2 FAMILY PROTEINS; RETINOBLASTOMA PROTEIN; HEPATOCELLULAR-CARCINOMA; BREAST-CANCER; COLON-CANCER; INDUCED CYTOTOXICITY; TARGETING AUTOPHAGY; MOLECULAR MACHINERY; METABOLIC STRESS	Physiological processes, as autophagy, proliferation and apoptosis are affected during carcinogenesis. Restoring cellular sensitivity to apoptotic stimuli, such as the antineoplastic cocktails, has been explored as a strategy to eliminate cancer cells. Autophagy, a physiological process of recycling organelles and macromolecules can be deviated from homeostasis to support cancer cells survival, proliferation, escape from apoptosis, and therapy resistance. The relationship between autophagy and apoptosis is complex and many stimuli can induce both processes. Most chemotherapeutic agents induce autophagy and it is not clear whether and how this chemotherapy-induced autophagy might contribute to resistance to apoptosis. Here, we review current strategies to sensitize cancer cells by interfering with autophagy. Moreover, we discuss a new link between autophagy and apoptosis: the tumor suppressor retinoblastoma protein (RB). Inactivation of RB is one of the earliest and more frequent hallmarks of cancer transformation, known to control cell cycle progression and apoptosis. Therefore, understanding RB functions in controlling cell fate is essential for an effective translation of RB status in cancer samples to the clinical outcome.	[Delou, Joao M. A.; Biasoli, Deborah; Borges, Helena L.] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Av Carlos Chagas Filho 373, BR-21949590 Rio De Janeiro, RJ, Brazil		Borges, HL (corresponding author), Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Av Carlos Chagas Filho 373, BR-21949590 Rio De Janeiro, RJ, Brazil.	hborges@icb.ufrj.br	Borges, Helena/W-7533-2019; Borges, Helena L/E-5044-2013; Borges, Helena/AAG-3701-2020; Delou, João Marcos/N-8760-2014	Borges, Helena/0000-0003-2866-4223; Borges, Helena L/0000-0003-2866-4223; Delou, João Marcos/0000-0003-1141-5351	Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), BrazilCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), BrazilFundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio De Janeiro (FAPERJ); Fundacao do Cancer do Rio de Janeiro, Brazil	Deborah Biasoli, Joao M.A. Delou and Helena L. Borges are are supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), the Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), and by the Fundacao do Cancer do Rio de Janeiro, Brazil. We thank Dr. Rossana Colla Soletti for constructive comments of the manuscript.	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Acad. Bras. Cienc.	OCT-DEC	2016	88	4					2257	2275		10.1590/0001-3765201620160127			19	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	EH2FA	WOS:000391581800019	27991962	gold, Green Submitted, Green Published			2022-04-25	
J	D'Onofrio, N; Cacciola, NA; Martino, E; Borrelli, F; Fiorino, F; Lombardi, A; Neglia, G; Balestrieri, ML; Campanile, G				D'Onofrio, Nunzia; Cacciola, Nunzio Antonio; Martino, Elisa; Borrelli, Francesca; Fiorino, Ferdinando; Lombardi, Assunta; Neglia, Gianluca; Balestrieri, Maria Luisa; Campanile, Giuseppe			ROS-Mediated Apoptotic Cell Death of Human Colon Cancer LoVo Cells by Milk delta-Valerobetaine	SCIENTIFIC REPORTS			English	Article							COLORECTAL-CANCER; SIRT6; AUTOPHAGY; CONSUMPTION; PREVENTION; PATHWAYS; BUFFALO; TARGET; RISK	delta -Valerobetaine (delta VB) is a constitutive milk metabolite with antioxidant and anti-inflammatory activities. Here, we tested the antineoplastic properties of milk delta VB on human colorectal cancer cells. CCD 841 CoN (non-tumorigenic), HT-29 (p53 mutant adenocarcinoma) and LoVo (APC/RAS mutant adenocarcinoma) cells were exposed to 3kDa milk extract, delta VB (2mM) or milk+delta VB up to 72h. Results showed a time- and dose-dependent capability of delta VB to inhibit cancer cell viability, with higher potency in LoVo cells. Treatment with milk+delta VB arrested cell cycle in G2/M and SubG1 phases by upregulating p21, cyclin A, cyclin B1 and p53 protein expressions. Noteworthy, delta VB also increased necrosis (P<0.01) and when used in combination with milk it improved its activity on live cell reduction (P<0.05) and necrosis (P<0.05). <delta>VB-enriched milk activated caspase 3, caspase 9, Bax/Bcl-2 apoptotic pathway and reactive oxygen species (ROS) production, whereas no effects on ROS generation were observed in CCD 841 CoN cells. The altered redox homeostasis induced by milk+delta VB was accompanied by upregulation of sirtuin 6 (SIRT6). SIRT6 silencing by small interfering RNA blocked autophagy and apoptosis activated by milk+delta VB, unveiling the role of this sirtuin in the ROS-mediated apoptotic LoVo cell death.	[D'Onofrio, Nunzia; Martino, Elisa; Balestrieri, Maria Luisa] Univ Campania L Vanvitelli, Dept Precis Med, I-80138 Naples, Italy; [Cacciola, Nunzio Antonio; Neglia, Gianluca; Campanile, Giuseppe] Univ Naples Federico II, Dept Vet Med & Anim Prod, I-80137 Naples, Italy; [Cacciola, Nunzio Antonio] Natl Res Council CNR, Inst Sustainable Plant Protect IPSP, I-80055 Naples, Italy; [Borrelli, Francesca; Fiorino, Ferdinando] Univ Naples Federico II, Sch Med & Surg, Dept Pharm, I-80131 Naples, Italy; [Lombardi, Assunta] Univ Naples Federico II, Dept Biol, I-80126 Naples, Italy		Balestrieri, ML (corresponding author), Univ Campania L Vanvitelli, Dept Precis Med, I-80138 Naples, Italy.	marialuisa.balestrieri@unicampania.it	Borrelli, Francesca/AAC-6715-2022; D'Onofrio, Nunzia/M-2081-2019	D'Onofrio, Nunzia/0000-0002-5300-9530; Martino, Elisa/0000-0003-4070-2894; Balestrieri, Maria Luisa/0000-0001-6001-1789	VALERE 2019 Program University of Campania L. Vanvitelli, PSR Regione Campania 2014/2020 - STRABUF [B68H19005200009]; VALERE 2019 Program University of Campania L. Vanvitelli, PON I&C 2014-2020 - TABAREZO [F/200085/01-03/X45]; VALERE 2019 Program University of Campania L. Vanvitelli, PON I&C 2014-2020 - CAPSULE [F/200016/01-03/X45]	This work was supported by VALERE 2019 Program University of Campania L. Vanvitelli, PSR Regione Campania 2014/2020 - STRABUF -B68H19005200009, PON I&C 2014-2020 - TABAREZO - F/200085/01-03/X45, and PON I&C 2014-2020 - CAPSULE - F/200016/01-03/X45.	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J	Fyrst, H; Oskouian, B; Bandhuvula, P; Gong, YQ; Byun, HS; Bittman, R; Lee, AR; Saba, JD				Fyrst, Henrik; Oskouian, Babak; Bandhuvula, Padmavathi; Gong, Yaqiong; Byun, Hoe Sup; Bittman, Robert; Lee, Andrew R.; Saba, Julie D.			Natural Sphingadienes Inhibit Akt-Dependent Signaling and Prevent Intestinal Tumorigenesis	CANCER RESEARCH			English	Article							CANCER-CELL-LINES; DIETARY SPHINGOLIPIDS; COLON-CANCER; CF1 MICE; IN-VIVO; SPHINGOSINE; PROTEIN; SPHINGOSINE-1-PHOSPHATE; PATHWAY; SPHINGOMYELIN	Sphingolipid metabolites regulate cell proliferation, migration, and stress responses. Alterations in sphingolipid metabolism have been proposed to contribute to carcinogenesis, cancer progression, and drug resistance. We identified a family of natural sphingolipids called sphingadienes and investigated their effects in colon cancer. We find that sphingadienes induce colon cancer cell death in vitro and prevent intestinal tumorigenesis in vivo. Sphingadienes exert their influence by blocking Akt translocation from the cytosol to the membrane, thereby inhibiting protein translation and promoting apoptosis and autophagy. Sphingadienes are orally available, are slowly metabolized through the sphingolipid degradative pathway, and show limited short-term toxicity. Thus, sphingadienes represent a new class of therapeutic and/or chemopreventive agents that blocks Akt signaling in neoplastic and preneoplastic cells. [Cancer Res 2009;69(24):9457-64]	[Fyrst, Henrik; Oskouian, Babak; Bandhuvula, Padmavathi; Lee, Andrew R.; Saba, Julie D.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA; [Gong, Yaqiong; Byun, Hoe Sup; Bittman, Robert] CUNY, Queens Coll, Flushing, NY USA		Saba, JD (corresponding author), Childrens Hosp Oakland, Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA.	jsaba@chori.org		Lee, Andrew/0000-0003-1496-9253	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RAT005336A, CA129438, CA77528, GM66954, HL-083187]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA077528, R01CA129438] Funding Source: NIH RePORTER; NATIONAL CENTER FOR COMPLEMENTARY &ALTERNATIVE MEDICINEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Complementary & Alternative Medicine [R21AT005336] 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) [R24HL083187] 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) [R01GM066954] Funding Source: NIH RePORTER	Grant support: NIH grants RAT005336A, CA129438, CA77528 and GM66954 (J.D. Saba), and HL-083187 (R. Bittman).	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DEC 15	2009	69	24					9457	9464		10.1158/0008-5472.CAN-09-2341			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	534TP	WOS:000272920500038	19934323	Green Accepted			2022-04-25	
J	Kutuk, O; Aytan, N; Karakas, B; Kurt, AG; Acikbas, U; Temel, SG; Basaga, H				Kutuk, Ozgur; Aytan, Nurgul; Karakas, Bahriye; Kurt, Asli Giray; Acikbas, Ufuk; Temel, Sehime Gulsun; Basaga, Huveyda			Biphasic ROS production, p53 and BIK dictate the mode of cell death in response to DNA damage in colon cancer cells	PLOS ONE			English	Article							LYSOSOMAL MEMBRANE PERMEABILIZATION; BH3-ONLY PROTEIN BIK; BCL-X-L; ENDOPLASMIC-RETICULUM; MEDIATED APOPTOSIS; OXIDATIVE STRESS; FAMILY PROTEINS; INDUCTION; MITOCHONDRIA; ACTIVATION	Necrosis, apoptosis and autophagic cell death are the main cell death pathways in multicellular organisms, all with distinct and overlapping cellular and biochemical features. DNA damage may trigger different types of cell death in cancer cells but the molecular events governing the mode of cell death remain elusive. Here we showed that increased BH3-only protein BIK levels promoted cisplatin-and UV-induced mitochondrial apoptosis and biphasic ROS production in HCT-116 wild-type cells. Nonetheless, early single peak of ROS formation along with lysosomal membrane permeabilization and cathepsin activation regulated cisplatin-and UV-induced necrosis in p53-null HCT-116 cells. Of note, necrotic cell death in p53-null HCT-116 cells did not depend on BIK, mitochondrial outer membrane permeabilization or caspase activation. These data demonstrate how cancer cells with different p53 background respond to DNA-damaging agents by integrating distinct cell signaling pathways dictating the mode of cell death.	[Kutuk, Ozgur; Kurt, Asli Giray; Acikbas, Ufuk] Baskent Univ, Adana Dr Turgut Noyan Med & Res Ctr, Dept Med Genet, Sch Med, Adana, Turkey; [Aytan, Nurgul] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA; [Karakas, Bahriye; Basaga, Huveyda] Sabanci Univ, Genet & Bioengn Program, Mol Biol, Istanbul, Turkey; [Temel, Sehime Gulsun] Uludag Univ, Dept Histol & Embryol, Sch Med, Bursa, Turkey; [Temel, Sehime Gulsun] Near East Univ, Sch Med, Dept Histol & Embryol, Nicosia, Northern Cyprus, Turkey		Kutuk, O (corresponding author), Baskent Univ, Adana Dr Turgut Noyan Med & Res Ctr, Dept Med Genet, Sch Med, Adana, Turkey.	ozgurkutuk@sabanciuniv.edu	KUTUK, OZGUR/AAH-1671-2019; Temel, Sehime/AAG-8385-2021	KUTUK, OZGUR/0000-0001-9854-7220; 	TUBITAK, Baskent University Research Fund [SBAG-113S481]; Science Academy	This work was supported by grants from TUBITAK (SBAG-113S481), Baskent University Research Fund and The Science Academy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported by grants from TUBITAK (SBAG-113S481), Baskent University Research Fund and The Science Academy.	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J	Vense, R; Tosetti, F; Minghelli, S; Poggi, A; Ferrari, N; Benelli, R				Vense, Roberta; Tosetti, Francesca; Minghelli, Simona; Poggi, Alessandro; Ferrari, Nicoletta; Benelli, Roberto			Celecoxib increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation	ONCOTARGET			English	Article						EGFR; celecoxib; colon; fibroblast	EPIDERMAL-GROWTH-FACTOR; CANCER-ASSOCIATED FIBROBLASTS; FACTOR RECEPTOR EGFR; GENE COPY NUMBER; COLORECTAL-CANCER; SUBEPITHELIAL MYOFIBROBLASTS; ENDOCYTIC TRAFFICKING; ADENOMATOUS POLYPS; ASPARTIC PROTEASE; EPITHELIAL-CELLS	We previously demonstrated that non-toxic doses of Celecoxib induced the immediate phosphorylation of Erk1-2 in colon tumor associated fibroblasts (TAFs), increasing their responsiveness to epidermal growth factor (EGF). We have now identified two concomitant mechanisms explaining the EGF-Celecoxib cooperation. We found that a 24-48h Celecoxib priming increased EGF receptor (EGFR) mRNA and protein levels in colon TAFs, promoting EGF binding and internalization. Celecoxib-primed TAFs showed a reduced EGFR degradation after EGF challenge. This delay corresponded to a deferred dissociation of EEA1 from EGFR positive endosomes and the accumulation of Rab7, pro Cathepsin-D and SQSTM1/p62, suggesting a shared bottleneck in the pathways of late-endosomes/autophagosomes maturation. Celecoxib modulated the levels of target proteins similarly to the inhibitors of endosome/lysosome acidification Bafilomycin-A1 and NH4Cl. Cytoplasmic vesicles fractionation showed a reduced maturation of Cathepsin-D in late endosomes and an increased content of EGFR and Rab7 in lysosomes of Celecoxib-treated TAFs. Our data indicate a double mechanism mediating the increased response to EGF of colon TAFs treated with Celecoxib. While EGFR overexpression could be targeted using anti EGFR drugs, the effects on endosome trafficking and protein turnover represents a more elusive target and should be taken into account for any long-term therapy with Celecoxib.	[Vense, Roberta; Minghelli, Simona; Benelli, Roberto] IRCCS AOU San Martino IST, Immunol Lab, Genoa, Italy; [Vense, Roberta; Tosetti, Francesca; Minghelli, Simona; Poggi, Alessandro; Ferrari, Nicoletta] IRCCS AOU San Martino IST, Mol Oncol & Angiogenesis Lab, Genoa, Italy		Benelli, R (corresponding author), IRCCS AOU San Martino IST, Immunol Lab, Genoa, Italy.	roberto.benelli@hsanmartino.it	Ferrari, Nicoletta/AAG-6049-2019; Poggi, Alessandro/K-6664-2016; Benelli, Roberto/AAF-3143-2019; Tosetti, Francesca/AAE-5569-2021	Ferrari, Nicoletta/0000-0002-6027-1035; Poggi, Alessandro/0000-0002-1860-430X; Benelli, Roberto/0000-0002-9769-0954; Tosetti, Francesca/0000-0001-8772-4834	Compagnia di San Paolo, Ministero fondo 5 per mille Enti della Ricerca Sanitaria, Associazione Italiana per la Ricerca sul CancroFondazione AIRC per la ricerca sul cancro	This study was supported by grants from the Compagnia di San Paolo, Ministero fondo 5 per mille Enti della Ricerca Sanitaria, Associazione Italiana per la Ricerca sul Cancro.	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J	Wu, F; Liu, F; Dong, LM; Yang, H; He, XX; Li, LL; Zhao, LH; Jin, SS; Li, G				Wu, Fang; Liu, Fang; Dong, Lemei; Yang, Han; He, Xixi; Li, Lili; Zhao, Lihao; Jin, Sisi; Li, Gang			miR-1273g silences MAGEA3/6 to inhibit human colorectal cancer cell growth via activation of AMPK signaling	CANCER LETTERS			English	Article						Molecularly-targeted therapy; microRNA; Melanoma antigen A3/A6; AMP-activated protein kinase	INDUCED APOPTOSIS; PHOSPHORYLATION; AUTOPHAGY; PATHWAY; HYPOMETHYLATION; EXPRESSION; MICRORNAS; COMPLEXES; FAMILY	AMP-activated protein kinase (AMPK) is a metabolic regulator that acts to limit the growth of cancer cells. AMPK is downregulated by melanoma antigens A3/6 (MAGEA3/6), which are cancer-specific proteins that enhance the activity of specific E3 ubiquitin ligases to ubiquitinate and degrade AMP-activated protein kinase alpha 1 (AMPK alpha 1). Here, using a bioinformatic approach, we identified a microRNA, miR-1273g-3p, that is predicted to target the 3' untranslated region (UTR) of MAGEA3/6. Analyzing miR-1273g-3p expression in human colon cancer tissues, we found a reduction in miR-1273g-3p expression correlating with increased MAGEA3/6 expression and AMPK alpha 1 downregulation. Expression of miR-1273g in HT-29 cells and primary human colon cancer cells down regulated MAGEA3/6, leading to AMPK alpha 1 upregulation, inhibition of proliferation and cell apoptosis. The anti CRC activity of miR-1273g was blocked by AMPK alpha 1 knockout. MAGEA3/6 shRNA silencing mimicked and abolished miR-1273g-induced actions in HT-29 cells. In vivo, miR-1273g-or MAGEA3/6 shRNA-expressing HT-29 tumors grew significantly slower than control tumors. We propose a novel miRNA-based mechanism, whereby miR-1273g represses MAGEA3/6 expression in human CRC cells and tissues, which may provide a novel cancer-specific therapeutic.	[Wu, Fang; Dong, Lemei; He, Xixi; Jin, Sisi] Wenzhou Med Univ, Dept Gastroenterol, Affiliated Hosp 1, Wenzhou, Peoples R China; [Liu, Fang] Nanjing Med Univ, Dept Neurosurg, Affiliated Changzhou Peoples Hosp 2, Changzhou, Peoples R China; [Yang, Han; Li, Lili; Zhao, Lihao; Li, Gang] Wenzhou Med Univ, Dept Chemoradiat Oncol, Affiliated Hosp 1, South Bai Xiang St, Wenzhou 325000, Zhejiang, Peoples R China		Li, G (corresponding author), Wenzhou Med Univ, Dept Chemoradiat Oncol, Affiliated Hosp 1, South Bai Xiang St, Wenzhou 325000, Zhejiang, Peoples R China.	ligangwzyd@163.com			Natural Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province [LY15H030015]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81302181]	This project was supported by the Natural Science Foundation of Zhejiang Province (LY15H030015), and by National Natural Science Foundation of China (81302181). 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	Song, J; Seo, H; Kim, MR; Lee, SJ; Ahn, S; Song, M				Song, Jisu; Seo, Heejung; Kim, Mi-Ryung; Lee, Sang-Jae; Ahn, Sooncheol; Song, Minjung			Active Compound of Pharbitis Semen (Pharbitis nil Seeds) Suppressed KRAS-Driven Colorectal Cancer and Restored Muscle Cell Function during Cancer Progression	MOLECULES			English	Article						Pharbitis nil; colorectal cancer; KRAS; muscle function	COLON-CANCER; APOPTOSIS; PROLIFERATION; CETUXIMAB; PATHWAY; RESISTANCE; GLYCOSIDES; AUTOPHAGY; THERAPY; INHIBIT	Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven colorectal cancer (CRC) is notorious to target with drugs and has shown ineffective treatment response. The seeds ofPharbitis nil,also known as morning glory, have been used as traditional medicine in East Asia. We focused on whetherPharbitis nilseeds have a suppressive effect on mutated KRAS-driven CRC as well as reserving muscle cell functions during CRC progression. Seeds ofPharbitis nil(Pharbitissemen) were separated by chromatography and the active compound ofPharbitissemen (PN) was purified by HPLC. The compound PN efficiently suppressed the proliferation of mutated KRAS-driven CRC cells and their clonogenic potentials in a concentration-dependent manner. It also induced apoptosis of SW480 human colon cancer cells and cell cycle arrest at the G2/M phase. The CRC related pathways, including RAS/ERK and AKT/mTOR, were assessed and PN reduced the phosphorylation of AKT and mTOR. Furthermore, PN preserved muscle cell proliferation and myotube formation in cancer conditioned media. In summary, PN significantly suppressed mutated KRAS-driven cell growth and reserved muscle cell function. Based on the current study, PN could be considered as a promising starting point for the development of a nature-derived drug against KRAS-mutated CRC progression.	[Song, Jisu; Seo, Heejung; Kim, Mi-Ryung; Lee, Sang-Jae; Song, Minjung] Silla Univ, Sch Med & Life Sci, Dept Food Biotechnol, Busan 46958, South Korea; [Song, Jisu; Ahn, Sooncheol] Pusan Natl Univ, Sch Med, Dept Med Sci, Yangsan 50612, South Korea; [Seo, Heejung] Pusan Natl Univ, Dept Cognomechatron Engn, Coll Nanosci & Nanotechnol, Busan 46241, South Korea; [Song, Minjung] Univ Cambridge, WT MRC Inst Metab Sci, Cambridge CB2 0QQ, England		Song, M (corresponding author), Silla Univ, Sch Med & Life Sci, Dept Food Biotechnol, Busan 46958, South Korea.; Ahn, S (corresponding author), Pusan Natl Univ, Sch Med, Dept Med Sci, Yangsan 50612, South Korea.; Song, M (corresponding author), Univ Cambridge, WT MRC Inst Metab Sci, Cambridge CB2 0QQ, England.	jisu632@naver.com; ssk4623@naver.com; haha7kmr@silla.ac.kr; sans76@silla.ac.kr; ahnsc@pusan.ac.kr; ms2700@medschl.cam.ac.uk			Brain Korea 21Ministry of Education & Human Resources Development (MOEHRD), Republic of Korea [NRF-2016R1A1A1A05921948]; Basic Research of the NRF [NRF-2020R1F1A1076624]	This research was funded by Brain Korea 21 (NRF-2016R1A1A1A05921948) and by Basic Research of the NRF (NRF-2020R1F1A1076624). The APC was funded by NRF-2020R1F1A1076624.	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J	Chang, C; Liu, J				Chang, C.; Liu, Juan			Matrine Treatment Triggers Apoptosis in Colon Cancer Cells	INDIAN JOURNAL OF PHARMACEUTICAL SCIENCES			English	Article						Matrine; colon cancer Caco-2 cells; antiproliferative	EXPRESSION; PROLIFERATION; BCL-2; CHEMOTHERAPY; INHIBITION; AUTOPHAGY; CASPASE-3; PROMOTES; INVASION; EXTRACT	The aim of the present study was to investigate the role of matrine, a natural alkaloid from Sophora.flavescens with antiproliferative and proapoptotic activities, in human colon cancer using in vitro studies. Caco-2 cell line was treated with increasing doses (2.0 and 32 mg/ml) of matrine for 24 h. The MTT assay was used to measure abnormal cell multiplication, while flow cytometry was applied to determine the degree of apoptosis and cell growth. Western blot analysis was also used to detect the expression of various proteins. The results indicated that matrine blocked Caco-2 cell division in a dose -dependent and time-dependent manner. Matrine triggered apoptosis and blocked mitosis by altering the protein expression levels of B-cell lymphoma-2, B-cell lymphoma-2 -associated X protein, cytochrome c, caspase-9 and caspase-3. In conclusion, matrine is found to interfere with the proliferation of colon cancer cells in vitro by triggering apoptosis through enhancing the expression of X protein, caspase-3 and caspase-9, as well as suppressing B-cell lymphoma-2 expression. Therefore, matrine is a potential natural compound that could be used in colon cancer treatment..	[Chang, C.] Hubei Polytech Univ, Dept Gastroenterol, Huangshi Cent Hosp, Affiliated Hosp, Huangshi, Hubei, Peoples R China; [Liu, Juan] Hubei Polytech Univ, Dept Publ Hlth, Huangshi Cent Hosp, Affiliated Hosp, Huangshi, Hubei, Peoples R China		Liu, J (corresponding author), Hubei Polytech Univ, Dept Publ Hlth, Huangshi Cent Hosp, Affiliated Hosp, Huangshi, Hubei, Peoples R China.	hubeitcm@sina.com			Hubei Provincial Natural Scientific Foundation of China [2013CFC061]	the present study was supported by the Hubei Provincial Natural Scientific Foundation of China (NO. 2013CFC061).	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Pharm. Sci.		2020	82				3		59	65		10.36468/pharmaceutical-sciences.sp1.61			7	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	NK8IA	WOS:000566973300012					2022-04-25	
J	Kim, DH; Sung, B; Kang, YJ; Hwang, SY; Kim, MJ; Yoon, JH; Im, E; Kim, ND				Kim, Dong Hwan; Sung, Bokyung; Kang, Yong Jung; Hwang, Seong Yeon; Kim, Min Jeong; Yoon, Jeong-Hyun; Im, Eunok; Kim, Nam Deuk			Sulforaphane inhibits hypoxia-induced HIF-1 alpha and VEGF expression and migration of human colon cancer cells	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						sulforaphane; colon cancer cells; HIF-1; vascular endothelial growth factor	INDUCIBLE FACTOR-1; CYCLE ARREST; INDUCED ANGIOGENESIS; OXIDATIVE STRESS; APOPTOSIS; CHEMOPREVENTION; METASTASIS; PROTEASOME; AUTOPHAGY; ALPHA	The effects of sulforaphane (a natural product commonly found in broccoli) was investigated on hypoxia inducible factor-1 alpha (HIF-1 alpha) expression in HCT116 human colon cancer cells and AGS human gastric cancer cells. We found that hypoxia-induced HIF-1 alpha protein expression in HCT116 and AGS cells, while treatment with sulforaphane markedly and concentration-dependently inhibited HIF-1 alpha expression in both cell lines. Treatment with sulforaphane inhibited hypoxia-induced vascular endothelial growth factor (VEGF) expression in HCT116 cells. Treatment with sulforaphane modulated the effect of hypoxia on HIF-1 alpha stability. However, degradation of HIF-1 alpha by sulforaphane was not mediated through the 26S proteasome pathway. We also found that the inhibition of HIF-1 alpha by sulforaphane was not mediated through AKT and extracellular signal-regulated kinase phosphorylation under hypoxic conditions. Finally, hypoxiainduced HCT116 cell migration was inhibited by sulforaphane. These data suggest that sulforaphane may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting HIF-1 alpha and VEGF expression. Taken together, these results indicate that sulforaphane is a new and potent chemopreventive drug candidate for treating patients with human colon cancer.	[Kim, Dong Hwan; Sung, Bokyung; Kang, Yong Jung; Hwang, Seong Yeon; Kim, Min Jeong; Yoon, Jeong-Hyun; Im, Eunok; Kim, Nam Deuk] Pusan Natl Univ, Mol Inflammat Res Ctr Aging Intervent, Dept Pharm, Busan 46241, South Korea		Im, E (corresponding author), Pusan Natl Univ, Coll Pharm, Dept Pharm, Busandaehag Ro 63 Beon Gil 2, Busan 46241, South Korea.	eoim@pusan.ac.kr; nadkim@pusan.ac.kr	Sung, Bokyung/AAX-5697-2021		Post-doc Development Program of Pusan National University	This study was financially supported by the 2015 Post-doc Development Program of Pusan National University.	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J. Oncol.	DEC	2015	47	6					2226	2232		10.3892/ijo.2015.3200			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CX1OM	WOS:000365465500026	26498863	Bronze			2022-04-25	
J	Deroyer, C; Renert, AF; Merville, MP; Fillet, M				Deroyer, Celine; Renert, Anne-Francoise; Merville, Marie-Paule; Fillet, Marianne			New role for EMD (emerin), a key inner nuclear membrane protein, as an enhancer of autophagosome formation in the C16-ceramide autophagy pathway	AUTOPHAGY			English	Article						autophagy; ceramide; colon cancer cells; EMD; LEM-domain; phosphorylation; PRKACA	DREIFUSS MUSCULAR-DYSTROPHY; TO-AUTOINTEGRATION FACTOR; PROGRAMMED CELL-DEATH; TYROSINE-PHOSPHORYLATION; CANCER-CELLS; TRANSCRIPTIONAL REPRESSOR; PHOSPHOPROTEOME ANALYSIS; IN-VITRO; CERAMIDE; BARRIER	To date, precise roles of EMD (emerin) remain poorly described. In this paper, we investigated the role of EMD in the C16-ceramide autophagy pathway. Ceramides are bioactive signaling molecules acting notably in the regulation of cell growth, differentiation, or cell death. However, the mechanisms by which they mediate these pathways are not fully understood. We found that C16-ceramide induces EMD phosphorylation on its LEM domain through PRKACA. Upon ceramide treatment, phosphorylated EMD binds MAP1LC3B leading to an increase of autophagosome formation. These data suggest a new role of EMD as an enhancer of autophagosome formation in the C16-ceramide autophagy pathway in colon cancer cells.	[Deroyer, Celine; Renert, Anne-Francoise; Fillet, Marianne] Univ Liege, GIGA R Prote Unit, Liege, Belgium; [Merville, Marie-Paule] Ctr Hosp Univ Liege, Dept Clin Chem, Liege, Belgium; [Fillet, Marianne] Univ Liege, Ctr Interfacultaire Rech Medicament, Dept Pharm, Dept Analyt Pharmaceut Chem, Liege, Belgium		Fillet, M (corresponding author), Univ Liege, GIGA R Prote Unit, Liege, Belgium.	marianne.fillet@ulg.ac.be		Fillet, Marianne/0000-0002-1453-6282	ARCAustralian Research Council; University of LiegeUniversity of Liege	MP Merville is a senior research associate at the National Fund for Scientific Research (FR-FNRS), Belgium. This work was financially supported by ARC fund and Leon Fredericq grant from University of Liege. We thank the "Imaging Platform" (S Ormenese and G Moraes, GIGA, University of Liege) for the confocal imaging and the "Viral vector platform" (E Divalentin, GIGA, University of Liege) for stable cell lines generation.	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J	Kuranaga, Y; Sugito, N; Shinohara, H; Tsujino, T; Taniguchi, K; Komura, K; Ito, Y; Soga, T; Akao, Y				Kuranaga, Yuki; Sugito, Nobuhiko; Shinohara, Haruka; Tsujino, Takuya; Taniguchi, Kohei; Komura, Kazumasa; Ito, Yuko; Soga, Tomoyoshi; Akao, Yukihiro			SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						energy metabolism; alternative splicing; oncogenes	PYRUVATE-KINASE; COLORECTAL-CANCER; HNRNP PROTEINS; MESSENGER-RNA; EXPRESSION; TUMOR; PROLIFERATION; TRANSLATION; REPRESSES; ISOFORM	Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism.	[Kuranaga, Yuki; Sugito, Nobuhiko; Shinohara, Haruka; Akao, Yukihiro] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, 1-1 Yanagito, Gifu, Gifu 5011193, Japan; [Tsujino, Takuya; Komura, Kazumasa] Osaka Med Coll, Dept Urol, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan; [Taniguchi, Kohei] Osaka Med Coll, Dept Gen & Gastroenterol Surg, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan; [Taniguchi, Kohei; Komura, Kazumasa] Osaka Med Coll, Translat Res Program, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan; [Ito, Yuko] Osaka Med Coll, Dept Anat & Cell Biol, Div Life Sci, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan; [Soga, Tomoyoshi] Keio Univ, Inst Adv Biosci, 246-2 Mizukami, Tsuruoka, Yamagata 9970017, Japan		Akao, Y (corresponding author), Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, 1-1 Yanagito, Gifu, Gifu 5011193, Japan.	v3501001@edu.gifu-u.ac.jp; v3501002@edu.gifu-u.ac.jp; harukashinohara313@gmail.com; uro061@osaka-med.ac.jp; sur144@osaka-med.ac.jp; uro051@osaka-med.ac.jp; an1006@osaka-med.ac.jp; soga@sfc.keio.ac.jp; yakao@gifu-u.ac.jp		Kuranaga, Yuki/0000-0001-7418-6520; Taniguchi, Kohei/0000-0003-0648-1370	Japan Agency for Medical Research and Development (AMED)Japan Agency for Medical Research and Development (AMED) [16cm0106202h0001]; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [17J02701]	This work was supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and Development (AMED) (16cm0106202h0001 to Y.A.) and a grant-in-aid for a research fellow from the Japan Society for the Promotion of Science (17J02701 to Y.K.)	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J. Mol. Sci.	OCT	2018	19	10							3012	10.3390/ijms19103012			16	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	GY9HB	WOS:000448951000167	30279379	Green Published, gold, Green Submitted			2022-04-25	
J	Shimodaira, Y; Takahashi, S; Kinouchi, Y; Endo, K; Shiga, H; Kakuta, Y; Kuroha, M; Shimosegawa, T				Shimodaira, Yosuke; Takahashi, Seiichi; Kinouchi, Yoshitaka; Endo, Katsuya; Shiga, Hisashi; Kakuta, Yoichi; Kuroha, Masatake; Shimosegawa, Tooru			Modulation of endoplasmic reticulum (ER) stress-induced autophagy by C/EBP homologous protein (CHOP) and inositol-requiring enzyme 1 alpha (IRE1 alpha) in human colon cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						ER stress; Autophagy; IRE1 alpha; CHOP	XBP1 MESSENGER-RNA; DISEASE; SUSCEPTIBILITY; SURVIVAL; TRIGGERS; ATG16L1; ATF6; IRE1; LC3	To explore the relationship between UPR and autophagy in intestinal epithelial cells, we investigated whether autophagy was induced by endoplasmic reticulum (ER) stress in colon cancer cell lines. We demonstrated that autophagy was induced by ER stress in HT29, SW480, and Caco-2 cells. In these cells, inositol-requiring enzyme1 alpha (IRE1 alpha) and C/EBP homologous protein (CHOP) were involved in the ER stress-autophagy pathway, and CHOP was a regulator of IRE1 alpha, protein expression. Our findings suggest that CHOP promotes IRE1 alpha and autophagy especially in ER stress conditions. This study will provide important insights into the disclosure of the ER stress-autophagy pathway. (C) 2014 Elsevier Inc. All rights reserved.	[Shimodaira, Yosuke; Kinouchi, Yoshitaka; Endo, Katsuya; Shiga, Hisashi; Kakuta, Yoichi; Kuroha, Masatake; Shimosegawa, Tooru] Tohoku Univ, Grad Sch Med, Div Gastroenterol, Sendai, Miyagi 9808574, Japan; [Takahashi, Seiichi] Iwaki Kyoritsu Gen Hosp, Dept Gastroenterol, Fukushima, Japan		Shimodaira, Y (corresponding author), Tohoku Univ, Grad Sch Med, Div Gastroenterol, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan.	yosuke.shimodaira@med.tohoku.ac.jp	Kakuta, Yoichi/H-5046-2019	Kakuta, Yoichi/0000-0002-7042-009X			Bertolotti A, 2000, NAT CELL BIOL, V2, P326, DOI 10.1038/35014014; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Cadwell K, 2008, NATURE, V456, P259, DOI 10.1038/nature07416; Calfon M, 2002, NATURE, V415, P92, DOI 10.1038/415092a; Castillo K, 2011, EMBO J, V30, P4465, DOI 10.1038/emboj.2011.318; Ding WX, 2007, AM J PATHOL, V171, P513, DOI 10.2353/ajpath.2007.070188; Hampe J, 2007, NAT GENET, V39, P207, DOI 10.1038/ng1954; Harding HP, 2000, MOL CELL, V5, P897, DOI 10.1016/S1097-2765(00)80330-5; Jackson WT, 2005, PLOS BIOL, V3, P861, DOI 10.1371/journal.pbio.0030156; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kaser A, 2008, CELL, V134, P743, DOI 10.1016/j.cell.2008.07.021; Kouroku Y, 2007, CELL DEATH DIFFER, V14, P230, DOI 10.1038/sj.cdd.4401984; Li J, 2008, CELL DEATH DIFFER, V15, P1460, DOI 10.1038/cdd.2008.81; Marciniak SJ, 2004, GENE DEV, V18, P3066, DOI 10.1101/gad.1250704; Margariti A, 2013, J BIOL CHEM, V288, P859, DOI 10.1074/jbc.M112.412783; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Mizushima N, 2007, ANNU REV NUTR, V27, P19, DOI 10.1146/annurev.nutr.27.061406.093749; Ogata M, 2006, MOL CELL BIOL, V26, P9220, DOI 10.1128/MCB.01453-06; Parkes M, 2007, NAT GENET, V39, P830, DOI 10.1038/ng2061; Ron D, 2007, NAT REV MOL CELL BIO, V8, P519, DOI 10.1038/nrm2199; Uddin MN, 2011, BIOCHEM BIOPH RES CO, V407, P692, DOI 10.1016/j.bbrc.2011.03.077; Yamamoto A, 1998, CELL STRUCT FUNCT, V23, P33, DOI 10.1247/csf.23.33; Ye J, 2000, MOL CELL, V6, P1355, DOI 10.1016/S1097-2765(00)00133-7; Yoshida H, 2001, CELL, V107, P881, DOI 10.1016/S0092-8674(01)00611-0	24	42	43	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.	MAR 7	2014	445	2					524	533		10.1016/j.bbrc.2014.02.054			10	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	AD4NV	WOS:000333228700044	24565834				2022-04-25	
J	Chen, C; Kuo, YH; Lin, CC; Chao, CY; Pai, MH; Chiang, EPI; Tang, FY				Chen, Ching; Kuo, Yueh-Hsiung; Lin, Cheng-Chieh; Chao, Che-Yi; Pai, Man-Hui; Chiang, En-Pei Isabel; Tang, Feng-Yao			Decyl caffeic acid inhibits the proliferation of colorectal cancer cells in an autophagy-dependent manner in vitro and in vivo	PLOS ONE			English	Article							TUMOR; COLON; GROWTH; MTOR; SUPPRESSES; PROPOLIS; BECLIN-1; ARREST; CAPE; AKT	The treatment of human colorectal cancer (CRC) cells through suppressing the abnormal survival signaling pathways has recently become a significant area of focus. In this study, our results demonstrated that decyl caffeic acid (DC), one of the novel caffeic acid derivatives, remarkedly suppressed the growth of CRC cells both in vitro and in vivo. The inhibitory effects of DC on CRC cells were investigated in an in vitro cell model and in vivo using a xenograft mouse model. CRC cells were treated with DC at various dosages (0, 10, 20 and 40 mu M), and cell survival, the apoptotic index and the autophagy level were measured using an MTT assay and flow cytometry analysis, respectively. The signaling cascades in CRC were examined by Western blot assay. The anti-cancer effects of DC on tumor growth were examined by using CRC HCT-116 cells implanted in an animal model. Our results indicated that DC differentially suppressed the growth of CRC HT-29 and HCT-116 cells through an enhancement of cell-cycle arrest at the S phase. DC inhibited the expression of cell-cycle regulators, which include cyclin E and cyclin A proteins. The molecular mechanisms of action were correlated to the blockade of the STAT3 and Akt signaling cascades. Strikingly, a high dosage of DC prompted a self-protection action through inducing cell-dependent autophagy in HCT-116 cells. Suppression of autophagy induced cell death in the treatment of DC in HCT-116 cells. DC seemed to inhibit cell proliferation of CRC differentially, and the therapeutic advantage appeared to be autophagy dependent. Moreover, consumption of DC blocked the tumor growth of colorectal adenocarcinoma in an experimental animal model. In conclusion, our results suggested that DC could act as a therapeutic agent through the significant suppression of tumor growth of human CRC cells.	[Chen, Ching; Tang, Feng-Yao] China Med Univ, Dept Nutr, Biomed Sci Lab, Taichung, Taiwan; [Kuo, Yueh-Hsiung] China Med Univ, Dept Chinese Pharmaceut Sci & Chinese Med Resourc, Taichung, Taiwan; [Kuo, Yueh-Hsiung] Asia Univ, Dept Biotechnol, Taichung, Taiwan; [Lin, Cheng-Chieh] China Med Univ, Sch Med, Coll Med, Taichung, Taiwan; [Lin, Cheng-Chieh] China Med Univ Hosp, Dept Family Med, Taichung, Taiwan; [Lin, Cheng-Chieh] Asia Univ, Dept Healthcare Adm, Coll Hlth Sci, Taichung, Taiwan; [Chao, Che-Yi] Asia Univ, Dept Food Nutr & Hlth Biotechnol, Taichung, Taiwan; [Chao, Che-Yi] China Med Univ, China Med Univ Hosp, Dept Med Res, Taichung, Taiwan; [Pai, Man-Hui] Taipei Med Univ, Sch Med, Dept Anat & Cell Biol, Coll Med, Taipei, Taiwan; [Chiang, En-Pei Isabel] Natl Chung Hsing Univ, Dept Food Sci & Biotechnol, Taichung, Taiwan; [Chiang, En-Pei Isabel] Natl Chung Hsing Univ, Innovat & Dev Ctr Sustainable Agr IDCSA, Taichung, Taiwan		Tang, FY (corresponding author), China Med Univ, Dept Nutr, Biomed Sci Lab, Taichung, Taiwan.	vincenttang@mail.cmu.edu.tw	Chiang, EnPei/K-1694-2013	Chiang, EnPei/0000-0002-0158-0962	Ministry of Science and Technology (MOST), Taiwan, R.O.C. [MOST-104-2320-B-039-041-MY3, 107-2320-B039-008-MY3, MOST 107-2320-B-005 -003 MY3, 107-2621-M-005-008 -MY3, MOST1072321-B-005-009, 108-2321-B-005-004]; China Medical University (CMU)China Medical University [CMU102-ASIA-23, CMU103-ASIA-20, CMU103-S46, CMU104-S-32]; Ministry of Education (MOE) Taiwan under the Higher Education Sprout Project at NCHU-IDCSA	This research project is supported by the grant of Ministry of Science and Technology (MOST), Taiwan, R.O.C. under the agreements MOST-104-2320-B-039-041-MY3, 107-2320-B039-008-MY3, MOST 107-2320-B-005 -003 MY3, 107-2621-M-005-008 -MY3, MOST1072321-B-005-009, 108-2321-B-005-004, China Medical University (CMU) grant under agreements CMU102-ASIA-23, CMU103-ASIA-20, CMU103-S46, CMU104-S-32, and as well as in part by the Ministry of Education (MOE) Taiwan under the Higher Education Sprout Project at NCHU-IDCSA. Any results, conclusions, or implication described in this publication are from the author(s) of this manuscript and do not necessarily reflect the view of the MOST, MOE, Asia University and CMU.	Bao YH, 2016, ONCOTARGET, V7, P26780, DOI 10.18632/oncotarget.8511; Bondi J, 2005, J CLIN PATHOL, V58, P509, DOI 10.1136/jcp.2004.020347; Chen C, 2017, ONCOL REP, V38, P2901, DOI 10.3892/or.2017.5943; Chiang EPI, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0099631; Danielsen SA, 2015, BBA-REV CANCER, V1855, P104, DOI 10.1016/j.bbcan.2014.09.008; Demestre M, 2009, PHYTOTHER RES, V23, P226, DOI 10.1002/ptr.2594; Doherty J, 2018, NAT CELL BIOL, V20, P1110, DOI 10.1038/s41556-018-0201-5; Fu LL, 2013, INT J BIOCHEM CELL B, V45, P921, DOI 10.1016/j.biocel.2013.02.007; Giacinti C, 2006, ONCOGENE, V25, P5220, DOI 10.1038/sj.onc.1209615; Gonzalez-Sarrias A, 2013, FOOD CHEM, V136, P636, DOI 10.1016/j.foodchem.2012.08.023; Hay N, 2005, CANCER CELL, V8, P179, DOI 10.1016/j.ccr.2005.08.008; Huang YH, 2017, ONCOTARGET, V8, P52783, DOI 10.18632/oncotarget.17189; Koustas E, 2017, CANCER LETT, V396, P94, DOI 10.1016/j.canlet.2017.03.023; Lee DF, 2007, CELL, V130, P440, DOI 10.1016/j.cell.2007.05.058; Lee YS, 2013, J NAT PROD, V76, P2195, DOI 10.1021/np4005135; Liu JT, 2015, CLIN LUNG CANCER, V16, pE55, DOI 10.1016/j.cllc.2015.03.006; Mao MT, 2017, BIOCHEM BIOPH RES CO, V490, P1244, DOI 10.1016/j.bbrc.2017.07.002; Nazarko VY, 2013, NAT CELL BIOL, V15, P727, DOI 10.1038/ncb2797; Park JH, 2017, CLIN CANCER RES, V23, P1698, DOI 10.1158/1078-0432.CCR-16-1416; Pearce A, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0184360; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Strimpakos AS, 2009, CANCER TREAT REV, V35, P148, DOI 10.1016/j.ctrv.2008.09.006; Thome MP, 2016, J CELL SCI, V129, P4622, DOI 10.1242/jcs.195057; Vogt PK, 2007, TRENDS BIOCHEM SCI, V32, P342, DOI 10.1016/j.tibs.2007.05.005; Wu J, 2011, CANCER LETT, V308, P43, DOI 10.1016/j.canlet.2011.04.012	25	8	8	0	6	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1932-6203			PLOS ONE	PLoS One	MAY 13	2020	15	5							e0232832	10.1371/journal.pone.0232832			16	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	LU0VG	WOS:000537481000033	32401800	Green Published, gold			2022-04-25	
J	Liu, SP; Lin, HM; Wang, D; Li, Q; Luo, H; Li, GX; Chen, XH; Li, YQ; Chen, P; Zhai, BT; Wang, WG; Zhang, RN; Chen, B; Zhang, MM; Han, XM; Li, QJ; Chen, LX; Liu, Y; Chen, XY; Li, GH; Xiang, Y; Duan, T; Feng, J; Lou, JS; Huang, XX; Zhang, Q; Pan, T; Yan, LL; Jin, T; Zhang, WZ; Zhuo, LJ; Sun, YT; Xie, T; Sui, XB				Liu, Shuiping; Lin, Haoming; Wang, Da; Li, Qiang; Luo, Hong; Li, Guoxiong; Chen, Xiaohui; Li, Yongqiang; Chen, Peng; Zhai, Bingtao; Wang, Wengang; Zhang, Ruonan; Chen, Bi; Zhang, Mingming; Han, Xuemeng; Li, Qiujie; Chen, Liuxi; Liu, Ying; Chen, Xiaying; Li, Guohua; Xiang, Yu; Duan, Ting; Feng, Jiao; Lou, Jianshu; Huang, Xingxing; Zhang, Qin; Pan, Ting; Yan, Lili; Jin, Ting; Zhang, Wenzheng; Zhuo, Lvjia; Sun, Yitian; Xie, Tian; Sui, Xinbing			PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death	SIGNAL TRANSDUCTION AND TARGETED THERAPY			English	Article							TUMOR-SUPPRESSOR; PROTOCADHERIN-17	5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.	[Liu, Shuiping; Luo, Hong; Li, Guoxiong; Chen, Xiaohui; Li, Yongqiang; Chen, Peng; Zhai, Bingtao; Wang, Wengang; Zhang, Ruonan; Chen, Bi; Zhang, Mingming; Han, Xuemeng; Li, Qiujie; Chen, Liuxi; Chen, Xiaying; Li, Guohua; Xiang, Yu; Duan, Ting; Feng, Jiao; Lou, Jianshu; Huang, Xingxing; Zhang, Qin; Pan, Ting; Yan, Lili; Jin, Ting; Zhang, Wenzheng; Zhuo, Lvjia; Sun, Yitian; Xie, Tian; Sui, Xinbing] Hangzhou Normal Univ, Affiliated Hosp, Coll Med, Holist Integrat Pharm Inst & Comprehens Canc Diag, Hangzhou, Zhejiang, Peoples R China; [Liu, Shuiping; Xie, Tian; Sui, Xinbing] Hangzhou Normal Univ, Key Lab Elemene Class Anticanc Chinese Med Zhejia, Hangzhou, Zhejiang, Peoples R China; [Liu, Shuiping; Xie, Tian; Sui, Xinbing] Hangzhou Normal Univ, Engn Lab Dev & Applicat Tradit Chinese Med Zhejia, Hangzhou, Zhejiang, Peoples R China; [Lin, Haoming] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Hepatobiliary Pancreat Surg, Guangzhou, Guangdong, Peoples R China; [Wang, Da] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Colorectal Surg, Hangzhou, Zhejiang, Peoples R China; [Li, Qiang] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Dept Ultrasound Med, Hangzhou, Zhejiang, Peoples R China; [Liu, Ying] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Med Oncol, Hangzhou, Zhejiang, Peoples R China; [Sui, Xinbing] Nanjing Univ Chinese Med, Sch Pharm, Jiangsu Key Lab Pharmacol & Safety Evaluat Chines, Nanjing, Jiangsu, Peoples R China		Xie, T; Sui, XB (corresponding author), Hangzhou Normal Univ, Affiliated Hosp, Coll Med, Holist Integrat Pharm Inst & Comprehens Canc Diag, Hangzhou, Zhejiang, Peoples R China.; Xie, T; Sui, XB (corresponding author), Hangzhou Normal Univ, Key Lab Elemene Class Anticanc Chinese Med Zhejia, Hangzhou, Zhejiang, Peoples R China.; Xie, T; Sui, XB (corresponding author), Hangzhou Normal Univ, Engn Lab Dev & Applicat Tradit Chinese Med Zhejia, Hangzhou, Zhejiang, Peoples R China.; Sui, XB (corresponding author), Nanjing Univ Chinese Med, Sch Pharm, Jiangsu Key Lab Pharmacol & Safety Evaluat Chines, Nanjing, Jiangsu, Peoples R China.	xbs@hznu.edu.cn; hzzju@zju.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672932, 81730108, 81874380, 81802371, 81973635]; Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars [LR18H160001]; Zhejiang Province Science and Technology Project of TCM [2019ZZ016]; Zhejiang Province Medical Science and Technology Project [2017RC007]; Talent Project of Zhejiang Association for Science and Technology [2017YCGC002]; Key Project of Hangzhou Ministry of Science and Technology [20162013A07]; Zhejiang Provincial Project for the Key Discipline of Traditional Chinese Medicine [2017-XK-A09]; Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica [JKLPSE201807]; Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)	This research was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81672932, 81730108, 81874380, 81802371, and 81973635), Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars (Grant No. LR18H160001), Zhejiang Province Science and Technology Project of TCM (Grant No. 2019ZZ016), Zhejiang Province Medical Science and Technology Project (Grant No. 2017RC007), Talent Project of Zhejiang Association for Science and Technology (Grant No. 2017YCGC002), Key Project of Hangzhou Ministry of Science and Technology (Grant No. 20162013A07), Zhejiang Provincial Project for the Key Discipline of Traditional Chinese Medicine (Grant No. 2017-XK-A09), Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (No. JKLPSE201807) and Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).	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Target. Ther.	NOV 29	2019	4								53	10.1038/s41392-019-0087-0			10	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	JW2CU	WOS:000502866600004		gold, Green Published			2022-04-25	
J	Liu, XY; Abe-Kanoh, N; Liu, YJ; Zhu, BW; Munemasa, S; Nakamura, T; Murata, Y; Nakamura, Y				Liu, Xiaoyang; Abe-Kanoh, Naomi; Liu, Yujia; Zhu, Beiwei; Munemasa, Shintaro; Nakamura, Toshiyuki; Murata, Yoshiyuki; Nakamura, Yoshimasa			Inhibition of phosphatidylinositide 3-kinase impairs the benzyl isothiocyanate-induced accumulation of autophagic molecules and Nrf2 in human colon cancer cells	BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY			English	Article						autophagy; phosphatidylinositide 3-kinase; Nrf2; Keap1; benzyl isothiocyanate	PATHWAY; RESISTANCE	The regulating role of phosphatidylinositide 3-kinase (PI3K) in benzyl isothiocyanate (BITC)-induced Nrf2 activation, contributing to the inducible expression of cytoprotective genes, was investigated. BITC significantly enhanced the accumulation of Nrf2 as well as autophagic molecules in human colorectal cancer HCT-116 cells. Experiments using a PI3K-specific inhibitor suggested that PI3K plays the key role in the non-canonical Nrf2 activation by BITC.	[Liu, Xiaoyang; Abe-Kanoh, Naomi; Liu, Yujia; Munemasa, Shintaro; Nakamura, Toshiyuki; Murata, Yoshiyuki; Nakamura, Yoshimasa] Okayama Univ, Grad Sch Environm & Life Sci, Okayama, Japan; [Liu, Xiaoyang; Liu, Yujia; Zhu, Beiwei] Dalian Polytech Univ, Sch Food Sci & Technol, Dalian, Peoples R China; [Abe-Kanoh, Naomi] Tokushima Univ, Inst Biomed Sci, Dept Food Sci, Grad Sch, Tokushima, Japan		Nakamura, Y (corresponding author), Okayama Univ, Grad Sch Environm & Life Sci, Okayama, Japan.	yossan@cc.okayama-u.ac.jp			MEXT KAKENHIMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) [25292073, 16K14928, 17H03818]; 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) [17H03818, 17K17923] Funding Source: KAKEN	This study was partly supported by MEXT KAKENHI [grant number 25292073], [grant number16K14928], [grant number17H03818] (YN).	Abe N, 2014, CELL DEATH DIS, V5, DOI 10.1038/cddis.2014.495; Danielsen SA, 2015, BBA-REV CANCER, V1855, P104, DOI 10.1016/j.bbcan.2014.09.008; Gottesman MM, 2002, NAT REV CANCER, V2, P48, DOI 10.1038/nrc706; Huang Y, 2015, J NUTR BIOCHEM, V26, P1401, DOI 10.1016/j.jnutbio.2015.08.001; Ichimura Y, 2008, AUTOPHAGY, V4, P1063, DOI 10.4161/auto.6826; Itakura E, 2008, MOL BIOL CELL, V19, P5360, DOI 10.1091/mbc.E08-01-0080; Jiang T, 2015, FREE RADICAL BIO MED, V88, P199, DOI 10.1016/j.freeradbiomed.2015.06.014; Kim EK, 2010, BBA-MOL BASIS DIS, V1802, P396, DOI 10.1016/j.bbadis.2009.12.009; Ma Q, 2013, ANNU REV PHARMACOL, V53, P401, DOI 10.1146/annurev-pharmtox-011112-140320; Nakamura Y, 2000, CANCER RES, V60, P219; Nakamura Y, 2010, BIOSCI BIOTECH BIOCH, V74, P242, DOI 10.1271/bbb.90731; Pankiv S, 2007, J BIOL CHEM, V282, P24131, DOI 10.1074/jbc.M702824200; Qin S, 2016, MOL NUTR FOOD RES, V60, P1731, DOI 10.1002/mnfr.201501017; Sakai R, 2012, J FOOD DRUG ANAL, V20, P389; Sui XB, 2011, AUTOPHAGY, V7, P565, DOI 10.4161/auto.7.6.14073; Xiao D, 2011, PLOS ONE, V7; Zhou XY, 2017, CELL DEATH DIS, V8, DOI 10.1038/cddis.2017.34	17	4	4	0	1	TAYLOR & FRANCIS LTD	ABINGDON	2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND	0916-8451	1347-6947		BIOSCI BIOTECH BIOCH	Biosci. Biotechnol. Biochem.		2017	81	11					2212	2215		10.1080/09168451.2017.1374830			4	Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry, Applied; Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry; Food Science & Technology	FO1PK	WOS:000416535100024	28934922	Bronze			2022-04-25	
J	Yim, NH; Jung, YP; Kim, A; Ma, CJ; Cho, WK; Ma, JY				Yim, Nam-Hui; Jung, Young Pil; Kim, Aeyung; Ma, Choong Je; Cho, Won-Kyung; Ma, Jin Yeul			Oyaksungisan, a Traditional Herbal Formula, Inhibits Cell Proliferation by Induction of Autophagy via JNK Activation in Human Colon Cancer Cells	EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article							TUMOR-GROWTH; APOPTOSIS; ANGIOGENESIS; METASTASIS; PATHWAYS; EXTRACTS; COCKTAIL; DISEASE; HEALTH; LC3	Oyaksungisan (OY) is a traditional herbal formula broadly used to treat beriberi, vomiting, diarrhea, and circulatory disturbance in Asian countries from ancient times. The effect of OY on cancer, however, was not reported until now. In this study, we have demonstrated that OY inhibits cell proliferation and induces cell death via modulating the autophagy on human colon cancer cells. In HCT116 cells, OY increased the ratio of LC3-II/LC3-I, a marker of autophagy, and treatment with 3-MA, an inhibitor of autophagy, and considerably reduced the formation of autophagosomes. In addition, OY regulated mitogen-activated protein kinase (MAPK) cascades; especially, JNK activation was closely related with autophagy effect by OY in HCT116 cells. Our results indicate that autophagy induction is responsible for the antiproliferative effect by OY, despite the weak apoptosis induction in HCT116 cells. In conclusion, OY might have a potential to be developed as an herbal anticancer remedy.	[Yim, Nam-Hui; Jung, Young Pil; Kim, Aeyung; Cho, Won-Kyung; Ma, Jin Yeul] Korea Inst Oriental Med KIOM, Korean Med KM Based Herbal Drug Res Grp, Taejon 305811, South Korea; [Ma, Choong Je] Kangwon Natl Univ, Dept Biomat Engn, Div Biosci & Biotechnol, Chunchon 200701, South Korea		Cho, WK (corresponding author), Korea Inst Oriental Med KIOM, Korean Med KM Based Herbal Drug Res Grp, Taejon 305811, South Korea.	wkcho@kiom.re.kr; jyma@kiom.re.kr	Ma, Choong Je/H-9986-2013	Ma, Choong Je/0000-0001-8818-6396	Ministry of Education, Science and Technology (MEST), Republic of KoreaMinistry of Education, Science and Technology, Republic of Korea [K12050]	This work was supported by Grant K12050 awarded to the Korean Institute of Oriental Medicine by the Ministry of Education, Science and Technology (MEST), Republic of Korea. Further, the authors thank Ju Hye Lee for the helpful experiment in this study.	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J	An, YJ; Quan, KT; Gwak, J; Ju, BG; Na, M; Oh, S				An, Younju; Khong Trong Quan; Gwak, Jungsug; Ju, Bong Gun; Na, MinKyun; Oh, Sangtaek			Activation of the p53 pathway with digiferrol isolated from Rubia philippinensis induces cell cycle arrest, apoptosis, and autophagy in colon cancer cells	FOOD AND CHEMICAL TOXICOLOGY			English	Article							MARINE SPONGE METABOLITES; BETA-CATENIN; IN-VITRO; PROLIFERATION; ILIMAQUINONE; INDUCTION; COMPLEX; GROWTH; ETHYLSMENOQUINONE; PHOSPHORYLATION		[An, Younju; Oh, Sangtaek] Kookmin Univ, PLUS Program BK21, Dept Bio & Fermentat Convergence Technol, Seoul 136702, South Korea; [Khong Trong Quan; Na, MinKyun] Chungnam Natl Univ, Coll Pharm, Daejeon 34134, South Korea; [Gwak, Jungsug; Ju, Bong Gun] Sogang Univ, Dept Life Sci, Seoul 121742, South Korea		Oh, S (corresponding author), Kookmin Univ, PLUS Program BK21, Dept Bio & Fermentat Convergence Technol, Seoul 136702, South Korea.; Na, M (corresponding author), Chungnam Natl Univ, Coll Pharm, Daejeon 34134, South Korea.	mkna@cnu.ac.kr; ohsa@kookmin.ac.kr		Na, MinKyun/0000-0002-4865-6506	Basic Science Research Program through the National Research Foundation of Korea (NRF) grant - Korean Government [NRF-2015R1A2A2A01004599, NRF- 2017R1A2A2A05001340]	This work was supported by the Basic Science Research Program (NRF-2015R1A2A2A01004599, NRF- 2017R1A2A2A05001340) through the National Research Foundation of Korea (NRF) grant funded by the Korean Government.	Altman BJ, 2012, CSH PERSPECT BIOL, V4, DOI 10.1101/cshperspect.a008763; Amado NG, 2014, J BIOL CHEM, V289, P35456, DOI 10.1074/jbc.M114.621599; Anderson CNG, 1999, J NEUROSCI, V19, P664; Bae SK, 2011, BIOCHEM BIOPH RES CO, V409, P75, DOI 10.1016/j.bbrc.2011.04.108; Brancho D, 2003, GENE DEV, V17, P1969, DOI 10.1101/gad.1107303; 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; Chiu SC, 2013, PROSTATE CANCER P D, V16, P315, DOI 10.1038/pcan.2013.38; Do MT, 2014, FOOD CHEM TOXICOL, V71, P51, DOI 10.1016/j.fct.2014.06.001; Du L, 2013, J NAT PROD, V76, P1175, DOI 10.1021/np400320r; Fukuda R, 2013, J BIOL CHEM, V288, P16117, DOI 10.1074/jbc.M112.442442; Hundley JE, 1997, MOL CELL BIOL, V17, P723, DOI 10.1128/MCB.17.2.723; Jaamaa S, 2010, CANCER RES, V70, P8630, DOI 10.1158/0008-5472.CAN-10-0937; Jackson CL, 2009, J CELL SCI, V122, P443, DOI 10.1242/jcs.032581; Quan KT, 2016, J NAT PROD, V79, P2559, DOI 10.1021/acs.jnatprod.6b00489; Kim JH, 2014, FOOD CHEM TOXICOL, V67, P87, DOI 10.1016/j.fct.2014.02.019; Kim TD, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0034618; Korinek V, 1997, SCIENCE, V275, P1784, DOI 10.1126/science.275.5307.1784; Lee HY, 2015, MAR DRUGS, V13, P543, DOI 10.3390/md13010543; Levine AJ, 2009, NAT REV CANCER, V9, P749, DOI 10.1038/nrc2723; Loughery J, 2014, NUCLEIC ACIDS RES, V42, P7664, DOI 10.1093/nar/gku501; McLeland CB, 2011, METHODS MOL BIOL, V697, P199, DOI 10.1007/978-1-60327-198-1_21; Michael D, 2003, SEMIN CANCER BIOL, V13, P49, DOI 10.1016/S1044-579X(02)00099-8; Moos PJ, 2000, P NATL ACAD SCI USA, V97, P9215, DOI 10.1073/pnas.160241897; Nieminen AI, 2013, P NATL ACAD SCI USA, V110, pE1839, DOI 10.1073/pnas.1208530110; Okada H, 2004, NAT REV CANCER, V4, P592, DOI 10.1038/nrc1412; Oren M, 2010, CSH PERSPECT BIOL, V2, DOI 10.1101/cshperspect.a001107; Park S, 2014, MAR DRUGS, V12, P3231, DOI 10.3390/md12063231; Permana D, 1999, J NAT PROD, V62, P1430, DOI 10.1021/np990101e; Roura S, 2003, BIOCHEM BIOPH RES CO, V309, P830, DOI 10.1016/j.bbrc.2003.08.075; Speidel D, 2010, TRENDS CELL BIOL, V20, P14, DOI 10.1016/j.tcb.2009.10.002; Sun Xiao-Xin, 2014, World J Biol Chem, V5, P75, DOI 10.4331/wjbc.v5.i2.75; Taylor SC, 2013, MOL BIOTECHNOL, V55, P217, DOI 10.1007/s12033-013-9672-6; Vousden KH, 2009, CELL, V137, P413, DOI 10.1016/j.cell.2009.04.037; Yang J, 2003, CARCINOGENESIS, V24, P1571, DOI 10.1093/carcin/bgg137	35	4	4	1	7	PERGAMON-ELSEVIER SCIENCE LTD	OXFORD	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND	0278-6915	1873-6351		FOOD CHEM TOXICOL	Food Chem. Toxicol.	AUG	2018	118						514	522		10.1016/j.fct.2018.05.054			9	Food Science & Technology; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology; Toxicology	GR5XD	WOS:000442714300052	29842910				2022-04-25	
J	Pandurangan, AK; Divya, T; Kumar, K; Dineshbabu, V; Velavan, B; Sudhandiran, G				Pandurangan, Ashok Kumar; Divya, Thomas; Kumar, Kalaivani; Dineshbabu, Vadivel; Velavan, Bakthavatchalam; Sudhandiran, Ganapasam			Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review	WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY			English	Review						Colorectal cancer; Cell death; Apoptosis; Autophagy; Inflammation; Hippo signalling; Nuclear factor erythroid 2-related factor 2; Wnt signaling	COLON-CANCER CELLS; NF-KAPPA-B; WNT/BETA-CATENIN; DOWN-REGULATION; HIPPO PATHWAY; INTESTINAL HOMEOSTASIS; ANIMAL-MODELS; MOUSE MODELS; KEY PLAYER; TNF-ALPHA	Colorectal carcinogenesis (CRC) imposes a major health burden in developing countries. It is the third major cause of cancer deaths. Despite several treatment strategies, novel drugs are warranted to reduce the severity of this disease. Adenomatous polyps in the colon are the major culprits in CRC and found in 45% of cancers, especially in patients 60 years of age. Inflammatory polyps are currently gaining attention in CRC, and a growing body of evidence denotes the role of inflammation in CRC. Several experimental models are being employed to investigate CRC in animals, which include the APC(min/+) mouse model, Azoxymethane, Dimethyl hydrazine, and a combination of Dextran sodium sulphate and dimethyl hydrazine. During CRC progression, several signal transduction pathways are activated. Among the major signal transduction pathways are p53, Transforming growth factor beta, Wnt/beta-catenin, Delta Notch, Hippo signalling, nuclear factor erythroid 2-related factor 2 and Kelch-like ECH-associated protein 1 pathways. These signalling pathways collaborate with cell death mechanisms, which include apoptosis, necroptosis and autophagy, to determine cell fate. Extensive research has been carried out in our laboratory to investigate these signal transduction and cell death mechanistic pathways in CRC. This review summarizes CRC pathogenesis and the related cell death and signal transduction pathways.	[Pandurangan, Ashok Kumar; Divya, Thomas; Dineshbabu, Vadivel; Velavan, Bakthavatchalam; Sudhandiran, Ganapasam] Univ Madras, Dept Biochem, Cell Biol Lab, Guindy Campus, Madras 600025, Tamil Nadu, India; [Pandurangan, Ashok Kumar; Kumar, Kalaivani] BS Abdur Rahman Crescent Inst Sci & Technol, Sch Life Sci, Madras 600048, Tamil Nadu, India		Sudhandiran, G (corresponding author), Univ Madras, Dept Biochem, Cell Biol Lab, Guindy Campus, Madras 600025, Tamil Nadu, India.	sudhandiran@unom.ac.in	Ganapasam, Sudhandiran/AAD-4264-2021; Pandurangan, Ashok Kumar/M-7335-2013; Sudhandiran, G/AAG-9967-2019	Pandurangan, Ashok Kumar/0000-0003-2824-1757; Sudhandiran, G/0000-0003-0066-7801	Council of Scientific and Industrial research (CSIR), New DelhiCouncil of Scientific & Industrial Research (CSIR) - India [37 (1364) /09/EMR-II]	GS acknowledges Council of Scientific and Industrial research (CSIR), New Delhi for funding Colon cancer project [37 (1364) /09/EMR-II].	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Gastrointest. Oncol.	SEP 15	2018	10	9					244	259		10.4251/wjgo.v10.i9.244			16	Oncology; Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Gastroenterology & Hepatology	GT7SA	WOS:000444727800004	30254720	hybrid, Green Published, Green Submitted			2022-04-25	
J	Ren, NSX; Ji, M; Tokar, EJ; Busch, EL; Xu, XJ; Lewis, D; Li, XC; Jin, AW; Zhang, YP; Wu, WKK; Huang, WC; Li, LP; Fargo, DC; Keku, TO; Sandler, RS; Li, XL				Ren, Natalie S. X.; Ji, Ming; Tokar, Erik J.; Busch, Evan L.; Xu, Xiaojiang; Lewis, DeAsia; Li, Xiangchun; Jin, Aiwen; Zhang, Yanping; Wu, William K. K.; Huang, Weichun; Li, Leping; Fargo, David C.; Keku, Temitope O.; Sandler, Robert S.; Li, Xiaoling			Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes Cancer Development	CURRENT BIOLOGY			English	Article							CARE OUTCOMES RESEARCH; CELL-SURVIVAL; P53; TUMORIGENESIS; ACTIVATION; EXPRESSION; MUTATIONS; PROTECTS; GAIN	SIRT1, the most conserved mammalian NAID(+)-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance, and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction, but not deletion, is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contribute to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1-small-molecule-activator/inhibitor-based therapeutic strategies for cancers.	[Ren, Natalie S. X.; Ji, Ming; Lewis, DeAsia; Li, Xiaoling] NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA; [Tokar, Erik J.] Natl Toxicol Program, Stem Cell Toxicol Grp, Res Triangle Pk, NC 27709 USA; [Busch, Evan L.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC 27599 USA; [Xu, Xiaojiang; Fargo, David C.] NIEHS, Integrat Bioinformat Branch, POB 12233, Res Triangle Pk, NC 27709 USA; [Huang, Weichun; Li, Leping] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA; [Li, Xiangchun; Wu, William K. K.] Chinese Univ Hong Kong, Inst Digest Dis, Dept Anaesthesia & Intens Care, Hong Kong, Hong Kong, Peoples R China; [Li, Xiangchun; Wu, William K. K.] Chinese Univ Hong Kong, State Key Lab Digest Dis, Hong Kong, Hong Kong, Peoples R China; [Jin, Aiwen; Zhang, Yanping] Univ North Carolina Chapel Hill, Dept Radiat Oncol, Chapel Hill, NC 27599 USA; [Jin, Aiwen; Zhang, Yanping] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA; [Keku, Temitope O.; Sandler, Robert S.] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC 27599 USA; [Busch, Evan L.] Harvard Med Sch, Channing Div Network Med, Dept Med, Boston, MA 02115 USA; [Busch, Evan L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA; [Busch, Evan L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA		Li, XL (corresponding author), NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA.	lix3@niehs.nih.gov	Li, Leping/F-6497-2019; xu, Xiaojiang/AAT-3851-2020; Wu, William K.K./A-3277-2009; Li, Xiaoling/A-2994-2015	Li, Leping/0000-0003-4208-0259; xu, Xiaojiang/0000-0001-5758-6581; Wu, William K.K./0000-0002-5662-5240; Li, Xiaoling/0000-0001-5920-7784	Intramural Research Program of National Institute of Environmental Health Sciences [Z01 ES102205]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P30DK034987, U01CA93326]; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [5T32CA009001, 3P30CA016086]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016086, T32CA009001, U01CA093326] 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) [P30DK056350, P30DK034987] 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) [ZIAES101765, P30ES010126, ZIAES102205, ZIAES102925, ZICES102445] Funding Source: NIH RePORTER	We thank Drs. Anton Jetten and Dmitry Gordenin and members of the Xiaoling Li laboratory for critical reading of the manuscript. We also thank Dr. Yi Fang and Ms. Qing Xu for technical support, Dr. E. Terence Adams from Integrated Laboratory Systems for histopathologic evaluation of colon tumors developed in mice, and Stephanie Cohen (image analysis) and Yongjuan Xia and Gabriela De la Cruz (staining) in the UNC Translational Pathology Laboratory (TPL) for expert technical assistance. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences to Xiaoling Li (Z01 ES102205) and was also supported, in part, by extramural grants from the NIH (P30DK034987 and U01CA93326). E.L.B. was supported in part by a grant from the National Cancer Institute (5T32CA009001). The UNC TPL is supported in part by grants from the National Cancer Institute (3P30CA016086).	Ayanian JZ, 2004, J CLIN ONCOL, V22, P2992, DOI 10.1200/JCO.2004.06.020; Banks AS, 2008, CELL METAB, V8, P333, DOI 10.1016/j.cmet.2008.08.014; Bordone L, 2007, AGING CELL, V6, P759, DOI 10.1111/j.1474-9726.2007.00335.x; Boroughs LK, 2015, NAT CELL BIOL, V17, P351, DOI 10.1038/ncb3124; Brooks CL, 2009, NAT REV CANCER, V9, P123, DOI 10.1038/nrc2562; Busch EL, 2016, CLIN EXP METASTAS, V33, P53, DOI 10.1007/s10585-015-9757-7; Chen WY, 2005, CELL, V123, P437, DOI 10.1016/j.cell.2005.08.011; Dang CV, 2009, CLIN CANCER RES, V15, P6479, DOI 10.1158/1078-0432.CCR-09-0889; Deng CX, 2009, INT J BIOL SCI, V5, P147, DOI 10.7150/ijbs.5.147; Eng CH, 2010, AUTOPHAGY, V6, P968, DOI 10.4161/auto.6.7.13082; Eng CH, 2010, SCI SIGNAL, V3, DOI 10.1126/scisignal.2000911; Firestein R, 2008, PLOS ONE, V3, DOI 10.1371/journal.pone.0002020; Gao P, 2009, NATURE, V458, P762, DOI 10.1038/nature07823; Guo XM, 2010, J BIOL CHEM, V285, P13223, DOI 10.1074/jbc.M110.102574; Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013; Herranz D, 2010, NAT COMMUN, V1, DOI 10.1038/ncomms1001; Hsu PP, 2008, CELL, V134, P703, DOI 10.1016/j.cell.2008.08.021; Imai S, 2014, TRENDS CELL BIOL, V24, P464, DOI 10.1016/j.tcb.2014.04.002; Kang M, 2013, CANCER BIOMARK, V13, P359, DOI 10.3233/CBM-130366; Kazgan N, 2014, GASTROENTEROLOGY, V146, P1006, DOI 10.1053/j.gastro.2013.12.029; Kim JW, 2006, CANCER RES, V66, P8927, DOI 10.1158/0008-5472.CAN-06-1501; Kruiswijk F, 2015, NAT REV MOL CELL BIO, V16, P393, DOI 10.1038/nrm4007; Li F, 2005, MOL CELL BIOL, V25, P6225, DOI 10.1128/MCB.25.14.6225-6234.2005; Li L, 2012, CANCER CELL, V21, P266, DOI 10.1016/j.ccr.2011.12.020; Lin Zhenghong, 2013, Genes Cancer, V4, P97, DOI 10.1177/1947601912475079; Lo Sasso G, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0102495; Malin JL, 2006, SUPPORT CARE CANCER, V14, P837, DOI 10.1007/s00520-005-0902-8; Menssen A, 2012, P NATL ACAD SCI USA, V109, pE187, DOI 10.1073/pnas.1105304109; Ming M, 2015, ONCOGENE, V34, P281, DOI 10.1038/onc.2013.583; Nazeer FI, 2011, ONCOGENE, V30, P3073, DOI 10.1038/onc.2011.29; Oberdoerffer P, 2008, CELL, V135, P907, DOI 10.1016/j.cell.2008.10.025; Palacios JA, 2010, J CELL BIOL, V191, P1299, DOI 10.1083/jcb.201005160; Pfluger PT, 2008, P NATL ACAD SCI USA, V105, P9793, DOI 10.1073/pnas.0802917105; Purushotham A, 2012, FASEB J, V26, P656, DOI 10.1096/fj.11-195172; Qiang L, 2015, CELL REP, V11, P1797, DOI 10.1016/j.celrep.2015.05.025; Rathore MG, 2012, INT J BIOCHEM CELL B, V44, P1448, DOI 10.1016/j.biocel.2012.05.011; RODRIGUES NR, 1990, P NATL ACAD SCI USA, V87, P7555, DOI 10.1073/pnas.87.19.7555; Schug TT, 2011, ANN MED, V43, P198, DOI 10.3109/07853890.2010.547211; Song NY, 2012, ANN NY ACAD SCI, V1271, P10, DOI 10.1111/j.1749-6632.2012.06762.x; Sur S, 2009, P NATL ACAD SCI USA, V106, P3964, DOI 10.1073/pnas.0813333106; Wang RH, 2008, MOL CELL, V32, P11, DOI 10.1016/j.molcel.2008.09.011; Wang RH, 2008, CANCER CELL, V14, P312, DOI 10.1016/j.ccr.2008.09.001; Warburg O, 1927, J GEN PHYSIOL, V8, P519, DOI 10.1085/jgp.8.6.519; Wise DR, 2008, P NATL ACAD SCI USA, V105, P18782, DOI 10.1073/pnas.0810199105; Xu F, 2010, ENDOCRINOLOGY, V151, P2504, DOI 10.1210/en.2009-1013	45	28	31	1	2	CELL PRESS	CAMBRIDGE	50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA	0960-9822	1879-0445		CURR BIOL	Curr. Biol.	FEB 20	2017	27	4					483	494		10.1016/j.cub.2016.12.047			12	Biochemistry & Molecular Biology; Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology	EL6IF	WOS:000394724600018	28162896	Bronze, Green Accepted			2022-04-25	
J	Roh, SA; Choi, EY; Cho, DH; Yoon, YS; Kim, TW; Kim, YS; Kim, JC				Roh, Seon Ae; Choi, Eun Young; Cho, Dong Hyung; Yoon, Yong Sik; Kim, Tae Won; Kim, Yong Sung; Kim, Jin Cheon			Characterization of biological responses of colorectal cancer cells to anticancer regimens	JOURNAL OF THE KOREAN SURGICAL SOCIETY			English	Article						Colorectal neoplasms; Chemotherapy; Pharmacological biomarkers	UP-REGULATION; CHEMOTHERAPY; APOPTOSIS; DEATH; AUTOPHAGY; IMMUNOGENICITY; RESISTANCE; SEQUENCE; THERAPY; AGENTS	Purpose: Identification of subgroups of patients who differ in their response to treatment could help to establish which of the best available chemotherapeutic options are best, based on biological activity. In metastatic colorectal cancer (CRC), novel molecular-targeted agents that act on pathways that regulate cell growth, the cell cycle, apoptosis, angiogenesis, and invasion are being developed. Here, we employed an in vitro chemosensitivity assay to evaluate the biological efficacy of conventional monotherapies and combination chemotherapy with targeted drugs. Methods: The chemosensitivities of 12 CRC cell lines to the established regimens FOLFOX (5-fluorouracil [5-FU] leucovorin + oxaliplatin) and FOLFIRI (5-FU + leucovorin + irinotecan) and to therapy with these regimens in combination with the biologically targeted drugs bevacizumab or cetuximab were comparatively evaluated for their effects on apoptotic and autophagic cell death processes, angiogenesis, and invasion. Results: Each of the chemotherapeutic regimens promoted apoptotic cell death and invasion. All drug regimens caused significantly greater apoptotic cell death with activation of caspase-3 in SW480 cells compared to other cells, effects that were associated with a remarkable reduction in matrix metalloproteinase-9 activity. The FOLFOX regimen more effectively promoted apoptotic cell death, angiogenesis, and invasion than the FOLFIRI regimen. Combination therapy with FOLFOX/FOLFIRI regimen and bevacizumab produced a moderate angiogenesis-blocking effect in most cell lines. Conclusion: The results validate our in vitro chemosensitivity assay, and suggest that it may be applied to help determine adequate regimens in individual CRC patients based on the biological characteristics of their tumors.	[Roh, Seon Ae; Choi, Eun Young; Yoon, Yong Sik; Kim, Jin Cheon] Univ Ulsan, Dept Surg, Coll Med, Asan Med Ctr, Seoul 138736, South Korea; [Roh, Seon Ae; Choi, Eun Young; Yoon, Yong Sik; Kim, Jin Cheon] Asan Inst Life Sci, Lab Canc Biol & Genet, Seoul, South Korea; [Cho, Dong Hyung] Kyung Hee Univ, Grad Sch EW Med Sci, Yongin, South Korea; [Kim, Tae Won] Univ Ulsan, Dept Oncol, Coll Med, Asan Med Ctr, Seoul 138736, South Korea; [Kim, Yong Sung] Korea Res Inst Biosci & Biotechnol, Div Med Genet, Taejon, South Korea		Kim, JC (corresponding author), Univ Ulsan, Dept Surg, Coll Med, Asan Med Ctr, 86 Asanbyeongwon Gil, Seoul 138736, South Korea.	jckim@amc.seoul.kr					Baehrecke EH, 2005, NAT REV MOL CELL BIO, V6, P505, DOI 10.1038/nrm1666; Baker EA, 2002, EUR J SURG ONCOL, V28, P24, DOI 10.1053/ejso.2001.1179; Baker EA, 2003, EUR J CANCER, V39, P981, DOI 10.1016/S0959-8049(03)00065-0; Casares N, 2005, J EXP MED, V202, P1691, DOI 10.1084/jem.20050915; Danese S, 2006, GASTROENTEROLOGY, V130, P2060, DOI 10.1053/j.gastro.2006.03.054; Edinger AL, 2004, CURR OPIN CELL BIOL, V16, P663, DOI 10.1016/j.ceb.2004.09.011; Fujita H, 2007, ONCOL REP, V18, P1129; Gozuacik D, 2007, CURR TOP DEV BIOL, V78, P217, DOI 10.1016/S0070-2153(06)78006-1; Hanahan D, 2000, CELL, V100, P57, DOI 10.1016/S0092-8674(00)81683-9; Hanrahan V, 2003, J PATHOL, V200, P183, DOI 10.1002/path.1339; Huerta S, 2007, J SURG RES, V142, P184, DOI 10.1016/j.jss.2006.12.551; Ju JH, 2007, INT J COLORECTAL DIS, V22, P855, DOI 10.1007/s00384-007-0293-z; Kelly C, 2007, SURG ONCOL, V16, P65, DOI 10.1016/j.suronc.2007.04.006; Kim J, 2009, INT J COLORECTAL DIS, V24, P209, DOI 10.1007/s00384-008-0590-1; Kohne CH, 2009, ONCOLOGIST, V14, P478, DOI 10.1634/theoncologist.2008-0202; LEIBOVITZ A, 1976, CANCER RES, V36, P4562; Leman ES, 2008, J CELL BIOCHEM, V104, P1988, DOI 10.1002/jcb.21363; Lesterhuis WJ, 2010, BRIT J CANCER, V103, P1415, DOI 10.1038/sj.bjc.6605935; Lubbe WJ, 2006, CLIN CANCER RES, V12, P1876, DOI 10.1158/1078-0432.CCR-05-2686; Nannizzi S, 2010, CANCER CHEMOTH PHARM, V66, P547, DOI 10.1007/s00280-009-1195-2; Rochette PJ, 2005, J MOL BIOL, V352, P44, DOI 10.1016/j.jmb.2005.06.033; Sabharwal A, 2007, EXPERT REV ANTICANC, V7, P477, DOI 10.1586/14737140.7.4.477; Sancho D, 2008, J CLIN INVEST, V118, P2098, DOI 10.1172/JCI34584; Sun QL, 2008, INT IMMUNOPHARMACOL, V8, P1854, DOI 10.1016/j.intimp.2008.08.009; Tesniere A, 2010, ONCOGENE, V29, P482, DOI 10.1038/onc.2009.356; Tol J, 2009, NEW ENGL J MED, V360, P563, DOI 10.1056/NEJMoa0808268; Toscano F, 2008, ONCOGENE, V27, P4161, DOI 10.1038/onc.2008.52; Tournigand C, 2004, J CLIN ONCOL, V22, P229, DOI 10.1200/JCO.2004.05.113; Waldner MJ, 2010, MOL ASPECTS MED, V31, P171, DOI 10.1016/j.mam.2010.02.005; West NJ, 2009, CANCER EPIDEM BIOMAR, V18, P1680, DOI 10.1158/1055-9965.EPI-09-0006	30	4	8	0	2	KOREAN SURGICAL SOCIETY	SEOUL	3304HO, 101 DONG, BROWNSTONE SEOUL, 335, JUNGMIN-DONG, JUNG-GU, SEOUL, 100-859, SOUTH KOREA	2233-7903			J KOREAN SURG SOC	J. Korean Surg. Soc.	JUL	2012	83	1					21	29		10.4174/jkss.2012.83.1.21			9	Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Surgery	967QI	WOS:000305922500004	22792530	Green Published, gold, Green Submitted			2022-04-25	
J	Vallianou, NG; Evangelopoulos, A; Schizas, N; Kazazis, C				Vallianou, Natalia G.; Evangelopoulos, Angelos; Schizas, Nikos; Kazazis, Christos			Potential Anticancer Properties and Mechanisms of Action of Curcumin	ANTICANCER RESEARCH			English	Review						Curcumin; anti-cancer properties; autophagy; transcription factors; bioavailability; review	ENDOPLASMIC-RETICULUM STRESS; FACTOR-KAPPA-B; SIGNALING INDUCES APOPTOSIS; CONSTITUTIVE ACTIVATION; IN-VIVO; BIOLOGICAL EVALUATION; CELL-LINES; ANTIINFLAMMATORY PROPERTIES; CHEMOPREVENTIVE AGENTS; COLON CARCINOGENESIS	Curcumin, a yellow substance belonging to the polyphenols superfamily, is the active component of turmeric, a common Indian spice, which is derived from the dried rhizome of the Curcuma longa plant. Numerous studies have demonstrated that curcumin possesses anti-oxidant, antiinflammatory and anticancerous properties. The purpose of this review is to focus on the anti-tumor effects of curcumin. Curcumin inhibits the STAT3 and NF-kappa B signaling pathways, which play key-roles in cancer development and progression. Also, inhibition of Sp-1 and its housekeeping gene expressions may serve as an important hypothesis to prevent cancer formation, migration, and invasion. Recent data have suggested that curcumin may act by suppressing the Sp-1 activation and its downstream genes, including ADEM10, calmodulin, EPHB2, HDAC4, and SEPP1 in a concentration-dependent manner in colorectal cancer cell lines; these results are consistent with other studies, which have reported that curcumin could suppress the Sp-1 activity in bladder cancer and could decrease DNA binding activity of Sp-1 in non-small cell lung carcinoma cells. Recent data advocate that ER stress and autophagy may as well play a role in the apoptosis process, which is induced by the curcumin analogue B19 in an epithelial ovarian tumor cell line and that autophagy inhibition could increase curcumin analogue-induced apoptosis by inducing severe ER stress. The ability of curcumin to induce apoptosis in tumor cells and its anti-angiogenic potential will be discussed in this review.	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FEB	2015	35	2					645	651					7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CB4LG	WOS:000349598600005	25667441		Y	N	2022-04-25	
J	Blyufer, A; Lhamo, S; Tam, C; Tariq, I; Thavornwatanayong, T; Mahajan, SS				Blyufer, Angelina; Lhamo, Sonam; Tam, Cassey; Tariq, Iffat; Thavornwatanayong, Thongthai; Mahajan, Shahana S.			Riluzole: A neuroprotective drug with potential as a novel anti-cancer agent (Review)	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Review						riluzole; glutamate secretion and signaling; reactive oxygen species; DNA damage; apoptosis; cell cycle arrest; combination therapy	AMYOTROPHIC-LATERAL-SCLEROSIS; CANCER-CELLS; DISEASE PROGRESSION; SIGNALING PATHWAYS; OXIDATIVE STRESS; GLIOMA-CELLS; GLUTAMATE; MELANOMA; PROLIFERATION; EXPRESSION	Riluzole, a glutamate release inhibitor, has been in use for the treatment of amyotrophic lateral sclerosis for over two decades since its approval by the Food and Drug Administration. Recently, riluzole has been evaluated in cancer cells and indicated to block cell proliferation and/or induce cell death. Riluzole has been proven effective as an anti-neoplastic drug in cancers of various tissue origins, including the skin, breast, pancreas, colon, liver, bone, brain, lung and nasopharynx. While cancer cells expressing glutamate receptors frequently respond to riluzole treatment, numerous types of cancer cell lacking glutamate receptors unexpectedly responded to riluzole treatment as well. Riluzole was demonstrated to interfere with glutamate secretion, growth signaling pathways, Ca2+ homeostasis, glutathione synthesis, reactive oxygen species generation and integrity of DNA, as well as autophagic and apoptotic pathways. Of note, riluzole is highly effective in inducing cell death in cisplatin-resistant lung cancer cells. Furthermore, riluzole pretreatment sensitizes glioma and melanoma to radiation therapy. In addition, in triple-negative breast cancer, colorectal cancer, melanoma and glioblastoma, riluzole has synergistic effects in combination with select drugs. In an effort to highlight the therapeutic potential of riluzole, the current study reviewed the effect and outcome of riluzole treatment on numerous cancer types investigated thus far. The mechanism of action and the various molecular pathways affected by riluzole are discussed.	[Blyufer, Angelina; Lhamo, Sonam; Tam, Cassey; Tariq, Iffat; Mahajan, Shahana S.] CUNY, Dept Med Lab Sci, Hunter Coll, 425 East,25th St, New York, NY 10010 USA; [Thavornwatanayong, Thongthai; Mahajan, Shahana S.] CUNY, PhD Program Biol, Grad Ctr, New York, NY 10016 USA; [Mahajan, Shahana S.] CUNY, PhD Program Biochem, Grad Ctr, New York, NY 10016 USA; [Mahajan, Shahana S.] Weill Cornell Med Coll, Brain Mind Res Inst, New York, NY 10021 USA		Mahajan, SS (corresponding author), CUNY, Dept Med Lab Sci, Hunter Coll, 425 East,25th St, New York, NY 10010 USA.	smahajan@hunter.cuny.edu			National Institute of General Medical Sciences, National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [1 SC1 GM131929-01A1]; City University of New York [62504 00 50]	The study was funded by the following grants: National Institute of General Medical Sciences, National Institute of Health (grant no. 1 SC1 GM131929-01A1) and the Professional Staff Congress and The City University of New York (grant no. 62504 00 50).	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J. Oncol.	NOV	2021	59	5							95	10.3892/ijo.2021.5275			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	WR6YK	WOS:000714643600001	34713302	Green Published, hybrid			2022-04-25	
J	Sun, YM; Liu, Z; Zou, X; Lan, YD; Sun, XJ; Wang, X; Zhao, SR; Jiang, CC; Liu, H				Sun, Yiming; Liu, Zhe; Zou, Xue; Lan, Yadong; Sun, Xiaojin; Wang, Xiu; Zhao, Surong; Jiang, Chenchen; Liu, Hao			Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer	JOURNAL OF BIOENERGETICS AND BIOMEMBRANES			English	Article						3-Bromopyruvate; ATP; Apoptosis; Autophagy; Necroptosis	CYTOCHROME-C; AUTOPHAGY; APOPTOSIS; PROMOTES; GLYCOLYSIS; INHIBITOR; NECROSIS; PROTEIN; MITOCHONDRIA; THERAPY	3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores.	[Sun, Yiming; Liu, Zhe; Zou, Xue; Sun, Xiaojin; Wang, Xiu; Zhao, Surong; Liu, Hao] Bengbu Med Coll, Fac Pharm, Bengbu 233000, Anhui, Peoples R China; [Lan, Yadong] Bengbu Med Coll, Affiliated Hosp 1, Dept Surg Oncol, Bengbu 233004, Peoples R China; [Jiang, Chenchen] Univ Newcastle, Fac Hlth, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia		Liu, H (corresponding author), Bengbu Med Coll, Fac Pharm, Bengbu 233000, Anhui, Peoples R China.	liuhao6886@foxmail.com			Natural Science Foundation of Anhui provinceNatural Science Foundation of Anhui Province [1508085MH166]; National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81372899, 81000992]; Foundation of Bengbu Medical College [Byycx1432]	This work was supported by the Natural Science Foundation of Anhui province (No. 1508085MH166), the National Science Foundation of China (No. 81372899, No. 81000992) and the Foundation of Bengbu Medical College (No. Byycx1432).	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Bioenerg. Biomembr.	AUG	2015	47	4					319	329		10.1007/s10863-015-9612-1			11	Biophysics; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biophysics; Cell Biology	CP9DC	WOS:000360192900003	26054380	hybrid, Green Published, Green Submitted			2022-04-25	
J	Lindner, P; Christensen, SB; Nissen, P; Moller, JV; Engedal, N				Lindner, Paula; Christensen, Soren Brogger; Nissen, Poul; Moller, Jesper Vuust; Engedal, Nikolai			Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components	CELL COMMUNICATION AND SIGNALING			English	Article						Thapsigargin; SERCA; Unfolded protein response; DR5; Caspase-8; PERK; ATF4; CHOP; IRE1; XBP1s; JNK; LC3B; Cell death; Apoptosis; Autophagy	ENDOPLASMIC-RETICULUM STRESS; PROSTATE-CANCER CELLS; INDUCED APOPTOSIS; CASPASE-8 ACTIVATION; INTERACTING PROTEIN; CALCIUM-BINDING; CA2+ DEPLETION; KINASE; INHIBITION; PATHWAY	Background Cell death triggered by unmitigated endoplasmic reticulum (ER) stress plays an important role in physiology and disease, but the death-inducing signaling mechanisms are incompletely understood. To gain more insight into these mechanisms, the ER stressor thapsigargin (Tg) is an instrumental experimental tool. Additionally, Tg forms the basis for analog prodrugs designed for cell killing in targeted cancer therapy. Tg induces apoptosis via the unfolded protein response (UPR), but how apoptosis is initiated, and how individual effects of the various UPR components are integrated, is unclear. Furthermore, the role of autophagy and autophagy-related (ATG) proteins remains elusive. Methods To systematically address these key questions, we analyzed the effects of Tg and therapeutically relevant Tg analogs in two human cancer cell lines of different origin (LNCaP prostate- and HCT116 colon cancer cells), using RNAi and inhibitory drugs to target death receptors, UPR components and ATG proteins, in combination with measurements of cell death by fluorescence imaging and propidium iodide staining, as well as real-time RT-PCR and western blotting to monitor caspase activity, expression of ATG proteins, UPR components, and downstream ER stress signaling. Results In both cell lines, Tg-induced cell death depended on death receptor 5 and caspase-8. Optimal cytotoxicity involved a non-autophagic function of MAP1LC3B upstream of procaspase-8 cleavage. PERK, ATF4 and CHOP were required for Tg-induced cell death, but surprisingly acted in parallel rather than as a linear pathway; ATF4 and CHOP were independently required for Tg-mediated upregulation of death receptor 5 and MAP1LC3B proteins, whereas PERK acted via other pathways. Interestingly, IRE1 contributed to Tg-induced cell death in a cell type-specific manner. This was linked to an XBP1-dependent activation of c-Jun N-terminal kinase, which was pro-apoptotic in LNCaP but not HCT116 cells. Molecular requirements for cell death induction by therapy-relevant Tg analogs were identical to those observed with Tg. Conclusions Together, our results provide a new, integrated understanding of UPR signaling mechanisms and downstream mediators that induce cell death upon Tg-triggered, unmitigated ER stress.	[Lindner, Paula; Engedal, Nikolai] Univ Oslo, Ctr Mol Med Norway NCMM, Nordic EMBL Partnership Mol Med, POB 1137, N-0318 Oslo, Norway; [Lindner, Paula; Nissen, Poul] Aarhus Univ, Danish Res Inst Translat Neurosci DANDRITE, Dept Mol Biol & Genet, Nordic EMBL Partnership Mol Med, Aarhus, Denmark; [Christensen, Soren Brogger] Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark; [Moller, Jesper Vuust] Aarhus Univ, Dept Biomed, Aarhus, Denmark		Engedal, N (corresponding author), Univ Oslo, Ctr Mol Med Norway NCMM, Nordic EMBL Partnership Mol Med, POB 1137, N-0318 Oslo, Norway.	k.n.engedal@ncmm.uio.no	Christensen, Søren Brøgger/H-4526-2019; Engedal, Nikolai/AAJ-8951-2020; Lindner, Paula/A-5234-2017	Christensen, Søren Brøgger/0000-0002-5773-6874; Engedal, Nikolai/0000-0003-3718-3464; Lindner, Paula/0000-0003-0734-6429	Research Council of NorwayResearch Council of Norway; University of Oslo [230686]; Nansen Foundation; Anders Jahre Foundation; Lundbeck FoundationLundbeckfonden [R191-2015-1512]	This work was generously supported by grants (to NE) from the Research Council of Norway and the University of Oslo (grant number 230686), the Nansen Foundation, and the Anders Jahre Foundation. PL is supported by a grant from The Lundbeck Foundation (to PN and NE; grant number R191-2015-1512). The funding bodies did not influence or take part in the design of the study, the collection, analysis, and interpretation of data, or in the writing of the manuscript.	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J	Zhao, C; Qiu, SZ; He, J; Peng, Y; Xu, HM; Feng, ZQ; Huang, HL; Du, YL; Zhou, YJ; Nie, YQ				Zhao, Chong; Qiu, ShaoZhuang; He, Jie; Peng, Yao; Xu, Haoming; Feng, Zhiqiang; Huang, Hongli; Du, Yanlei; Zhou, Yongjian; Nie, Yuqiang			Prodigiosin impairs autophagosome-lysosome fusion that sensitizes colorectal cancer cells to 5-fluorouracil-induced cell death	CANCER LETTERS			English	Article						Prodigiosin; Colorectal cancer; Autophagy flux; Chemotherapy; Apoptosis	PROTEASOME INHIBITION; STEM-CELLS; OXALIPLATIN; HYDROXYCHLOROQUINE; COMBINATION; SUPPRESSION; APOPTOSIS; THERAPY; PATHWAY; MTORC1	Chemotherapy failure is a major cause of recurrence and poor prognosis in colorectal cancer (CRC) patients. Inhibition of autophagy is a promising strategy to augment the cytotoxicity of chemotherapeutic agents. We identified prodigiosin, a secondary metabolite produced by various bacteria, as a novel autophagy inhibitor that interfered with the autophagic flux in CRC cells by blocking autophagosome-lysosome fusion and lysosomal cathepsin maturation, resulting in the accumulation of LC3B-II and SQSTM. Suppression of autophagy by prodigiosin sensitized the CRC cells to 5-fluorouracil (5-Fu) in vitro, and the combination treatment markedly reduced cancer cell viability partly via caspase-dependent apoptosis. Furthermore, prodigiosin and 5-Fu synergistically inhibited CRC xenograft growth in vivo without any adverse effects. In conclusion, prodigiosin inhibits late stage autophagy and sensitizes tumor cells to 5-Fu, indicating its therapeutic potential in CRC.	[Zhao, Chong; Qiu, ShaoZhuang; He, Jie; Peng, Yao; Xu, Haoming; Feng, Zhiqiang; Huang, Hongli; Du, Yanlei; Zhou, Yongjian; Nie, Yuqiang] Guangzhou Med Univ, Guangzhou Peoples Hosp 1, Guangzhou Digest Dis Ctr, Dept Gastroenterol, Guangzhou 510180, Peoples R China; [Zhao, Chong; Qiu, ShaoZhuang; He, Jie; Peng, Yao; Xu, Haoming; Feng, Zhiqiang; Huang, Hongli; Du, Yanlei; Zhou, Yongjian; Nie, Yuqiang] South China Univ Technol, Guangzhou Peoples Hosp 1, Sch Med, Dept Gastroenterol, Guangzhou 510180, Peoples R China		Nie, YQ (corresponding author), South China Univ Technol, Affiliated Hosp 2, Guangzhou Peoples Hosp 1, Guangzhou 510180, Peoples R China.	eynieyuqiang@scut.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81871905, 81700486]; Guangzhou Science, Technology and Innovation Commission [201906010052]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [2017Q113]	This work was supported by the National Natural Science Foundation of China (No. 81871905, No. 81700486), the Guangzhou Science, Technology and Innovation Commission (201906010052), and the Fundamental Research Funds for the Central Universities (2017Q113).	Bartlett BJ, 2011, AUTOPHAGY, V7, P572, DOI 10.4161/auto.7.6.14943; Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI 10.3322/caac.21492; Cartwright TH, 2012, CLIN COLORECTAL CANC, V11, P155, DOI 10.1016/j.clcc.2011.11.001; Chen PJ, 2017, FREE RADICAL BIO MED, V104, P280, DOI 10.1016/j.freeradbiomed.2017.01.033; Cheng SY, 2018, APOPTOSIS, V23, P314, DOI 10.1007/s10495-018-1456-9; Chiu WJ, 2018, J CLIN MED, V7, DOI 10.3390/jcm7100321; Dahan L, 2009, BRIT J PHARMACOL, V158, P610, DOI 10.1111/j.1476-5381.2009.00341.x; Dalby KN, 2010, AUTOPHAGY, V6, P322, DOI 10.4161/auto.6.3.11625; Darshan N, 2015, J FOOD SCI TECH MYS, V52, P5393, DOI 10.1007/s13197-015-1740-4; Espona-Fiedler M, 2012, BIOCHEM PHARMACOL, V83, P489, DOI 10.1016/j.bcp.2011.11.027; Gustavsson B, 2015, CLIN COLORECTAL CANC, V14, P1, DOI 10.1016/j.clcc.2014.11.002; Hurley JH, 2014, CELL, V157, P300, DOI 10.1016/j.cell.2014.01.070; Jiang PD, 2014, CELL RES, V24, P69, DOI 10.1038/cr.2013.161; Kaizuka T, 2016, MOL CELL, V64, P835, DOI 10.1016/j.molcel.2016.09.037; Katunuma N., 2010, J SIGNAL TRANSDUCT; Kuma A, 2004, NATURE, V432, P1032, DOI 10.1038/nature03029; Levy JMM, 2017, ELIFE, V6, DOI 10.7554/eLife.19671; Levy JMM, 2014, CANCER DISCOV, V4, P773, DOI 10.1158/2159-8290.CD-14-0049; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Lu L, 2011, EUR J PHARMACOL, V658, P242, DOI 10.1016/j.ejphar.2011.02.043; Mahalingam D, 2014, AUTOPHAGY, V10, P1403, DOI 10.4161/auto.29231; Mauvezin C, 2015, AUTOPHAGY, V11, P1437, DOI 10.1080/15548627.2015.1066957; Maycotte P, 2012, AUTOPHAGY, V8, P200, DOI 10.4161/auto.8.2.18554; Mei LF, 2015, BRIT J PHARMACOL, V172, P2232, DOI 10.1111/bph.13045; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Mizushima N, 2007, ANNU REV NUTR, V27, P19, DOI 10.1146/annurev.nutr.27.061406.093749; Molenaar RJ, 2017, BMJ OPEN, V7, DOI 10.1136/bmjopen-2016-014961; Noh SH, 2014, LANCET ONCOL, V15, P1389, DOI 10.1016/S1470-2045(14)70473-5; O'Connell MJ, 2009, J CLIN ONCOL, V27, P3082, DOI 10.1200/JCO.2009.22.2919; Pan JX, 2010, CANCER LETT, V293, P167, DOI 10.1016/j.canlet.2010.01.006; Pellegrini P, 2014, AUTOPHAGY, V10, P562, DOI 10.4161/auto.27901; Perez-Tomas R, 2010, CURR MED CHEM, V17, P2222, DOI 10.2174/092986710791331103; Prabhu VV, 2016, CANCER RES, V76, P1989, DOI 10.1158/0008-5472.CAN-14-2430; Rangwala R, 2014, AUTOPHAGY, V10, P1391, DOI 10.4161/auto.29119; Repnik U, 2012, BBA-PROTEINS PROTEOM, V1824, P22, DOI 10.1016/j.bbapap.2011.08.016; Rosenfeld MR, 2010, J CLIN ONCOL, V28; Rosenfeldt MT, 2009, EXPERT REV MOL MED, V11, DOI 10.1017/S1462399409001306; Sasaki K, 2010, BMC CANCER, V10, DOI 10.1186/1471-2407-10-370; Schonewolf CA, 2014, WORLD J GASTRO ONCOL, V6, P74, DOI 10.4251/wjgo.v6.i3.74; Shi XP, 2014, CLIN CANCER RES, V20, P151, DOI 10.1158/1078-0432.CCR-13-1063; Siegel RL, 2017, CA-CANCER J CLIN, V67, P7, DOI 10.3322/caac.21387; Sui XB, 2014, SCI REP-UK, V4, DOI 10.1038/srep04694; Vogl DT, 2014, AUTOPHAGY, V10, P1380, DOI 10.4161/auto.29264; Wang ZY, 2016, P NATL ACAD SCI USA, V113, P13150, DOI 10.1073/pnas.1616336113; Yang HZ, 2015, CANCER LETT, V361, P128, DOI 10.1016/j.canlet.2015.02.045; Zhao C, 2016, ONCOGENE, V35, P5916, DOI 10.1038/onc.2016.114; Zheng K, 2016, AUTOPHAGY, V12, P1593, DOI 10.1080/15548627.2016.1192751; Zhou J, 2013, CELL RES, V23, P508, DOI 10.1038/cr.2013.11; Zhou J, 2012, AUTOPHAGY, V8, P338, DOI 10.4161/auto.18721	49	10	10	6	39	ELSEVIER IRELAND LTD	CLARE	ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND	0304-3835	1872-7980		CANCER LETT	Cancer Lett.	JUL 1	2020	481						15	23		10.1016/j.canlet.2020.03.010			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	LG7QS	WOS:000528291300002	32184145				2022-04-25	
J	Nahdi, A; Hammami, I; Kouidhi, W; Chargui, A; Ben Ammar, A; Hamdaoui, MH; El May, A; El May, M				Nahdi, Afef; Hammami, Imen; Kouidhi, Wided; Chargui, Abderrahman; Ben Ammar, Awatef; Hamdaoui, Mohamed Hedi; El May, Ahmed; El May, Michele			Protective effects of crude garlic by reducing iron-mediated oxidative stress, proliferation and autophagy in rats	JOURNAL OF MOLECULAR HISTOLOGY			English	Article						Garlic; Iron supplementation; Oxidative stress; Proliferation; Autophagy; Electron microscopy	INDUCED CELL-DEATH; COLORECTAL-CANCER; NEOPLASTIC-CELLS; OVERLOAD; DAMAGE; TOXICITY; CARCINOGENESIS; APOPTOSIS; FERRITIN; OXIDANT	The impact of garlic, known for its antioxidant activities, on iron metabolism has been poorly investigated. The aim of this work was to study the effect of crude garlic pre-treatment on iron-mediated lipid peroxidation, proliferation and autophagy for 5 weeks. Rats were fed distilled water or garlic solution (1 g/kg body weight) by gavage for the first 3 weeks as pre-treatment and received a basal diet supplemented or not with ferrous sulfate (650 mg Fe/kg diet) for the last 2 weeks of treatment. Immunohistochemistry labeling and ultrastuctural observations were used to evaluate the iron deleterious effects in the liver. Iron supplementation induced cell proliferation predominantly in non parenchymal cells comparing to hepatocytes, but not apoptosis. In addition, iron was accumulated within the hepatic lysosomes where it triggers autophagy as evidenced by the formation of autophagic vesicles detected by LC3-II staining. It also induced morphologic alterations of the mitochondrial membranes due to increased lipid peroxidation as shown by elevated iron and malondialdehyde concentrations in serum and tissues. Garlic pre-treatment reduced iron-catalyzed lipid peroxidation by decreasing the malondialdehyde level in the liver and colon and by enhancing the status of antioxidants. In addition, garlic reduced the iron-mediated cell proliferation and autophagy by lowering iron storage in the liver and protected mitochondrial membrane. Based on these results, garlic treatment significantly prevented iron-induced oxidative stress, proliferation and autophagy at both biochemical and histological levels due to its potent free radical scavenging and antioxidant properties.	[Nahdi, Afef; Hammami, Imen; Kouidhi, Wided; Chargui, Abderrahman; El May, Michele] Fac Med, Lab Histol Embryol & Cell Biol, Res Unit UR 08 07 01, Tunis 1007, Tunisia; [Ben Ammar, Awatef] Fac Med, Electron Microscopy Lab, Tunis 1007, Tunisia; [Hamdaoui, Mohamed Hedi] High Sch Hlth Sci & Techn, Res Unit Nutr Anaemia & Trace Element Bioavailabi, Tunis 1006, Tunisia; [El May, Ahmed] Salah Azaiez Inst, Lab Immunohistocytol, Tunis 1006, Tunisia		El May, M (corresponding author), Fac Med, Lab Histol Embryol & Cell Biol, Res Unit UR 08 07 01, 15 Rue Djebel Lakhdar, Tunis 1007, Tunisia.	elmay_michele@yahoo.fr	Kouidhi, Wided/J-1840-2014		Tunisian Ministry of Higher Education and Scientific Research	We are grateful to the Tunisian Ministry of Higher Education and Scientific Research for its financial support.	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Mol. Histol.	OCT	2010	41	4-5					233	245		10.1007/s10735-010-9283-5			13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	735XC	WOS:000288452900007	20700633				2022-04-25	
J	Wang, XJ; Yu, J; Wong, SH; Cheng, ASL; Chan, FKL; Ng, SSM; Cho, CH; Sung, JJY; Wu, WKK				Wang, Xiao J.; Yu, Jun; Wong, Sunny H.; Cheng, Alfred S. L.; Chan, Francis K. L.; Ng, Simon S. M.; Cho, Chi H.; Sung, Joseph J. Y.; Wu, William K. K.			A novel crosstalk between two major protein degradation systems Regulation of proteasomal activity by autophagy	AUTOPHAGY			English	Article						autophagy; proteasome; chloroquine; protein degradation; SQSTM1	CANCER CELLS; INHIBITION; MACROAUTOPHAGY; STRESS; NEURODEGENERATION; PATHWAY; DISEASE; HDAC6	Eukaryotes have two major intracellular protein degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Inhibition of proteasomal activities has been previously shown to induce autophagy, indicating a coordinated and complementary relationship between these two systems. However, little is known about the regulation of the UPS by autophagy. In this study, we showed for the first time that proteasomes were activated in response to pharmacological inhibition of autophagy as well as disruption of autophagy-related genes by RNA interference under nutrient-deficient conditions in cultured human colon cancer cells. The induction was evidenced by the increased proteasomal activities and the upregulation of proteasomal subunits, including the proteasome 5 subunit, PSMB5. Co-inhibition of the proteasome and autophagy also synergistically increased the accumulation of polyubiquitinated proteins. Collectively, our findings suggest that proteasomes are activated in a compensatory manner for protein degradation upon autophagy inhibition. Our studies unveiled a novel regulatory mechanism between the two protein degradation pathways.	[Wang, Xiao J.; Yu, Jun; Wong, Sunny H.; Cheng, Alfred S. L.; Chan, Francis K. L.; Sung, Joseph J. Y.; Wu, William K. K.] Chinese Univ Hong Kong, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China; [Wang, Xiao J.; Yu, Jun; Wong, Sunny H.; Cheng, Alfred S. L.; Chan, Francis K. L.; Sung, Joseph J. Y.; Wu, William K. K.] Chinese Univ Hong Kong, State Key Lab Digest Dis, Hong Kong, Hong Kong, Peoples R China; [Wang, Xiao J.; Yu, Jun; Wong, Sunny H.; Cheng, Alfred S. L.; Chan, Francis K. L.; Sung, Joseph J. Y.; Wu, William K. K.] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China; [Wang, Xiao J.; Yu, Jun; Wong, Sunny H.; Cheng, Alfred S. L.; Chan, Francis K. L.; 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, Fac Med, Dept Surg, Hong Kong, Hong Kong, Peoples R China; [Cho, Chi H.] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China		Wu, WKK (corresponding author), Chinese Univ Hong Kong, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China.	junyu@cuhk.edu.hk; jjysung@cuhk.edu.hk; wukakei@cuhk.edu.hk	Wong, Sunny H/N-3754-2015; Cho, Chi Hin/C-6543-2014; Wu, William K.K./A-3277-2009; Ng, Simon S. M./M-1219-2018; Yu, Jun/D-8569-2015; Cheng, Alfred SL/C-3327-2014; Chan, Francis K. L./F-4851-2010; Sung, Joseph J. Y./R-3203-2018	Wong, Sunny H/0000-0002-3354-9310; Cho, Chi Hin/0000-0002-7658-3260; Wu, William K.K./0000-0002-5662-5240; Ng, Simon S. M./0000-0002-5389-9297; Yu, Jun/0000-0001-5008-2153; Cheng, Alfred SL/0000-0003-2345-6951; Chan, Francis K. L./0000-0001-7388-2436; Sung, Joseph J. Y./0000-0003-3125-5199; WANG, Echo/0000-0001-6229-5690	Research Fund for the Control of Infectious Diseases/Health and Medical Research Fund [11100082, 12110332]; CUHK Direct Grant for Research [2041734]	Work in the authors' laboratory is supported by Research Fund for the Control of Infectious Diseases/Health and Medical Research Fund (11100082 and 12110332) and CUHK Direct Grant for Research (2041734).	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J	Coriat, R; Marut, W; Leconte, M; Ba, LB; Vienne, A; Chereau, C; Alexandre, J; Weill, B; Doering, M; Jacob, C; Nicco, C; Batteux, F				Coriat, R.; Marut, W.; Leconte, M.; Ba, L. B.; Vienne, A.; Chereau, C.; Alexandre, J.; Weill, B.; Doering, M.; Jacob, C.; Nicco, C.; Batteux, F.			The organotelluride catalyst LAB027 prevents colon cancer growth in the mice	CELL DEATH & DISEASE			English	Article						tellurium; colon cancer; mice; reactive oxygen species; oxaliplatin	SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; CELL-DEATH; BUTHIONINE SULFOXIMINE; IMMUNOMODULATOR AS101; PHASE-I; GLUTATHIONE; ROS; APOPTOSIS	Organotellurides are newly described redox-catalyst molecules with original pro-oxidative properties. We have investigated the in vitro and in vivo antitumoral effects of the organotelluride catalyst LAB027 in a mouse model of colon cancer and determined its profile of toxicity in vivo. LAB027 induced an overproduction of H2O2 by both human HT29 and murine CT26 colon cancer cell lines in vitro. This oxidative stress was associated with a decrease in proliferation and survival rates of the two cell lines. LAB027 triggered a caspase-independent, ROS-mediated cell death by necrosis associated with mitochondrial damages and autophagy. LAB027 also synergized with the cytotoxic drug oxaliplatin to augment its cytostatic and cytotoxic effects on colon cancer cell lines but not on normal fibroblasts. The opposite effects of LAB027 on tumor and on non-transformed cells were linked to differences in the modulation of reduced glutathione metabolism between the two types of cells. In mice grafted with CT26 tumor cells, LAB027 alone decreased tumor growth compared with untreated mice, and synergized with oxaliplatin to further decrease tumor development compared with mice treated with oxaliplatin alone. LAB027 an organotelluride catalyst compound synergized with oxaliplatin to prevent both in vitro and in vivo colon cancer cell proliferation while decreasing the in vivo toxicity of oxaliplatin. No in vivo adverse effect of LAB027 was observed in this model. Cell Death and Disease (2011) 2, e191; doi: 10.1038/cddis.2011.73; published online 11 August 2011	[Coriat, R.; Marut, W.; Leconte, M.; Vienne, A.; Chereau, C.; Alexandre, J.; Weill, B.; Nicco, C.; Batteux, F.] Univ Paris 05, Fac Med, Hop Cochin, AP HP,Lab Immunol,EA 1833, F-75679 Paris 14, France; [Ba, L. B.; Doering, M.; Jacob, C.] Univ Saarland, Div Bioorgan Chem, Sch Pharm, D-66123 Saarbrucken, Germany		Batteux, F (corresponding author), Univ Paris 05, Immunol Lab, UPRES EA 1833, 24 Rue Faubourg St Jacques, F-75679 Paris 14, France.	frederic.batteux@cch.aphp.fr	ALEXANDRE, JEROME/O-8350-2017; Coriat, Romain/O-7902-2017; Nicco, Carole/O-8169-2017; Nicco, Carole/X-6726-2019; Batteux, Frederic/O-7889-2017	Nicco, Carole/0000-0001-8211-2556; Nicco, Carole/0000-0001-8211-2556; Batteux, Frederic/0000-0002-1265-7996	European CommunityEuropean Commission [FP7/2007-2013, 215009]	This research has been funded by a grant from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement no (215009). The authors thank Ms Agnes Colle for editing the manuscript and Ms Marie Mianowski for reviewing the manuscript.	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AUG	2011	2								e191	10.1038/cddis.2011.73			10	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	811VQ	WOS:000294244700005	21833029	Green Published, gold			2022-04-25	
J	Chira, S; Raduly, L; Braicu, C; Jurj, A; Cojocneanu-Petric, R; Pop, L; Pileczki, V; Ionescu, C; Berindan-Neagoe, I				Chira, Sergiu; Raduly, Lajos; Braicu, Cornelia; Jurj, Ancuta; Cojocneanu-Petric, Roxana; Pop, Laura; Pileczki, Valentina; Ionescu, Calin; Berindan-Neagoe, Ioana			Premature senescence activation in DLD-1 colorectal cancer cells through adjuvant therapy to induce a miRNA profile modulating cellular death	EXPERIMENTAL AND THERAPEUTIC MEDICINE			English	Article						colorectal cancer; adjuvant therapy; cell death; senescence; exosomal miRNAs pattern	DEUTERIUM-DEPLETED WATER; CARCINOMA-CELLS; MICRORNA REGULATORS; PROSTATE-CANCER; DOWN-REGULATION; HEAVY-WATER; IN-VITRO; APOPTOSIS; EXPRESSION; PROLIFERATION	Cancer, and particularly colon cancer, is associated with an increasing number of cases resistant to chemotherapy. One approach to overcome this, and to improve the prognosis and outcome of patients, is the use of adjuvant therapy alongside the standard chemotherapy regiment. In the present study, the effect of deuterium-depleted water (DDW) as a potential modulator of adjuvant therapy on DLD-1 colorectal cancer models was assessed. A number of functionality assays were performed, including MTT, apoptosis and autophagy, and mitochondria' activity and senescence assays, in addition to assessing the capacity to modify the pattern of released miRNA via microarray technology. No significant effect on cell viability was identified, but an increase in mitochondria' activity and a weak pro-apoptotic effect were observed in the treated DLD-1 cells cultured in DDW-prepared medium compared with those grown in standard conditions (SC). Furthermore, the findings revealed the capacity of DDW medium to promote senescence to a higher degree compared with SC. The exosome-released miRNA pattern was significantly modified for the cells maintained in DDW compared with those maintained in SC. These findings suggest that DDW may serve as an adjuvant treatment; however, a better understanding of the underlying molecular mechanism of action will be useful for developing novel and efficient therapeutic strategies, in which the transcriptomic pattern serves an important role.	[Chira, Sergiu; Raduly, Lajos; Braicu, Cornelia; Jurj, Ancuta; Cojocneanu-Petric, Roxana; Pop, Laura; Pileczki, Valentina; Berindan-Neagoe, Ioana] Iuliu Hatieganu Univ Med & Pharm, Res Ctr Funct Genom Biomed & Translat Med, Cluj Napoca 400337, Romania; [Raduly, Lajos] Univ Agr Sci & Vet Med, Fac Vet Med, Dept Pathophysiol, Cluj Napoca 400372, Romania; [Ionescu, Calin] Iuliu Hatieganu Univ Med & Pharm, Dept Surg, 23 Marinescu St, Cluj Napoca 40015, Romania; [Ionescu, Calin] Iuliu Hatieganu Univ Med & Pharm, Municipal Clin Hosp, Dept Surg, Cluj Napoca 400337, Romania; [Berindan-Neagoe, Ioana] Iuliu Hatieganu Univ Med & Pharm, MEDFUTURE Res Ctr Adv Med, Cluj Napoca 400337, Romania; [Berindan-Neagoe, Ioana] Oncol Inst Prof Dr Ion Chiricuta, Dept Funct Genom & Expt Pathol, Cluj Napoca 400015, Romania		Ionescu, C (corresponding author), Iuliu Hatieganu Univ Med & Pharm, Dept Surg, 23 Marinescu St, Cluj Napoca 40015, Romania.	calin.ionescu@umfcluj.ro	Chira, Sergiu/AAD-4885-2020; Pileczki, Valentina/ABB-6273-2020; Pop, Laura/AAY-8349-2020; Berindan-Neagoe, Ioana/AAH-9854-2019	Chira, Sergiu/0000-0001-6075-7468; Pop, Laura/0000-0002-5806-0220; Cojocneanu, Roxana-Maria/0000-0002-7450-9454; Raduly, Lajos/0000-0002-3926-5423	research grant 'New strategies for improving life quality and survival in cancer patients: Molecular and clinical studies of the tumor genome in deuterium-depleted water treatment augmentation-GenCanD'; Iuliu-Hatieganu University of Medicine and Pharmacy (Cluj-Napoca, Romania) [128/2014, PN-II-PT-PCCA-2013-4-2166]	The present study is part of the research grant 'New strategies for improving life quality and survival in cancer patients: Molecular and clinical studies of the tumor genome in deuterium-depleted water treatment augmentation-GenCanD'. The research grant was supplied by Iuliu-Hatieganu University of Medicine and Pharmacy (Cluj-Napoca, Romania; grant no. 128/2014; PN-II-PT-PCCA-2013-4-2166).	Basov A. 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Ther. Med.	AUG	2018	16	2					1241	1249		10.3892/etm.2018.6324			9	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	GR1GO	WOS:000442280500107	30116375	Green Published, Green Submitted, gold			2022-04-25	
J	Chen, LL; Han, HT; Amin, A; Zhang, L; Ma, SL				Chen, Lili; Han, Haote; Amin, Awais; Zhang, Lin; Ma, Shenglin			Hydrolysis product of Nigella A obtained from Nigella glandulifera Freyn seeds promotes apoptosis and AMPK-mediated autophagy in human colon cancer SW620 cells	ARCHIVES OF BIOLOGICAL SCIENCES			English	Article						nigella A; nigella B; apoptosis; autophagy; AMPK; mTOR	TRITERPENOID SAPONINS; PROSTATE-CANCER; DEATH; ROOTS; LC3	Nigella B (NB) is the hydrolysis product of Nigella A (NA), which is extracted from the seeds of Nigella glandulifera Freyn. NB has several beneficial characteristics, including antiproliferative activity against several cancer cell lines. In this study, we analyzed the in vitro and in vivo anticancer activity of both NA and NB as well as the potential molecular mechanisms behind the actions of NB. We found that NB treatment led to autophagy and soft apoptosis in colon cancer cells (SW620). NA treatment had no effect on either. Further study showed that NB treatment in SW620 cells led to inhibited phosphorylated mammalian target of rapamycin (p-mTOR) expression but increased phosphorylated-5' adenosine monophosphate protein kinase (AMPK) expression, a key regulator of autophagy. This suggests that the AMPK-mTOR pathway plays a crucial role in autophagy induction. Separate in vivo studies using NA (40 mg/kg, intragastric administration (i.g.)) and NB (40 mg/kg, i.g.) resulted in inhibited tumor growth in nude mice by 42.82% and 37.20% respectively, when compared with vehicle-administered animals. In vitro tumor protein expression was consistent with its expression in vitro. Taken together, our results reveal an anticancer function for NA and NB in colon cancer and support the use of NA as an antitumor prodrug, and NB as a novel therapeutic drug.	[Chen, Lili; Ma, Shenglin] Wenzhou Med Univ, Wenzhou 325035, Peoples R China; [Chen, Lili] Wenzhou Med Univ, Huangyan Hosp, Wenzhou 318020, Peoples R China; [Han, Haote; Amin, Awais; Zhang, Lin] Zhejiang Univ, Dept Biomed Engn, Key Lab Biomed Engn, Minist Educ, Hangzhou 310028, Peoples R China; [Han, Haote; Amin, Awais; Zhang, Lin] Zhejiang Univ, Zhejiang Malaysia Joint Res Ctr Tradit Med, Hangzhou 310028, Peoples R China; [Ma, Shenglin] Hangzhou First Peoples Hosp, Dept Oncol, Hangzhou 310006, Zhejiang, Peoples R China		Ma, SL (corresponding author), Wenzhou Med Univ, Wenzhou 325035, Peoples R China.; Zhang, L (corresponding author), Zhejiang Univ, Dept Biomed Engn, Key Lab Biomed Engn, Minist Educ, Hangzhou 310028, Peoples R China.; Zhang, L (corresponding author), Zhejiang Univ, Zhejiang Malaysia Joint Res Ctr Tradit Med, Hangzhou 310028, Peoples R China.; Ma, SL (corresponding author), Hangzhou First Peoples Hosp, Dept Oncol, Hangzhou 310006, Zhejiang, Peoples R China.	zhanglin@zju.edu.cn; mashenglin@medmail.com.cn			Zhejiang-Malaysia Joint Research Center for Traditional Medicine [2016C04005]; Jiangsu Provincial Natural Science Foundation of ChinaNatural Science Foundation of Jiangsu Province [BK20161269]	This work was supported by Zhejiang-Malaysia Joint Research Center for Traditional Medicine (2016C04005) and the Jiangsu Provincial Natural Science Foundation of China (BK20161269).	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Biol. Sci.		2018	70	4					603	612		10.2298/ABS171108021C			10	Biology	Science Citation Index Expanded (SCI-EXPANDED)	Life Sciences & Biomedicine - Other Topics	HD0GX	WOS:000452187000001		gold, Green Submitted			2022-04-25	
J	Kitajima, S; Thummalapalli, R; Barbie, DA				Kitajima, Shunsuke; Thummalapalli, Rohit; Barbie, David A.			Inflammation as a driver and vulnerability of KRAS mediated oncogenesis	SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY			English	Review						KRAS; Inflammation; NF-kappa B; STAT3; Cytokines; Autophagy	MOUSE COLON TUMORS; PROMOTES T-CELL; COLORECTAL-CANCER; LUNG-CANCER; PANCREATIC-CANCER; BOWEL-DISEASE; ACTIVATION; MUTATIONS; AUTOPHAGY; STAT3	While important strides have been made in cancer therapy by targeting certain oncogenes, KRAS, the most common among them, remains refractory to this approach. In recent years, a deeper understanding of the critical importance of inflammation in promoting KRAS-driven oncogenesis has emerged, and applies across the different contexts of lung, pancreatic, and colorectal tumorigenesis. Here we review why these tissue types are particularly prone to developing KRAS mutations, and how inflammation conspires with KRAS signaling to fuel carcinogenesis. We discuss multiple lines of evidence that have established NF-kappa B, STAT3, and certain cytokines as key transducers of these signals, and data to suggest that targeting these pathways has significant clinical potential. Furthermore, recent work has begun to uncover how inflammatory signaling interacts with other KRAS regulated survival pathways such as autophagy and MAPK signaling, and that co-targeting these multiple nodes may be required to achieve real benefit. In addition, the impact of KRAS associated inflammatory signaling on the greater tumor microenvironment has also become apparent, and taking advantage of this inflammation by incorporating approaches that harness T cell anti-tumor responses represents another promising therapeutic strategy. Finally, we highlight the likelihood that the genomic complexity of KRAS mutant tumors will ultimately require tailored application of these therapeutic approaches, and that targeting inflammation early in the course of tumor development could have the greatest impact on eradicating this deadly disease. (C) 2016 Elsevier Ltd. All rights reserved.	[Kitajima, Shunsuke; Thummalapalli, Rohit; Barbie, David A.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA; [Thummalapalli, Rohit] Harvard Med Sch, Div Hlth Sci & Technol, 25 Shattuck St, Boston, MA 02115 USA		Barbie, DA (corresponding author), 450 Brookline Ave,D819, Boston, MA 02215 USA.	shunsuke_kitajima@dfci.harvard.edu; rohit_thummalapalli@hms.harvard.edu; dbarbie@partners.org			strategic young researcher overseas visits program for accelerating brain circulation [NCI-R01 CA190394-01, NCI-K08 CA138918-01A1]; Gloria T. Maheu Fund for Lung Cancer Research; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [K08CA138918, R01CA190394] Funding Source: NIH RePORTER	This work was supported by the strategic young researcher overseas visits program for accelerating brain circulation (S.K.), NCI-R01 CA190394-01 (D.B.), NCI-K08 CA138918-01A1 (D.B.), and the Gloria T. Maheu Fund for Lung Cancer Research (D.B.).	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Cell Dev. Biol.	OCT	2016	58						127	135		10.1016/j.semcdb.2016.06.009			9	Cell Biology; Developmental Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Developmental Biology	DV9TD	WOS:000383284000015	27297136	Green Accepted			2022-04-25	
J	Wang, M; Zhu, JY; Chen, S; Qing, Y; Wu, D; Lin, YM; Luo, JZ; Han, W; Li, YQ				Wang, Min; Zhu, Jing-Yu; Chen, Shuo; Qing, Ying; Wu, Dong; Lin, Ying-Min; Luo, Ji-Zhuang; Han, Wei; Li, Yan-Qing			Effects of co-treatment with sulforaphane and autophagy modulators on uridine 5 '-diphospho-glucuronosyltransferase 1A isoforms and cytochrome P450 3A4 expression in Caco-2 human colon cancer cells	ONCOLOGY LETTERS			English	Article						uridine 5 '-diphospho-glucuronosyltransferase 1A; Caco-2 cells; sulforaphane; chemoprevention; cytochrome P450 3A4; autophagy	PREGNANE X-RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; PHENETHYL ISOTHIOCYANATE; INDUCED APOPTOSIS; GENE-EXPRESSION; INHIBITION; INDUCTION; METABOLISM; PREVENTION; GLUCURONOSYLTRANSFERASES	Sulforaphane (SFN), which is highly enriched in cruciferous vegetables, has been investigated for its cancer chemopreventive properties and ability to induce autophagy. Uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT)1A induction is one of the mechanisms that is responsible for the cancer chemopreventive activity of SFN. The current study. demonstrates that rapamycin may enhance the chemopreventive effects of SFN on Caco-2 cells; this may be partially attributed to nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2)- and human pregnane X receptor (hPXR)-mediated UGT1A1, UGT1A8 and UGT1A10 induction. These results indicate that targeting autophagy modulation may be a promising strategy for increasing the chemopreventive effects of SFN in cases of colon cancer.	[Wang, Min; Qing, Ying; Lin, Ying-Min] Shandong Univ, Qi Lu Hosp, Dept Geriatr & Gastroenterol, Key Lab Prote Shandong, Jinan 250012, Shandong, Peoples R China; [Zhu, Jing-Yu] Shandong Univ, Jinan Cent Hosp, Dept Gastroenterol, Jinan 250013, Shandong, Peoples R China; [Chen, Shuo] China Japan Friendship Hosp, Dept Gastroenterol, Beijing, Peoples R China; [Chen, Shuo] Peking Union Med Coll, Grad Sch, Beijing 100029, Peoples R China; [Chen, Shuo] Chinese Acad Med Sci, Beijing 100029, Peoples R China; [Wu, Dong] Shandong Univ, Qi Lu Hosp, Dept Gen Surg, Jinan 250012, Shandong, Peoples R China; [Luo, Ji-Zhuang] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200030, Peoples R China; [Han, Wei; Li, Yan-Qing] Shandong Univ, Qi Lu Hosp, Dept Gastroenterol, Jinan 250012, Shandong, Peoples R China		Wang, M (corresponding author), Shandong Univ, Qi Lu Hosp, Dept Geriatr & Gastroenterol, Key Lab Prote Shandong, 107 Wenhuaxi Rd, Jinan 250012, Shandong, Peoples R China.	doctorminmin@163.com		Qing, Ying/0000-0001-6763-6204	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81372681]	This study was supported by the National Natural Science Foundation of China (grant no. 81372681).	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Lett.	DEC	2014	8	6					2407	2416		10.3892/ol.2014.2536			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AU9YT	WOS:000345948600009	25364403	Green Published, Green Submitted, gold			2022-04-25	
J	Ding, WX; Ni, HM; Gao, WT; Hou, YF; Melan, MA; Chen, XY; Stolz, DB; Shao, ZM; Yin, XM				Ding, Wen-Xing; Ni, Hong-Min; Gao, Wentao; Hou, Yi-Feng; Melan, Melissa A.; Chen, Xiaoyun; Stolz, Donna B.; Shao, Zhi-Ming; Yin, Xiao-Ming			Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival	JOURNAL OF BIOLOGICAL CHEMISTRY			English	Article							MISFOLDED PROTEINS; DEATH; APOPTOSIS; INHIBITION; DISSECTION; DISEASE; ABSENCE; ROLES; BAX	Autophagy is a cellular response to adverse environment and stress, but its significance in cell survival is not always clear. Here we show that autophagy could be induced in the mammalian cells by chemicals, such as A23187, tunicamycin, thapsigargin, and brefeldin A, that cause endoplasmic reticulum stress. Endoplasmic reticulum stress-induced autophagy is important for clearing polyubiquitinated protein aggregates and for reducing cellular vacuolization in HCT116 colon cancer cells and DU145 prostate cancer cells, thus mitigating endoplasmic reticulum stress and protecting against cell death. In contrast, autophagy induced by the same chemicals does not confer protection in a normal human colon cell line and in the non-transformed murine embryonic fibroblasts but rather contributes to cell death. Thus the impact of autophagy on cell survival during endoplasmic reticulum stress is likely contingent on the status of cells, which could be explored for tumor-specific therapy.	Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA; Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA; Fudan Univ, Dept Surg, Canc Hosp, Shanghai 200032, Peoples R China		Yin, XM (corresponding author), Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA.	xmyin@pitt.edu	Chen, Xiaoyun/K-4786-2019	Melan, Melissa/0000-0001-6088-7801	NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA111456, CA83817] Funding Source: Medline; NINDS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [NS45252] Funding Source: Medline; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA111456, R01CA083817] 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) [R01NS045252] Funding Source: NIH RePORTER		Baehrecke EH, 2005, NAT REV MOL CELL BIO, V6, P505, DOI 10.1038/nrm1666; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Breckenridge DG, 2003, ONCOGENE, V22, P8608, DOI 10.1038/sj.onc.1207108; Bursch W, 2001, CELL DEATH DIFFER, V8, P569, DOI 10.1038/sj.cdd.4400852; Chandra D, 2005, J BIOL CHEM, V280, P19051, DOI 10.1074/jbc.M501391200; Ding WX, 2004, HEPATOLOGY, V40, P403, DOI 10.1002/hep.20310; Edinger AL, 2004, CURR OPIN CELL BIOL, V16, P663, DOI 10.1016/j.ceb.2004.09.011; Hara T, 2006, NATURE, V441, P885, DOI 10.1038/nature04724; Harding HP, 2002, ANNU REV CELL DEV BI, V18, P575, DOI 10.1146/annurev.cellbio.18.011402.160624; Johnston JA, 1998, J CELL BIOL, V143, P1883, DOI 10.1083/jcb.143.7.1883; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Kamada Y, 2003, CURR TOP MICROBIOL, V279, P73; Kamimoto T, 2006, J BIOL CHEM, V281, P4467, DOI 10.1074/jbc.M509409200; Kaufman RJ, 1999, GENE DEV, V13, P1211, DOI 10.1101/gad.13.10.1211; Komatsu M, 2006, NATURE, V441, P880, DOI 10.1038/nature04723; Kopito RR, 2000, NAT CELL BIOL, V2, pE207, DOI 10.1038/35041139; KOUROKU Y, 2006, CELL DEATH DIFF 0623; Kuma A, 2004, NATURE, V432, P1032, DOI 10.1038/nature03029; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Lum JJ, 2005, CELL, V120, P237, DOI 10.1016/j.cell.2004.11.046; Meijer AJ, 2004, INT J BIOCHEM CELL B, V36, P2445, DOI 10.1016/j.biocel.2004.02.002; Meusser B, 2005, NAT CELL BIOL, V7, P766, DOI 10.1038/ncb0805-766; Mizushima N, 2001, J CELL BIOL, V152, P657, DOI 10.1083/jcb.152.4.657; Mizushima N, 2002, CELL STRUCT FUNCT, V27, P421, DOI 10.1247/csf.27.421; Ohsumi Y, 2004, SEMIN CELL DEV BIOL, V15, P231, DOI 10.1016/j.semcdb.2003.12.004; Perlmutter DH, 1999, LAB INVEST, V79, P623; Pyo JO, 2005, J BIOL CHEM, V280, P20722, DOI 10.1074/jbc.M413934200; Rao RV, 2004, CELL DEATH DIFFER, V11, P372, DOI 10.1038/sj.cdd.4401378; Rao RV, 2004, CURR OPIN CELL BIOL, V16, P653, DOI 10.1016/j.ceb.2004.09.012; Ravikumar B, 2004, NAT GENET, V36, P585, DOI 10.1038/ng1362; SEGLEN PO, 1982, P NATL ACAD SCI-BIOL, V79, P1889, DOI 10.1073/pnas.79.6.1889; Shibata M, 2006, J BIOL CHEM, V281, P14474, DOI 10.1074/jbc.M600364200; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Shintani T, 2004, SCIENCE, V306, P990, DOI 10.1126/science.1099993; Talloczy Z, 2002, P NATL ACAD SCI USA, V99, P190, DOI 10.1073/pnas.012485299; Teckman JH, 2000, AM J PHYSIOL-GASTR L, V279, pG961, DOI 10.1152/ajpgi.2000.279.5.G961; Yoneda T, 2002, GENE DEV, V16, P1307, DOI 10.1101/gad.1000902; Yorimitsu T, 2006, J BIOL CHEM, V281, P30299, DOI 10.1074/jbc.M607007200; Yu L, 2004, SCIENCE, V304, P1500, DOI 10.1126/science.1096645; Zhang L, 2000, SCIENCE, V290, P989, DOI 10.1126/science.290.5493.989	40	382	406	3	31	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC	ROCKVILLE	11200 ROCKVILLE PIKE, SUITE 302, ROCKVILLE, MD, UNITED STATES	0021-9258	1083-351X		J BIOL CHEM	J. Biol. Chem.	FEB 16	2007	282	7					4702	4710		10.1074/jbc.M609267200			9	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	140CX	WOS:000244482000051	17135238	hybrid			2022-04-25	
J	Hiratsuka, T; Inomata, M; Kon, Y; Yokoyama, S; Shiraishi, N; Kitano, S				Hiratsuka, Takahiro; Inomata, Masafumi; Kon, Yohei; Yokoyama, Shigeo; Shiraishi, Norio; Kitano, Seigo			DHL-TauZnNa, a newly synthesized alpha-lipoic acid derivative, induces autophagy in human colorectal cancer cells	ONCOLOGY REPORTS			English	Article						DHL-TauZnNa; antioxidant; alpha-lipoic acid derivative; G2/M arrest; autophagy	OXYGEN SPECIES GENERATION; JNK ACTIVATION; IN-VIVO; PANCREATIC-CANCER; APOPTOSIS; DEATH; INHIBITION; PATHWAYS; PROTEINS; THERAPY	In recent years, several antioxidant substances have been found to have an antiproliferative effect on various types of carcinomas. alpha-lipoic acid (ALA) induces apoptosis in several types of cancer cell lines, but it is difficult to apply alpha-lipoic acid in clinical use as it is easily oxidized and unstable. Recently, we succeeded in synthesizing the alpha-lipoic acid derivative sodium N-[6,8-dimercaptooctanoyl]-2-aminoethanesulfonate zinc complex (DHL-TauZnNa), which has highly stable antioxidant effects. We investigated whether DHL-TauZnNa elicits its antiproliferative effects in vivo and in vitro by inducing apoptosis, autophagy or cell cycle arrest, and we analyzed the expression of proteins related to these phenomena and their phosphorylation in HT-29 human colon cancer cells. Subcutaneously administered DHL-TauZnNa treatment applied daily for 41 days significantly inhibited tumor growth by 43% in a xenograft mouse model (P=0.0271). DHL-TauZnNa significantly reduced cell viability over that of controls in the trypan-blue exclusion test in a time- and dose-dependent manner (P<0.05). DHL-TauZnNa increased the proportion of cells in S phase and decreased that of cells in G0/G1 phase in the cell cycle analysis of HT-29 cells. Although DHL-TauZnNa did not increase caspase-3/7 activity and DNA fragmentation in flow cytometry analysis, it increased the expression of microtubule-associated protein light chain 3-II. Autophagosomes and autolysosomes were observed by electron microscopy in the cytoplasm of HT-29 cells treated with DHL-TauZnNa. These results suggest that DHL-TauZnNa inhibited the proliferation of HT-29 cells through the mechanisms of G2/M cell cycle arrest and autophagy but not that of apoptosis. The newly synthesized ALA derivative DHL-TauZnNa may be expected to become a novel cancer therapeutic strategy through its induction of autophagy.	[Hiratsuka, Takahiro; Inomata, Masafumi; Kon, Yohei; Shiraishi, Norio] Oita Univ, Fac Med, Dept Gastroenterol Surg, Yufu City, Oita 8795593, Japan; [Yokoyama, Shigeo] Oita Univ, Fac Med, Dept Diagnost Pathol, Yufu City, Oita 8795593, Japan; [Kitano, Seigo] Oita Univ, Oita 8701124, Japan		Hiratsuka, T (corresponding author), Oita Univ, Fac Med, Dept Gastroenterol Surg, 1-1 Idaigaoka,Hasama Machi, Yufu City, Oita 8795593, Japan.	htakahiru@oita-u.ac.jp		Hiratsuka, Takahiro/0000-0002-6483-6013	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 [23591967]	We would like to express our gratitude to Dr Kazumi Ogata, who synthesized and provided the drugs used in this study, and to Ms. Yuiko Asou, Ms. Aiko Yasuda and Ms. Kaori Sakai for their technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) (no. 23591967).	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J	Li, CW; Zhu, GD; Cui, ZH; Zhang, JH; Zhang, ST; Wei, YL				Li, Congwen; Zhu, Guodong; Cui, Zihong; Zhang, Jihong; Zhang, Shengting; Wei, Yunlin			The strong inhibitory effect of combining anti-cancer drugs AT406 and rocaglamide with blue LED irradiation on colorectal cancer cells	PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY			English	Article						Colorectal cancer; Blue LED irradiation; Multi-targeted anticancer drugs; Inhibitory effect	ORALLY-ACTIVE ANTAGONIST; LIGHT-EMITTING DIODE; APOPTOSIS PROTEINS; MULTIPLE INHIBITOR; COLON-CANCER; RESISTANCE; CASPASE-8; POTENT; IAPS	There is still no satisfying method to treat colorectal cancer (CRC) currently. Inspired by cocktail therapy, the combination of 465 nm blue LED irradiation and two multi-target anticancer agents AT406 and Rocaglamide has been investigated as an innovative way to treat colorectal cancer cells in vitro. It showed a strong inhibitory effect on colorectal cancer cells, and its side effects on human normal cells are negligible. When applied to HCT116 cells, it can achieve an apoptotic rate up to 95%. It is also seen to significantly inhibit proliferation of HT29 cells. Furthermore, little to no cell inhibition or damage of normal MRC-5 cells were seen after treatment. The combination of blue LED irradiation and two anti-cancer drugs causes apoptosis of colorectal cancer cells by activating the apoptotic pathway, inhibiting autophagy and proliferation pathways as well as the production of reactive oxygen species (ROS).	[Li, Congwen; Zhu, Guodong; Cui, Zihong; Zhang, Shengting; Wei, Yunlin] Kunming Univ Sci & Technol, Fac Life Sci & Technol, Kunming 650500, Yunnan, Peoples R China; [Zhang, Jihong] Kunming Univ Sci & Technol, Med Sch, Kunming 650500, Yunnan, Peoples R China		Zhang, ST; Wei, YL (corresponding author), Kunming Univ Sci & Technol, Fac Life Sci & Technol, Kunming 650500, Yunnan, Peoples R China.	747585404@qq.com; weiyunlin18@163.com					Becker MS, 2016, ONCOTARGET, V7, P51908, DOI 10.18632/oncotarget.10188; Brunckhorst MK, 2012, CANCER BIOL THER, V13, P804, DOI 10.4161/cbt.20563; Cai Q, 2011, J MED CHEM, V54, P2714, DOI 10.1021/jm101505d; CHAKRABARTY S, 1992, INT J CANCER, V50, P968, DOI 10.1002/ijc.2910500624; Chen Z, 2018, CELL PHYSIOL BIOCHEM, V49, P2035, DOI 10.1159/000493714; Choi SR, 2000, INT J ONCOL, V17, P141; Chubb D, 2015, J CLIN ONCOL, V33, P426, DOI 10.1200/JCO.2014.56.5689; Agnol MAD, 2009, LASER MED SCI, V24, P909, DOI 10.1007/s10103-009-0648-5; Dietrich JB, 1997, ARCH PHYSIOL BIOCHEM, V105, P125, DOI 10.1076/apab.105.2.125.12927; ENNEVER JF, 1983, J PEDIATR-US, V103, P295, DOI 10.1016/S0022-3476(83)80370-9; Greco C, 2007, CANCER-AM CANCER SOC, V109, P1227, DOI 10.1002/cncr.22542; Grossi V, 2014, WORLD J GASTROENTERO, V20, P9744, DOI 10.3748/wjg.v20.i29.9744; Haga Raquel B, 2016, Small GTPases, V7, P207; Hnasko TS, 2015, METHODS MOL BIOL, V1318, P87, DOI 10.1007/978-1-4939-2742-5_9; Jiang YS, 2016, BIOCHEM BIOPH RES CO, V478, P293, DOI 10.1016/j.bbrc.2016.07.011; Kamata E, 2017, ANTICANCER RES, V37, P6097, DOI 10.21873/anticanres.12058; Kumagai T, 2018, NUTRIENTS, V10, DOI 10.3390/nu10101405; Li Robert, 2016, React Oxyg Species (Apex), V1, P9, DOI 10.20455/ros.2016.803; Ling Y., 2020, CURR MED CHEM; Luan Z, 2015, MOL MED REP, V11, P203, DOI 10.3892/mmr.2014.2718; Mahalingam D, 2019, CANCERS, V11; Mulsow J, 2011, BRIT J SURG, V98, P1785, DOI 10.1002/bjs.7653; Nalli AD, 2018, SCI REP-UK, V8, DOI 10.1038/s41598-018-35908-0; Oberoi-Khanuja TK, 2013, CELL DEATH DIS, V4, DOI 10.1038/cddis.2013.311; 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; Rawla P, 2019, GASTROENTEROL REV, V14, P89, DOI 10.5114/pg.2018.81072; Reinhold T, 2007, PLANT J, V50, P293, DOI 10.1111/j.1365-313X.2007.03049.x; Schaaf MBE, 2016, FASEB J, V30, P3961, DOI 10.1096/fj.201600698R; Tamas K, 2015, CANCER TREAT REV, V41, P671, DOI 10.1016/j.ctrv.2015.06.007; Toubai T, 2017, BLOOD ADV, V1, P1517, DOI 10.1182/bloodadvances.2017004242; Tummers B, 2017, IMMUNOL REV, V277, P76, DOI 10.1111/imr.12541; Wagner EF, 2009, NAT REV CANCER, V9, P537, DOI 10.1038/nrc2694; Walker NA, 2007, J ATHL TRAINING, V42, P530; Wang BC, 2016, AM J TRANSL RES, V8, P1047; Waris Gulam, 2006, J Carcinog, V5, P14; Wu Y, 2017, CANCER LETT, V389, P70, DOI 10.1016/j.canlet.2016.12.010; Yao C, 2018, AUTOPHAGY, V14, P1831, DOI 10.1080/15548627.2018.1489946; Zhao XG, 2016, BIOCHEM BIOPH RES CO, V479, P166, DOI 10.1016/j.bbrc.2016.08.121; Zhuang JJ, 2018, INT J MOL SCI, V19, DOI 10.3390/ijms19051464	40	1	1	1	9	ELSEVIER	AMSTERDAM	RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS	1572-1000	1873-1597		PHOTODIAGN PHOTODYN	Photodiagnosis Photodyn. Ther.	JUN	2020	30								101797	10.1016/j.pdpdt.2020.101797			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	LZ0BX	WOS:000540895900108	32360851				2022-04-25	
J	Kretowski, R; Stypulkowska, A; Cechowska-Pasko, M				Kretowski, Rafal; Stypulkowska, Anna; Cechowska-Pasko, Marzanna			Efficient apoptosis and necrosis induction by proteasome inhibitor: bortezomib in the DLD-1 human colon cancer cell line	MOLECULAR AND CELLULAR BIOCHEMISTRY			English	Article						Apoptosis; Bortezomib; DLD-1; Necrosis; ORP150; NF-kappa B	UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; MULTIPLE-MYELOMA CELLS; ER STRESS; 26S PROTEASOME; MESSENGER-RNA; RESISTANCE; AUTOPHAGY; THERAPY; GROWTH	The inhibition of the 26S proteasome evokes endoplasmic reticulum stress, which has been shown to be implicated in the antitumoral effects of proteasome inhibitors. The cellular and molecular effects of the proteasome inhibitor-bortezomib-on human colon cancer cells are as yet poorly characterized. Bortezomib selectively induces apoptosis in some cancer cells. However, the nature of its selectivity remains unknown. Previously, we demonstrated that, in contrast to normal fibroblasts, bortezomib treatment evoked strong effect on apoptosis of breast cancer cells incubated in hypoxic and normoxic conditions. The study presented here provides novel information on the cellular effects of bortezomib in DLD-1 colon cancer cells line. We observe twofold higher percentage of apoptotic cells incubated for 48 h with 25 and 50 nmol/l of bortezomib in hypoxic conditions and four-, fivefold increase in normoxic conditions in comparison to control cells, incubated without bortezomib. It is of interest that bortezomib evokes strong effect on necrosis of DLD-1 colon cancer cell line. We observe the sixfold increase in necrosis of DLD-1 cells incubated with 25 or 50 nmol/l of bortezomib for 48 h in hypoxia and fourfold increase in normoxic conditions in comparison to adequate controls. We suggest that bortezomib may be candidates for further evaluation as chemotherapeutic agents for human colon cancer.	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Cell. Biochem.	JAN	2015	398	1-2					165	173		10.1007/s11010-014-2216-y			9	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	AT7BF	WOS:000345090500017	25292312	Green Published, hybrid			2022-04-25	
J	Song, CF; Xu, W; Wu, HK; Wang, XT; Gong, QY; Liu, C; Liu, JW; Zhou, L				Song, Changfeng; Xu, Wen; Wu, Hongkun; Wang, Xiaotong; Gong, Qianyi; Liu, Chang; Liu, Jianwen; Zhou, Lin			Photodynamic therapy induces autophagy-mediated cell death in human colorectal cancer cells via activation of the ROS/JNK signaling pathway	CELL DEATH & DISEASE			English	Article							IN-VIVO; APOPTOSIS; PHOTOSENSITIZERS; INHIBITION; MECHANISMS; CARCINOMA; EFFICACY; SAFETY; HEAD; NECK	Evidence has shown that m-THPC and verteporfin (VP) are promising sensitizers in photodynamic therapy (PDT). In addition, autophagy can act as a tumor suppressor or a tumor promoter depending on the photosensitizer (PS) and the cancer cell type. However, the role of autophagy in m-THPC- and VP-mediated PDT in in vitro and in vivo models of human colorectal cancer (CRC) has not been reported. In this study, m-THPC-PDT or VP-PDT exhibited significant phototoxicity, inhibited proliferation, and induced the generation of large amounts of reactive oxygen species (ROS) in CRC cells. From immunoblotting, fluorescence image analysis, and transmission electron microscopy, we found extensive autophagic activation induced by ROS in cells. In addition, m-THPC-PDT or VP-PDT treatment significantly induced apoptosis in CRC cells. Interestingly, the inhibition of m-THPC-PDT-induced autophagy by knockdown of ATG5 or ATG7 substantially inhibited the apoptosis of CRC cells. Moreover, m-THPC-PDT treatment inhibited tumorigenesis of subcutaneous HCT116 xenografts. Meanwhile, antioxidant treatment markedly inhibited autophagy and apoptosis induced by PDT in CRC cells by inactivating JNK signaling. In conclusion, inhibition of autophagy can remarkably alleviate PDT-mediated anticancer efficiency in CRC cells via inactivation of the ROS/JNK signaling pathway. Our study provides evidence for the therapeutic application of m-THPC and VP in CRC.	[Song, Changfeng; Xu, Wen; Wang, Xiaotong; Gong, Qianyi; Liu, Jianwen] East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China; [Song, Changfeng; Xu, Wen; Wang, Xiaotong; Gong, Qianyi; Liu, Jianwen] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; [Wu, Hongkun; Liu, Chang; Zhou, Lin] Naval Med Univ, Changzheng Hosp, Dept Lab Med, Shanghai 200003, Peoples R China		Liu, JW (corresponding author), East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China.; Liu, JW (corresponding author), East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China.; Zhou, L (corresponding author), Naval Med Univ, Changzheng Hosp, Dept Lab Med, Shanghai 200003, Peoples R China.	liujian@ecust.edu.cn; lynnzhou36@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [82072371, 81873050, 81803082, 81772283]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2018M632046]; Shanghai Science and Technology CommitteeShanghai Science & Technology Committee [15PJD004]; Shanghai Municipal Commission of Health and Family Planning [2018BR35]	This work was supported by the National Natural Science Foundation of China (Grant nos. 82072371, 81873050, 81803082, and 81772283), the China Postdoctoral Science Foundation (Grant no. 2018M632046), the Shanghai Science and Technology Committee (Grant no. 15PJD004), and Shanghai Municipal Commission of Health and Family Planning (Grant no. 2018BR35).	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OCT 31	2020	11	10							938	10.1038/s41419-020-03136-y			14	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	OP4MT	WOS:000588056500001	33130826	gold, Green Published			2022-04-25	
J	Pattingre, S; Petiot, A; Codogno, P				Pattingre, S; Petiot, A; Codogno, P			Analyses of G alpha-interacting protein and activator of G-protein-signaling-3 functions in macroautophagy	REGULATORS OF G-PROTEIN SIGNALING, PT B	METHODS IN ENZYMOLOGY		English	Review							ISOLATED RAT HEPATOCYTES; LYSOSOMOTROPIC AGENT MONODANSYLCADAVERINE; CONTROLS AUTOPHAGIC SEQUESTRATION; CANCER HT-29 CELLS; SIGNALING PATHWAYS; REGULATOR AGS3; CULTURED RAT; VACUOLE; DEGRADATION; GAIP	Macroautophagy or autophagy is an ubiquitous and conserved degradative pathway of cytosolic components, macromolecules or organelles, into the lysosome. By using biochemical and microscopic methods, which allow one to measure the rate of autophagy, the role of two regulators of G(i3) protein activity, activator of G-protein-signaling-3 (AGS3) and Galpha-interacting protein (GAIP), was studied in the control of autophagy in human colon cancer HT-29 cells. In HT-29 cells, autophagy is under the control of the G(i3) protein and, when bound to the GTP, the Galpha(i3) protein inhibits autophagy, whereas it stimulates autophagy when bound to the GDP. GAIP, which enhances the intrinsic GTPase-activating protein activity of the Galpha(i3) protein, stimulates autophagy by favoring the GDP-bound form of Galpha(i3). We showed that GAIP is phosphorylated on its serine 151 and that this phosphorylation is dependent on the presence of amino acids that modulate Raf-1 activity, the kinase upstream of Erk1/2. AGS3, a guanine nucleotide dissociation inhibitor, stimulates autophagy by binding Galpha(i3) proteins. The intracellular localization of AGS3 (Golgi apparatus and endoplasmic reticulum, two membranes known to be at the origin of autophagosomes) is consistent with its role in autophagy.	SW Med Sch, Div Infect Dis, Dallas, TX 75390 USA; INSERM U504, Inst Andre Lwofff, F-94807 Villejuif, France		Pattingre, S (corresponding author), SW Med Sch, Div Infect Dis, Dallas, TX 75390 USA.		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J	Assumpcao, JAF; Magalhaes, KG; Correa, JR				Fagundes Assumpcao, Jose Antonio; Magalhaes, Kelly Grace; Correa, Jose Raimundo			The role of ppar gamma and autophagy in ros production, lipid droplets biogenesis and its involvement with colorectal cancer cells modulation	CANCER CELL INTERNATIONAL			English	Article						Colorectal cancer; Autophagy; PPAR; ROS; Lipid bodies; Cancer stem cells	ACTIVATED RECEPTOR-GAMMA; TUMOR-SUPPRESSOR; UP-REGULATION; INHIBITION; MTOR; INFLAMMATION; APOPTOSIS; PTEN; AGONISTS; STRESS	Background: In cancer cells, autophagy can act as both tumor suppressor, when autophagic event eliminates cellular contends which exceeds the cellular capacity of regenerate promoting cell death, and as a pro-survival agent removing defective organelles and proteins and helping well-established tumors to maintain an accelerated metabolic state while still dealing with harsh conditions, such as inflammation. Many pathways can coordinate the autophagic process and one of them involves the transcription factors called PPARs, which also regulate cellular differentiation, proliferation and survival. The PPAR. activation and autophagy initiation seems to be interrelated in a variety of cell types. Methods: Caco-2 cells were submitted to treatment with autophagy and PPAR gamma modulators and the relationship between both pathways was determined by western blotting and confocal microscopy. The effects of such modulations on Caco-2 cells, such as lipid bodies biogenesis, cell death, proliferation, cell cycle, ROS production and cancer stem cells profiling were analyzed by flow cytometry. Results: PPAR. and autophagy pathways seem to be overlap in Caco-2 cells, modulating each other in different ways and determining the lipid bodies biogenesis. In general, inhibition of autophagy by 3-MA leaded to reduced cell proliferation, cell cycle arrest and, ultimately, cell death by apoptosis. In agreement with these results, ROS production was increased in 3-MA treated cells. Autophagy also seems to play an important role in cancer stem cells profiling. Rapamycin and 3-MA induced epithelial and mesenchymal phenotypes, respectively. Conclusions: This study helps to elucidate in which way the induction or inhibition of these pathways regulate each other and affect cellular properties, such as ROS production, lipid bodies biogenesis and cell survive. We also consolidate autophagy as a key factor for colorectal cancer cells survival in vitro, pointing out a potential side effect of autophagic inhibition as a therapeutic application for this disease and demonstrate a novel regulation of PPAR. expression by inhibition of PI3K III.	[Fagundes Assumpcao, Jose Antonio; Magalhaes, Kelly Grace; Correa, Jose Raimundo] Univ Brasilia, Inst Ciencias Biol, Dept Biol Celular, Brasilia, DF, Brazil		Assumpcao, JAF (corresponding author), Univ Brasilia, Inst Ciencias Biol, Dept Biol Celular, Brasilia, DF, Brazil.	zeassumpcao@gmail.com	Magalhaes, Kelly G/A-6966-2010; Assumpção, José AF/P-6588-2018; Magalhaes, Kelly Grace/L-6081-2019; Correa, Jose R/K-6270-2012	Magalhaes, Kelly G/0000-0002-7435-5272; Assumpção, José AF/0000-0002-2836-1583; Magalhaes, Kelly Grace/0000-0002-7435-5272; Correa, Jose R/0000-0003-2752-5395	Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)	Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil).	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SEP 15	2017	17								82	10.1186/s12935-017-0451-5			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FG9YP	WOS:000410796400001	28932171	gold, Green Published			2022-04-25	
J	Denisenko, TV; Pivnyuk, AD; Zhivotovsky, B				Denisenko, Tatiana V.; Pivnyuk, Anastasia D.; Zhivotovsky, Boris			p53-Autophagy-Metastasis Link	CANCERS			English	Review						autophagy; apoptosis; p53; cancer; metastasis	EPITHELIAL-MESENCHYMAL TRANSITION; TUMOR-SUPPRESSOR P53; AUTOPHAGIC CELL-DEATH; MUTANT P53; CANCER-CELLS; REGULATES AUTOPHAGY; MEDIATED REGULATION; SIGNALING PATHWAYS; COLORECTAL-CANCER; STRESS RESPONSES	The tumor suppressor p53 as the guardian of the genome plays an essential role in numerous signaling pathways that control the cell cycle, cell death and in maintaining the integrity of the human genome. p53, depending on the intracellular localization, contributes to the regulation of various cell death pathways, including apoptosis, autophagy and necroptosis. Accumulated evidence suggests that this function of p53 is closely involved in the process of cancer development. Here, present knowledge concerning a p53-autophagy-metastasis link, as well as therapeutic approaches that influence this link, are discussed.	[Denisenko, Tatiana V.; Pivnyuk, Anastasia D.; Zhivotovsky, Boris] Moscow MV Lomonosov State Univ, Fac Med, Moscow 119991, Russia; [Zhivotovsky, Boris] Karolinska Inst, Div Toxicol, Inst Environm Med, Box 210, SE-17177 Stockholm, Sweden		Zhivotovsky, B (corresponding author), Moscow MV Lomonosov State Univ, Fac Med, Moscow 119991, Russia.; Zhivotovsky, B (corresponding author), Karolinska Inst, Div Toxicol, Inst Environm Med, Box 210, SE-17177 Stockholm, Sweden.	de_tanya@yahoo.com; a.pivnuk@gmail.com; Boris.Zhivotovsky@ki.se	Denisenko, Tatyana/U-9986-2018; Zhivotovsky, Boris/A-4346-2014	Zhivotovsky, Boris/0000-0002-2238-3482	Russian Science FoundationRussian Science Foundation (RSF) [14-25-00056]; Stockholm Cancer Society [161292]; Swedish Cancer SocietySwedish Cancer Society [160733]; Swedish Childhood Cancer FoundationEuropean Commission [PR2016-0090]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [521-2014-2258]	This work was supported by Russian Science Foundation (grant number 14-25-00056). The work in the authors' laboratories is being supported from the Stockholm (grant number 161292) and Swedish (grant number 160733) Cancer Societies, the Swedish Childhood Cancer Foundation (grant number PR2016-0090), the Swedish Research Council (grant number 521-2014-2258).	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J	Ganesan, T; Sinniah, A; Chik, Z; Alshawsh, MA				Ganesan, Thanusha; Sinniah, Ajantha; Chik, Zamri; Alshawsh, Mohammed Abdullah			Punicalagin Regulates Apoptosis-Autophagy Switch via Modulation of Annexin A1 in Colorectal Cancer	NUTRIENTS			English	Article						pomegranate; annexin A1; colorectal neoplasms; apoptosis; autophagy	PROGRAMMED CELL-DEATH; ELLAGIC ACID; DNA-DAMAGE; POLYPHENOLS; INHIBITION; METABOLISM	Punicalagin (PU), a polyphenol extracted from pomegranate (Punica granatum) husk is proven to have anti-cancer effects on different types of cancer including colorectal cancer (CRC). Its role in modulating endogenous protein as a means of eliciting its anti-cancer effects, however, has not been explored to date. Hence, this study aimed to investigate the role of PU in modulating the interplay between apoptosis and autophagy by regulating Annexin A1 (Anx-A1) expression in HCT 116 colorectal adenocarcinoma cells. In the study, selective cytotoxicity, pro-apoptotic, autophagic and Anx-A1 downregulating properties of PU were shown which indicate therapeutic potential that this polyphenol has against CRC. Autophagy flux analysis via flow cytometry showed significant autophagosomes degradation in treated cells, proving the involvement of autophagy. Proteome profiling of 35 different proteins in the presence and absence of Anx-A1 antagonists in PU-treated cells demonstrated a complex interplay that happens between apoptosis and autophagy that suggests the possible simultaneous induction and inhibition of these two cell death mechanisms by PU. Overall, this study suggests that PU induces autophagy while maintaining basal level of apoptosis as the main mechanisms of cytotoxicity via the modulation of Anx-A1 expression in HCT 116 cells, and thus has a promising translational potential.	[Ganesan, Thanusha; Sinniah, Ajantha; Chik, Zamri; Alshawsh, Mohammed Abdullah] Univ Malaya, Dept Pharmacol, Fac Med, Kuala Lumpur 50603, Malaysia		Sinniah, A (corresponding author), Univ Malaya, Dept Pharmacol, Fac Med, Kuala Lumpur 50603, Malaysia.	thanushaganesan@gmail.com; ajantha.sinniah@um.edu.my; zamrichik@ummc.edu.my; alshaweshmam@um.edu.my	Alshawsh, Mohammed Abdullah/B-2887-2010; Ganesan, Thanusha M/AAJ-6469-2021; Sinniah, Ajantha/L-5684-2017; Chik, Zamri/C-1208-2010	Alshawsh, Mohammed Abdullah/0000-0001-8342-5183; Sinniah, Ajantha/0000-0002-7572-9926; Chik, Zamri/0000-0003-1770-8382; Ganesan, Thanusha/0000-0002-6514-4123	Ministry of Higher EducationScience and Technology Development Fund (STDF)Ministry of Higher Education & Scientific Research (MHESR) [FRGS/1/2019/SKK10/UM/02/2]; University of MalayaUniversiti Malaya [BK015-2017]	This work is supported by FRGS/1/2019/SKK10/UM/02/2 and BK015-2017 grant from the Ministry of Higher Education and University of Malaya, respectively.	Abdulhadi HL., 2015, EGYPT J BASIC APPL S, V2, P247, DOI [10.1016/j.ejbas.2015.09.004, DOI 10.1016/j.ejbas.2015.09.004, DOI 10.1016/J.EJBAS.2015.09.004]; Adaramoye O, 2017, CHEM-BIOL INTERACT, V274, P100, DOI 10.1016/j.cbi.2017.07.009; Cerda B, 2003, EUR J NUTR, V42, P18, DOI 10.1007/s00394-003-0396-4; Cheng X, 2016, RSC ADV, V6, P68485, DOI 10.1039/c6ra13431a; Crighton D, 2006, CELL, V126, P121, DOI 10.1016/j.cell.2006.05.034; El-Khattouti Abdelouahid, 2013, J Cell Death, V6, P37, DOI 10.4137/JCD.S11034; Elmore S, 2007, TOXICOL PATHOL, V35, P495, DOI 10.1080/01926230701320337; Feng ZH, 2010, CSH PERSPECT BIOL, V2, DOI 10.1101/cshperspect.a001057; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Fouad YA, 2017, AM J CANCER RES, V7, P1016; Fujiwara K, 2008, J BIOL CHEM, V283, P388, DOI 10.1074/jbc.M611043200; Gonzalez-Sarrias A, 2014, EUR J NUTR, V53, P853, DOI 10.1007/s00394-013-0589-4; Grootaert C, 2015, NUTRIENTS, V7, P9229, DOI 10.3390/nu7115462; Kozovska Z, 2014, BIOMED PHARMACOTHER, V68, P911, DOI 10.1016/j.biopha.2014.10.019; Kuribayashi K, 2008, ADV EXP MED BIOL, V615, P201, DOI 10.1007/978-1-4020-6554-5_10; Larrosa M, 2006, J NUTR BIOCHEM, V17, P611, DOI 10.1016/j.jnutbio.2005.09.004; LIAN WS, 2018, CELL DEATH DIS, V0009; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038/nrm2239; Moroni MC, 2001, NAT CELL BIOL, V3, P552, DOI 10.1038/35078527; Muller M, 1998, J EXP MED, V188, P2033, DOI 10.1084/jem.188.11.2033; Nazzaro F, 2012, CURR OPIN BIOTECH, V23, P182, DOI 10.1016/j.copbio.2011.10.001; Onozawa H, 2017, ONCOL REP, V37, P235, DOI 10.3892/or.2016.5234; Parisi JD, 2019, CELLS-BASEL, V8, DOI 10.3390/cells8010051; Reuter S, 2008, BIOCHEM PHARMACOL, V76, P1340, DOI 10.1016/j.bcp.2008.07.031; Sajid M, 2019, NEW LOOK TO PHYTOMEDICINE: ADVANCEMENTS IN HERBAL PRODUCTS AS NOVEL DRUG LEADS, P597, DOI 10.1016/B978-0-12-814619-4.00024-0; Santiago-O'Farrill JM, 2018, ONCOTARGET, V9, P1602, DOI 10.18632/oncotarget.20308; Sato Y, 2011, EXP THER MED, V2, P239, DOI 10.3892/etm.2011.210; Seeram NP, 2005, J NUTR BIOCHEM, V16, P360, DOI 10.1016/j.jnutbio.2005.01.006; Su MF, 2013, J ONCOL, V2013, DOI 10.1155/2013/102735; UK World Cancer Research Fund, 2018, COLORECTAL CANC; Vecchi L, 2018, BBA-MOL CELL RES, V1865, P1368, DOI 10.1016/j.bbamcr.2018.06.010; Wang SG, 2013, ACTA PHARMACOL SIN, V34, P1411, DOI 10.1038/aps.2013.98; Wang Y, 2016, REPRODUCTION, V151, P97, DOI 10.1530/REP-15-0287; White JP, 2018, STEM CELL REP, V11, P425, DOI 10.1016/j.stemcr.2018.06.014; Yaidikar L, 2015, MOL CELL BIOCHEM, V402, P141, DOI 10.1007/s11010-014-2321-y; Yao X, 2017, NUTR RES, V47, P63, DOI 10.1016/j.nutres.2017.09.001; Yu L, 2006, P NATL ACAD SCI USA, V103, P4952, DOI 10.1073/pnas.0511288103; Zorova LD, 2018, ANAL BIOCHEM, V552, P50, DOI 10.1016/j.ab.2017.07.009	38	6	6	0	5	MDPI	BASEL	ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND		2072-6643		NUTRIENTS	Nutrients	AUG	2020	12	8							2430	10.3390/nu12082430			17	Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Nutrition & Dietetics	OA5RX	WOS:000577843200001	32823596	gold, Green Published			2022-04-25	
J	Kim, J; Choi, S; Kim, JO; Kim, KK				Kim, Jaewhan; Choi, Sunkyung; Kim, Jong Ok; Kim, Kee K.			Autophagy-mediated upregulation of cytoplasmic claudin 1 stimulates the degradation of SQSTM1/p62 under starvation	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article							HUNTINGTON-DISEASE; TIGHT JUNCTIONS; CANCER; ULK1; PHOSPHORYLATION; PROMOTES; MODELS; FAMILY; CELLS; LC3	Claudin 1, a major tight junction protein, is highly expressed in various types of tumors such as thyroid, breast, and colorectal cancers. Moreover, claudin 1 is frequently found in the cytoplasm in various types of tumor cells. However, the cytoplasmic function of claudin 1 in tumors still remains largely unknown. Here, we investigated the novel function of cytoplasmic claudin 1 in autophagy. The mRNA expression level of claudin 1 was higher in several types of tumors than in normal tissues. Furthermore, colon tumor tissues showed increased autophagy compared with the adjacent normal tissues. Both endogenous and exogenous claudin 1 showed a cytoplasmic punctate staining pattern and were co-stained with the lysosome-associated membrane protein 1 (LAMP1). Importantly, autophagy-induced conditions, including starvation, increased the protein stability of claudin 1. Moreover, the increased level of claudin 1 stimulated autophagy by decreasing the level of the autophagy substrate, sequestosome1/p62 (SQSTM1), under autophagy-inducing conditions; activation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR). Taken together, we demonstrate that the novel function of cytoplasmic claudin 1 is related to autophagy. This study is the first to show a cytoplasmic function of claudin 1 as an autophagy regulator and provides the evidence that claudin 1 mediated autophagy regulation is an integral part of the mechanism by which claudin 1 regulates cancer progression. (C) 2018 Elsevier Inc. All rights reserved.	[Kim, Jaewhan; Choi, Sunkyung; Kim, Kee K.] Chungnam Natl Univ, Coll Nat Sci, Dept Biochem, Daejeon 34134, South Korea; [Kim, Jong Ok] Catholic Univ Korea, Daejeon St Marys Hosp, Dept Pathol, Daejeon 34943, South Korea		Kim, KK (corresponding author), Chungnam Natl Univ, Coll Nat Sci, Dept Biochem, Daejeon 34134, South Korea.; Kim, JO (corresponding author), Catholic Univ Korea, Daejeon St Marys Hosp, Dept Pathol, Daejeon 34943, South Korea.	jkim@catholic.ac.kr; kimkk@cnu.ac.kr	Kim, Kee/F-8784-2011	Kim, Keekwang/0000-0002-1088-3383	National Research Foundation of Korea through the Ministry of Education [NRF-2015R1C1A1A02036324]	This work was supported by the National Research Foundation of Korea within the Basic Science Research Program through the Ministry of Education under Grant NRF-2015R1C1A1A02036324.	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Biophys. Res. Commun.	JAN 29	2018	496	1					159	166		10.1016/j.bbrc.2018.01.017			8	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	FU7YF	WOS:000424068000026	29307823				2022-04-25	
J	Bae, H; Lee, W; Song, J; Hong, T; Kim, MH; Ham, J; Song, G; Lim, W				Bae, Hyocheol; Lee, Woonghee; Song, Jisoo; Hong, Taeyeon; Kim, Myung Hyun; Ham, Jiyeon; Song, Gwonhwa; Lim, Whasun			Polydatin Counteracts 5-Fluorouracil Resistance by Enhancing Apoptosis via Calcium Influx in Colon Cancer	ANTIOXIDANTS			English	Article						polydatin; colon cancer; calcium; apoptosis; 5-fluorouracil	ENDOPLASMIC-RETICULUM STRESS; ER STRESS; INTRACELLULAR CA2+; AUTOPHAGY; CELLS; INDUCE; INJURY	Colon cancer is a disease with a high prevalence rate worldwide, and for its treatment, a 5-fluorouracil (5-FU)-based chemotherapeutic strategy is generally used. However, conventional anticancer agents have some limitations, including the development of drug resistance. Therefore, there has recently been a demand for the improvement of antitumor agents using natural products with low side effects and high efficacy. Polydatin is a natural active compound extracted from an annual plant, and widely known for its anticancer effects in diverse types of cancer. However, it is still not clearly understood how polydatin ameliorates several drawbacks of standard anticancer drugs by reinforcing the chemosensitivity against 5-FU, and neither are the intrinsic mechanisms behind this process. In this study, we examined how polydatin produces anticancer effects in two types of colon cancer, called HCT116 and HT-29 cells. Polydatin has the ability to repress the progression of colon cancer, and causes a modification of distribution in the cell cycle by a flow cytometry analysis. It also induces mitochondrial dysfunctions through oxidative stress and the loss of mitochondrial membrane potential. The present study investigated the apoptosis caused by the disturbance of calcium regulation and the expression levels of related proteins through flow cytometry and immunoblotting analysis. It was revealed that polydatin suppresses the signaling pathways of the mitogen-activated protein kinase (MAPK) and PI3K/AKT. In addition, it was shown that polydatin combined with 5-FU counteracts drug resistance in 5-FU-resistant cells. Therefore, this study suggests that polydatin has the potential to be developed as an innovative medicinal drug for the treatment of colon cancer.	[Bae, Hyocheol] Kyung Hee Univ, Coll Life Sci, Dept Oriental Biotechnol, Yongin 17104, South Korea; [Lee, Woonghee; Ham, Jiyeon; Song, Gwonhwa] Korea Univ, Coll Life Sci & Biotechnol, Inst Anim Mol Biotechnol, Dept Biotechnol, Seoul 02841, South Korea; [Song, Jisoo; Hong, Taeyeon; Lim, Whasun] Kookmin Univ, Coll Sci & Technol, Dept Food & Nutr, Seoul 02707, South Korea; [Kim, Myung Hyun] Sookmyung Womens Univ, Dept Food & Nutr, Seoul 04310, South Korea		Song, G (corresponding author), Korea Univ, Coll Life Sci & Biotechnol, Inst Anim Mol Biotechnol, Dept Biotechnol, Seoul 02841, South Korea.; Lim, W (corresponding author), Kookmin Univ, Coll Sci & Technol, Dept Food & Nutr, Seoul 02707, South Korea.	bhc7@khu.ac.kr; cleverwhl@korea.ac.kr; js_song97@kookmin.ac.kr; taeyeon97@kookmin.ac.kr; kimmh@sookmyung.ac.kr; glorijy76@korea.ac.kr; ghsong@korea.ac.kr; wlim@kookmin.ac.kr	Lim, Whasun/AAP-3156-2020; Bae, Hyocheol/AAS-7245-2021	Lim, Whasun/0000-0002-1328-0465; Bae, Hyocheol/0000-0002-9643-7797	National Research Foundation of Korea (NRF) - Korea government (MSIT) [2019R1A2C2089914, 2021R1A2C2005841, 2021R1C1C1009807]	This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT). (No. 2019R1A2C2089914& 2021R1A2C2005841& 2021R1C1C1009807).	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J	Smith, E; Palethorpe, HM; Tomita, Y; Pei, JXV; Townsend, AR; Price, TJ; Young, JP; Yool, AJ; Hardingham, JE				Smith, Eric; Palethorpe, Helen M.; Tomita, Yoko; Pei, Jinxin, V; Townsend, Amanda R.; Price, Timothy J.; Young, Joanne P.; Yool, Andrea J.; Hardingham, Jennifer E.			The Purified Extract from the Medicinal Plant Bacopa monnieri, Bacopaside II, Inhibits Growth of Colon Cancer Cells In Vitro by Inducing Cell Cycle Arrest and Apoptosis	CELLS			English	Article						Bacopa monnieri; bacopaside II; colorectal cancer; anti-tumour agents; aquaporin-1; cell cycle arrest; apoptosis	TRITERPENE SAPONINS; GLYCOSIDES; AUTOPHAGY	Aquaporin-1 (AQP1), a transmembrane pore-forming molecule, facilitates the rapid movement of water and small solutes across cell membranes. We have previously shown that bacopaside II, an extract from the medicinal herb Bacopa monnieri, blocks the AQP1 water channel and impairs migration of cells that express AQP1. The aim of this study was to further elucidate the anti-tumour potential of bacopaside II in colon cancer cells. Expression of AQP1 in HT-29, SW480, SW620 and HCT116 was determined by quantitative PCR and western immunoblot. Cells were treated with bacopaside II, and morphology, growth, autophagy, cell cycle and apoptosis assessed by time-lapse microscopy, crystal violet, acridine orange, propidium iodide (PI) and annexin V/PI staining respectively. AQP1 expression was significantly higher in HT-29 than SW480, SW620 and HCT116. Bacopaside II significantly reduced growth at >20 mu M for HT-29 and >15 mu M for SW480, SW620 and HCT116. Inhibition of HT-29 at 20 mu M was primarily mediated by G0/G1 cell cycle arrest, and at 30 mu M by G2/M arrest and apoptosis. Inhibition of SW480, SW620 and HCT116 at >15 mu M was mediated by G2/M arrest and apoptosis. These results are the first to show that bacopaside II inhibits colon cancer cell growth by inducing cell cycle arrest and apoptosis.	[Smith, Eric; Palethorpe, Helen M.; Tomita, Yoko; Hardingham, Jennifer E.] Queen Elizabeth Hosp, Basil Hetzel Inst, Mol Oncol, Woodville South, SA 5011, Australia; [Smith, Eric; Palethorpe, Helen M.; Tomita, Yoko; Pei, Jinxin, V; Townsend, Amanda R.; Price, Timothy J.; Young, Joanne P.; Yool, Andrea J.; Hardingham, Jennifer E.] Univ Adelaide, Adelaide Med Sch, Adelaide, SA 5000, Australia; [Townsend, Amanda R.; Price, Timothy J.] Queen Elizabeth Hosp, Med Oncol, Woodville South, SA 5011, Australia		Hardingham, JE (corresponding author), Queen Elizabeth Hosp, Basil Hetzel Inst, Mol Oncol, Woodville South, SA 5011, Australia.; Hardingham, JE (corresponding author), Univ Adelaide, Adelaide Med Sch, Adelaide, SA 5000, Australia.	eric.smith@adelaide.edu.au; helen.palethorpe@adelaide.edu.au; yoko.tomita@sa.gov.au; jinxin.pei@adelaide.edu.au; amanda.townsend@sa.gov.au; timothy.price@sa.gov.au; joanne.young@adelaide.edu.au; andrea.yool@adelaide.edu.au; jenny.hardingham@sa.gov.au	Palethorpe, Helen Marie/AAC-4219-2022; Yool, Andrea/AAK-9907-2020; Smith, Eric/ABG-7104-2020	Palethorpe, Helen Marie/0000-0003-3803-5113; Yool, Andrea/0000-0003-1283-585X; Smith, Eric/0000-0003-2958-3492; Tomita, Yoko/0000-0001-7934-2203			Aguiar S, 2013, REJUV RES, V16, P313, DOI 10.1089/rej.2013.1431; Blanc L, 2009, BLOOD, V114, P3928, DOI 10.1182/blood-2009-06-230086; Chakravarty AK, 2002, CHEM PHARM BULL, V50, P1616, DOI 10.1248/cpb.50.1616; Das DN, 2016, PHYTOTHER RES, V30, P1794, DOI 10.1002/ptr.5682; Dorward HS, 2016, J EXP CLIN CANC RES, V35, DOI 10.1186/s13046-016-0310-6; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Fosang AJ, 2015, J BIOL CHEM, V290, P29692, DOI 10.1074/jbc.E115.000002; Garai S, 1996, PHYTOCHEMISTRY, V42, P815, DOI 10.1016/0031-9422(95)00936-1; Mallick MN, 2017, PHARMACOGN MAG, V13, pS595, DOI 10.4103/pm.pm_397_16; Mallick MN, 2015, J PHARM BIOALLIED SC, V7, P325, DOI 10.4103/0975-7406.168038; Paglin S, 2001, CANCER RES, V61, P439; Palethorpe HM, 2018, INT J MOL SCI, V19, DOI 10.3390/ijms19030653; Palethorpe HM, 2017, DIGEST DIS SCI, V62, P3402, DOI 10.1007/s10620-017-4794-5; Pei JXV, 2016, MOL PHARMACOL, V90, P496, DOI 10.1124/mol.116.105882; Peng L, 2010, PHYTOTHER RES, V24, P864, DOI 10.1002/ptr.3034; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Singh R, 2015, XENOBIOTICA, V45, P741, DOI 10.3109/00498254.2015.1017752; Sivaramakrishna C, 2005, PHYTOCHEMISTRY, V66, P2719, DOI 10.1016/j.phytochem.2005.09.016; Smith E, 2016, DIGEST DIS SCI, V61, P433, DOI 10.1007/s10620-015-3909-0; Van Cutsem E, 2016, ANN ONCOL, V27, P1386, DOI 10.1093/annonc/mdw235; Young PE, 2014, J CANCER, V5, P262, DOI 10.7150/jca.7988; Zhou Y, 2007, J NAT PROD, V70, P652, DOI 10.1021/np060470s	22	28	29	0	4	MDPI	BASEL	ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND		2073-4409		CELLS-BASEL	Cells	JUL	2018	7	7							81	10.3390/cells7070081			11	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	GO7BG	WOS:000440209500018	30037060	gold, Green Published			2022-04-25	
J	He, QL; Li, ZQ; Yin, JB; Li, YL; Yin, YT; Lei, X; Zhu, W				He, Qinglian; Li, Ziqi; Yin, Jinbao; Li, Yuling; Yin, Yuting; Lei, Xue; Zhu, Wei			Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer	FRONTIERS IN ONCOLOGY			English	Article						colorectal cancer; autophagy; prognostic model; splicing; markers	COLON-CANCER; SIGNATURE; IDENTIFICATION; VALIDATION; DEATH; CELLS	Background Colorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. However, there is no consensus on the value of autophagy-associated genes in predicting the prognosis of CRC patients. This work screens autophagy-related markers and signaling pathways that may participate in the development of CRC, and establishes a prognostic model of CRC based on autophagy-associated genes. Methods Gene transcripts from the TCGA database and autophagy-associated gene data from the GeneCards database were used to obtain expression levels of autophagy-associated genes, followed by Wilcox tests to screen for autophagy-related differentially expressed genes. Then, 11 key autophagy-associated genes were identified through univariate and multivariate Cox proportional hazard regression analysis and used to establish prognostic models. Additionally, immunohistochemical and CRC cell line data were used to evaluate the results of our three autophagy-associated genes EPHB2, NOL3, and SNAI1 in TCGA. Based on the multivariate Cox analysis, risk scores were calculated and used to classify samples into high-risk and low-risk groups. Kaplan-Meier survival analysis, risk profiling, and independent prognosis analysis were carried out. Receiver operating characteristic analysis was performed to estimate the specificity and sensitivity of the prognostic model. Finally, GSEA, GO, and KEGG analysis were performed to identify the relevant signaling pathways. Results A total of 301 autophagy-related genes were differentially expressed in CRC. The areas under the 1-year, 3-year, and 5-year receiver operating characteristic curves of the autophagy-based prognostic model for CRC were 0.764, 0.751, and 0.729, respectively. GSEA analysis of the model showed significant enrichment in several tumor-relevant pathways and cellular protective biological processes. The expression of EPHB2, IL-13, MAP2, RPN2, and TRAF5 was correlated with microsatellite instability (MSI), while the expression of IL-13, RPN2, and TRAF5 was related to tumor mutation burden (TMB). GO analysis showed that the 11 target autophagy genes were chiefly enriched in mRNA processing, RNA splicing, and regulation of the mRNA metabolic process. KEGG analysis showed enrichment mainly in spliceosomes. We constructed a prognostic risk assessment model based on 11 autophagy-related genes in CRC. Conclusion A prognostic risk assessment model based on 11 autophagy-associated genes was constructed in CRC. The new model suggests directions and ideas for evaluating prognosis and provides guidance to choose better treatment strategies for CRC.	[He, Qinglian; Li, Ziqi; Yin, Jinbao; Yin, Yuting; Lei, Xue; Zhu, Wei] Guangdong Med Univ, Dept Pathol, Dongguan, Peoples R China; [Li, Yuling] Southern Med Univ, Dongguan Peoples Hosp, Dept Pathol, Dongguan, Peoples R China		Zhu, W (corresponding author), Guangdong Med Univ, Dept Pathol, Dongguan, Peoples R China.	zhuwei@gdmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472275, 81702399]; Guangdong Basic and Applied Basic Research Foundation [2020A151501303, 2014A030313542, 2017A030313618]	This work was supported by the National Natural Science Foundation of China (81472275, 81702399) and the Guangdong Basic and Applied Basic Research Foundation (2020A151501303, 2014A030313542, 2017A030313618).	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Oncol.	APR 15	2021	11								566539	10.3389/fonc.2021.566539			16	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	RU3CV	WOS:000645027700001	33937013	gold, Green Published			2022-04-25	
J	Wu, WKK; Volta, V; Cho, CH; Wu, YC; Li, HT; Yu, L; Li, ZJ; Sung, JJY				Wu, William Ka Kei; Volta, Viviana; Cho, Chi Hin; Wu, Ya Chun; Li, Hai Tao; Yu, Le; Li, Zhi Jie; Sung, Joseph Jao Yiu			Repression of protein translation and mTOR signaling by proteasome inhibitor in colon cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Proteasome; Colon cancer; Proliferation; Protein translation; Mammalian target of rapamycin	MAMMALIAN TARGET; DEGRADATION; MG-132; P53; UBIQUITINATION; PROLIFERATION; MECHANISMS; BORTEZOMIB; APOPTOSIS; AUTOPHAGY	Protein homeostasis relies on a balance between protein synthesis and protein degradation. The ubiquitin-proteasome system is a major catabolic pathway for protein degradation. In this respect, proteasome inhibition has been used therapeutically for the treatment of cancer. Whether inhibition of protein degradation by proteasome inhibitor can repress protein translation via a negative feedback mechanism, however, is unknown. In this study, proteasome inhibitor MG-132 lowered the proliferation of colon cancer cells HT-29 and SW1116. In this connection, MG-132 reduced the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and Ser2481 and the phosphorylation of its downstream targets 4E-BP1 and p70/p85 S6 kinases. Further analysis revealed that MG-132 inhibited protein translation as evidenced by the reductions of S-35-methionine incorporation and polysomes/80S ratio. Knockdown of raptor, a structural component of mTOR complex 1, mimicked the anti-proliferative effect of MG-132. To conclude, we demonstrate that the inhibition of protein degradation by proteasome inhibitor represses mTOR signaling and protein translation in colon cancer cells. (C) 2009 Elsevier Inc. All rights reserved.	[Wu, William Ka Kei; Cho, Chi Hin; Yu, Le; Sung, Joseph Jao Yiu] Chinese Univ Hong Kong, Fac Med, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China; [Wu, William Ka Kei; Sung, Joseph Jao Yiu] Chinese Univ Hong Kong, Fac Med, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China; [Wu, William Ka Kei; Cho, Chi Hin; Wu, Ya Chun; Li, Hai Tao; Yu, Le; Li, Zhi Jie] Chinese Univ Hong Kong, Fac Med, Dept Pharmacol, Hong Kong, Hong Kong, Peoples R China; [Volta, Viviana] Ist Sci San Raffaele, DiBiT, Mol Histol & Cellular Growth Unit, Milan, Italy		Cho, CH (corresponding author), Chinese Univ Hong Kong, Fac Med, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China.	wukakei@cuhk.edu.hk; chcho@cuhk.edu.hk; joesung@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; Volta, Viviana/0000-0001-9999-3732	Hong Kong Research Grants CouncilHong Kong Research Grants Council [CUHK7499/05M]	This work was supported by the Hong Kong Research Grants Council (CUHK7499/05M).	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Biophys. Res. Commun.	SEP 4	2009	386	4					598	601		10.1016/j.bbrc.2009.06.080			4	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	476RS	WOS:000268462100010	19540199				2022-04-25	
J	Revelant, G; Huber-Villaume, S; Dunand, S; Kirsch, G; Schohn, H; Hesse, S				Revelant, Germain; Huber-Villaume, Sophie; Dunand, Sandrine; Kirsch, Gilbert; Schohn, Herve; Hesse, Stephanie			Synthesis and biological evaluation of novel 2-heteroarylimino-1,3-thiazolidin-4-ones as potential anti-tumor agents	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY			English	Article						Thiazolidinone; Thiophene; Thiazole; Antiproliferative activity; Colon cancer	CANCER-CELLS; THIAZOLIDINONE DERIVATIVES; 4-THIAZOLIDINONES; INHIBITORS; AUTOPHAGY; DESIGN	A series of 35 heteroarylimino-1,3-thiazolidinones with three sites of functionalization were synthesized and their antiproliferative properties were studied. The in vitro screening by MTT assay was performed against five cancer cell lines (human colon cancer cell lines HT29, HCT116 and SW620 and breast cancer cell lines MCF7 and MDA-MB-231). It was observed that N3-substituted thiazolidinones had moderate activities whereas 5-benzylidene thiazolidinones showed promising activities. To investigate the mechanism of action, detailed biological studies of six selected compounds (those presenting the lower mitotic index) were carried out on the human colon cancer HT29 cell line. Cell cycle assay revealed that those compounds induced cell accumulation in G2/M and in subG0/G1 phases of cell cycle. Moreover, dissipation of mitochondria membrane potential was observed as well as redox changes in treated cells. (C) 2015 Elsevier Masson SAS. All rights reserved.	[Revelant, Germain; Dunand, Sandrine; Kirsch, Gilbert; Hesse, Stephanie] Univ Lorraine, Equipe HECRIN 3, UMR CNRS 7565, Struct & React Syst Mol Complexes, F-57070 Metz Technople, France; [Huber-Villaume, Sophie; Schohn, Herve] Univ Lorraine, Equipe 2MIC 5, UMR CNRS 7565, Struct & React Syst Mol Complexes, F-57070 Metz, France		Hesse, S (corresponding author), Univ Lorraine, Equipe HECRIN 3, UMR CNRS 7565, Struct & React Syst Mol Complexes, 1 Blvd Arago, F-57070 Metz Technople, France.	herve.schohn@univ-lorraine.fr; stephanie.hesse@univ-lorraine.fr			Ministere de l'Enseignement Superieur et de la Recherche	We thank the 'Ministere de l'Enseignement Superieur et de la Recherche' for Ph.D. grants to G.R. and S. H.-V.	Abdillahi I, 2010, SYNTHESIS-STUTTGART, P2543, DOI 10.1055/s-0029-1218780; Deep A, 2014, ARAB J CHEM, V7, P287, DOI 10.1016/j.arabjc.2010.10.032; Dodson M, 2013, FREE RADICAL BIO MED, V63, P207, DOI 10.1016/j.freeradbiomed.2013.05.014; Hippert MM, 2006, CANCER RES, V66, P9349, DOI 10.1158/0008-5472.CAN-06-1597; Jain AK, 2012, BIOORGAN MED CHEM, V20, P3378, DOI 10.1016/j.bmc.2012.03.069; Lewicki K, 2006, TALANTA, V70, P876, DOI 10.1016/j.talanta.2006.02.009; Liu ZH, 2007, DEV CELL, V12, P484, DOI 10.1016/j.devcel.2007.03.016; LOWRY OH, 1951, J BIOL CHEM, V193, P265; Maccari R, 2014, EUR J MED CHEM, V81, P1, DOI 10.1016/j.ejmech.2014.05.003; Nikalje APG, 2014, BIOORG MED CHEM LETT, V24, P5558, DOI 10.1016/j.bmcl.2014.11.016; Niture SK, 2010, TOXICOL APPL PHARM, V244, P37, DOI 10.1016/j.taap.2009.06.009; Omar K, 2010, BIOORGAN MED CHEM, V18, P426, DOI 10.1016/j.bmc.2009.10.041; Ottana R, 2005, BIOORG MED CHEM LETT, V15, P3930, DOI 10.1016/j.bmcl.2005.05.093; Pasquier E, 2006, DRUG RESIST UPDATE, V9, P74, DOI 10.1016/j.drup.2006.04.003; Revelant G, 2011, TETRAHEDRON, V67, P9352, DOI 10.1016/j.tet.2011.09.134; Revelant G, 2010, SYNTHESIS-STUTTGART, P3319, DOI 10.1055/s-0030-1257867; Teraishi F, 2005, CANCER RES, V65, P6380, DOI 10.1158/0008-5472.CAN-05-0575; Trachootham D, 2009, NAT REV DRUG DISCOV, V8, P579, DOI 10.1038/nrd2803; Tripathi AC, 2014, EUR J MED CHEM, V72, P52, DOI 10.1016/j.ejmech.2013.11.017; UNANGST PC, 1994, J MED CHEM, V37, P322, DOI 10.1021/jm00028a017; Vassilev LT, 2006, P NATL ACAD SCI USA, V103, P10660, DOI 10.1073/pnas.0600447103; Vicini P, 2008, BIOORGAN MED CHEM, V16, P3714, DOI 10.1016/j.bmc.2008.02.001; Wang SB, 2011, EUR J MED CHEM, V46, P3509, DOI 10.1016/j.ejmech.2011.05.017; Wu JF, 2014, FOOD CHEM TOXICOL, V64, P307, DOI 10.1016/j.fct.2013.12.006; Xie T, 1996, BIOCHEM PHARMACOL, V51, P771, DOI 10.1016/0006-2952(95)02394-1; Xu S., 2006, MED CHEM, P597; Zhou HY, 2008, J MED CHEM, V51, P1242, DOI 10.1021/jm7012024	27	29	29	0	17	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER	PARIS	23 RUE LINOIS, 75724 PARIS, FRANCE	0223-5234	1768-3254		EUR J MED CHEM	Eur. J. Med. Chem.	APR 13	2015	94						102	112		10.1016/j.ejmech.2015.02.053			11	Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED); Index Chemicus (IC)	Pharmacology & Pharmacy	CH0RU	WOS:000353730900010	25757093				2022-04-25	
J	Matsumoto, N; Yoshikawa, K; Shimada, M; Kurita, N; Sato, H; Iwata, T; Higashijima, J; Chikakiyo, M; Nishi, M; Kashihara, H; Takasu, C; Eto, S; Takahashi, A; Akutagawa, M; Emoto, T				Matsumoto, Noriko; Yoshikawa, Kozo; Shimada, Mitsuo; Kurita, Nobuhiro; Sato, Hirohiko; Iwata, Takashi; Higashijima, Jun; Chikakiyo, Motoya; Nishi, Masaaki; Kashihara, Hideya; Takasu, Chie; Eto, Shohei; Takahashi, Akira; Akutagawa, Masatake; Emoto, Takahiro			Effect of Light Irradiation by Light Emitting Diode on Colon Cancer Cells	ANTICANCER RESEARCH			English	Article						Light-emitting diode; colon cancer; HT29; HCT116 cells	RED-LIGHT; AUTOPHAGY; GROWTH; DEATH; LASER; APOPTOSIS; PATHWAYS; THERAPY	Background/Aim: Recent studies have demonstrated the efficacy of irradiation from light emitting diodes (LED) for wound healing, anti-inflammation and anticancer therapies. However, little is known about the effects of visible light in colon cancer cells. The purpose of this study was to evaluate the biological response (including gene expression changes) of human colon cancer cells to different wavelengths of LED irradiation. Materials and Methods: Human colon cancer cells (HT29 or HCT116) were seeded onto laboratory dishes that were then put on LED irradiation equipment with a 465 nm-, 525 nm-, or 635 nm-LED. Irradiation at 15 or 30 mW was performed 10 min/day, each day for 5 days. The cell counting kit8 was then used to measure cell viability. Apoptosis and expression of several mRNAs (caspase, MAPK and autophagy pathway) in HT29 cultures irradiated with 465 nm LED were evaluated via AnnexinV/PI and RT-PCR, respectively. Results: Viability of HT29 and HCT116 cells was lower in 465 nm-LED irradiated cultures than in control cultures, but viability of HT29 cells did not differ between control cultures and 525 nm-LED or 635 nm-LED irradiated cultures. Moreover, the expression of FAS, caspase-3, capase-8, and JUK were significantly higher in 465 nm-LED irradiated cultures than in control cultures, and expression of ERK1/2 and LC3 was lower in blue-irradiated cells. Conclusion: LED irradiation at 465 nm inhibited the proliferation of HT29 cells and of HCT116 cells. Notably, LED irradiation at 465 nm promoted apoptosis inHT29 cultures via the extrinsic apoptosis pathway and the MAPK pathway.	[Matsumoto, Noriko; Yoshikawa, Kozo; Shimada, Mitsuo; Kurita, Nobuhiro; Sato, Hirohiko; Iwata, Takashi; Higashijima, Jun; Chikakiyo, Motoya; Nishi, Masaaki; Kashihara, Hideya; Takasu, Chie; Eto, Shohei] Univ Tokushima, Inst Hlth Biosci, Dept Surg, Tokushima 7708503, Japan; [Takahashi, Akira] Univ Tokushima, Inst Hlth Biosci, Dept Prevent Environm & Nutr, Tokushima 770, Japan; [Akutagawa, Masatake; Emoto, Takahiro] Univ Tokushima, Inst Sci & Technol, Dept Life Syst, Tokushima 770, Japan		Yoshikawa, K (corresponding author), Univ Tokushima, Inst Hlth Biosci, Dept Surg, Grad Sch, 3-18-15 Kuramoto Cho, Tokushima 7708503, Japan.	yoshikawa.kozo@tokushima-u.ac.jp					Almeida RD, 2004, BBA-REV CANCER, V1704, P59, DOI 10.1016/j.bbcan.2004.05.003; Canu N, 2005, J NEUROCHEM, V92, P1228, DOI 10.1111/j.1471-4159.2004.02956.x; de Sousa APC, 2013, LASER MED SCI, V28, P981, DOI 10.1007/s10103-012-1187-z; Agnol MAD, 2009, LASER MED SCI, V24, P909, DOI 10.1007/s10103-009-0648-5; 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; Dhillon AS, 2007, ONCOGENE, V26, P3279, DOI 10.1038/sj.onc.1210421; Dikic I, 2010, CANCER RES, V70, P3431, DOI 10.1158/0008-5472.CAN-09-4027; Dougherty TJ, 1998, JNCI-J NATL CANCER I, V90, P889, DOI 10.1093/jnci/90.12.889; Fiandalo M. V., 2012, Experimental Oncology, V34, P165; Glick D, 2010, J PATHOL, V221, P3, DOI 10.1002/path.2697; Greco C, 2007, CANCER-AM CANCER SOC, V109, P1227, DOI 10.1002/cncr.22542; Green DR, 2005, CELL, V121, P671, DOI 10.1016/j.cell.2005.05.019; Jemal A, 2011, CA-CANCER J CLIN, V61, P69, DOI [10.3322/caac.20107, 10.3322/caac.20115]; Kim EK, 2010, BIOCHIM BIOPHYS ACTA, V1802, P396, DOI DOI 10.1016/J.BBADIS.2009.12.009; Kim HK, 2009, LASER MED SCI, V24, P214, DOI 10.1007/s10103-008-0550-6; Klionsky DJ, 2007, NAT REV MOL CELL BIO, V8, P931, DOI 10.1038/nrm2245; Kroemer G, 2005, NAT REV CANCER, V5, P886, DOI 10.1038/nrc1738; Mulsow J, 2011, BRIT J SURG, V98, P1785, DOI 10.1002/bjs.7653; Ohara M, 2002, JPN J CANCER RES, V93, P551, DOI 10.1111/j.1349-7006.2002.tb01290.x; Peng Q, 1997, CANCER-AM CANCER SOC, V79, P2282; Reinhold T, 2007, PLANT J, V50, P293, DOI 10.1111/j.1365-313X.2007.03049.x; Schindl A, 1999, J AM ACAD DERMATOL, V40, P481, DOI 10.1016/S0190-9622(99)70503-7; Seo YK, 2014, LASER MED SCI, V29, P245, DOI 10.1007/s10103-013-1322-5; Sivaprasad U, 2008, J CELL MOL MED, V12, P1265, DOI 10.1111/j.1582-4934.2008.00282.x; Vinck EM, 2005, PHOTOMED LASER SURG, V23, P167, DOI 10.1089/pho.2005.23.167; Walker NA, 2007, J ATHL TRAINING, V42, P530; Xavier M, 2010, LASER SURG MED, V42, P553, DOI 10.1002/lsm.20896; Zhang L, 2009, J RADIAT RES, V50, P109, DOI 10.1269/jrr.08003	29	17	17	1	5	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.	SEP	2014	34	9					4709	4716					8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AP1VS	WOS:000341860700010	25202048				2022-04-25	
J	Jing, ZL; He, XY; Jia, ZR; Sa, YL; Yang, BL; Liu, P				Jing, Zuolei; He, Xinyuan; Jia, Zhirong; Sa, Yunli; Yang, Bolin; Liu, Ping			NCAPD2 inhibits autophagy by regulating Ca2+/CAMKK2/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis to promote colorectal cancer	CANCER LETTERS			English	Article						Colorectal cancer; NCAPD2; Autophagy; PARP-1/SIRT1; CAMKK/AMPK pathway	CHROMOSOME 12P13 LOCUS; CELL-DEATH; PROTEIN; MTOR; TUMORIGENESIS; CONDENSATION; METABOLISM; INTERACTS; HOMOLOG; DISEASE	Non-SMC condensin I complex subunit D2 (NCAPD2) is one of the three non-SMC subunits in condensin I. Previous studies have shown that NCAPD2 plays an important role in the chromosome condensation and segregation. However, its role in the development of colorectal cancer (CRC) and specific molecular mechanisms still need to be further studied. Here we show that NCAPD2 inhibits autophagy and blocks autophagic flux via Ca2+/CAMKK/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis. NCAPD2 acts as a tumor promoter both in vitro and in vivo. NCAPD2 knockout suppresses colorectal cancer development in AOM/DSS induced mice model. Therefore, our findings support a role for NCAPD2 in autophagy to promote CRC development and highlight NCAPD2 as a potential target for CRC therapy.	[Jing, Zuolei; He, Xinyuan; Jia, Zhirong; Sa, Yunli; Liu, Ping] Nanjing Normal Univ, Coll Life Sci, 1 Wenyuan Rd, Nanjing 210023, Jiangsu, Peoples R China; [Yang, Bolin] Nanjing Univ Chinese Med, Dept Colorectal Surg, Jiangsu Prov Hosp Chinese Med, Affiliated Hosp, Nanjing, Jiangsu, Peoples R China		Jing, ZL; Liu, P (corresponding author), Nanjing Normal Univ, Coll Life Sci, 1 Wenyuan Rd, Nanjing 210023, Jiangsu, Peoples R China.	Jingzuolei0212@163.com; liuping0805@njnu.edu.cn		Jing, Zuolei/0000-0002-0749-2197; Liu, Ping/0000-0001-5366-4618	National Natural Science Foundation of China (NNSFC)National Natural Science Foundation of China (NSFC) [81872104, 81472415]	This work was supported by the National Natural Science Foundation of China (NNSFC) (grant no. 81872104 and 81472415) .	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NOV 1	2021	520						26	37		10.1016/j.canlet.2021.06.029		JUL 2021	12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	UR7MB	WOS:000696927600003	34229059				2022-04-25	
J	Wang, YY; Zhao, Z; Zhuang, J; Wu, XX; Wang, ZZ; Zhang, B; Gao, G; Zhang, YP; Guo, CL; Xia, QX				Wang, Yuanyuan; Zhao, Zhi; Zhuang, Jing; Wu, Xinxin; Wang, Zhizhong; Zhang, Bing; Gao, Ge; Zhang, Yinping; Guo, Caili; Xia, Qingxin			Prognostic Value of Autophagy, Microsatellite Instability, and KRAS Mutations in Colorectal Cancer	JOURNAL OF CANCER			English	Article						Beclin 1; LC3; MSI; KRAS; prognosis; CRC	CLINICAL-PRACTICE GUIDELINES; WILD-TYPE KRAS; COLON-CANCER; STAGE-II; BRAF; CHEMOTHERAPY; SURVIVAL; REPAIR; 5-FLUOROURACIL; FLUOROURACIL	Introduction: Autophagy plays pivotal role in various tumors, including colorectal cancer (CRC). Microsatellite instability (MSI) and KRAS mutations are also involved in response to the adjuvant therapy of CRC. We aimed to investigate the relationships among autophagy, KRAS mutations, MSI, clinicopathological parameters, and prognosis in CRC patients. Methods and Results: We tested 200 CRC tumors for autophagy-related protein expression (Beclin 1 and LC3), MSI status, and KRAS mutations. Results: Expression of Beclin 1 and LC3 was higher in CRC, with Beclin 1 significantly correlating with the depth of invasion, whereas LC3 was not associated with clinicopathological parameters. Patients expressing the LC3 proteins experienced a shorter overall survival (OS) after surgery with adjuvant therapy, especially in the MSS/L-CRC subgroup and the mutated KRAS subgroup. MSS/L-CRC patients with KRAS mutations positively expressed the LC3 protein and suffered a shorter OS than LC3 non-expressing patients. In CRC patients who received either capecitabine or capecitabine combined with oxaliplatin post-surgery, the positive expression of LC3 correlated with worse OS compared to patients who did not express LC3. Sequencing showed BRCA1/2 as the most variant genes in all patients. Nevertheless, deleterious variations were more frequent in patients with MSI-H CRC. Conclusions: High LC3 protein expression shows a certain prognostic value in CRC patients. LC3, the MSI status, and KRAS mutations must be considered when selecting an adjuvant therapy for CRC. The detection of these indexes is of great significance to identify high-risk patients who would benefit from autophagy-related anticancer drugs or help to explore more effective treatment options for patients who are resistant to conventional chemotherapy or relapse.	[Wang, Yuanyuan; Zhang, Bing; Gao, Ge; Zhang, Yinping; Xia, Qingxin] Zhengzhou Univ, Affiliated Canc Hosp, Henan Canc Hosp, Dept Pathol, 127 Dongming Rd, Zhengzhou 450008, Henan, Peoples R China; [Zhao, Zhi] Henan Univ, Yihe Hosp, Dept Pathol, 69 Agr East Rd, Zhengzhou 450008, Peoples R China; [Zhuang, Jing] Zhengzhou Univ, Affiliated Canc Hosp, Henan Canc Hosp, Dept Gen Surg, 127 Dongming Rd, Zhengzhou 450008, Peoples R China; [Wu, Xinxin; Wang, Zhizhong] Zhengzhou Univ, Affiliated Canc Hosp, Henan Canc Hosp, Dept Mol Pathol, 127 Dongming Rd, Zhengzhou 450008, Peoples R China; [Guo, Caili] Zhengzhou Univ, Affiliated Childrens Hosp, Dept Crit Care Med, 255 Gangdu Rd,Dongsan St, Zhengzhou 450008, Peoples R China		Xia, QX (corresponding author), Zhengzhou Univ, Affiliated Canc Hosp, Henan Canc Hosp, Dept Pathol, 127 Dongming Rd, Zhengzhou 450008, Henan, Peoples R China.; Guo, CL (corresponding author), Zhengzhou Univ, Affiliated Childrens Hosp, Dept Crit Care Med, 255 Gangdu Rd,Dongsan St, Zhengzhou 450008, Peoples R China.	guocaili8888@163.com; tudou414135404@163.com			Medical Technology Research and Development Program of Henan Province [201701029, 182102310343]	This work was supported by The Medical Technology Research and Development Program of Henan Province [grant numbers 201701029, 182102310343].	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Cancer		2021	12	12					3515	3528		10.7150/jca.51430			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	RZ4TW	WOS:000648591100010	33995628	gold, Green Published			2022-04-25	
J	Zhu, DR; Chen, C; Xia, YZ; Kong, LY; Luo, JG				Zhu, Dongrong; Chen, Chen; Xia, Yuanzheng; Kong, Ling-Yi; Luo, Jianguang			A Purified Resin Glycoside Fraction from Pharbitidis Semen Induces Paraptosis by Activating Chloride Intracellular Channel-1 in Human Colon Cancer Cells	INTEGRATIVE CANCER THERAPIES			English	Article						Pharbitidis Semen; resin glycoside; paraptosis; CLIC1; cytoplasmic vacuolization	SEEDS; AUTOPHAGY; DEATH	Pharbitidis Semen has worldwide recognition in traditional medicine for the treatment of several illnesses apart from its purgative properties, and it is also reported to show anticancer effect. However, limited pharmacological studies are available on the extract or resin glycosides fraction of Pharbitidis Semen. The purpose of this study was to determine the mechanism of the colon cancer cell cytotoxic effect of a purified resin glycoside fraction from Pharbitidis Semen (RFP). Our results showed that the RFP-induced cell death was mediated by the caspase-independent and autophagy-protective paraptosis, a type of cell death that is characterized by the accumulation of cytoplasmic vacuoles and mitochondria swelling. RFP significantly stimulated endoplasmic reticulum stress, inhibited proteasome-dependent degradation, and activated the MAPK signaling pathway in human colon cancer cell lines. Furthermore, we found that RFP activated chloride intracellular channel-1 (CLIC1) and increased the intracellular Cl-concentration. Blockage of CLIC1 by DIDS (disodium 4,4'-diisothiocyanato-2,2'-stilbenedisulfonate hydrate) attenuated cell death, cytoplasmic vacuolization, and endoplasmic reticulum stress, suggesting that CLIC1 acts as a critical early signal in RFP-induced paraptosis. In conclusion, results obtained indicated that the cytotoxic effect of RFP in colon cancer cells was the outcome of paraptosis mediated by activation of CLIC1.	[Zhu, Dongrong; Chen, Chen; Xia, Yuanzheng; Kong, Ling-Yi; Luo, Jianguang] China Pharmaceut Univ, Sch Tradit Chinese Pharm, Jiangsu Key Lab Bioact Nat Prod Res, Nanjing, Jiangsu, Peoples R China; [Zhu, Dongrong; Chen, Chen; Xia, Yuanzheng; Kong, Ling-Yi; Luo, Jianguang] China Pharmaceut Univ, Sch Tradit Chinese Pharm, State Key Lab Nat Med, Nanjing, Jiangsu, Peoples R China		Kong, LY; Luo, JG (corresponding author), China Pharmaceut Univ, Nanjing 210009, Jiangsu, Peoples R China.	cpu_lykong@126.com; luojg@cpu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81573570]; Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); Program for Chang Jiang Scholars and Innovative Research Team in UniversityProgram for Changjiang Scholars & Innovative Research Team in University (PCSIRT) [IRT_15R63]	The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported financially by the National Natural Science Foundation of China (No. 81573570), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Program for Chang Jiang Scholars and Innovative Research Team in University (IRT_15R63).	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Cancer Ther.	JAN 7	2019	18									10.1177/1534735418822120			13	Oncology; Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Integrative & Complementary Medicine	HN8YF	WOS:000460483500001	30614302	Green Published, gold			2022-04-25	
J	Zheng, BA; Yu, XJ; Chai, R				Zheng, Bo'an; Yu, Xiaojun; Chai, Rui			Myotubularin-Related Phosphatase 3 Promotes Growth of Colorectal Cancer Cells	SCIENTIFIC WORLD JOURNAL			English	Article							CARCINOMA CELLS; AUTOPHAGY; APOPTOSIS; DEATH; EXPRESSION; INHIBITORS; PATHWAYS; MTMR3	Due to changes in lifestyle, particularly changes in dietary habits, colorectal cancer (CRC) increased in recent years despite advances in treatment. Nearly one million new cases diagnosed worldwide and half a million deaths make CRC a leading cause of cancer mortality. In the present study, we aimed to investigate the role of myotubularin-related phosphatase 3 (MTMR3) in CRC cell growth via lentivirus-mediated small interfering RNA (siRNA) transduction in human colon cancer cell lines HCT116 and SW1116. The effect of MTMR3 knockdown on cell growth was evaluated by MTT, colony formation, and flow cytometry assays. The effect of MTMR3 knockdown on cell apoptosis was evaluated by flow cytometry with Annexin V/7-AAD double staining. The activation of apoptotic markers, Bad and PARP, was detected using Intracellular Signaling Array. Knockdown of MTMR3 resulted in a significant reduction in cell proliferation in both HCT116 and SW1116 cells. Moreover, knockdown of MTMR3 led to S phase cell cycle arrest. Furthermore, knockdown of MTMR3 induced cell apoptosis via phosphorylation of Bad and cleavage of PARP. These results indicate that MTMR3 may play an important role in the progression of CRC and suggest that siRNA mediated silencing of MTMR3 could be an effective tool in CRC treatment.	[Zheng, Bo'an; Chai, Rui] Zhejiang Prov Peoples Hosp, Dept Colorectal Surg, Hangzhou 310014, Zhejiang, Peoples R China; [Yu, Xiaojun] Zhejiang Prov Peoples Hosp, Dept Surg Gastroenterol, Hangzhou 310014, Zhejiang, Peoples R China		Chai, R (corresponding author), Zhejiang Prov Peoples Hosp, Dept Colorectal Surg, Hangzhou 310014, Zhejiang, Peoples R China.	ruichaidr@163.com					Aparo S, 2012, CRIT REV ONCOL HEMAT, V83, P47, DOI 10.1016/j.critrevonc.2011.08.006; Bialik S, 2010, TRENDS BIOCHEM SCI, V35, P556, DOI 10.1016/j.tibs.2010.04.008; Bolocan A, 2012, CHIRURGIA-BUCHAREST, V107, P555; Chang KH, 2013, ONCOL LETT, V6, P1435, DOI 10.3892/ol.2013.1548; Clague MJ, 2005, TRAFFIC, V6, P1063, DOI 10.1111/j.1600-0854.2005.00338.x; Do Yoo Y, 2004, ONCOL REP, V12, P667; Eisenberg-Lerner A, 2009, CELL DEATH DIFFER, V16, P966, DOI 10.1038/cdd.2009.33; Ellis L, 2009, BLOOD, V114, P380, DOI 10.1182/blood-2008-10-182758; Gurzu S, 2013, ROM J MORPHOL EMBRYO, V54, P241; He CC, 2009, ANNU REV GENET, V43, P67, DOI 10.1146/annurev-genet-102808-114910; Konishi Y, 2002, MOL CELL, V9, P1005, DOI 10.1016/S1097-2765(02)00524-5; Kroemer G, 2008, NAT REV MOL CELL BIO, V9, P1004, DOI 10.1038/nrm2529; Kuo YZ, 2014, ORAL DIS, V20, pe65, DOI 10.1111/odi.12133; Liu B, 2010, ACTA PHARMACOL SIN, V31, P1154, DOI 10.1038/aps.2010.118; Lorenzo O, 2005, J CELL SCI, V118, P2005, DOI 10.1242/jcs.02325; Lorenzo O, 2006, J CELL SCI, V119, P2953, DOI 10.1242/jcs.03040; Luo ZG, 2012, CANCER RES, V72, P3360, DOI 10.1158/0008-5472.CAN-12-0388; Ma D, 2014, ANTI-CANCER DRUG, V25, P406, DOI 10.1097/CAD.0000000000000068; Puglisi MA, 2013, WORLD J GASTROENTERO, V19, P2997, DOI 10.3748/wjg.v19.i20.2997; Shimizu S, 2014, INT J MOL SCI, V15, P3145, DOI 10.3390/ijms15023145; Shiokawa D, 1997, FEBS LETT, V413, P99, DOI 10.1016/S0014-5793(97)00887-9; Sung JJY, 2005, LANCET ONCOL, V6, P871, DOI 10.1016/S1470-2045(05)70422-8; Surh YJ, 2003, NAT REV CANCER, V3, P768, DOI 10.1038/nrc1189; Taguchi-Atarashi N, 2010, TRAFFIC, V11, P468, DOI 10.1111/j.1600-0854.2010.01034.x; Uversky Alexey V, 2013, F1000Res, V2, P190, DOI 10.12688/f1000research.2-190.v1; Wang YC, 2013, WORLD J GASTROENTERO, V19, P5159, DOI 10.3748/wjg.v19.i31.5159; Wei P., 2013, J TRANSL MED, VII; Wei SH, 2014, ONCOL LETT, V7, P635, DOI 10.3892/ol.2013.1773; White E, 2012, NAT REV CANCER, V12, P401, DOI 10.1038/nrc3262; Wolmarans E, 2014, CELL MOL BIOL LETT, V19, P98, DOI 10.2478/s11658-014-0183-7	30	8	8	0	1	HINDAWI LTD	LONDON	ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND	1537-744X			SCI WORLD J	Sci. World J.		2014									703804	10.1155/2014/703804			8	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	AR4PO	WOS:000343568900001	25215329	Green Published, Green Submitted, gold			2022-04-25	
J	New, J; Subramaniam, D; Ramalingam, S; Enders, J; Sayed, AAA; Ponnurangam, S; Standing, D; Ramamoorthy, P; O'Neil, M; Dixon, DA; Saha, S; Umar, S; Gunewardena, S; Jensen, RA; Thomas, SM; Anant, S				New, Jacob; Subramaniam, Dharmalingam; Ramalingam, Satish; Enders, Jonathan; Sayed, Afreen Asif Ali; Ponnurangam, Sivapriya; Standing, David; Ramamoorthy, Prabhu; O'Neil, Maura; Dixon, Dan A.; Saha, Subhrajit; Umar, Shahid; Gunewardena, Sumedha; Jensen, Roy A.; Thomas, Sufi Mary; Anant, Shrikant			Pleotropic role of RNA binding protein CELF2 in autophagy induction	MOLECULAR CARCINOGENESIS			English	Article						autophagy; colorectal cancer; radiotherapy; RNA binding protein	CANCER CELLS; DEATH; GUIDELINES; RADIATION; ASSAYS	We previously reported that ionizing radiation (IR) mediates cell death through the induction of CUGBP elav-like family member 2 (CELF2), a tumor suppressor. CELF2 is an RNA binding protein that modulates mRNA stability and translation. Since IR induces autophagy, we hypothesized that CELF2 regulates autophagy-mediated colorectal cancer (CRC) cell death. For clinical relevance, we determined CELF2 levels in The Cancer Genome Atlas (TCGA). Role of CELF2 in radiation response was carried out in CRC cell lines by immunoblotting, immunofluorescence, autophagic vacuole analyses, RNA stability assay, quantitative polymerase chain reaction and electron microscopy. In vivo studies were performed in a xenograft tumor model. TCGA analyses demonstrated that compared to normal tissue, CELF2 is expressed at significantly lower levels in CRC, and is associated with better overall 5-year survival in patients receiving radiation. Mechanistically, CELF2 increased levels of critical components of the autophagy cascade including Beclin-1, ATG5, and ATG12 by modulating mRNA stability. CELF2 also increased autophagic flux in CRC. IR significantly induced autophagy in CRC which correlates with increased levels of CELF2 and autophagy associated proteins. Silencing CELF2 with siRNA, mitigated IR induced autophagy. Moreover, knockdown of CELF2 in vivo conferred tumor resistance to IR. These studies elucidate an unrecognized role for CELF2 in inducing autophagy and potentiating the effects of radiotherapy in CRC.	[New, Jacob; Enders, Jonathan; Thomas, Sufi Mary] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Lawrence, KS 66045 USA; [New, Jacob; Thomas, Sufi Mary] Univ Kansas, Med Ctr, Dept Otolaryngol, Lawrence, KS 66045 USA; [Subramaniam, Dharmalingam; Ramalingam, Satish; Sayed, Afreen Asif Ali; Ponnurangam, Sivapriya; Standing, David; Ramamoorthy, Prabhu; Thomas, Sufi Mary; Anant, Shrikant] Univ Kansas, Med Ctr, Dept Canc Biol, Lawrence, KS 66045 USA; [O'Neil, Maura; Jensen, Roy A.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Lawrence, KS 66045 USA; [Dixon, Dan A.] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA; [Saha, Subhrajit] Univ Kansas, Med Ctr, Dept Radiat Oncol, Lawrence, KS 66045 USA; [Umar, Shahid] Univ Kansas, Med Ctr, Dept Gen Surg, Lawrence, KS 66045 USA; [Gunewardena, Sumedha] Univ Kansas, Med Ctr, Dept Mol Integrat Physiol, Lawrence, KS 66045 USA		Thomas, SM; Anant, S (corresponding author), Dept Canc Biol, 3901 Rainbow Blvd,MS 1071, Kansas City, KS 66160 USA.; Thomas, SM; Anant, S (corresponding author), Dept Otolaryngol, 3901 Rainbow Blvd,MS 1071, Kansas City, KS 66160 USA.	sthomas7@kumc.edu; sanant@kumc.edu	Anant, Shrikant/AAF-8020-2020; SAHA, SUBHRAJIT/AAJ-9272-2021	SAHA, SUBHRAJIT/0000-0002-7287-073X; New, Jacob/0000-0003-0707-9324	National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI); NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P30CA168524, CA227838, CA182872, U01AI138323]; Kansas Bioscience Authority; Thomas P. O'Sullivan IV, and Marina O'Sullivan Family Fund; Braden's Hope Foundation; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA182872, P30CA168524, R01CA190291, R01CA227838] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [U01AI138323] Funding Source: NIH RePORTER	National Cancer Institute; NIH, Grant/Award Numbers: P30CA168524, CA227838, CA182872, U01AI138323; Kansas Bioscience Authority; Thomas P. O'Sullivan IV, and Marina O'Sullivan Family Fund; Braden's Hope Foundation	Berry DL, 2007, CELL, V131, P1137, DOI 10.1016/j.cell.2007.10.048; BIEDERBICK A, 1995, EUR J CELL BIOL, V66, P3; Blech-Hermoni Y, 2013, DEV DYNAM, V242, P767, DOI 10.1002/dvdy.23959; Chulada PC, 2000, CANCER RES, V60, P4705; Galluzzi L, 2015, CELL DEATH DIFFER, V22, P58, DOI 10.1038/cdd.2014.137; Galluzzi L, 2009, CELL DEATH DIFFER, V16, P1093, DOI 10.1038/cdd.2009.44; Jakstaite A, 2016, LANGENBECK ARCH SURG, V401, P99, DOI 10.1007/s00423-015-1364-1; Kai M, 2016, INT J MOL SCI, V17, DOI 10.3390/ijms17030310; Klionsky DJ, 2016, AUTOPHAGY, V12, P1, DOI 10.1080/15548627.2015.1100356; Laane E, 2009, CELL DEATH DIFFER, V16, P1018, DOI 10.1038/cdd.2009.46; Martinez NM, 2015, GENE DEV, V29, P2054, DOI 10.1101/gad.267245.115; Maskey D, 2013, NAT COMMUN, V4, DOI 10.1038/ncomms3130; Mohseni N, 2009, AUTOPHAGY, V5, P329, DOI 10.4161/auto.5.3.7444; Mukhopadhyay D, 2003, MOL CELL, V11, P113, DOI 10.1016/S1097-2765(03)00012-1; Natarajan G, 2008, AM J PHYSIOL-GASTR L, V294, pG1235, DOI 10.1152/ajpgi.00037.2008; Niranjanakumari S, 2002, METHODS, V26, P182, DOI 10.1016/S1046-2023(02)00021-X; Palumbo S, 2013, J CELL PHYSIOL, V228, P1, DOI 10.1002/jcp.24118; Ramalingam Satish, 2012, Immunogastroenterology, V1, P27; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Stojcheva N, 2016, ONCOTARGET, V7, P12937, DOI 10.18632/oncotarget.7346; Subramaniam D, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0016958; Wang D, 2010, ONCOGENE, V29, P781, DOI 10.1038/onc.2009.421; Wen YF, 2014, CELL REP, V7, P488, DOI 10.1016/j.celrep.2014.03.009; Wu LL, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-02992-7; Yousefi S, 2006, NAT CELL BIOL, V8, P1124, DOI 10.1038/ncb1482; Zhu JH, 2007, AM J PATHOL, V170, P75, DOI 10.2353/ajpath.2007.060524	27	8	8	1	4	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0899-1987	1098-2744		MOL CARCINOGEN	Mol. Carcinog.	AUG	2019	58	8					1400	1409		10.1002/mc.23023			10	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	IH1UG	WOS:000474276900006	31020708	Green Accepted			2022-04-25	
J	Hu, YT; Qian, YC; Wei, JS; Jin, T; Kong, XX; Cao, HF; Ding, KF				Hu, Yeting; Qian, Yucheng; Wei, Jingsun; Jin, Tian; Kong, Xiangxing; Cao, Hongfeng; Ding, Kefeng			The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1	FRONTIERS IN PHARMACOLOGY			English	Article						disulfiram; autophagy; ULK1; CRISPR library; colorectal cancer	INHIBITION; DRUG; CHEMOTHERAPY; APOPTOSIS	Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.	[Hu, Yeting; Qian, Yucheng; Wei, Jingsun; Jin, Tian; Kong, Xiangxing; Cao, Hongfeng; Ding, Kefeng] Zhejiang Univ, Affiliated Hosp 2, Dept Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent,Sch Med, Hangzhou, Peoples R China; [Ding, Kefeng] Zhejiang Univ, Canc Ctr, Hangzhou, Peoples R China		Ding, KF (corresponding author), Zhejiang Univ, Affiliated Hosp 2, Dept Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent,Sch Med, Hangzhou, Peoples R China.; Ding, KF (corresponding author), Zhejiang Univ, Canc Ctr, Hangzhou, Peoples R China.	dingkefeng@zju.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81802750, 81772545, 82072624]; Key Technology Research and Development Program of Zhejiang Province	This study was supported by grants from the National Natural Science Foundation of China (No. 81802750, 81772545, 82072624) and the Key Technology Research and Development Program of Zhejiang Province (No. 2021C01180).	Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Cen DZ, 2004, J MED CHEM, V47, P6914, DOI 10.1021/jm049568z; Chen D, 2006, CANCER RES, V66, P10425, DOI 10.1158/0008-5472.CAN-06-2126; Guo XX, 2010, CANCER LETT, V290, P104, DOI 10.1016/j.canlet.2009.09.002; Huang JY, 2019, J NEURO-ONCOL, V142, P537, DOI 10.1007/s11060-019-03125-y; Huang X, 2021, ONCOGENESIS, V10, DOI 10.1038/s41389-020-00295-7; Iljin K, 2009, CLIN CANCER RES, V15, P6070, DOI 10.1158/1078-0432.CCR-09-1035; Jemal A, 2008, CA-CANCER J CLIN, V58, P71, DOI 10.3322/CA.2007.0010; Jiang K, 2021, J EXP CLIN CANC RES, V40, DOI 10.1186/s13046-020-01816-3; Kim J, 2011, NAT CELL BIOL, V13, P132, DOI 10.1038/ncb2152; Lewison E F, 1977, Prog Clin Biol Res, V12, P47; Li YQ, 2020, CANCERS, V12, DOI 10.3390/cancers12010138; Marin JJG, 2012, DRUG METAB REV, V44, P148, DOI 10.3109/03602532.2011.638303; Nechushtan H, 2015, ONCOLOGIST, V20, P366, DOI 10.1634/theoncologist.2014-0424; Ren XY, 2021, REDOX BIOL, V46, DOI 10.1016/j.redox.2021.102122; Said ES, 2021, EUR J PHARMACOL, V912, DOI 10.1016/j.ejphar.2021.174511; SELLERS EM, 1981, NEW ENGL J MED, V305, P1255; Skrott Z, 2017, NATURE, V552, P194, DOI 10.1038/nature25016; Tardito S, 2011, J AM CHEM SOC, V133, P6235, DOI 10.1021/ja109413c; Towers CG, 2016, EBIOMEDICINE, V14, P15, DOI 10.1016/j.ebiom.2016.10.034; Udristioiu A, 2019, BIOMED PHARMACOTHER, V115, DOI 10.1016/j.biopha.2019.108892; Wang Z, 2021, ORAL DIS, V27, P1148, DOI 10.1111/odi.13652; Wu X, 2018, EUR J PHARMACOL, V827, P1, DOI 10.1016/j.ejphar.2018.02.039; Xia HJ, 2021, NAT REV CANCER, V21, P281, DOI 10.1038/s41568-021-00344-2; Yip NC, 2011, BRIT J CANCER, V104, P1564, DOI 10.1038/bjc.2011.126	25	0	0	5	5	FRONTIERS MEDIA SA	LAUSANNE	AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND		1663-9812		FRONT PHARMACOL	Front. Pharmacol.	NOV 23	2021	12								752825	10.3389/fphar.2021.752825			10	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	XK7VN	WOS:000727668400001	34887757	gold, Green Published			2022-04-25	
J	Henidi, HA; Al-Abd, AM; Al-Abbasi, FA; BinMahfouz, HA; El-Deeb, IM				Henidi, Hanan A.; Al-Abd, Ahmed M.; Al-Abbasi, Fahad A.; BinMahfouz, Hawazen A.; El-Deeb, Ibrahim M.			Design and synthesis of novel phenylaminopyrimidines with antiproliferative activity against colorectal cancer	RSC ADVANCES			English	Article							SELECTIVE INHIBITOR; KINASE INHIBITORS; ACTIVATION; AUTOPHAGY; POTENT; ARREST	New phenylaminopyrimidine (PAP) derivatives have been designed and synthesised as potential tyrosine kinase inhibitors for the treatment of cancer. The synthesized compounds share a general structure and vary in the substitution pattern at position-2 of the pyridine ring. Several derivatives have demonstrated potent anticancer activities against HCT-116, HT-29 and LS-174T colorectal cancer cells. Furthermore, a number of hits showed good selectivity to Src-kinase. The cytotoxic mechanisms of these compounds were also investigated by studying their effects on cell-cycle distribution. Among all the compounds examined, compound 8b (with a terminal pyridin-3-yl moiety at the pyridine ring) showed the highest inhibitory selectivity towards src-kinase, which was coupled with cell cycle arrest, and apoptotic and autophagic interference, in colorectal cancer cells. This report introduces a novel category of PAP derivatives with promising kinase inhibitory and anticancer effects against colon cancer.	[Henidi, Hanan A.; Al-Abbasi, Fahad A.; BinMahfouz, Hawazen A.] King Abdulaziz Univ, Fac Sci, Dept Biochem, Jeddah, Saudi Arabia; [Al-Abd, Ahmed M.] Gulf Med Univ, Coll Pharm, Dept Pharmaceut Sci, Ajman, U Arab Emirates; [Al-Abd, Ahmed M.] Natl Res Ctr, Div Med, Dept Pharmacol, Giza, Egypt; [El-Deeb, Ibrahim M.] Royal Coll Surg Ireland Med Univ Bahrain, Busaiteen, Bahrain; [El-Deeb, Ibrahim M.] Griffith Univ, Inst Glyc, Gold Coast, Qld, Australia		Al-Abd, AM (corresponding author), Gulf Med Univ, Coll Pharm, Dept Pharmaceut Sci, Ajman, U Arab Emirates.; Al-Abd, AM (corresponding author), Natl Res Ctr, Div Med, Dept Pharmacol, Giza, Egypt.; El-Deeb, IM (corresponding author), Royal Coll Surg Ireland Med Univ Bahrain, Busaiteen, Bahrain.; El-Deeb, IM (corresponding author), Griffith Univ, Inst Glyc, Gold Coast, Qld, Australia.	ahmedmalabd@pharma.asu.edu.eg; i.el-deeb@griffith.edu.au		Al-Abbasi, Fahad/0000-0001-5609-4913; Al-Abd, Ahmed/0000-0001-7872-4867	Royal College of Surgeons in Ireland-Medical University of Bahrain [BR00063]	This research was supported by the Royal College of Surgeons in Ireland-Medical University of Bahrain (Grant number BR00063). The authors are grateful for Dr Marc Devocelle and Ms Siobhan O'Flaherty for their assistance in characterising the synthesized compounds using spectroscopy facility in RCSI (Royal College of Surgeons in Ireland).	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JUL 10	2019	9	37					21578	21586		10.1039/c9ra03359a			9	Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry	II8ZO	WOS:000475483100063		gold			2022-04-25	
J	Ren, F; Shu, GS; Liu, GL; Liu, DC; Zhou, JP; Yuan, LW; Zhou, JP				Ren, Feng; Shu, Guoshun; Liu, Ganglei; Liu, Dongcai; Zhou, Jiapeng; Yuan, Lianwen; Zhou, Jianping			Knockdown of p62/sequestosome 1 attenuates autophagy and inhibits colorectal cancer cell growth	MOLECULAR AND CELLULAR BIOCHEMISTRY			English	Article						Colorectal cancer; p62/sequestosome 1; Autophagy; Knockdown	HEPATOCELLULAR-CARCINOMA; SELECTIVE AUTOPHAGY; DEFICIENT MICE; P62; OVEREXPRESSION; TUMORIGENESIS; P62/SQSTM1; UBIQUITIN; TUMORS	p62/sequestosome-1 is a multifunctional adapter protein implicated in selective autophagy, cell signaling pathways, and tumorigenesis, and plays an important role at the crossroad between autophagy and cancer. But, the connection between autophagy and cancer is complex and in some cases contradictory. Human colorectal cancer tissues from patients were analyzed for expression of p62 and Microtubule-associated protein light chain 3 (LC3, an autophagosome marker) using immunostaining, western blotting, real-time PCR, and confocal microscopy. To study the effects of p62 on autophagy and cell growth, shRNA for p62 was applied and cell growth curve was monitored in human colorectal cancer cell. In vivo experiments were done using the mouse xenograft model. We showed that up-regulated expression of p62 and LC3 in colorectal cancer tissues. We also demonstrated that specifically knockdown the expression of p62 showed significantly inhibitory effects not only on autophagy activation, but also on tumor growth both in vitro and xenograft tumors model. The ectopic overexpression of p62 and autophagy activation contributes to colorectal tumorigenesis. p62 and autophagy will be therapy targets for the treatment of colorectal cancer.	[Ren, Feng; Shu, Guoshun; Liu, Ganglei; Liu, Dongcai; Zhou, Jiapeng; Yuan, Lianwen; Zhou, Jianping] Cent S Univ, Xiangya Hosp 2, Dept Geriatr Surg, Changsha 410011, Hunan, Peoples R China		Zhou, JP (corresponding author), Cent S Univ, Xiangya Hosp 2, Dept Geriatr Surg, 139 RenMin Rd, Changsha 410011, Hunan, Peoples R China.	jpz2013@126.com			Hunan Provincial Science and Technology Department [2013TT2022]	This work was supported by Grants No. 2013TT2022 from Hunan Provincial Science and Technology Department.	Bampton ETW, 2005, AUTOPHAGY, V1, P23, DOI 10.4161/auto.1.1.1495; Duran A, 2011, MOL CELL, V44, P134, DOI 10.1016/j.molcel.2011.06.038; 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; Johansen T, 2011, AUTOPHAGY, V7, P279, DOI 10.4161/auto.7.3.14487; Kirkin V, 2009, MOL CELL, V34, P259, DOI 10.1016/j.molcel.2009.04.026; 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; Komatsu M, 2011, AUTOPHAGY, V7, P1088, DOI 10.4161/auto.7.9.16474; Mathew R, 2009, CELL, V137, P1062, DOI 10.1016/j.cell.2009.03.048; Mizushima N, 2010, CELL, V140, P313, DOI 10.1016/j.cell.2010.01.028; Moscat J, 2012, TRENDS BIOCHEM SCI, V37, P230, DOI 10.1016/j.tibs.2012.02.008; Moscat J, 2009, CELL, V137, P1001, DOI 10.1016/j.cell.2009.05.023; Myung Park J, 2012, CANCER BIOL THER, V14, P100; Nezis IP, 2012, ANTIOXID REDOX SIGN, V17, P786, DOI 10.1089/ars.2011.4394; Pankiv S, 2007, J BIOL CHEM, V282, P24131, DOI 10.1074/jbc.M702824200; Parkhitko A, 2011, P NATL ACAD SCI USA, V108, P12455, DOI 10.1073/pnas.1104361108; Puissant A, 2012, AM J CANCER RES, V2, P397; 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; Viiri J, 2010, MOL VIS, V16, P1399; Zatloukal K, 2002, AM J PATHOL, V160, P255, DOI 10.1016/S0002-9440(10)64369-6; Zheng QW, 2011, CIRC RES, V109, P296, DOI 10.1161/CIRCRESAHA.111.244707	26	38	39	4	29	SPRINGER	DORDRECHT	VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS	0300-8177	1573-4919		MOL CELL BIOCHEM	Mol. Cell. Biochem.	JAN	2014	385	1-2					95	102		10.1007/s11010-013-1818-0			8	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	264EG	WOS:000327859200011	24065390				2022-04-25	
J	Talero, E; Garcia-Maurino, S; Avila-Roman, J; Rodriguez-Luna, A; Alcaide, A; Motilva, V				Talero, Elena; Garcia-Maurino, Sofia; Avila-Roman, Javier; Rodriguez-Luna, Azahara; Alcaide, Antonio; Motilva, Virginia			Bioactive Compounds Isolated from Microalgae in Chronic Inflammation and Cancer	MARINE DRUGS			English	Review						chronic inflammation; colon cancer; skin cancer; chemoprevention; microalgae	NF-KAPPA-B; POLYUNSATURATED FATTY-ACIDS; INDUCED COLON CARCINOGENESIS; INDUCED SKIN CARCINOGENESIS; ACTIVATED PROTEIN-KINASE; SQUAMOUS-CELL CARCINOMAS; INDUCED OXIDATIVE DAMAGE; CAROTENE-RICH ALGA; BETA-CAROTENE; EICOSAPENTAENOIC ACID	The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-B) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. 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 and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.	[Talero, Elena; Avila-Roman, Javier; Rodriguez-Luna, Azahara; Alcaide, Antonio; Motilva, Virginia] Univ Seville, Fac Pharm, Dept Pharmacol, E-41012 Seville, Spain; [Garcia-Maurino, Sofia] Univ Seville, Dept Plant Biol & Ecol, Fac Biol, E-41012 Seville, Spain		Talero, E (corresponding author), Univ Seville, Fac Pharm, Dept Pharmacol, E-41012 Seville, Spain.	etalero@us.es; sgarma@us.es; javieravila@us.es; arodriguez53@us.es; aalcaide@us.es; motilva@us.es	Rodriguez-Luna, Azahara/AAS-2533-2021; Talero, Elena/I-2613-2015; Avila-Roman, Javier/B-5337-2017; García-Mauriño, Sofía/E-6707-2010	Rodriguez-Luna, Azahara/0000-0002-1529-7674; García-Mauriño, Sofía/0000-0002-7698-5112; Avila-Roman, Francisco Javier/0000-0001-9766-8178	Consejeria de Economia, Innovacion, Ciencia y Empleo, Junta de AndaluciaJunta de Andalucia [P12-AGR-430]	This work was supported by Consejeria de Economia, Innovacion, Ciencia y Empleo, Junta de Andalucia (grant number P12-AGR-430).	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Drugs	OCT	2015	13	10					6152	6209		10.3390/md13106152			58	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	CV0YO	WOS:000363980000008	26437418	Green Published, Green Submitted, gold			2022-04-25	
J	Lebovitz, CB; Bortnik, SB; Gorski, SM				Lebovitz, Chandra B.; Bortnik, Svetlana B.; Gorski, Sharon M.			Here, There Be Dragons: Charting Autophagy-Related Alterations in Human Tumors	CLINICAL CANCER RESEARCH			English	Review							HUMAN BREAST-CANCER; BECLIN 1; MAMMALIAN TARGET; SIGNALING PATHWAYS; COLON-CANCER; PROGNOSTIC-SIGNIFICANCE; MONITORING AUTOPHAGY; REDUCED EXPRESSION; RAPAMYCIN PATHWAY; POOR-PROGNOSIS	Macroautophagy (or autophagy) is a catabolic cellular process that is both homeostatic and stress adaptive. Normal cells rely on basal levels of autophagy to maintain cellular integrity (via turnover of long-lived proteins and damaged organelles) and increased levels of autophagy to buoy cell survival during various metabolic stresses (via nutrient and energy provision through lysosomal degradation of cytoplasmic components). Autophagy can function in both tumor suppression and tumor progression, and is under investigation in clinical trials as a novel target for anticancer therapy. However, its role in cancer pathogenesis has yet to be fully explored. In particular, it remains unknown whether in vitro observations will be applicable to human cancer patients. Another outstanding question is whether there exists tumor-specific selection for alterations in autophagy function. In this review, we survey reported mutations in autophagy genes and key autophagy regulators identified in human tumor samples and summarize the literature regarding expression levels of autophagy genes and proteins in various cancer tissues. Although it is too early to draw inferences from this collection of in vivo studies of autophagy-related alterations in human cancers, their results highlight the challenges that must be overcome before we can accurately assess the scope of autophagy's predicted role in tumorigenesis. Clin Cancer Res; 18(5); 1214-26. (C)2012 AACR.	[Lebovitz, Chandra B.; Bortnik, Svetlana B.; Gorski, Sharon M.] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada; [Bortnik, Svetlana B.; Gorski, Sharon M.] Univ British Columbia, Interdisciplinary Oncol Program, Vancouver, BC V5Z 1M9, Canada; [Lebovitz, Chandra B.; Gorski, Sharon M.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada		Gorski, SM (corresponding author), BC Canc Agcy, Genome Sci Ctr, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada.	sgorski@bcgsc.ca	Gorski, Sharon M/E-9375-2012	Gorski, Sharon M/0000-0002-3821-8289; Lebovitz, Chandra/0000-0002-8679-0431	Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [GPG102167]	Canadian Institutes of Health Research (New Investigator award and team grant GPG102167 to S.M.G.).	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Cancer Res.	MAR 1	2012	18	5					1214	1226		10.1158/1078-0432.CCR-11-2465			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	902LW	WOS:000301040700006	22253413				2022-04-25	
J	Liu, J; Yang, MP; Kong, R; Chen, H; Wang, YW; Pan, SH; Jiang, HC; Sun, B				Liu, Ji; Yang, Maopeng; Kong, Rui; Chen, Hua; Wang, Yongwei; Pan, Shangha; Jiang, Hongchi; Sun, Bei			Icotinib Enhances Bufalin-Induced Apoptosis via the Suppression of PI3K/Akt Signaling Pathway in Human Colon Cancer Cells	INTERNATIONAL JOURNAL OF PHARMACOLOGY			English	Article						Colon cancer; PI3K/Akt; bufalin; icotinib; apoptosis	CBL-B; GROWTH; INHIBITION; RESISTANCE; AUTOPHAGY	This study sought to uncover whether icotinib can enhance bufalin-induced apoptosis of human colon cancer cells and the roles of PI3K/Akt signaling pathway in the apoptosis. The cell proliferation of human colon cancer cell lines RKO, HT29, CACO-2 and SW480 treated by bufalin was detected by MTT assay. Then, the apoptosis rate of RKO and SW480 cells treated by bufalin alone and combination of bufalin and icotinib was detected by flow cytometry. Afterwards, the levels of Cbl-b, p-AKT, p-ERK, PARP, Bax and Bcl-2 in RKO and SW480 cells were determined by Western blotting. Additionally, the effect of K-Ras silencing on the synergy of bufalin and icotinib was assessed. Bufalin decreased RKO, HT29, CACO-2 and SW480 (EX12 mutation) cell viability in a dose dependent manner and induced apoptosis of RKO and SW480 cells in vitro. In the cells treated by combination of bufalin and icotinib, the levels of Cbl-b, cleaved PARP and Bax were increased, while the levels of p-Akt and Bcl-2 were reduced, comparing with that in the bufalin treated cells. Furthermore, K-Ras silencing (including EX12 mutated K-Ras and wild-type K-Ras) did not significantly affect the apoptosis rate of cells treated by the combination of bufalin and icotinib. Icotinib synergizes with bufalin to induce the apoptosis of colon cancer cells through PI3K/Akt signal pathway and regulating the apoptosis related proteins (Bcl-2, Cbl-b, cleaved PARP and Bax). K-Ras may not participate in the combination of bufalin and icotinib induced apoptosis in human colon cancer cells.	[Liu, Ji; Kong, Rui; Chen, Hua; Wang, Yongwei; Jiang, Hongchi; Sun, Bei] Harbin Med Univ, Affiliated Hosp 1, Dept Pancreat & Biliary Surg, Harbin 150001, Peoples R China; [Yang, Maopeng] Harbin Med Univ, Affiliated Hosp 3, Dept Med Oncol, Harbin 150001, Peoples R China; [Pan, Shangha] Harbin Med Univ, Affiliated Hosp 1, Dept Gen Surg, Key Lab Hepatosplen Surg, Harbin 150001, Peoples R China		Sun, B (corresponding author), Harbin Med Univ, Affiliated Hosp 1, Dept Pancreat & Biliary Surg, Harbin 150001, Peoples R China.						Allemani C, 2015, LANCET, V385, P977, DOI 10.1016/S0140-6736(14)62038-9; De Luca A, 2012, EXPERT OPIN THER TAR, V16, pS17, DOI 10.1517/14728222.2011.639361; Fang DY, 2001, NAT IMMUNOL, V2, P870, DOI 10.1038/ni0901-870; Garcia-Alfonso P, 2014, ANGIOGENESIS, V17, P805, DOI 10.1007/s10456-014-9433-6; Guerrero S, 2000, CANCER RES, V60, P6750; Harashima N, 2012, CANCER IMMUNOL IMMUN, V61, P667, DOI 10.1007/s00262-011-1132-1; Kang XH, 2013, EVID-BASED COMPL ALT, V2013, DOI 10.1155/2013/243859; Khoo BY, 2010, INT J MOL SCI, V11, P2188, DOI 10.3390/ijms11052188; Kroemer G, 1997, NAT MED, V3, P614, DOI 10.1038/nm0697-614; Li D, 2009, ANTI-CANCER DRUG, V20, P59, DOI 10.1097/CAD.0b013e3283160fd6; Li W, 2011, INT J MOL SCI, V12, P668, DOI 10.3390/ijms12010668; Mu XD, 2013, BIOMED RES INT, V2013, DOI 10.1155/2013/726375; Nakao R, 2009, MOL CELL BIOL, V29, P4798, DOI 10.1128/MCB.01347-08; Park IH, 2010, INVEST NEW DRUG, V28, P791, DOI 10.1007/s10637-009-9319-4; Qu XJ, 2009, FEBS LETT, V583, P2255, DOI 10.1016/j.febslet.2009.05.054; Sahlberg SH, 2012, INT J ONCOL, V40, P176, DOI 10.3892/ijo.2011.1177; Santarpia L, 2012, EXPERT OPIN THER TAR, V16, P103, DOI 10.1517/14728222.2011.645805; Sos ML, 2009, P NATL ACAD SCI USA, V106, P18351, DOI 10.1073/pnas.0907325106; Takezawa K, 2011, CLIN CANCER RES, V17, P2140, DOI 10.1158/1078-0432.CCR-10-2798; Tashiro J, 2014, WORLD J SURG ONCOL, V12, DOI 10.1186/1477-7819-12-145; Vivanco I, 2002, NAT REV CANCER, V2, P489, DOI 10.1038/nrc839; Watabe M, 1996, J BIOL CHEM, V271, P14067, DOI 10.1074/jbc.271.24.14067; Xie CM, 2011, FREE RADICAL BIO MED, V51, P1365, DOI 10.1016/j.freeradbiomed.2011.06.016; Yang C. L., 2013, J XINXIANG MED U, V30, P622; Zhao QO, 2011, LUNG CANCER, V73, P195, DOI 10.1016/j.lungcan.2010.11.007; Zhu ZT, 2012, WORLD J SURG ONCOL, V10, DOI 10.1186/1477-7819-10-228; Zhu ZT, 2012, INT J MOL SCI, V13, P2025, DOI 10.3390/ijms13022025	27	1	1	0	7	ASIAN NETWORK SCIENTIFIC INFORMATION-ANSINET	FAISALABAD	308-LASANI TOWN, SARGODHA RD, FAISALABAD, 38090, PAKISTAN	1811-7775	1812-5700		INT J PHARMACOL	Int. J. Pharmacol.		2015	11	8					910	919		10.3923/ijp.2015.910.919			10	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	DC4TY	WOS:000369214400003					2022-04-25	
J	Siri, M; Behrouj, H; Dastghaib, S; Zamani, M; Likus, W; Rezaie, S; Hudecki, J; Khazayel, S; Los, MJ; Mokarram, P; Ghavami, S				Siri, Morvarid; Behrouj, Hamid; Dastghaib, Sanaz; Zamani, Mozhdeh; Likus, Wirginia; Rezaie, Sedigheh; Hudecki, Jacek; Khazayel, Saeed; Los, Marek J.; Mokarram, Pooneh; Ghavami, Saeid			Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition	ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS			English	Article						5-Fluorouracil; Casein kinase 1 alpha inhibitor; Colorectal cancer; Combination treatment; Autophagy; Chemoresistance	UNFOLDED PROTEIN RESPONSE; DRUG-RESISTANCE; CYCLIN D1; COLON-CANCER; AUTOPHAGY; MECHANISMS; APOPTOSIS; GROWTH; MULTIPLE; ABCG2	Adjuvant chemotherapy with 5-fluorouracil (5-FU) does not improve survival of patients suffering from a form of colorectal cancer (CRC) characterized by high level of microsatellite instability (MSI-H). Given the importance of autophagy and multi-drug-resistant (MDR) proteins in chemotherapy resistance, as well as the role of casein kinase 1-alpha (CK1 alpha) in the regulation of autophagy, we tested the combined effect of 5-FU and CK1 alpha inhibitor (D4476) on HCT116 cells as a model of MSI-H colorectal cancer. To achieve this goal, the gene expression of Beclinl and MDR genes, ABCG2 and ABCC3 were analyzed using quantitative real-time polymerase chain reaction. We used immunoblotting to measure autophagy flux (LC3, p62) and flow cytometry to detect apoptosis. Our findings showed that combination treatment with 5-FU and D4476 inhibited autophagy flux. Moreover, 5-FU and D4476 combination therapy induced G2, S and G1 phase arrests and it depleted mRNA of both cell proliferation-related genes and MDR-related genes (ABCG2, cyclin DI and c-myc). Hence, our data indicates that targeting of CK1 alpha may increase the sensitivity of HCT116 cells to 5-FU. To our knowledge, this is the first description of sensitization of CRC cells to 5-FU chemotherapy by CK1 alpha inhibitor.	[Siri, Morvarid; Zamani, Mozhdeh; Los, Marek J.; Mokarram, Pooneh; Ghavami, Saeid] Shiraz Univ Med Sci, Autophagy Res Ctr, Shiraz, Iran; [Siri, Morvarid; Behrouj, Hamid; Dastghaib, Sanaz; Rezaie, Sedigheh; Mokarram, Pooneh] Shiraz Univ Med Sci, Sch Med, Dept Biochem, POB 1167, Shiraz, Iran; [Dastghaib, Sanaz] Shiraz Univ Med Sci, Endocrinol & Metab Res Ctr, Shiraz, Iran; [Likus, Wirginia] Med Univ Silesia, Sch Hlth Sci Katowice, Dept Anat, Ul Medykow 18, PL-40762 Katowice, Poland; [Hudecki, Jacek] Med Univ Silesia, Sch Med Katowice, Laryngol Dept, Katowice, Poland; [Khazayel, Saeed] Kermanshah Univ Med Sci, Dept Res & Technol, Kermanshah, Iran; [Los, Marek J.] Pomeranian Med Univ, Dept Pathol, Unii Lubelskiej 1, PL-71344 Szczecin, Poland; [Ghavami, Saeid] Univ Manitoba, Res Inst Oncol & Hematol, Canc Care Manitoba, Winnipeg, MB, Canada; [Ghavami, Saeid] Katowice Sch Technol, Fac Med, Katowice, Poland; [Ghavami, Saeid] Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada		Los, MJ; Mokarram, P; Ghavami, S (corresponding author), Shiraz Univ Med Sci, Autophagy Res Ctr, Shiraz, Iran.; Mokarram, P (corresponding author), Shiraz Univ Med Sci, Sch Med, Dept Biochem, POB 1167, Shiraz, Iran.; Los, MJ (corresponding author), Pomeranian Med Univ, Dept Pathol, Unii Lubelskiej 1, PL-71344 Szczecin, Poland.; Ghavami, S (corresponding author), Univ Manitoba, Res Inst Oncol & Hematol, Canc Care Manitoba, Winnipeg, MB, Canada.; Ghavami, S (corresponding author), Katowice Sch Technol, Fac Med, Katowice, Poland.; Ghavami, S (corresponding author), Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada.	mjelos@gmail.com; mokaram2@gmail.com; saeid.ghavami@umanitoba.ca	Mokarram, Pooneh/E-1613-2012; Behrouj, Hamid/AAC-1604-2022; Dastghaib, Sanaz/ABD-5899-2021	Mokarram, Pooneh/0000-0002-9717-0473; Dastghaib, Sanaz/0000-0001-8553-9221; Likus, Wirginia/0000-0002-4738-6102; Ghavami, Saeid/0000-0001-5948-508X; Los, Marek/0000-0001-9518-1411	Shiraz University of Medical Sciences [97-01-01-18115]; National Institute for Medical Research Development (NIMAD) [943267]	This study was supported financially by Shiraz University of Medical Sciences [Grant No.: 97-01-01-18115]. This project was also supported by the National Institute for Medical Research Development (NIMAD) Grant No: 943267.	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Immunol. Ther. Exp.	DEC	2021	69	1							26	10.1007/s00005-021-00629-2			16	Immunology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology	UR9OY	WOS:000697070300001	34536148	Green Published, hybrid			2022-04-25	
J	Sipos, F; Kiss, AL; Constantinovits, M; Tulassay, Z; Muzes, G				Sipos, Ferenc; Kiss, Anna L.; Constantinovits, Miklos; Tulassay, Zsolt; Muzes, Gyoergyi			Modified Genomic Self-DNA Influences In Vitro Survival of HT29 Tumor Cells via TLR9-and Autophagy Signaling	PATHOLOGY & ONCOLOGY RESEARCH			English	Article						HT29; Colon cancer; TLR9; Autophagy; Colonosphere; Self-DNA	TOLL-LIKE RECEPTORS; NF-KAPPA-B; CANCER STEM-CELLS; CPG-OLIGODEOXYNUCLEOTIDES; COLON-CANCER; LYMPHOMA-CELLS; BACTERIAL-DNA; UP-REGULATION; STRANDED-RNA; APOPTOSIS	In relation of immunobiology, the consequence of the crosstalk between TLR9-signaling and autophagy is poorly documented in HT29 cancer cells. To assess the TLR9-mediated biologic effects of modified self-DNA sequences on cell kinetics and autophagy response HT29 cells were incubated separately with intact genomic (g), hypermethylated (m), fragmented (f), and hypermethylated/fragmented (m/f) self-DNAs. Cell viability, apoptosis, cell proliferation, colonosphere-formation were determined. Moreover, the relation of TLR9-signaling to autophagy response was assayed by real-time RT-PCR, immunocytochemistry and transmission electron microscopy (TEM). After incubation with g-, m-, and m/f-DNAs cell viability and proliferation decreased, while apoptosis increased. F-DNA treatment resulted in an increase of cell survival. Methylation of self-DNA resulted in decrease of TLR9 expression, while it did not influence the positive effect of DNA fragmentation on MyD88 and TRAF6 overexpression, and TNF alpha downregulation. Fragmentation of DNA abrogated the positive effect of methylation on IRAK2, NF kappa B and IL-8 mRNA upregulations. In case of the autophagy genes and proteins, g- and f-DNAs caused significant upregulation of Beclin1, Atg16L1, and LC3B. According to TEM analyses, autophagy was present in each group of tumor cells, but to a varying degree. Incubation with m-DNA suppressed tumor cell survival by inducing features of apoptotic cell death, and activated mitophagy. F-DNA treatment enhanced cell survival, and activated macroautophagy and lipophagy. Colonospheres were only present after m-DNA incubation. Our data provided evidence for a close existing interplay between TLR9-signaling and the autophagy response with remarkable influences on cell survival in HT29 cells subjected to modified self-DNA treatments.	[Sipos, Ferenc; Constantinovits, Miklos; Tulassay, Zsolt; Muzes, Gyoergyi] Semmelweis Univ, Dept Internal Med 2, Szentkiralyi St 46, H-1088 Budapest, Hungary; [Kiss, Anna L.] Semmelweis Univ, Dept Human Morphol & Dev Biol, H-1094 Budapest, Hungary; [Tulassay, Zsolt] Hungarian Acad Sci, Mol Med Res Unit, H-1051 Budapest, Hungary		Sipos, F (corresponding author), Semmelweis Univ, Dept Internal Med 2, Szentkiralyi St 46, H-1088 Budapest, Hungary.	dr.siposf@gmail.com		Sipos, Ferenc/0000-0002-2767-7746	Hungarian Scientific Research FundOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA-K111743]; StartUp Program of Semmelweis University Faculty of Medicine [11720, Ikt. sz.: 5127/AOKGIE/2018, SE10332470]	Supported by the Hungarian Scientific Research Fund (OTKA-K111743 grant) to ZT and the StartUp Program of Semmelweis University Faculty of Medicine (CO No.: 11720, Ikt. sz.: 5127/AOKGIE/2018; SE10332470) to FS. The funders had no role in data collection, decision to publish, or preparation of the manuscript.	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Oncol. Res.	OCT	2019	25	4					1505	1517		10.1007/s12253-018-0544-z			13	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	JH3JE	WOS:000492663100027	30465163				2022-04-25	
J	Gariboldi, MB; Taiana, E; Bonzi, MC; Craparotta, I; Giovannardi, S; Mancini, M; Monti, E				Gariboldi, Marzia B.; Taiana, Elisa; Bonzi, Maria Chiara; Craparotta, Ilaria; Giovannardi, Stefano; Mancini, Monica; Monti, Elena			The BH3-mimetic obatoclax reduces HIF-1 alpha levels and HIF-1 transcriptional activity and sensitizes hypoxic colon adenocarcinoma cells to 5-fluorouracil	CANCER LETTERS			English	Article						HIF-1; Obatoclax; Drug resistance; 5-Fluorouracil; Colon cancer; Oxaliplatin	HIPPEL-LINDAU PROTEIN; INDUCED APOPTOSIS; FAMILY INHIBITOR; DRUG-RESISTANCE; DOWN-REGULATION; CANCER-CELLS; BCL-XL; GX15-070; TUMORS; ALPHA	Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2 family dynamics. Resetting the balance in favor of proapoptotic family members is an attractive therapeutic goal that has been pursued by developing BH3-mimetic compounds. In the present study we evaluated the response of human colon adenocarcinoma cells to the BH3-mimetic obatoclax (OBX), in terms of growth arrest, apoptosis and autophagy, in the presence or absence of HIF-1 alpha-stabilizing conditions; its possible effect on HIF-1 alpha expression and HIF-1 activity; and the possibility to improve the response of colon cancer cells to cytotoxic chemotherapeutics by combining them with OBX. Colon cancer cell response to the BH3-mimetic was unmodified by HIF-1 activation and OBX induced a decrease in HIF-1 alpha protein levels and HIF-1 transcriptional activity, probably by decreasing HIF-1 alpha synthesis and facilitating a VHL-independent proteasomal degradation pathway. Finally, a chemosensitizing effect of OBX with respect to 5-fluorouracil or oxaliplatin treatment was observed, highlighting the possibility that patients with hypoxic colon tumors might benefit from combined regimens including OBX. (C) 2015 Elsevier Ireland Ltd. All rights reserved.	[Gariboldi, Marzia B.; Taiana, Elisa; Bonzi, Maria Chiara; Craparotta, Ilaria; Giovannardi, Stefano; Mancini, Monica; Monti, Elena] Univ Insubria, Div Biomed Res, Dept Theoret & Appl Sci, I-21052 Busto Arsizio, Varese, Italy		Monti, E (corresponding author), Univ Insubria, Div Biomed Res, Dept Theoret & Appl Sci, Via A da Giussano 10, I-21052 Busto Arsizio, Varese, Italy.	elena.monti@uninsubria.it	Craparotta, Ilaria/ABG-6626-2021; Gariboldi, Marzia Bruna/U-1331-2019	Craparotta, Ilaria/0000-0002-0846-9634; Taiana, Elisa/0000-0003-4940-1318; Mancini, Monica/0000-0003-4128-9018; gariboldi, marzia bruna/0000-0002-5683-0885			Acoca S, 2011, PROTEINS, V79, P2624, DOI 10.1002/prot.23083; Adamski J, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0065304; Chen N, 2009, J BIOL CHEM, V284, P10004, DOI 10.1074/jbc.M805997200; Comerford KM, 2002, CANCER RES, V62, P3387; Cosse JP, 2008, ANTI-CANCER AGENT ME, V8, P790, DOI 10.2174/187152008785914798; Cragg MS, 2009, NAT REV CANCER, V9, P321, DOI 10.1038/nrc2615; Cruickshanks N, 2012, MOL PHARMACOL, V81, P748, DOI 10.1124/mol.112.077586; Dasmahapatra G, 2012, MOL CANCER THER, V11, P1122, DOI 10.1158/1535-7163.MCT-12-0021; Erler JT, 2004, MOL CELL BIOL, V24, P2875, DOI 10.1128/MCB.24.7.2875-2889.2004; Espona-Fiedler M, 2012, BIOCHEM PHARMACOL, V83, P489, DOI 10.1016/j.bcp.2011.11.027; Flamant L, 2010, MOL CANCER, V9, DOI 10.1186/1476-4598-9-191; Gariboldi MB, 2007, CANCER LETT, V258, P181, DOI 10.1016/j.canlet.2007.08.019; Harrison LRE, 2011, J CLIN INVEST, V121, P1075, DOI 10.1172/JCI43505; Jona A, 2011, EXP HEMATOL, V39, P1007, DOI 10.1016/j.exphem.2011.07.002; Klymenko T, 2011, MOL CANCER THER, V10, P2373, DOI 10.1158/1535-7163.MCT-11-0326; Koehler BC, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0106571; Koh MY, 2008, TRENDS BIOCHEM SCI, V33, P526, DOI 10.1016/j.tibs.2008.08.002; Kong XG, 2007, J BIOL CHEM, V282, P15498, DOI 10.1074/jbc.M700704200; Konopleva M, 2008, CANCER RES, V68, P3413, DOI 10.1158/0008-5472.CAN-07-1919; Koshiji M, 2005, MOL CELL, V17, P793, DOI 10.1016/j.molcel.2005.02.015; Krishnamurthy P, 2004, J BIOL CHEM, V279, P24218, DOI 10.1074/jbc.M313599200; Lessene G, 2008, NAT REV DRUG DISCOV, V7, P989, DOI 10.1038/nrd2658; Li J, 2008, CANCER CHEMOTH PHARM, V61, P525, DOI 10.1007/s00280-007-0499-3; Lu X, 2010, CLIN CANCER RES, V16, P5928, DOI 10.1158/1078-0432.CCR-10-1360; Masson N, 2001, EMBO J, V20, P5197, DOI 10.1093/emboj/20.18.5197; Mayes PA, 2011, CANCER RES, V71, P5265, DOI 10.1158/0008-5472.CAN-11-1383; Moeller BJ, 2004, CANCER CELL, V5, P429, DOI 10.1016/S1535-6108(04)00115-1; Monti Elena, 2011, Curr Mol Pharmacol, V4, P62; Muller A, 2013, INT J CANCER, V133, P1813, DOI 10.1002/ijc.28206; Nguyen M, 2007, P NATL ACAD SCI USA, V104, P19512, DOI 10.1073/pnas.0709443104; Pan JX, 2010, CANCER LETT, V293, P167, DOI 10.1016/j.canlet.2010.01.006; Peter B, 2014, J LEUKOCYTE BIOL, V95, P95, DOI 10.1189/jlb.1112609; Piret JP, 2005, J BIOL CHEM, V280, P9336, DOI 10.1074/jbc.M411858200; Pollak M, 2012, NAT REV CANCER, V12, P159, DOI 10.1038/nrc3215; Rahmani M, 2012, BLOOD, V119, P6089, DOI 10.1182/blood-2011-09-378141; Ravizza R, 2009, EUR J CANCER, V45, P890, DOI 10.1016/j.ejca.2008.12.021; Rohwer N, 2011, DRUG RESIST UPDATE, V14, P191, DOI 10.1016/j.drup.2011.03.001; Schimmer AD, 2008, CLIN CANCER RES, V14, P8295, DOI 10.1158/1078-0432.CCR-08-0999; Semenza GL, 2010, ONCOGENE, V29, P625, DOI 10.1038/onc.2009.441; Semenza GL, 2003, NAT REV CANCER, V3, P721, DOI 10.1038/nrc1187; Shore Gordon C, 2005, Hematology Am Soc Hematol Educ Program, P226; Tang Y, 2012, MOL PHARMACOL, V81, P527, DOI 10.1124/mol.111.076851; Vaupel P, 2001, MED ONCOL, V18, P243, DOI 10.1385/MO:18:4:243; Vogler M, 2009, CELL DEATH DIFFER, V16, P1030, DOI 10.1038/cdd.2009.48; Witters LM, 2007, ONCOL REP, V17, P465; Yuan Y, 2003, J BIOL CHEM, V278, P15911, DOI 10.1074/jbc.M300463200; Zhai D, 2006, CELL DEATH DIFFER, V13, P1419, DOI 10.1038/sj.cdd.4401937	47	17	18	1	19	ELSEVIER IRELAND LTD	CLARE	ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND	0304-3835	1872-7980		CANCER LETT	Cancer Lett.	AUG 10	2015	364	2					156	164		10.1016/j.canlet.2015.05.008			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CL7GL	WOS:000357140400008	25979228				2022-04-25	
J	Morselli, E; Tasdemir, E; Maiuri, MC; Galluzzi, L; Kepp, O; Criollo, A; Vicencio, JM; Soussi, T; Kroemer, G				Morselli, Eugenia; Tasdemir, Ezgi; Maiuri, Maria Chiara; Galluzzi, Lorenzo; Kepp, Oliver; Criollo, Alfredo; Vicencio, Jose Miguel; Soussi, Thierry; Kroemer, Guido			Mutant p53 protein localized in the cytoplasm inhibits autophagy	CELL CYCLE			English	Article						Bcl-2; cancer; GFP-LC3; human colon carcinoma HCT 116 cells; MDM2; p53 hot-spot mutations	DNA-BINDING DOMAIN; HUMAN CANCER; CELL-SURVIVAL; INSTABILITY; DAMAGE; MDM2	The knockout, knockdown or chemical inhibition of p53 stimulates autophagy. Moreover, autophagy-inducing stimuli such as nutrient depletion, rapamycin or lithium cause the depletion of cytoplasmic p53, which in turn is required for the induction of autophagy. Here, we show that retransfection of p53(-/-) HCT 116 colon carcinoma cells with wild type p53 decreases autophagy down to baseline levels. Surprisingly, one third among a panel of 22 cancer-associated p53 single amino acid mutants also inhibited autophagy when transfected into p53(-/-) cells. Those variants of p53 that preferentially localize to the cytoplasm effectively repressed autophagy, whereas p53 mutants that display a prominently nuclear distribution failed to inhibit autophagy. The investigation of a series of deletion mutants revealed that removal of the DNA-binding domain from p53 fails to interfere with its role in the regulation of autophagy. Altogether, these results identify the cytoplasmic localization of p53 as the most important feature for p53-mediated autophagy inhibition. Moreover, the structural requirements for the two biological activities of extranuclear p53, namely induction of apoptosis and inhibition of autophagy, are manifestly different.	[Kroemer, Guido] Inst Gustave Roussy, INSERM, U848, F-94805 Villejuif, France; [Morselli, Eugenia; Tasdemir, Ezgi; Maiuri, Maria Chiara; Galluzzi, Lorenzo; Kepp, Oliver; Criollo, Alfredo; Vicencio, Jose Miguel; Kroemer, Guido] Univ Paris 11, Orsay, France; [Maiuri, Maria Chiara] Univ Naples Federico II, Fac Sci Biotecnol, Naples, Italy; [Soussi, Thierry] Univ Paris 06, Paris, France; [Soussi, Thierry] Canc Ctr Karolinska, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden		Kroemer, G (corresponding author), Inst Gustave Roussy, INSERM, U848, PR1,39 Rue Camille Desmoulins, F-94805 Villejuif, France.	kroemer@igr.fr	Galluzzi, Lorenzo/AAG-6294-2019; Galluzzi, Lorenzo/K-2709-2012; KROEMER, Guido/B-4263-2013; Kepp, Oliver/N-2763-2017; Galluzzi, Lorenzo/AAG-6432-2019; Galluzzi, Lorenzo/AAH-3286-2021	Galluzzi, Lorenzo/0000-0003-2257-8500; KROEMER, Guido/0000-0002-9334-4405; Kepp, Oliver/0000-0002-6081-9558; Criollo, Alfredo/0000-0002-2737-7751; soussi, thierry/0000-0001-8184-3293	EUEuropean Commission; Institut National contre le Cancer (INCa)Institut National du Cancer (INCA) France; CONICYT, ChileComision Nacional de Investigacion Cientifica y Tecnologica (CONICYT); CancerfondenSwedish Cancer Society; Swedish Research CouncilSwedish Research CouncilEuropean Commission; EMBOEuropean Molecular Biology Organization (EMBO); Ligue Nationale contre le Cancer (equipe labellisee)Ligue nationale contre le cancer; European CommissionEuropean CommissionEuropean Commission Joint Research Centre; Agence Nationale pour la RechercheFrench National Research Agency (ANR); Canceropole Ile-de-FranceRegion Ile-de-France	We thank Dr. B. Vogelstein (John Hopkins University, Bethesda, USA) for WT and p53<SUP>-/-</SUP> HCT 116 cells. E. M. is recipient of a Ph.D. student fellowship from the EU Apop-Train network. E. T. receives a Ph.D. student fellowship from Institut National contre le Cancer (INCa). J. M. V. and A. C. are recipients of Ph. D. student fellowships from CONICYT, Chile. The work of T. S. is supported by Cancerfonden and the Swedish Research Council (VR). O. K. is funded by an EMBO Ph. D. fellowship. G. K. is supported by the Ligue Nationale contre le Cancer (equipe labellisee), European Commission (Active p53, RIGHT, Apo-Sys, Apop-Train), Agence Nationale pour la Recherche, Canceropole Ile-de-France, and INCa.	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J	Tan, YZ; Peng, C; Hu, CJ; Li, HX; Li, WB; He, JL; Li, YZ; Zhang, H; Zhang, RQ; Wang, LX; Cao, ZX				Tan, Yu-Zhu; Peng, Cheng; Hu, Chang-Jiang; Li, Hong-Xiang; Li, Wen-Bing; He, Jun-Lin; Li, Yu-Zhi; Zhang, Hai; Zhang, Ruo-Qi; Wang, Li-Xia; Cao, Zhi-Xing			Iridoids from Valeriana jatamansi induce autophagy-associated cell death via the PDK1/Akt/mTOR pathway in HCT116 human colorectal carcinoma cells	BIOORGANIC CHEMISTRY			English	Article						Valeriana jatamansi; Caprifoliaceae; Iridoids; Cytotoxicity; PDK1/Akt/mTOR	NATURAL-PRODUCTS; PLUS CETUXIMAB; ROOTS; PI3K/AKT/MTOR; CANCER; SESQUITERPENOIDS; MUTATIONS; DIVERSITY; DRUGS	Chlorovaltrates U-W (1-3), three previously undescribed iridoids, together with four known analogues were isolated from the roots of Valeriana jatamansi. Their structures were elucidated by means of spectroscopic analyses (HRESIMS, NMR). The cytotoxicity of all isolates was evaluated. Compounds 5-7 exhibited selective cytotoxicity against HCT116 cells, with IC50 values of 9.3, 1.7 and 2.2 mu M, respectively. The preliminary mechanistic study revealed that, the cytotoxicity effect of 6 was attributed to Akt/mTOR activation blockade via inhibition of PDK1 phosphorylation. Meanwhile, compound 6 could induce autophagosome formation in HCT116 cells via suppressing its downstream Akt/mTOR. These findings show that compound 6 could be of great importance to the development of anti-colon cancer agents.	[Tan, Yu-Zhu; Peng, Cheng; He, Jun-Lin; Li, Yu-Zhi; Zhang, Hai; Zhang, Ruo-Qi; Wang, Li-Xia; Cao, Zhi-Xing] Chengdu Univ Tradit Chinese Med, State Key Lab Breeding Base Systemat Res Dev & Ut, Chengdu 611137, Sichuan, Peoples R China; [Tan, Yu-Zhu; Peng, Cheng; Hu, Chang-Jiang; He, Jun-Lin; Li, Yu-Zhi; Zhang, Hai; Zhang, Ruo-Qi; Wang, Li-Xia; Cao, Zhi-Xing] Chengdu Univ Tradit Chinese Med, Sch Pharm, Chengdu 611137, Sichuan, Peoples R China; [Li, Hong-Xiang] Chengdu Univ Tradit Chinese Med, Innovat Inst Chinese Med & Pharm, Chengdu 611137, Sichuan, Peoples R China; [Li, Wen-Bing] Sichuan New Green Med Sci & Technol Dev Co Ltd, Key Lab Qual Control & Efficacy Evaluat Tradit Ch, Pengzhou 611930, Peoples R China		Peng, C; Cao, ZX (corresponding author), Chengdu Univ Tradit Chinese Med, Sch Pharm, State Key Lab Breeding Base Systemat Res Dev & Ut, Chengdu 611137, Sichuan, Peoples R China.	pengchengchengdu@126.com; caozhixing007@163.com	Hai, Zhang/AAE-3173-2019	Hu, Changjiang/0000-0002-6080-5594	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81703693, 81503346]; key fund project for Education Department of Sichuan [18ZA0181]; Youth Science and Technology Innovative Research Team fund project of Sichuan [2016TD0006]; Fund Project of Science and Technology of Chengdu [2016-HM01-00457-SF]	This work was financially supported by the National Natural Science Foundation of China (No. 81703693, 81503346), the key fund project for Education Department of Sichuan (No. 18ZA0181), the Youth Science and Technology Innovative Research Team fund project of Sichuan (No. 2016TD0006), and the Fund Project of Science and Technology of Chengdu [No. 2016-HM01-00457-SF].	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J	Zhang, XY; Xu, RT; Feng, WJ; Xu, JP; Liang, YL; Mu, JH				Zhang, Xianyi; Xu, Runtao; Feng, Wenjing; Xu, Jiapeng; Liang, Yulong; Mu, Jinghui			Autophagy-related genes contribute to malignant progression and have a clinical prognostic impact in colon adenocarcinoma	EXPERIMENTAL AND THERAPEUTIC MEDICINE			English	Article						colon adenocarcinoma; autophagy; The Cancer Genome Atlas; GTEx; DAPK1; ATG4B; SERPINA1; risk signature	CANCER; METABOLISM; RESISTANCE	Autophagy has an important role in regulating tumor cell survival. However, the roles of autophagy-related genes (ARGs) during colon adenocarcinoma (COAD) progression and their prognostic value have remained elusive. The present study aimed to identify the correlation between ARGs and the progression of COAD, as well as the prognostic significance of ARGs. The transcriptome pro?les and the corresponding clinicopathological information of patients with COAD were downloaded from The Cancer Genome Atlas and Genotype-Tissue Expression databases. A list of ARGs was obtained from the Human Autophagy Database and bioinformatics analysis was performed to investigate the functions of these ARGs. Statistical analyses of these genes were performed to identify independent prognostic markers. The selected prognostic markers were then validated in 15 patients with COAD via immunohistochemistry. Differentially expressed ARGs between normal and tumor tissues were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that the differentially expressed ARGs were mainly enriched in toxoplasmosis and pathways in cancer. The ATG4B, DAPK1 and SERPINA1 genes were determined to be associated with COAD progression. In addition, a risk signature was proposed that may serve as an independent prognostic marker. In conclusion, ATG4B, DAPK1 and SERPINA1 are crucial participants in tumorigenesis of COAD. The present study may promote the development of novel treatment strategies for COAD.	[Zhang, Xianyi; Xu, Runtao; Feng, Wenjing; Xu, Jiapeng; Liang, Yulong; Mu, Jinghui] Hebei Med Univ, Hosp 3, Dept Gen Surg, 139 Ziqiang Rd, Shijiazhuang 050051, Hebei, Peoples R China		Mu, JH (corresponding author), Hebei Med Univ, Hosp 3, Dept Gen Surg, 139 Ziqiang Rd, Shijiazhuang 050051, Hebei, Peoples R China.	jinghuimutgy@163.com					Akkoc Y, 2018, TURK J GASTROENTEROL, V29, P270, DOI 10.5152/tjg.2018.150318; [Anonymous], 2018, AM FAM PHYS, V97; Auberger P, 2017, BLOOD, V129, P547, DOI 10.1182/blood-2016-07-692707; Bhat P, 2018, BIOCHEM PHARMACOL, V147, P170, DOI 10.1016/j.bcp.2017.11.021; Chan LL, 2015, CLIN BIOCHEM, V48, P962, DOI 10.1016/j.clinbiochem.2015.04.022; Chen C, 2018, ANTI-CANCER DRUG, V29, P1, DOI 10.1097/CAD.0000000000000572; Chen PW, 2014, AUTOPHAGY, V10, P192, DOI 10.4161/auto.26927; Dienstmann R, 2015, J CLIN ONCOL, V33, P1787, DOI 10.1200/JCO.2014.60.0213; Erickson LA, 2018, MAYO CLIN PROC, V93, P669, DOI 10.1016/j.mayocp.2018.03.010; Fu YY, 2019, AUTOPHAGY, V15, P295, DOI 10.1080/15548627.2018.1517073; Fulda S, 2015, ONCOGENE, V34, P5105, DOI 10.1038/onc.2014.458; Gomes LR, 2017, INT J MOL SCI, V18, DOI 10.3390/ijms18112351; Griffith OL, 2006, J CLIN ONCOL, V24, P5043, DOI 10.1200/JCO.2006.06.7330; Guo JYX, 2016, COLD SH Q B, V81, P73, DOI 10.1101/sqb.2016.81.030981; Han YY, 2018, INT J ONCOL, V52, P1057, DOI 10.3892/ijo.2018.4270; Kriegsmann M, 2017, BBA-PROTEINS PROTEOM, V1865, P858, DOI 10.1016/j.bbapap.2016.11.018; Kuipers EJ, 2015, NAT REV DIS PRIMERS, V1, DOI 10.1038/nrdp.2015.65; Lachaux A, 2014, REV MAL RESPIR, V31, P357, DOI 10.1016/j.rmr.2013.10.651; Li M, 2020, CANCER GENE THER, V27, P715, DOI 10.1038/s41417-019-0143-5; Li XH, 2020, MOL CANCER, V19, DOI 10.1186/s12943-020-1138-4; Li YJ, 2017, CHIN J CANCER, V52, DOI 10.1186/s40880-017-0219-2; Liu GB, 2017, INT J MOL SCI, V18, DOI 10.3390/ijms18020367; Liu PF, 2017, CELL PHYSIOL BIOCHEM, V44, P728, DOI 10.1159/000485286; Lonsdale J, 2013, NAT GENET, V45, P580, DOI 10.1038/ng.2653; Mitchell EL, 2017, CURR PATHOBIOL REP, V5, P243, DOI 10.1007/s40139-017-0147-5; Ravanan P, 2017, LIFE SCI, V188, P53, DOI 10.1016/j.lfs.2017.08.029; Rosen AW., 2016, UGESKRLAEGER, V178; Singh P, 2016, FRONT MOL NEUROSCI, V9, DOI 10.3389/fnmol.2016.00046; Su ZY, 2015, MOL CANCER, V14, DOI 10.1186/s12943-015-0321-5; Wan LD, 2019, GUT, V68, P118, DOI 10.1136/gutjnl-2017-314983; Wang ZN, 2016, METHODS MOL BIOL, V1418, P111, DOI 10.1007/978-1-4939-3578-9_6; White A, 2017, CANCER-AM CANCER SOC, V123, P5014, DOI 10.1002/cncr.31076; White E, 2015, CLIN CANCER RES, V21, P5037, DOI 10.1158/1078-0432.CCR-15-0490; Yuan WZ, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0184959	34	1	1	0	0	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-0981	1792-1015		EXP THER MED	Exp. Ther. Med.	SEP	2021	22	3							932	10.3892/etm.2021.10364			11	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	TK7BL	WOS:000674309500001	34306201	gold, Green Published			2022-04-25	
J	Ghecham, A; Senator, A; Pawlowska, E; Bouafia, W; Blasiak, J				Ghecham, Abdelmoudjib; Senator, Abderrahmane; Pawlowska, Elzbieta; Bouafia, Waffa; Blasiak, Janusz			Epigenetic modifiers, 5-aza-2 '-deoxycytidine and valproic acid, differentially change viability, DNA damage and gene expression in metastatic and non-metastatic colon cancer cell lines	ACTA BIOCHIMICA POLONICA			English	Article						epigenetic modifiers; anticancer therapy; 5-Aza-dC; VPA; colorectal cancer; metastatic and non-metastatic cancer cells; DNA damage; gene expression	NF-KAPPA-B; HISTONE DEACETYLASE INHIBITION; ACUTE MYELOID-LEUKEMIA; METHYLATION; COMBINATION; AZACITIDINE; DECITABINE; THERAPY; DEMETHYLATION; MECHANISMS	DNA methylation and histone modifications are major components of cellular epigenetic pattern determining gene expression. Cancer cells have their own epigenetic array, which can be different in cells of primary and metastatic tumors. In the work presented here, we investigated effects of 1 mM valproic acid (VPA), a histone deacetylase inhibitor, and 0.2 mu M 5-aza-2'-deoxycytidine (5-aza-dC), a DNA demethylation agent, singly or in combination in two colorectal cancer cell lines: Caco-2 (non- metastatic) and LoVo (metastatic). Cell viability, DNA damage and mRNA expression of the CDC25C (cell division cycle 25C), CDKN1A (cyclin dependent kinase inhibitor 1A) and CHEK1 (checkpoint kinase 1), SQSTM1 (p62, sequestosome 1), ULK1 (unc-51 like autophagy activating kinase 1), RELA (RELA proto-oncogene, NF-KB subu- nit) and TP53BP1 (tumor protein p53 binding protein 1) genes important for cell cycle regulation, autophagy and cancer progression were investigated. Both drugs induced a moderate decrease in cell viability and a significant DNA damage in both cell lines. The LoVo cells were more sensitive to VPA and combined treatment than Caco-2. The LoVo cells also showed higher expression of genes that are often associated with more aggressive tumors than the Caco-2 cells and treatment with modifiers had increased this difference. In conclusion, 5-aza-dC and VPA can induce different effects in metastatic and non-metastatic cancer cell lines and this may be important in determination of an epigenetic profile responsible for metastatic properties of cancer cells.	[Ghecham, Abdelmoudjib] Univ Batna 2, Biotechnol Lab Bioact Mol & Cellular Physiopathol, Fac Life Sci, Batna, Algeria; [Senator, Abderrahmane; Bouafia, Waffa] Univ Batna 2, Fac Life Sci, Batna, Algeria; [Pawlowska, Elzbieta] Med Univ Lodz, Dept Orthodont, Lodz, Poland; [Blasiak, Janusz] Univ Lodz, Dept Mol Genet, Fac Biol & Environm Protect, Lodz, Poland		Blasiak, J (corresponding author), Univ Lodz, Dept Mol Genet, Fac Biol & Environm Protect, Lodz, Poland.	janusz.blasiak@biol.uni.lodz.pl		Blasiak, Janusz/0000-0001-9539-9584; Pawlowska, Elzbieta/0000-0002-5373-4783; Abderrahmane, Senator/0000-0002-3472-0538			Al-Temaimi RA, 2016, INT J MOL SCI, V17, DOI 10.3390/ijms17050598; Basseres DS, 2006, ONCOGENE, V25, P6817, DOI 10.1038/sj.onc.1209942; Bertolini F, 2015, NAT REV CLIN ONCOL, V12, P732, DOI 10.1038/nrclinonc.2015.169; Bhadury J, 2014, P NATL ACAD SCI USA, V111, pE2721, DOI 10.1073/pnas.1406722111; Cameron EE, 1999, NAT GENET, V21, P103, DOI 10.1038/5047; Caswell DR, 2017, BMC MED, V15, DOI 10.1186/s12916-017-0900-y; De Greef K, 2016, WORLD J GASTROENTERO, V22, P7215, DOI 10.3748/wjg.v22.i32.7215; DREWINKO B, 1979, CANCER RES, V39, P2630; Elshafay A, 2019, CNS DRUGS, V33, P239, DOI 10.1007/s40263-019-00606-6; Fiskus W, 2017, LEUKEMIA, V31, P1658, DOI 10.1038/leu.2017.77; Fiskus W, 2009, BLOOD, V114, P2733, DOI 10.1182/blood-2009-03-213496; Gobble RM, 2011, CANCER RES, V71, P2697, DOI 10.1158/0008-5472.CAN-10-3588; Habano W, 2011, BMC CANCER, V11, DOI 10.1186/1471-2407-11-81; Hollenbach PW, 2010, PLOS ONE, V5, DOI 10.1371/journal.pone.0009001; Hu Xin, 2010, Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, V24, P678; Huber MA, 2004, J CLIN INVEST, V114, P569, DOI 10.1172/JCI200421358; Juergens RA, 2011, CANCER DISCOV, V1, P598, DOI 10.1158/2159-8290.CD-11-0214; Julien S, 2007, ONCOGENE, V26, P7445, DOI 10.1038/sj.onc.1210546; Jung Y, 2007, J MOL MED, V85, P1137, DOI 10.1007/s00109-007-0216-z; Khan C, 2012, THER ADV HEMATOL, V3, P355, DOI 10.1177/2040620712464882; Kirschbaum M, 2014, BRIT J HAEMATOL, V167, P185, DOI 10.1111/bjh.13016; Klaude M, 1996, MUTAT RES-DNA REPAIR, V363, P89, DOI 10.1016/0921-8777(95)00063-1; Kondo Y, 2003, MOL CELL BIOL, V23, P206, DOI 10.1128/MCB.23.1.206-215.2003; Kondo Y, 2009, YONSEI MED J, V50, P455, DOI 10.3349/ymj.2009.50.4.455; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Lobbezoo DJA, 2016, ANN ONCOL, V27, P256, DOI 10.1093/annonc/mdv544; Macaluso M, 2003, ONCOGENE, V22, P6472, DOI 10.1038/sj.onc.1206955; Mohammad HP, 2019, NAT MED, V25, P403, DOI 10.1038/s41591-019-0376-8; Momparler RL, 2012, LEUKEMIA RES, V36, P1049, DOI 10.1016/j.leukres.2012.03.001; Naugler WE, 2008, CURR OPIN GENET DEV, V18, P19, DOI 10.1016/j.gde.2008.01.020; Papi A, 2012, ANTICANCER RES, V32, P2855; Pawlowska E, 2014, INT J MOL SCI, V15, P16649, DOI 10.3390/ijms150916649; Prasetyanti PR, 2017, MOL CANCER, V16, DOI 10.1186/s12943-017-0600-4; Raynal NJM, 2017, MOL CANCER THER, V16, P397, DOI 10.1158/1535-7163.MCT-16-0588; Rountree MR, 2001, ONCOGENE, V20, P3156, DOI 10.1038/sj.onc.1204339; Sampath D, 2003, ONCOGENE, V22, P9063, DOI 10.1038/sj.onc.1207229; Schuh AC, 2017, CRIT REV ONCOL HEMAT, V116, P159, DOI 10.1016/j.critrevonc.2017.05.010; Schulpis KH, 2006, TOXICOLOGY, V217, P228, DOI 10.1016/j.tox.2005.10.004; Seelan RS, 2018, DRUG METAB REV, V50, P193, DOI 10.1080/03602532.2018.1437446; SINGH NP, 1988, EXP CELL RES, V175, P184, DOI 10.1016/0014-4827(88)90265-0; Strey CW, 2011, EXP THER MED, V2, P301, DOI 10.3892/etm.2011.202; Suzuki H, 2002, NAT GENET, V31, P141, DOI 10.1038/ng892; Taby R, 2010, CA-CANCER J CLIN, V60, P376, DOI 10.3322/caac.20085; Toh TB, 2017, MOL CANCER, V16, DOI 10.1186/s12943-017-0596-9; Tung EWY, 2011, REPROD TOXICOL, V32, P255, DOI 10.1016/j.reprotox.2011.05.020; van Zijl F, 2011, MUTAT RES-REV MUTAT, V728, P23, DOI 10.1016/j.mrrev.2011.05.002; Verlinden L, 2007, CANCER RES, V67, P6574, DOI 10.1158/0008-5472.CAN-06-3545; Wang XB, 2007, NAT CELL BIOL, V9, P470, DOI 10.1038/ncb1559; Yao Hongliang, 2010, Zhong Nan Da Xue Xue Bao Yi Xue Ban, V35, P1080, DOI 10.3969/j.issn.1672-7347.2010.10.008; You JS, 2012, CANCER CELL, V22, P9, DOI 10.1016/j.ccr.2012.06.008; Zhao L, 2018, CURR TOP MED CHEM, V18, P2395, DOI 10.2174/1568026619666181224095449	51	2	2	0	1	ACTA BIOCHIMICA POLONICA	WARSAW	PASTEURA 3, 02-093 WARSAW, POLAND	0001-527X	1734-154X		ACTA BIOCHIM POL	Acta Biochim. Pol.		2019	66	3					355	360		10.18388/abp.2019_2814			6	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	IY4XT	WOS:000486397000017	31284710	gold, Green Submitted			2022-04-25	
J	Zhang, T; Qi, YL; Liao, MJ; Xu, M; Bower, KA; Frank, JA; Shen, HM; Luo, J; Shi, XL; Chen, G				Zhang, Tao; Qi, Yuanlin; Liao, Mingjun; Xu, Mei; Bower, Kimberley A.; Frank, Jacqueline A.; Shen, Han-Ming; Luo, Jia; Shi, Xianglin; Chen, Gang			Autophagy Is a Cell Self-Protective Mechanism Against Arsenic-Induced Cell Transformation	TOXICOLOGICAL SCIENCES			English	Article						arsenic; autophagy; oxidative stress; transformation; tumorigenesis	MOLECULAR-MECHANISMS; OXIDATIVE STRESS; NEURONAL DEATH; ACTIVATION; CANCER; BECLIN-1; TUMORIGENESIS; GENERATION; DAMAGE; MOUSE	Subchronic exposure to arsenic increases the incidence of human cancers such as skin, lung, colon, and rectal cancer. The mechanism for arsenic-induced tumorigenesis is still not clear. It is generally believed that DNA damage and genomic instability, generated by arsenic-promoted oxidative stress, account largely for this process. The major sources of reactive oxygen species (ROS) are arsenic-damaged mitochondria. Autophagy is a catabolic process functioning in turnover of long-lived proteins and dysfunctional organelles such as mitochondria. Defects of autophagy under stress conditions promote genomic instability and increase the risk of tumorigenesis. In the present study using a human bronchial epithelial cell line, BEAS-2B cells, we investigated the role of autophagy in arsenic-induced cell transformation, an important step in arsenic tumorigenesis. Our results show that subchronic arsenic exposure induces BEAS-2B cell transformation accompanied with increased ROS generation and autophagy activation. However, the patterns for ROS and autophagy alteration are different. Arsenic exposure generated a prolonged and steady increase of ROS levels, whereas the activation of autophagy, after an initial boost by arsenic administration, decreases in response to subchronic arsenic exposure, although the activity is still higher than a nontreated control. Further stimulation of autophagy increases mitochondria turnover and decreases ROS generation and arsenic-induced cell transformation. Contrarily, inhibition of autophagy activity decreases mitochondria turnover and enhances arsenic-induced ROS generation and cell transformation. In addition, the mammalian target of rapamycin signaling pathway is involved in arsenic-mediated autophagy activation. Our results suggest that autophagy is a cell self-protective mechanism against arsenic-induced cell transformation.	[Zhang, Tao; Qi, Yuanlin; Liao, Mingjun; Xu, Mei; Bower, Kimberley A.; Frank, Jacqueline A.; Luo, Jia; Chen, Gang] Univ Kentucky, Coll Med, Dept Internal Med, Lexington, KY 40536 USA; [Zhang, Tao] Fujian Med Univ, Sch Basic Med Sci, Dept Immunol, Fuzhou 350004, Fujian, Peoples R China; [Qi, Yuanlin] Fujian Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Fuzhou 350004, Fujian, Peoples R China; [Shen, Han-Ming] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore; [Shi, Xianglin] Univ Kentucky, Coll Med, Grad Ctr Toxicol, Lexington, KY 40536 USA		Chen, G (corresponding author), Univ Kentucky, Coll Med, Dept Internal Med, 125 Hlth Sci Res Bldg,1095 Vet Dr, Lexington, KY 40536 USA.	gangchen6@uky.edu	Luo, Jia/E-4674-2012; SHEN, Han-Ming/B-5942-2011; Shi, Xianglin/B-8588-2012	Luo, Jia/0000-0002-6968-3618; SHEN, Han-Ming/0000-0001-7369-5227; Qi, Yuanlin/0000-0002-5253-9732	American Cancer SocietyAmerican Cancer Society [RSG-11-116-01-CNE]	American Cancer Society [RSG-11-116-01-CNE to G.C.].	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Sci.	DEC	2012	130	2					298	308		10.1093/toxsci/kfs240			11	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	040FN	WOS:000311307600009	22869613	Green Published, Bronze			2022-04-25	
J	Russo, R; Cassiano, MGV; Ciociaro, A; Adornetto, A; Varano, GP; Chiappini, C; Berliocchi, L; Tassorelli, C; Bagetta, G; Corasaniti, MT				Russo, Rossella; Cassiano, Maria Gilda Valentina; Ciociaro, Antonella; Adornetto, Annagrazia; Varano, Giuseppe Pasquale; Chiappini, Carlotta; Berliocchi, Laura; Tassorelli, Cristina; Bagetta, Giacinto; Corasaniti, Maria Tiziana			Role of D-Limonene in Autophagy Induced by Bergamot Essential Oil in SH-SY5Y Neuroblastoma Cells	PLOS ONE			English	Article							COLON-CANCER CELLS; IN-VITRO ACTIVITY; RAT; GROWTH; COMPLEX; DEATH; PREVENTION; INHIBITION; MECHANISM; SIGNALS	Bergamot (Citrus bergamia, Risso et Poiteau) essential oil (BEO) is a well characterized, widely used plant extract. BEO exerts anxiolytic, analgesic and neuroprotective activities in rodents through mechanisms that are only partly known and need to be further investigated. To gain more insight into the biological effects of this essential oil, we tested the ability of BEO (0.005-0.03%) to modulate autophagic pathways in human SH-SY5Y neuroblastoma cells. BEO-treated cells show increased LC3II levels and appearance of dot-like formations of endogenous LC3 protein that colocalize with the lysosome marker LAMP-1. Autophagic flux assay using bafilomycin A1 and degradation of the specific autophagy substrate p62 confirmed that the observed increase of LC3II levels in BEO-exposed cells is due to autophagy induction rather than to a decreased autophagosomal turnover. Induction of autophagy is an early and not cell-line specific response to BEO. Beside basal autophagy, BEO also enhanced autophagy triggered by serum starvation and rapamycin indicating that the underlying mechanism is mTOR independent. Accordingly, BEO did not affect the phosphorylation of ULK1 (Ser757) and p70(S6K) (Thr389), two downstream targets of mTOR. Furthermore, induction of autophagy by BEO is beclin-1 independent, occurs in a concentration-dependent manner and is unrelated to the ability of BEO to induce cell death. In order to identify the active constituents responsible for these effects, the two most abundant monoterpenes found in the essential oil, d-limonene (125-750 mu M) and linalyl acetate (62.5-375 mu M), were individually tested at concentrations comparable to those found in 0.005-0.03% BEO. The same features of stimulated autophagy elicited by BEO were reproduced by d-limonene, which rapidly increases LC3II and reduces p62 levels in a concentration-dependent manner. Linalyl acetate was ineffective in replicating BEO effects; however, it greatly enhanced LC3 lipidation triggered by d-limonene.	[Russo, Rossella; Adornetto, Annagrazia; Varano, Giuseppe Pasquale; Bagetta, Giacinto] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Sect Preclin & Translat Pharmacol, I-87036 Cosenza, Italy; [Cassiano, Maria Gilda Valentina; Ciociaro, Antonella; Chiappini, Carlotta; Berliocchi, Laura; Corasaniti, Maria Tiziana] Magna Graecia Univ Catanzaro, Dept Hlth Sci, Catanzaro, Italy; [Tassorelli, Cristina] Univ Pavia, Headache Sci Ctr, Natl Neurol Inst C Mondino, I-27100 Pavia, Italy; [Tassorelli, Cristina] Univ Pavia, Dept Brain & Behav Sci, I-27100 Pavia, Italy		Russo, R (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, Sect Preclin & Translat Pharmacol, I-87036 Cosenza, Italy.	rossella.russo@unical.it; mtcorasa@unicz.it	Tassorelli, Cristina/AAC-1483-2019; Adornetto, Annagrazia/AAG-5467-2020; Bagetta, Giacinto/E-8402-2012; Bagetta, Giacinto/N-9716-2018; Corasaniti, Maria Tiziana/N-1332-2015	Tassorelli, Cristina/0000-0003-1513-2113; Adornetto, Annagrazia/0000-0003-1869-2642; Bagetta, Giacinto/0000-0001-8540-6218; Bagetta, Giacinto/0000-0001-8540-6218; Corasaniti, Maria Tiziana/0000-0001-6472-0697; Russo, Rossella/0000-0001-8758-6523; Berliocchi, Laura/0000-0002-3014-1838			Amantea D, 2009, INT REV NEUROBIOL, V85, P389, DOI 10.1016/S0074-7742(09)85027-7; Bagetta G, 2010, FITOTERAPIA, V81, P453, DOI 10.1016/j.fitote.2010.01.013; Banerjee R, 2010, TRENDS NEUROSCI, V33, P541, DOI 10.1016/j.tins.2010.09.001; Berliocchi L, 2011, MOL PAIN, V7, DOI 10.1186/1744-8069-7-83; Berliocchi L, 2011, FOOD CHEM TOXICOL, V49, P2780, DOI 10.1016/j.fct.2011.08.017; Bicas JL, 2011, FOOD CHEM TOXICOL, V49, P1610, DOI 10.1016/j.fct.2011.04.012; Bjorkoy G, 2005, J CELL BIOL, V171, P603, DOI 10.1083/jcb.200507002; Chaudhary SC, 2012, HUM EXP TOXICOL, V31, P798, DOI 10.1177/0960327111434948; Codogno P, 2012, NAT REV MOL CELL BIO, V13, P7, DOI 10.1038/nrm3249; Corasaniti MT, 2007, BRIT J PHARMACOL, V151, P518, DOI 10.1038/sj.bjp.0707237; Cosentino M, 2014, PHYTOTHER RES; CROWELL PL, 1991, J BIOL CHEM, V266, P17679; Dugo P, 2000, J PHARMACEUT BIOMED, V24, P147, DOI 10.1016/S0731-7085(00)00400-3; 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J	Tao, XX; Yan, YF; Lu, LM; Chen, B				Tao, Xiangxiang; Yan, Yifeng; Lu, Linming; Chen, Bing			HDAC10 expression is associated with DNA mismatch repair gene and is a predictor of good prognosis in colon carcinoma	ONCOLOGY LETTERS			English	Article						colon cancer; HDAC10; prognosis; tissue microarray; immunohistochemistry	CANCER PATIENTS; POOR-PROGNOSIS; AUTOPHAGY; DEACETYLATION	Despite increasing evidence of the involvement of histone deacetylase (HDAC) 10 in cancer tumorigenesis, the potential role of HDAC10 in colon cancer remains unclear. Oncomine database analysis revealed that HDAC10 mRNA was significantly upregulated in colon cancer. In an independent cohort, consistent with mRNA expression levels, constitutively high HDAC10 expression was observed in the cytoplasm and nucleus compared with in adjacent normal tissues (cytoplasm, 93.12 +/- 12.98 vs. 31.65 +/- 26.50%; nucleus, 84.16 +/- 19.23 vs. 68.64 +/- 19.00%). Cytoplasmic HDAC expression correlated with gender (r=0.265; P<0.05), lymph node metastasis (N stage; r=0.256; P<0.05) and distant metastasis (M stage; r=0.331; P<0.05) in paracarcinoma tissues. Cytoplasmic HDAC10 expression in tumors was not associated with the four DNA mismatch repair genes examined, but was negatively correlated with mutL homolog 1 (MLH1) (r=-0.244; P<0.05), mutS homolog (MSH)2 (r=-0.410; P<0.01) and MSH6 (r=-0.240; P<0.05) in paracarcinoma tissues. Similarly, nuclear HDAC10 expression was negatively correlated with MLH1 expression (r=-0.288; P<0.05). The findings of the current study suggest that HDAC10 expression is associated with good prognosis in colon cancer tissues and poor prognosis in paracarcinoma tissues with a potential involvement in DNA mismatch repair.	[Tao, Xiangxiang; Lu, Linming; Chen, Bing] Wannan Med Coll, Dept Pathol, 22 Wenchang West Rd, Wuhu 241001, Anhui, Peoples R China; [Yan, Yifeng] Wannan Med Coll, Dept Forens Pathol, Wuhu 241001, Anhui, Peoples R China		Chen, B (corresponding author), Wannan Med Coll, Dept Pathol, 22 Wenchang West Rd, Wuhu 241001, Anhui, Peoples R China.	281993214@qq.com					Bauer KM, 2012, MOL CARCINOGEN, V51, P411, DOI 10.1002/mc.20804; Chen WQ, 2016, CA-CANCER J CLIN, V66, P115, DOI 10.3322/caac.21338; Clocchiatti A, 2011, J CELL MOL MED, V15, P1833, DOI 10.1111/j.1582-4934.2011.01321.x; Fan WX, 2015, INT J CLIN EXP MED, V8, P3734; Islam MM, 2017, GYNECOL ONCOL, V144, P613, DOI 10.1016/j.ygyno.2017.01.009; Jin ZL, 2014, INT J CLIN EXP PATHO, V7, P5872; Kotian S, 2011, J BIOL CHEM, V286, P7722, DOI 10.1074/jbc.C110.194233; Lai IL, 2010, J BIOL CHEM, V285, P7187, DOI 10.1074/jbc.M109.061861; Lee JH, 2010, MOL CELLS, V30, P107, DOI 10.1007/s10059-010-0094-z; Li YX, 2015, MOL CELL BIOL, V35, P3547, DOI 10.1128/MCB.00400-15; Oehme I, 2013, AUTOPHAGY, V9, P2163, DOI 10.4161/auto.26450; Oehme I, 2013, P NATL ACAD SCI USA, V110, pE2592, DOI 10.1073/pnas.1300113110; Osada H, 2004, INT J CANCER, V112, P26, DOI 10.1002/ijc.20395; Park BL, 2007, BIOCHEM BIOPH RES CO, V363, P776, DOI 10.1016/j.bbrc.2007.09.026; Petrelli F., 2016, JAMA ONCOL; Pinto G, 2016, J NUTR BIOCHEM, V27, P171, DOI 10.1016/j.jnutbio.2015.08.031; Powers J, 2016, METHODS MOL BIOL, V1436, P129, DOI 10.1007/978-1-4939-3667-0_10; Radhakrishnan R, 2015, J BIOL CHEM, V290, P22795, DOI 10.1074/jbc.M114.612945; Song CL, 2013, J BIOL CHEM, V288, P28021, DOI 10.1074/jbc.M113.498758; Wang XJ, 2014, KIDNEY INT, V86, P712, DOI 10.1038/ki.2014.111; Yang YW, 2016, ONCOTARGET, V7, P59388, DOI 10.18632/oncotarget.10673; Yuan ZG, 2010, J BIOL CHEM, V285, P39329, DOI 10.1074/jbc.M110.179333	22	9	9	0	5	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-1074	1792-1082		ONCOL LETT	Oncol. Lett.	OCT	2017	14	4					4923	4929		10.3892/ol.2017.6818			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FK0DU	WOS:000413151300151	29085502	Green Published, gold			2022-04-25	
J	Zhang, B; Liu, LT				Zhang, Bo; Liu, Lantao			Autophagy is a double-edged sword in the therapy of colorectal cancer	ONCOLOGY LETTERS			English	Review						autophagy; Beclin 1; chemotherapy; colorectal cancer; apoptosis		Colorectal cancer is one of the leading causes of cancer-associated mortality worldwide. The limitations of colorectal cancer treatment include various types of multidrug resistance and the contingent damage to neighboring normal cells caused by chemotherapy. Macroautophagy/autophagy and apoptosis are essential mechanisms involved in cancer cell regulation of chemotherapy. Autophagy can either cause cancer cell death or promote tumor survival during colorectal cancer. Given that autophagy is involved in chemotherapy of colorectal cancer, an improved insight into the potential interactions between apoptosis and autophagy is crucial. The present review aimed to summarize the involvement of autophagy in the regulation of colorectal cancer and its association with chemotherapy. Furthermore, the role of natural product extraction, novel chemicals and small molecules, as well as radiation, which induce autophagy in colorectal cancer cells, were reviewed. Finally, the present review aimed to provide an outlook for the regulation of autophagy as a novel approach to the treatment of cancer, particularly chemotherapy-resistant colorectal cancer.	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Lett.	MAY	2021	21	5							378	10.3892/ol.2021.12639			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	RC6VQ	WOS:000632936600001	33777202	Green Published, gold			2022-04-25	
S	Chen, LX; Zhou, YX; Sun, QH; Zhou, JC; Pan, HM; Sui, XB		Galluzzi, L; Vitale, I		Chen, Liuxi; Zhou, Yuxia; Sun, Qiuhua; Zhou, Jichun; Pan, Hongming; Sui, Xinbing			Regulation of Autophagy by MiRNAs and Their Emerging Roles in Tumorigenesis and Cancer Treatment	MIRNAS IN AGING AND CANCER	International Review of Cell and Molecular Biology		English	Review; Book Chapter							HEPATOCELLULAR-CARCINOMA CELLS; HYPOXIA-INDUCED AUTOPHAGY; DOWN-REGULATION; INHIBITING AUTOPHAGY; COLORECTAL-CANCER; NUCLEAR EXPORT; MICRORNA GENES; RNA-INTERFERENCE; CERVICAL-CANCER; FAMILY-MEMBERS	Autophagy is a conserved catabolic process for the degradation and recycling of cytosolic components or organelles through a lysosome-dependent pathway. Autophagy can be induced in response to multiple stress conditions, such as nutrient deprivation, hypoxia, energy depletion, etc. As a result, autophagy can regulate many biological processes, including cell survival, metabolism, differentiation, senescence, and cell death. MicroRNAs (MiRNAs) are small noncoding molecules that regulate gene expression by silencing mRNA targets. MiRNA dysregulation exhibits great regulatory potential during organismal development, hematopoiesis, immunity, cell proliferation and death, and autophagy. Recently, increasing studies have linked MiRNAs to autophagic regulation during cancer initiation and development. Although the relationship between MiRNAs and autophagy is quite complicated and has not been well elucidated, MiRNAs may underlie key aspects of autophagy and cancer biology. Increasing evidence shows that MiRNAs play important roles as both oncogenic MiRNAs and tumor suppressive MiRNAs in cancer initiation and development. Thus, understanding the novel relationship between MiRNAs and autophagy may allow us to develop promising cancer biomarkers and therapeutic targets.	[Chen, Liuxi; Zhou, Jichun; Pan, Hongming; Sui, Xinbing] Zhejiang Univ, Coll Med, Sir Run Run Shaw Hosp, Hangzhou, Zhejiang, Peoples R China; [Zhou, Yuxia] Shandong Maternal & Child Hlth Hosp, Jinan, Shandong, Peoples R China; [Sun, Qiuhua; Sui, Xinbing] Zhejiang Chinese Med Univ, Hangzhou, Zhejiang, Peoples R China		Zhou, JC; Pan, HM; Sui, XB (corresponding author), Zhejiang Univ, Coll Med, Sir Run Run Shaw Hosp, Hangzhou, Zhejiang, Peoples R China.; Sui, XB (corresponding author), Zhejiang Chinese Med Univ, Hangzhou, Zhejiang, Peoples R China.	zjc@live.com; drpanhm@aliyun.com; hzzju@aliyun.com	Zhou, Jichun/Q-8646-2019	Zhou, Jichun/0000-0002-0727-4034			Ali S, 2010, CANCER RES, V70, P3606, DOI 10.1158/0008-5472.CAN-09-4598; Ambros V, 2004, NATURE, V431, P350, DOI 10.1038/nature02871; An Y, 2015, CELL DEATH DIS, V6, DOI 10.1038/cddis.2015.123; Bagga S, 2005, CELL, V122, P553, DOI 10.1016/j.cell.2005.07.031; Bartel DP, 2009, CELL, V136, P215, DOI 10.1016/j.cell.2009.01.002; Bartel DP, 2004, CELL, V116, P281, DOI 10.1016/S0092-8674(04)00045-5; 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Rev. Cell Mol. Biol.		2017	334						1	26		10.1016/bs.ircmb.2017.03.003			26	Biochemistry & Molecular Biology; Oncology; Cell Biology; Geriatrics & Gerontology	Book Citation Index – Science (BKCI-S); Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology; Cell Biology; Geriatrics & Gerontology	BI7LN	WOS:000414404700001	28838537				2022-04-25	
J	Guo, JB; Ma, YB; Peng, XQ; Jin, HY; Liu, JG				Guo, Jianbo; Ma, Yingbo; Peng, Xueqiang; Jin, Hongyuan; Liu, Jingang			LncRNA CCAT1 promotes autophagy via regulating ATG7 by sponging miR-181 in hepatocellular carcinoma	JOURNAL OF CELLULAR BIOCHEMISTRY			English	Article						autophagy-related gene 7; autophagy; colon cancer associated transcript 1; hepatocellular carcinoma; long noncoding RNA	LONG NONCODING RNAS; CANCER; PROLIFERATION; EXPRESSION	Background Hepatocellular carcinoma (HCC) is a significant clinical challenge, and the mechanisms underlying HCC pathogenesis remain incompletely understood. Colon cancer associated transcript 1 (CCAT1), is one novel long noncoding RNA (lncRNA) which is upregulated in HCC. Autophagy is a vital process in HCC progression, and it is unknown whether CCAT1 regulates autophagy in HCC. Materials and methods Immunofluorescence staining and transmission electron microscopy were used to analyze autophagy activity. Luciferase assay was performed to confirm miRNA-181a-5p (miR-181a-5p) bind CCAT1 and ATG7. Results CCAT1 levels were higher in tissue and cell lines of HCC. In function research, we found that CCAT1 facilitates HCC cell autophagy and cell proliferation. Our results show that, mechanistically, CCAT1 promotes autophagy through functioning as a sponge for miR-181a-5p, and then regulating ATG7 expression. Conclusion Our findings indicate CCAT1 may play a role in regulating autophagy by sponging miR-181a-5p in HCC.	[Guo, Jianbo; Ma, Yingbo; Peng, Xueqiang; Jin, Hongyuan; Liu, Jingang] China Med Univ, Affiliated Hosp 4, Dept Gen Surg, Shenyang 110032, Liaoning, Peoples R China		Liu, JG (corresponding author), China Med Univ, Affiliated Hosp 4, Dept Gen Surg, Shenyang 110032, Liaoning, Peoples R China.	liujg0347@126.com					Bhardwaj N, 2016, J TRANSPLANT, V2016, DOI 10.1155/2016/7926264; Chen S, 2013, CLIN CANCER RES, V19, P6853, DOI 10.1158/1078-0432.CCR-13-1617; Chen SN, 2010, BBA-REV CANCER, V1806, P220, DOI 10.1016/j.bbcan.2010.07.003; Czaja MJ, 2013, AUTOPHAGY, V9, P1131, DOI 10.4161/auto.25063; Deng L, 2015, J EXP CLIN CANC RES, V34, DOI 10.1186/s13046-015-0136-7; Dou CQ, 2017, TUMOR BIOL, V39, DOI 10.1177/1010428317697572; Esteller M, 2011, NAT REV GENET, V12, P861, DOI 10.1038/nrg3074; Goldsmith J, 2014, METHOD ENZYMOL, V542, P25, DOI 10.1016/B978-0-12-416618-9.00002-9; Granito A, 2017, LANCET ONCOL, V18, pE101, DOI 10.1016/S1470-2045(16)30569-1; Guo XL, 2012, CANCER LETT, V320, P171, DOI 10.1016/j.canlet.2012.03.002; Hall DP, 2014, CANCER CELL, V26, P738, DOI 10.1016/j.ccell.2014.09.015; He XL, 2014, TUMOR BIOL, V35, P12181, DOI 10.1007/s13277-014-2526-4; He Y, 2014, CANCER LETT, V344, P20, DOI 10.1016/j.canlet.2013.10.021; Huang JL, 2018, MOL CANCER, V17, DOI 10.1186/s12943-018-0841-x; Hui X, 2013, BIOMED RES INT, V2013; Long B, 2018, BIOCHEM BIOPH RES CO, V495, P312, DOI 10.1016/j.bbrc.2017.11.030; Ma MZ, 2015, CELL DEATH DIS, V6, DOI 10.1038/cddis.2014.541; Naganuma T, 2013, RNA BIOL, V10, P456, DOI 10.4161/rna.23547; Ozawa T, 2017, ANN ONCOL, V28, P1882, DOI 10.1093/annonc/mdx248; Sacco R, 2017, J HEPATOCELL CARCINO, V4, P105, DOI 10.2147/JHC.S103661; Shen HM, 2014, TRENDS BIOCHEM SCI, V39, P61, DOI 10.1016/j.tibs.2013.12.001; Shi LX, 2016, VIRUS RES, V223, P131, DOI 10.1016/j.virusres.2016.06.008; Sun JF, 2018, J EXP CLIN CANC RES, V37, DOI 10.1186/s13046-018-0771-x; Suzuki K, 2013, J CELL SCI, V126, P2534, DOI 10.1242/jcs.122960; Wu YY, 2017, MOL CANCER, V16, DOI 10.1186/s12943-017-0715-7; Xin XR, 2018, MOL CANCER, V17, DOI 10.1186/s12943-018-0843-8; Yang L, 2016, MOL BIOSYST, V12, P2605, DOI 10.1039/c6mb00114a; Ye RF, 2018, BIOMED PHARMACOTHER, V105, P962, DOI 10.1016/j.biopha.2018.06.065; Zhu Hua-Qiang, 2015, Asian Pac J Cancer Prev, V16, P5181; Zhu HQ, 2015, INT J CLIN EXP PATHO, V8, P5427	30	22	25	0	5	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0730-2312	1097-4644		J CELL BIOCHEM	J. Cell. Biochem.	OCT	2019	120	10					17975	17983		10.1002/jcb.29064			9	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	IU4IQ	WOS:000483551100149	31218739				2022-04-25	
J	Mokri, N; Sepehri, Z; Faninam, F; Khaleghi, S; Kazemi, NM; Hashemi, M				Mokri, Negin; Sepehri, Zahra; Faninam, Farnaz; Khaleghi, Sepideh; Kazemi, Negar Motakef; Hashemi, Mehrdad			Chitosan-coated Zn-metal-organic framework nanocomposites for effective targeted delivery of LNA-antisense miR-224 to colon tumor: in vitro studies	GENE THERAPY			English	Article; Early Access							DRUG-DELIVERY; G4 DENDRIMER; CANCER; PROLIFERATION; NANOPARTICLES; EXPRESSION; CELLS; APOPTOSIS; INVASION	Nowadays, nano-compartments are considered as an effective drug delivery system (DDS) for cancer therapy. Targeted delivery of therapeutic agents is an advantageous approach by which cancer cells can be targeted without harming normal cells, and eliminates the negative effects of conventional therapies such as chemotherapy. In this research, a novel zinc-based nanoscale metal-organic framework (Zn-NMOF) coated with folic acid (FA) functionalized chitosan (CS) has been constructed and applied as efficient delivery of LNA (locked nucleic acid)-antisense miR-224 to colon cancer cell lines. LNA-antisense miR-224 as a therapeutic sequence was able to considerably block highly expressed miR-224 and downregulated cancer cell growth. The prepared nano-complex was characterized by analytical devices such as FT-IR, UV-Vis spectrophotometry, DLS, TEM, and XRD. The size range of NMOF-CS-FA-LNA-antisense miR-224 (MCFL224) nano-complex was obtained nearly at 200 nm. The entrapment efficiency of LNA-antisense miR-224 was calculated 72 +/- 5% and a significant release profile of LNA-antisense miR-224 was observed at first 6 h (about 50%). Then, in vitro assays were implemented on HCT116 (folic acid receptor-positive colon cancer cell line) and CRL1831 (normal colon cell line) to evaluate the therapeutic efficiency of the MCFL224 nano-complex. In these investigations, decreased cell viability (14.22 +/- 0.3% after 72 h treatment), increased apoptotic and autophagy-related genes expression level (BECLIN1: 34-folds, BAX: 36-folds, mTORC1: 10-folds, and Caspase-9: 9-folds more than control), higher cell cycle arrest in sub-G1 phase (19.53% of cells in sub-G1 phase), and more apoptosis analyses (late apoptosis: 67.7%) were evaluated in colon cancer cells treated with MCFL224 nano-complex. Results remarkably indicate the inhibited growth of colon cancer cells and induced cell apoptosis which suggests MCFL224 as a promising nanocomposite for colon cancer therapy.	[Mokri, Negin; Khaleghi, Sepideh] Islamic Azad Univ, Tehran Med Sci, Fac Adv Sci & Technol, Dept Biotechnol, Tehran, Iran; [Sepehri, Zahra; Faninam, Farnaz] Islamic Azad Univ, North Tehran Branch, Dept Life Sci, Fac Biol, Tehran, Iran; [Kazemi, Negar Motakef] Islamic Azad Univ, Dept Med Nanotechnol, Fac Adv Sci & Technol, Tehran Med Sci, Tehran, Iran; [Hashemi, Mehrdad] Islamic Azad Univ, Dept Genet, Fac Adv Sci & Technol, Tehran Med Sci, Tehran, Iran		Khaleghi, S (corresponding author), Islamic Azad Univ, Tehran Med Sci, Fac Adv Sci & Technol, Dept Biotechnol, Tehran, Iran.	s.khaleghi@iautmu.ac.ir		Khaleghi, Sepideh/0000-0002-1817-3116; Hashemi, Mehrdad/0000-0003-0627-6991			Abazari R, 2018, INORG CHEM, V57, P13364, DOI 10.1021/acs.inorgchem.8b01955; Ali MEA, 2018, SEP SCI TECHNOL, V53, P2870, DOI 10.1080/01496395.2018.1489845; Bwatanglang IB, 2016, J COLLOID INTERF SCI, V480, P146, DOI 10.1016/j.jcis.2016.07.011; Chalati T, 2011, J MATER CHEM, V21, P2220, DOI 10.1039/c0jm03563g; Chen Y, 2018, NANOMATERIALS-BASEL, V8, DOI 10.3390/nano8070486; Cosco D, 2015, SCI REP-UK, V5, DOI 10.1038/srep17579; Daryasari MP, 2016, RSC ADV, V6, P105578, DOI 10.1039/c6ra23182a; Deng XW, 2014, BIOMATERIALS, V35, P4333, DOI 10.1016/j.biomaterials.2014.02.006; Ding SC, 2020, MATER TODAY, V37, P112, DOI 10.1016/j.mattod.2020.02.001; Duan JJ, 2015, MACROMOLECULES, V48, P2706, DOI 10.1021/acs.macromol.5b00117; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Ghaffar I, 2019, MAT SCI ENG C-MATER, V105, DOI 10.1016/j.msec.2019.110111; Hajiashrafi S, 2019, HELIYON, V5, DOI 10.1016/j.heliyon.2019.e02152; Hidalgo T, 2017, SCI REP-UK, V7, DOI 10.1038/srep43099; Howe EN, 2011, BREAST CANCER RES, V13, DOI 10.1186/bcr2867; Huang L, 2012, BIOCHEM BIOPH RES CO, V425, P127, DOI 10.1016/j.bbrc.2012.07.025; Jiang YW, 2012, MOL MED REP, V5, P890, DOI 10.3892/mmr.2012.776; Ju EG, 2020, ACS NANO, V14, P476, DOI 10.1021/acsnano.9b06333; Karsy Michael, 2012, Genes Cancer, V3, P3, DOI 10.1177/1947601912448068; Krishna M, 2017, J CLIN EPIGENET, V3, P38, DOI [10.21767/2472-1158.100072, DOI 10.21767/2472-1158.100072]; Kumari R, 2020, J CONTROL RELEASE, V319, P135, DOI 10.1016/j.jconrel.2019.12.041; Levy JMM, 2020, CELL DEATH DIFFER, V27, P843, DOI [10.1038/s41418-019-0474, 10.1038/s41418-019-0474-7]; Liang K, 2017, CHEM COMMUN, V53, P1249, DOI 10.1039/c6cc09680h; Liao WT, 2013, CLIN CANCER RES, V19, P4662, DOI 10.1158/1078-0432.CCR-13-0244; Lin Q, 2015, MOL MED REP, V12, P5709, DOI 10.3892/mmr.2015.4185; Liu L, 2019, DALTON T, V48, P6951, DOI 10.1039/c9dt00503j; Mombini S, 2019, INT J BIOL MACROMOL, V140, P278, DOI 10.1016/j.ijbiomac.2019.08.046; Murad H, 2016, CANCER CELL INT, V16, DOI 10.1186/s12935-016-0315-4; Narmani A, 2020, BIOMED MICRODEVICES, V22, DOI 10.1007/s10544-020-00485-5; Narmani A, 2019, DRUG DEVELOP RES, V80, P404, DOI 10.1002/ddr.21545; Narmani A, 2019, J DRUG DELIV SCI TEC, V50, P278, DOI 10.1016/j.jddst.2019.01.037; Narmani A, 2018, PROCESS BIOCHEM, V69, P178, DOI 10.1016/j.procbio.2018.01.014; Narmani A, 2018, J DRUG DELIV SCI TEC, V44, P457, DOI 10.1016/j.jddst.2018.01.011; Narmani A, 2018, PROCESS BIOCHEM, V65, P46, DOI 10.1016/j.procbio.2017.10.009; Narmani A, 2017, COLLOID SURFACE B, V159, P232, DOI 10.1016/j.colsurfb.2017.07.089; Rezvani M, 2018, INT J BIOL MACROMOL, V113, P1287, DOI 10.1016/j.ijbiomac.2018.02.141; Roldo C, 2006, J CLIN ONCOL, V24, P4677, DOI 10.1200/JCO.2005.05.5194; SPECIFICATIONS Q., 2000, TRANSF REAG; Stein CA, 2017, MOL THER, V25, P1069, DOI 10.1016/j.ymthe.2017.03.023; Tekie FSM, 2015, INT J BIOL MACROMOL, V81, P828, DOI 10.1016/j.ijbiomac.2015.09.014; Towers CG, 2020, J CELL BIOL, V219, DOI 10.1083/jcb.201909033; Tu L, 2017, MAT SCI ENG C-MATER, V72, P177, DOI 10.1016/j.msec.2016.10.052; Wang L, 2013, INORG CHEM, V52, P5119, DOI 10.1021/ic400019r; Wang XG, 2015, NANOSCALE, V7, P16061, DOI 10.1039/c5nr04045k; Wu DJ, 2020, CARBOHYD POLYM, V238, DOI 10.1016/j.carbpol.2020.116126; Wu JM, 2012, CARCINOGENESIS, V33, P519, DOI 10.1093/carcin/bgr304; Yang L, 2015, CATAL SCI TECHNOL, V5, P2777, DOI 10.1039/c4cy01609b; Yousefi M, 2020, ADV COLLOID INTERFAC, V278, DOI 10.1016/j.cis.2020.102125; Zheng HQ, 2016, J AM CHEM SOC, V138, P962, DOI 10.1021/jacs.5b11720; Zhuang J, 2014, ACS NANO, V8, P2812, DOI 10.1021/nn406590q; Zou MJ, 2012, CELL SIGNAL, V24, P1722, DOI 10.1016/j.cellsig.2012.04.009	51	1	1	8	16	SPRINGERNATURE	LONDON	CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND	0969-7128	1476-5462		GENE THER	Gene Ther.												10.1038/s41434-021-00265-7		JUN 2021	11	Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine	SP0YT	WOS:000659399600002	34108628				2022-04-25	
J	Priault, M; Hue, E; Marhuenda, F; Pilet, P; Oliver, L; Vallette, FM				Priault, Muriel; Hue, Erika; Marhuenda, Fanny; Pilet, Paul; Oliver, Lisa; Vallette, Francois M.			Differential Dependence on Beclin 1 for the Regulation of Pro-Survival Autophagy by Bcl-2 and Bcl-xL in HCT116 Colorectal Cancer Cells	PLOS ONE			English	Article							3-KINASE COMPLEX; APOPTOTIC DEATH; MECHANISMS; PROTEINS; DEPRIVATION; MACROAUTOPHAGY; NOMENCLATURE; PROGRESSION; INHIBITION; HOMOLOG	Autophagy is described to be involved in homeostasis, development and disease, both as a survival and a death process. Its involvement in cell death proceeds from interrelationships with the apoptotic pathway. We focused on survival autophagy and investigated its interplays with the apoptotic machinery. We found that while Mcl-1 remained ineffective, Bcl-2 and BclxL were required for starved cells to display a fully functional autophagic pathway as shown by proteolysis activity and detection of autophagic vesicles. Such pro-autophagic functions of Bcl-2 and Bcl-xL were independent of Bax. However they appeared to operate through non redundant mechanisms as Bcl-xL wielded a tighter control than Bcl-2 over the regulation of autophagy: unlike Bcl-2, Bcl-xL and Atg7 manipulation yielded identical phenotypes suggesting they could be components of the same signalling pathway; Bcl-xL subcellular localisation was modified upon starvation, and importantly Bcl-xL acted independently of Beclin 1. Still an intact BH3-binding site was required for Bcl-xL to stimulate a fully functional autophagic pathway. This study highlights that, in addition to their well-established anti-death function during apoptosis, Bcl-2 and Bcl-xL have a broader role in cell survival. Should Bcl-2 and Bcl-xL stand at the cross-roads between pro-survival and pro-death autophagy, this study introduces the new concept that the regulation of autophagy by Bcl-2 and Bcl-xL is adjusted according to its survival or death outcome.	[Priault, Muriel] CNRS, IBGC, UMR 5095, Bordeaux, France; [Priault, Muriel] Univ Bordeaux 2, F-33076 Bordeaux, France; [Hue, Erika; Marhuenda, Fanny; Oliver, Lisa; Vallette, Francois M.] INSERM, UMR 892, Nantes, France; [Hue, Erika; Marhuenda, Fanny; Oliver, Lisa; Vallette, Francois M.] Univ Nantes, Fac Med, Nantes, France; [Pilet, Paul] INSERM, UMR 791, Nantes, France		Priault, M (corresponding author), CNRS, IBGC, UMR 5095, Bordeaux, France.	muriel.priault@ibgc.cnrs.fr	Paul, Pilet/A-3755-2015; Vallette, Francois/N-2361-2018; Oliver, Lisa J/L-3070-2015; Vallette, Francois M/K-9047-2015	Oliver, Lisa J/0000-0002-5588-7564; Vallette, Francois M/0000-0002-3296-8572; Vallette, Francois/0000-0003-0802-0519; Priault, Muriel/0000-0001-8193-0389; HUE, Erika/0000-0001-6930-3606	Institut National de la Santeet de la Recherche Medicale (INSERM)Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS)Centre National de la Recherche Scientifique (CNRS); Universitede Nantes, Universitede Bordeaux, the Conseil Regional d'Aquitaine; Agence Nationale pour la RechercheFrench National Research Agency (ANR)	This work was supported by the Institut National de la Santeet de la Recherche Medicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), Universitede Nantes, Universitede Bordeaux, the Conseil Regional d'Aquitaine (to UMR 5095), and the Agence Nationale pour la Recherche (project MABA to F. V.). M. P. was supported by a post-doctoral fellowship from INSERM. 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, K; Zhou, Y; Karges, J; Du, KJ; Shen, JC; Lin, MW; Wei, FM; Kou, JF; Chen, Y; Ji, LN; Chao, H				Xiong, Kai; Zhou, Ying; Karges, Johannes; Du, Kejie; Shen, Jinchao; Lin, Mingwei; Wei, Fangmian; Kou, Junfeng; Chen, Yu; Ji, Liangnian; Chao, Hui			Autophagy-Dependent Apoptosis Induced by Apoferritin-Cu(II) Nanoparticles in Multidrug-Resistant Colon Cancer Cells	ACS APPLIED MATERIALS & INTERFACES			English	Article						antitumor; apoferritin; autophagy-dependent apoptosis; copper(II) complex; multidrug resistance	IRIDIUM(III) COMPLEXES; INHIBITION; ENCAPSULATION; RELEASE; PROTEIN; STRESS; DESIGN; COPPER; DEATH	Chemotherapy continues to be the most commonly applied strategy for cancer. Despite the impressive clinical success obtained with several drugs, increasing numbers of (multi)drug-resistant tumors are reported. To overcome this shortcoming, novel drug candidates and delivery systems are urgently needed. Herein, a therapeutic copper polypyridine complex encapsulated in natural nanocarrier apoferritin is reported. The generated nanoparticles showed higher cytotoxicity toward various (drugresistant) cancer cell lines than noncancerous cells. The study of the mechanism revealed that the compound triggers cell autophagy-dependent apoptosis. Promisingly, upon injection of the nanodrug conjugate into the bloodstream of a mouse model bearing a multidrug-resistant colon tumor, a strong tumor growth inhibition effect was observed. To date, this is the first study describing the encapsulation of a copper complex in apoferritin that acts by autophagy-dependent apoptosis.	[Xiong, Kai; Zhou, Ying; Du, Kejie; Shen, Jinchao; Lin, Mingwei; Wei, Fangmian; Kou, Junfeng; Chen, Yu; Ji, Liangnian; Chao, Hui] Sun Yat Sen Univ, Sch Chem, MOE Key Lab Bioinorgan & Synthet Chem, Guangzhou 510275, Peoples R China; [Karges, Johannes] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA		Chen, Y; Chao, H (corresponding author), Sun Yat Sen Univ, Sch Chem, MOE Key Lab Bioinorgan & Synthet Chem, Guangzhou 510275, Peoples R China.	chenyu63@mail.sysu.edu.cn; ceschh@mail.sysu.edu.cn		Xiong, kai/0000-0002-8170-0273; jinchao, shen/0000-0002-8436-9360; Karges, Johannes/0000-0001-5258-0260	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21525105, 21778079, 21977126]; Pearl River S&T Nova Program of Guangzhou [201806010136]; Guangdong Natural Funds for Distinguished Young Scientists [2021B1515020102]	This work was supported by the National Natural Science Foundation of China (Nos. 21525105, 21778079, and 21977126), the Pearl River S&T Nova Program of Guangzhou (No. 201806010136), and Guangdong Natural Funds for Distinguished Young Scientists (No. 2021B1515020102). The authors thank Dr. Susan E Bates for the SW620 and SW620 AD300 cell lines (Columbia University, New York).	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Mater. Interfaces	AUG 25	2021	13	33					38959	38968		10.1021/acsami.1c07223		AUG 2021	10	Nanoscience & Nanotechnology; Materials Science, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics; Materials Science	UK2DJ	WOS:000691785200003	34379404				2022-04-25	
J	Hu, CE; Gan, J				Hu, Cheng-En; Gan, Jun			TRIM37 promotes epithelial-mesenchymal transition in colorectal cancer	MOLECULAR MEDICINE REPORTS			English	Article						tripartite motif containing 37; colorectal cancer; epithelial-mesenchymal transition	PROTEINS REGULATE AUTOPHAGY; COLON-CANCER; MULIBREY NANISM; CROSSROADS; METASTASIS	There is substantial research on the oncogenic role of tripartite motif containing 37 (TRIM37); however, its importance in colorectal cancer (CRC) remains to be elucidated. The present study used reverse transcription -quantitative polymerase chain reaction, immunohistochemistry and western blotting to detect the expression level of TRIM37 in CRC. The importance of TRIM37 in cell proliferation, invasion and metastasis of CRC were investigated through overexpressing or knocking -down of TRIM37 in CRC cell lines, to observe its function. The present study revealed that TRIM37 was overexpressed in human CRC tissues. High TRIM37 expression resulted in increased CRC proliferation, migration and invasion. Mechanistically, it was confirmed that TRIM37 enhanced invasion and metastasis of CRC via the epithelial-mesenchymal transition pathway. In conclusion, the present study suggested that TRIM3 may contribute to CRC and act as a potential therapeutic target for CRC treatment.	[Hu, Cheng-En; Gan, Jun] Fudan Univ, Huashan Hosp, Dept Gen Surg, 12 Wurumuqizhong Rd, Shanghai 200040, Peoples R China		Gan, J (corresponding author), Fudan Univ, Huashan Hosp, Dept Gen Surg, 12 Wurumuqizhong Rd, Shanghai 200040, Peoples R China.	jungan2015@163.com					Baum B, 2008, SEMIN CELL DEV BIOL, V19, P294, DOI 10.1016/j.semcdb.2008.02.001; Bertucci F, 2004, ONCOGENE, V23, P1377, DOI 10.1038/sj.onc.1207262; Bhatnagar S, 2014, NATURE, V516, P116, DOI 10.1038/nature13955; Cao H, 2015, PATHOL RES PRACT, V211, P557, DOI 10.1016/j.prp.2015.05.010; Fan Q, 2015, ONCOL REP, V34, P1787, DOI 10.3892/or.2015.4143; Fu BJ, 2012, AM J CLIN PATHOL, V138, P356, DOI 10.1309/AJCPVT7LC4CRPZSK; Godde NJ, 2010, J MAMMARY GLAND BIOL, V15, P149, DOI 10.1007/s10911-010-9180-2; Jiang JX, 2016, TUMOR BIOL, V37, P2629, DOI 10.1007/s13277-015-4078-7; Jiang JX, 2015, BIOCHEM BIOPH RES CO, V464, P1120, DOI 10.1016/j.bbrc.2015.07.089; Kallijarvi J, 2002, AM J HUM GENET, V70, P1215, DOI 10.1086/340256; Kalluri R, 2009, J CLIN INVEST, V119, P1420, DOI 10.1172/JCI39104; Karlberg S, 2009, MODERN PATHOL, V22, P570, DOI 10.1038/modpathol.2009.13; Lamouille S, 2014, NAT REV MOL CELL BIO, V15, P178, DOI 10.1038/nrm3758; Lee OH, 2015, BBA-MOL CELL RES, V1853, P409, DOI 10.1016/j.bbamcr.2014.11.007; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Mandell MA, 2014, AUTOPHAGY, V10, P2387, DOI 10.4161/15548627.2014.984278; Mandell MA, 2014, DEV CELL, V30, P394, DOI 10.1016/j.devcel.2014.06.013; Pasquier J, 2015, J ONCOL, V2015, DOI 10.1155/2015/792182; Qiu F, 2015, INT J CLIN EXP PATHO, V8, P5053; Rubin MA, 2014, CANCER DISCOV, V4, P1262, DOI 10.1158/2159-8290.CD-14-1075; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; 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]; Tejpar S, 2010, ONCOLOGIST, V15, P390, DOI 10.1634/theoncologist.2009-0233; Thiery JP, 2006, NAT REV MOL CELL BIO, V7, P131, DOI 10.1038/nrm1835; Wang Y, 2015, BIOCHEM BIOPH RES CO, V463, P458, DOI 10.1016/j.bbrc.2015.05.117; Wang YX, 2004, J CLIN ONCOL, V22, P1564, DOI 10.1200/JCO.2004.08.186; Wicki A, 2006, CANCER CELL, V9, P261, DOI 10.1016/j.ccr.2006.03.010; Yang J, 2008, DEV CELL, V14, P818, DOI 10.1016/j.devcel.2008.05.009; Ye X, 2015, TRENDS CELL BIOL, V25, P675, DOI 10.1016/j.tcb.2015.07.012; Zhang PJ, 2015, CELL CYCLE, V14, P481, DOI 10.1080/15384101.2015.1006048; Zoni E, 2015, J ONCOL, V2015, DOI 10.1155/2015/198967	31	24	24	1	8	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1791-2997	1791-3004		MOL MED REP	Mol. Med. Rep.	MAR	2017	15	3					1057	1062		10.3892/mmr.2017.6125			6	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	EP1VS	WOS:000397173000008	28098873	Green Published, Green Submitted, hybrid			2022-04-25	
J	Lan, L; Liu, H; Smith, AR; Appelman, C; Yu, J; Larsen, S; Marquez, RT; Wu, XQ; Liu, FY; Gao, P; Gowthaman, R; Karanicolas, J; De Guzman, RN; Rogers, S; Aube, J; Neufeld, KL; Xu, L				Lan, Lan; Liu, Hao; Smith, Amber R.; Appelman, Carl; Yu, Jia; Larsen, Sarah; Marquez, Rebecca T.; Wu, Xiaoqing; Liu, Frank Y.; Gao, Philip; Gowthaman, Ragul; Karanicolas, John; De Guzman, Roberto N.; Rogers, Steven; Aube, Jeffrey; Neufeld, Kristi L.; Xu, Liang			Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins	BMC CANCER			English	Article						Gossypolone; Musashi; RNA-binding protein; Colon cancer; Liposomes	STEM-CELL MARKERS; PEGYLATED LIPOSOMAL DOXORUBICIN; IN-VITRO; PROSTATE-CANCER; MYELOID-LEUKEMIA; EXPRESSION; CARCINOMA; MSI2; (-)-GOSSYPOL; AUTOPHAGY	Background: The Musashi (MSI) family of RNA-binding proteins is best known for the role in post-transcriptional regulation of target mRNAs. Elevated MSI1 levels in a variety of human cancer are associated with up-regulation of Notch/Wnt signaling. MSI1 binds to and negatively regulates translation of Numb and APC (adenomatous polyposis coli), negative regulators of Notch and Wnt signaling respectively. Methods: Previously, we have shown that the natural product (-)-gossypol as the first known small molecule inhibitor of MSI1 that down-regulates Notch/Wnt signaling and inhibits tumor xenograft growth in vivo. Using a fluorescence polarization (FP) competition assay, we identified gossypolone (Gn) with a > 20-fold increase in Ki value compared to (-)-gossypol. We validated Gn binding to MSI1 using surface plasmon resonance, nuclear magnetic resonance, and cellular thermal shift assay, and tested the effects of Gn on colon cancer cells and colon cancer DLD-1 xenografts in nude mice. Results: In colon cancer cells, Gn reduced Notch/Wnt signaling and induced apoptosis. Compared to (-)-gossypol, the same concentration of Gn is less active in all the cell assays tested. To increase Gn bioavailability, we used PEGylated liposomes in our in vivo studies. Gn-lip via tail vein injection inhibited the growth of human colon cancer DLD-1 xenografts in nude mice, as compared to the untreated control (P < 0.01, n = 10). Conclusion: Our data suggest that PEGylation improved the bioavailability of Gn as well as achieved tumor-targeted delivery and controlled release of Gn, which enhanced its overall biocompatibility and drug efficacy in vivo. This provides proof of concept for the development of Gn-lip as a molecular therapy for colon cancer with MSI1/MSI2 overexpression.	[Lan, Lan; Liu, Hao; Smith, Amber R.; Appelman, Carl; Yu, Jia; Larsen, Sarah; Marquez, Rebecca T.; Wu, Xiaoqing; Liu, Frank Y.; De Guzman, Roberto N.; Neufeld, Kristi L.; Xu, Liang] Univ Kansas, Dept Mol Biosci, 4002 Haworth Hall,1200 Sunnyside Ave, Lawrence, KS 66045 USA; [Gao, Philip] NIH COBRE Prot Struct & Funct, Prot Prod Grp, Lawrence, KS USA; [Gowthaman, Ragul] Univ Kansas, Ctr Computat Biol, Lawrence, KS 66045 USA; [Yu, Jia] Southeast Univ, Sch Chem & Chem Engn, Nanjing, Jiangsu, Peoples R China; [Karanicolas, John] Fox Chase Canc Ctr, Program Mol Therapeut, 7701 Burholme Ave, Philadelphia, PA 19111 USA; [Rogers, Steven; Aube, Jeffrey] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27515 USA; [Xu, Liang] Univ Kansas, Canc Ctr, Dept Radiat Oncol, Kansas City, KS 66160 USA; [Liu, Hao] Southwest Med Univ, Sch Pharm, Luzhou City, Peoples R China		Xu, L (corresponding author), Univ Kansas, Dept Mol Biosci, 4002 Haworth Hall,1200 Sunnyside Ave, Lawrence, KS 66045 USA.; Xu, L (corresponding author), Univ Kansas, Canc Ctr, Dept Radiat Oncol, Kansas City, KS 66160 USA.	xul@ku.edu	Liu, Hao/J-1911-2014	Liu, Hao/0000-0003-2343-4998; Neufeld, Kristi/0000-0003-3653-9385; Gowthaman, Ragul/0000-0002-0008-6401	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 CA178831, CA191785, AI074856]; NIH COBRE-PSF at KUUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P30 GM110761]; Department of Defense Breast Cancer Research Program Breakthrough Level II grantUnited States Department of Defense [BC151845]; Kansas Bioscience Authority Rising Star Award; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA191785, R01CA178831] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R01AI074856] 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) [P30GM110761] Funding Source: NIH RePORTER	This study was supported in part by National Institutes of Health grants R01 CA178831 and CA191785 (to LX, JA, KN); AI074856 (to R.N.D.); NIH COBRE-PSF at KU (P30 GM110761) Pilot Project, Department of Defense Breast Cancer Research Program Breakthrough Level II grant BC151845, and Kansas Bioscience Authority Rising Star Award (to LX). No involvement of the funding bodies in any part of the study.	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J	Mikula, M; Najjar, S; El Jabbour, T; Dalvi, S; Umrau, K; Li, H; Koo, BH; Lee, H				Mikula, Michael; Najjar, Saleh; El Jabbour, Tony; Dalvi, Siddhartha; Umrau, Kavita; Li, Hua; Koo, Brandon H.; Lee, Hwajeong			Increased Cytoplasmic Yes-associated Protein (YAP) Expression in Mismatch Repair Protein-Proficient Colorectal Cancer With High-grade Tumor Budding and Reduced Autophagy Activity	APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY			English	Article						YAP; autophagy; p62; tumor budding; colon	EPITHELIAL-MESENCHYMAL TRANSITION; HIPPO PATHWAY; EMT; APOPTOSIS; SWITCH	Yes-associated protein (YAP) is a transcriptional coactivator regulated by autophagy that stimulates colorectal cancer (CRC) progression through activation of epithelial-mesenchymal transition (EMT), represented by tumor budding. The associations between these components in CRC are unknown. Archived surgically resected CRCs with known mismatch repair protein (MMR) status were retrieved (n=81; 2010 to 2016). Electronic medical records were reviewed for clinicopathologic variables including pathologic TNM stage and clinical stage. Tumor budding was graded according to consensus guidelines. Cytoplasmic and nuclear YAP and p62 (autophagy substrate) immunoreactivity were semiquantitatively scored within tumor samples. The Student t test, Fisher exact test, chi(2) test, and Spearman correlation coefficient were performed with P<0.05 as a significance level. MMR proficiency (MMR-P) status correlated with high-grade tumor budding. The extent of cytoplasmic YAP staining and pathologic N stage was associated with tumor budding in multivariate analysis. Cytoplasmic YAP expression correlated with higher cytoplasmic p62 expression, suggesting an inverse correlation between autophagy activation and cytoplasmic YAP expression. Nuclear YAP expression correlated with pathologic N stage and clinical stage. A correlation between MMR-P status and tumor budding, combined with correlations between cytoplasmic YAP, tumor budding and p62 raise the possibility of 2 distinct neoplastic pathways concerning autophagy and YAP; one displaying relative activation of YAP and EMT, being commonly observed in MMR-P, and another with less active YAP and EMT, but active autophagy, being commonly seen in MMR-deficient CRC. Nuclear YAP staining could be useful in prognostication.	[Mikula, Michael] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA; [Mikula, Michael; Koo, Brandon H.] Albany Med Coll, Albany, NY 12208 USA; [Najjar, Saleh; El Jabbour, Tony; Dalvi, Siddhartha; Umrau, Kavita; Li, Hua; Lee, Hwajeong] Albany Med Ctr, Dept Pathol & Lab Med, Albany, NY 12208 USA		Lee, H (corresponding author), 47 New Scotland Ave,MC81, Albany, NY 12208 USA.	leeh5@amc.edu	Umrau, Kavita/AAA-2597-2022				Amin MB., 2017, AJCC CANC STAGING MA, V8th ed.; Azzolin L, 2014, CELL, V158, P157, DOI 10.1016/j.cell.2014.06.013; Barry ER, 2013, NATURE, V493, P106, DOI 10.1038/nature11693; Burada F, 2015, WORLD J GASTRO ONCOL, V7, P271, DOI 10.4251/wjgo.v7.i11.271; Guinney J, 2015, NAT MED, V21, P1350, DOI 10.1038/nm.3967; Harvey K, 2007, NAT REV CANCER, V7, P182, DOI 10.1038/nrc2070; Hewish M, 2010, NAT REV CLIN ONCOL, V7, P197, DOI 10.1038/nrclinonc.2010.18; Jiang PD, 2015, METHODS, V75, P13, DOI 10.1016/j.ymeth.2014.11.021; Katsuragi Y, 2015, FEBS J, V282, P4672, DOI 10.1111/febs.13540; Le Corre D, 2019, EBIOMEDICINE, V46, P94, DOI 10.1016/j.ebiom.2019.07.036; Lee YA, 2018, NAT COMMUN, V9, DOI 10.1038/s41467-018-07338-z; Ling HH, 2017, EXP CELL RES, V350, P218, DOI 10.1016/j.yexcr.2016.11.024; Liu Y, 2017, SCI REP-UK, V7, DOI 10.1038/srep45523; Loboda A, 2011, BMC MED GENOMICS, V4, DOI 10.1186/1755-8794-4-9; Lugli A, 2017, MODERN PATHOL, V30, P1299, DOI 10.1038/modpathol.2017.46; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Moroishi T, 2015, NAT REV CANCER, V15, P73, DOI 10.1038/nrc3876; Moscat J, 2009, CELL, V137, P1001, DOI 10.1016/j.cell.2009.05.023; Ou CL, 2017, ONCOTARGET, V8, P75727, DOI 10.18632/oncotarget.20155; Park J, 2019, NAT COMMUN, V10, DOI 10.1038/s41467-019-10729-5; Pino MS, 2010, GASTROENTEROLOGY, V138, P1406, DOI 10.1053/j.gastro.2009.12.010; Platel V, 2019, J ONCOL, V2019, DOI 10.1155/2019/8361945; Sakabe M, 2017, P NATL ACAD SCI USA, V114, P10918, DOI 10.1073/pnas.1704030114; Shao DD, 2014, CELL, V158, P171, DOI 10.1016/j.cell.2014.06.004; Wang LJ, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0065539; Wang Y, 2013, TUMOR BIOL, V34, P2169, DOI 10.1007/s13277-013-0751-x; Weinstein N, 2020, FRONT GENET, V11, DOI 10.3389/fgene.2020.00040; White E, 2012, NAT REV CANCER, V12, P401, DOI 10.1038/nrc3262; Wierzbicki PM, 2015, FOLIA HISTOCHEM CYTO, V53, P105, DOI 10.5603/FHC.a2015.0015; Zlobec I, 2018, NAT REV CANCER, V18, P203, DOI 10.1038/nrc.2018.1; Zlobec I, 2010, ONCOTARGET, V1, P651, DOI 10.18632/oncotarget.199	31	1	1	0	1	LIPPINCOTT WILLIAMS & WILKINS	PHILADELPHIA	TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA	1541-2016	1533-4058		APPL IMMUNOHISTO M M	Appl. Immunohistochem.	APR	2021	29	4					305	312		10.1097/PAI.0000000000000888			8	Anatomy & Morphology; Medical Laboratory Technology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Anatomy & Morphology; Medical Laboratory Technology; Pathology	RY2PL	WOS:000647759200011	33264106				2022-04-25	
J	Kakiuchi, Y; Kuroda, S; Kanaya, N; Kumon, K; Tsumura, T; Hashimoto, M; Yagi, C; Sugimoto, R; Hamada, Y; Kikuchi, S; Nishizaki, M; Kagawa, S; Tazawa, H; Urata, Y; Fujiwara, T				Kakiuchi, Yoshihiko; Kuroda, Shinji; Kanaya, Nobuhiko; Kumon, Kento; Tsumura, Tomoko; Hashimoto, Masashi; Yagi, Chiaki; Sugimoto, Ryoma; Hamada, Yuki; Kikuchi, Satoru; Nishizaki, Masahiko; Kagawa, Shunsuke; Tazawa, Hiroshi; Urata, Yasuo; Fujiwara, Toshiyoshi			Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles	MOLECULAR THERAPY			English	Article							CANCER; EXOSOMES; TROPISM; MODULATION; RADIATION; DELIVERY	Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.	[Kakiuchi, Yoshihiko; Kuroda, Shinji; Kanaya, Nobuhiko; Kumon, Kento; Tsumura, Tomoko; Hashimoto, Masashi; Yagi, Chiaki; Sugimoto, Ryoma; Hamada, Yuki; Kikuchi, Satoru; Nishizaki, Masahiko; Kagawa, Shunsuke; Tazawa, Hiroshi; Fujiwara, Toshiyoshi] Okayama Univ, Dept Gastroenterol Surg, Grad Sch Med Dent & Pharmaceut Sci, Kita Ku, 2-5-1 Shikata Cho, Okayama 7008558, Japan; [Kuroda, Shinji; Tazawa, Hiroshi] Okayama Univ Hosp, Ctr Innovat Clin Med, Okayama 7008558, Japan; [Kikuchi, Satoru; Kagawa, Shunsuke] Okayama Univ Hosp, Minimally Invas Therapy Ctr, Okayama 7008558, Japan; [Urata, Yasuo] Oncolys BioPharma Inc, Tokyo 1050001, Japan		Kuroda, S (corresponding author), Okayama Univ, Dept Gastroenterol Surg, Grad Sch Med Dent & Pharmaceut Sci, Kita Ku, 2-5-1 Shikata Cho, Okayama 7008558, Japan.	shinkuro@okayama-u.ac.jp	TAZAWA, Hiroshi/B-2247-2011	TAZAWA, Hiroshi/0000-0003-4658-1050; Masashi, Hashimoto/0000-0002-0329-5110; Kuroda, Shinji/0000-0002-4484-1253	JSPS KAKENHIMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) [JP20K17617]	The authors would like to thank Tomoko Sueishi, Tae Yamanishi, and Yuko Hoshijima for excellent technical support. This work was supported by JSPS KAKENHI (grant no. JP16K19893 to S. Kuroda) and JSPS KAKENHI (grant no. JP20K17617 to Y.K.).	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Ther.	OCT 6	2021	29	10					2920	2930		10.1016/j.ymthe.2021.05.015			11	Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine	WI4HY	WOS:000708324600008	34023506				2022-04-25	
J	Saponaro, C; Sergio, S; Coluccia, A; De Luca, M; La Regina, G; Mologni, L; Famiglini, V; Naccarato, V; Bonetti, D; Gautier, C; Gianni, S; Vergara, D; Salzet, M; Fournier, I; Bucci, C; Silvestri, R; Passerini, CG; Maffia, M; Coluccia, AML				Saponaro, Concetta; Sergio, Sara; Coluccia, Antonio; De Luca, Maria; La Regina, Giuseppe; Mologni, Luca; Famiglini, Valeria; Naccarato, Valentina; Bonetti, Daniela; Gautier, Candice; Gianni, Stefano; Vergara, Daniele; Salzet, Michel; Fournier, Isabelle; Bucci, Cecilia; Silvestri, Romano; Passerini, Carlo Gambacorti; Maffia, Michele; Coluccia, Addolorata Maria Luce			beta-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy	ONCOGENE			English	Article							SMALL-MOLECULE INHIBITION; REGULATORY FACTOR-1; NUCLEAR NHERF1; PROTEIN; GROWTH; COLON; PTEN; PHOSPHORYLATION; ASSOCIATION; ACTIVATION	Nuclear activated beta-catenin plays a causative role in colorectal cancers (CRC) but remains an elusive therapeutic target. Using human CRC cells harboring different Wnt/beta-catenin pathway mutations in APC/KRAS or beta-catenin/KRAS genes, and both genetic and pharmacological knockdown approaches, we show that oncogenic beta-catenin signaling negatively regulates the expression of NHERF1 (Na+/H+ exchanger 3 regulating factor 1), a PDZ-adaptor protein that is usually lost or downregulated in early dysplastic adenomas to exacerbate nuclear beta-catenin activity. Chromatin immunoprecipitation (ChIP) assays demonstrated that beta-catenin represses NHERF1 via TCF4 directly, while the association between TCF1 and the Nherf1 promoter increased upon beta-catenin knockdown. To note, the occurrence of a cytostatic survival response in settings of single beta-catenin-depleted CRC cells was abrogated by combining NHERF1 inhibition via small hairpin RNA (shRNA) or RS5517, a novel PDZ1-domain ligand of NHERF1 that prevented its ectopic nuclear entry. Mechanistically, dual NHERF1/beta-catenin targeting promoted an autophagy-to-apoptosis switch consistent with the activation of Caspase-3, the cleavage of PARP and reduced levels of phospho-ERK1/2, Beclin-1, and Rab7 autophagic proteins compared with beta-catenin knockdown alone. Collectively, our data unveil novel beta-catenin/TCF-dependent mechanisms of CRC carcinogenesis, also offering preclinical proof of concept for combining beta-catenin and NHERF1 pharmacological inhibitors as a mechanism-based strategy to augment apoptotic death of CRC cells refractory to current Wnt/beta-catenin-targeted therapeutics.	[Saponaro, Concetta; Sergio, Sara; Vergara, Daniele; Maffia, Michele; Coluccia, Addolorata Maria Luce] Giovanni Paolo II Oncol Hosp, Lab Clin Prote, I-73100 Lecce, Italy; [Saponaro, Concetta] IRCCS Ist Tumori Giovanni Paolo II, Funct Biomorphol Lab, Bari, Italy; [Sergio, Sara; De Luca, Maria; Vergara, Daniele; Bucci, Cecilia; Maffia, Michele; Coluccia, Addolorata Maria Luce] Univ Salento, Dept Biol & Environm Sci & Technol, I-73100 Lecce, Italy; [Coluccia, Antonio; La Regina, Giuseppe; Famiglini, Valeria; Naccarato, Valentina; Silvestri, Romano] Sapienza Univ Rome, Ist Pasteur Italia, Fdn Cenci Bolognetti, Dept Drug Chem & Technol, Piazzale Aldo Moro 5, I-00185 Rome, Italy; [Mologni, Luca; Passerini, Carlo Gambacorti] Univ Milano Bicocca, San Gerardo Hosp, Dept Clin Med, I-20052 Monza, Italy; [Bonetti, Daniela; Gautier, Candice; Gianni, Stefano] Sapienza Univ Rome, Ist Pasteur Italia, Fdn Cenci Bolognetti, Dept Biochem, Piazzale Aldo Moro 5, I-00185 Rome, Italy; [Salzet, Michel; Fournier, Isabelle] U1192 Lab Prote Reponse Inflammatoire & Spectrome, F-59000 Lille, France		Coluccia, AML (corresponding author), Giovanni Paolo II Oncol Hosp, Lab Clin Prote, I-73100 Lecce, Italy.; Coluccia, AML (corresponding author), Univ Salento, Dept Biol & Environm Sci & Technol, I-73100 Lecce, Italy.	michele.maffia@unisalento.it; malu.coluccia@unisalento.it	Coluccia, Antonio/K-3114-2018; FOURNIER, Isabelle/H-9195-2015; Vergara, Daniele/K-3831-2014; sergio, sara/AAC-3849-2019; SERGIO, SARA/AAL-4019-2021; La Regina, Giuseppe/I-2161-2012; Saponaro, Concetta/K-7886-2018; Salzet, Michel/A-7675-2011; MAFFIA, MICHELE/AAC-2943-2020; BUCCI, CECILIA/F-6699-2012; Mologni, Luca/AAC-1065-2022	Coluccia, Antonio/0000-0002-7940-8206; FOURNIER, Isabelle/0000-0003-1096-5044; Vergara, Daniele/0000-0002-2396-7674; La Regina, Giuseppe/0000-0003-3252-1161; Salzet, Michel/0000-0003-4318-0817; BUCCI, CECILIA/0000-0002-6232-6183; Mologni, Luca/0000-0002-6365-5149; Sergio, Sara/0000-0002-4490-4189	Italian Association for Cancer Research (AIRC)-Investigator Grant (IG) [14236]; Italian Grant PRIN 2015 [2015FCHJ8E]; European Union's Horizon 2020 Research and Innovation program under the Marie Sklodowska-Curie grant [675341]; AIRC IG 2016 [19068]; Apulia Regione Cluster Project SISTEMA [T7WGSJ3]; Veronesi Foundation fellowship	We thank Dr. Hans Clevers (Hubrecht Laboratory, Utrecht, The Netherlands) for providing the pcDNA<INF>6</INF>TR and pTER vectors. We gratefully acknowledge funding from Italian Association for Cancer Research (AIRC)-Investigator Grant (IG) 2014 No. 14236 (AMLC). This work was partially supported by Italian Grant PRIN 2015 (2015FCHJ8E) (RS), European Union's Horizon 2020 Research and Innovation program under the Marie Sklodowska-Curie grant agreement No. 675341 (SG), AIRC IG 2016 No. 19068 (CB) and Apulia Regione Cluster Project SISTEMA No. T7WGSJ3 (MM). MDL was recipient of a Veronesi Foundation fellowship. We warmly thank Dr. Antonio Danieli for his technical assistance.	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J	Yang, X; Zheng, YT; Rong, W				Yang, Xiao; Zheng, Yao-tun; Rong, Wei			Sevoflurane induces apoptosis and inhibits the growth and motility of colon cancer in vitro and in vivo via inactivating Ras/Raf/MEK/ERK signaling	LIFE SCIENCES			English	Article						Sevoflurane; Colon cancer; Growth; Motility; ERK signaling pathway	EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCELLULAR-CARCINOMA; VOLATILE ANESTHETICS; CELL-DEATH; BREAST; EXPRESSION; SURGERY; RAF/MEK/ERK; PATHWAY; EMT	Aims: To investigate the effects of sevoflurane on proliferation, cell cycle, apoptosis, autophagy, invasion and epithelial-mesenchymal transition of colon cancer cell line SW480, and to explore its possible mechanism. Materials and methods: SW480 and SW620 cells were treated with a mixture of 95% O-2+5% CO2 containing different concentrations of sevoflurane (1.7% SAV, 3.4% SAV and 5.1% SAV) for 6 h. Meanwhile, we performed a rescue experiment by treating cells with the ERK pathway activator LM22B-10 prior to treatment of cells with 5.1% sevoflurane. Key findings: High concentration (5.1%) of sevoflurane significantly inhibited the proliferation and invasion of cells, causing G0/G1 phase arrest and promoted apoptosis and autophagy. 5.1% sevoflurane can participate in the regulation of EMT by regulating the expression of E-cadherin, Vimentin and N-cadherin proteins. LM22B-10 promoted proliferation and invasion of cancer cells and inhibited apoptosis and autophagy, while 5.1% sevoflurane could reverse the effect of LM22B-10 on the biological characteristics of cells. Sevoflurane can significantly inhibit tumor growth in SW480 cells transplanted nude mice. Moreover, 5.1% sevoflurane significantly increased the expression of p-Raf, p-MEK1/2, and p-ERK1/2 in SW480 cells and tumor tissues without affecting p-JNK and p-p38 proteins, meanwhile, 5.1% sevoflurane can inhibit the activation of ERK signaling pathway by LM22B-10 in vitro and in vivo. Significance: Sevoflurane can inhibit the proliferation and invasion of colon cancer cells, induce apoptosis and autophagy, and participate in the regulation of epithelial-mesenchymal transition, which may be related to its inhibition of the ERK signaling pathway.	[Yang, Xiao; Zheng, Yao-tun; Rong, Wei] Weihai Cent Hosp, Dept Anesthesiol, Unit18-2,Wenhua Rd, Weihai 264400, Shandong, Peoples R China		Rong, W (corresponding author), Weihai Cent Hosp, Dept Anesthesiol, Unit18-2,Wenhua Rd, Weihai 264400, Shandong, Peoples R China.	rongweirw123@126.com					Biki B, 2008, ANESTHESIOLOGY, V109, P180, DOI 10.1097/ALN.0b013e31817f5b73; BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3; Brozovic G, 2008, EUR J ANAESTH, V25, P642, DOI 10.1017/S0265021508004171; Center MM, 2009, CA-CANCER J CLIN, V59, P366, DOI 10.3322/caac.20038; Chang CY, 2015, IUBMB LIFE, V67, P869, DOI 10.1002/iub.1445; Chen HH, 2017, MOL MED REP, V16, P5807, DOI 10.3892/mmr.2017.7366; Chipuk JE, 2010, MOL CELL, V37, P299, DOI 10.1016/j.molcel.2010.01.025; Choi CH, 2010, FREE RADICAL BIO MED, V49, P245, DOI 10.1016/j.freeradbiomed.2010.04.014; Christopherson R, 2008, ANESTH ANALG, V107, P325, DOI 10.1213/ane.0b013e3181770f55; Dang Y., 2018, CAN J GASTROENTEROL, P1; Davies M, 2005, J CELL BIOCHEM, V95, P918, DOI 10.1002/jcb.20458; Delbridge ARD, 2016, NAT REV CANCER, V16, P99, DOI 10.1038/nrc.2015.17; Delfini MC, 2009, DEV BIOL, V333, P229, DOI 10.1016/j.ydbio.2009.05.544; Ecimovic P, 2013, ANTICANCER RES, V33, P4255; Ethier C, 2007, APOPTOSIS, V12, P2037, DOI 10.1007/s10495-007-0127-z; Guo L., 2017, JIANGSU AGR SCI, V45, P24; Hu XL, 2017, CANCER LETT, V397, P83, DOI 10.1016/j.canlet.2017.03.033; Huitink JM, 2010, ANESTH ANALG, V111, P1411, DOI 10.1213/ANE.0b013e3181fa3533; Kim JH, 2014, EXP CELL RES, V327, P340, DOI 10.1016/j.yexcr.2014.08.001; Kvolik S, 2005, LIFE SCI, V77, P2369, DOI 10.1016/j.lfs.2004.12.052; Kvolik S, 2009, ACTA ANAESTH SCAND, V53, P1192, DOI 10.1111/j.1399-6576.2009.02036.x; Lee JT, 2002, LEUKEMIA, V16, P486, DOI 10.1038/sj/leu/2402460; Lents NH, 2002, J BIOL CHEM, V277, P47469, DOI 10.1074/jbc.M207425200; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Li H, 2017, ONCOL LETT, V14, P5865, DOI 10.3892/ol.2017.6924; Li NY, 2013, SURGERY, V154, P404, DOI 10.1016/j.surg.2013.05.012; Li QR, 2018, NEUROSCI RES, V130, P47, DOI 10.1016/j.neures.2017.08.004; Liang H, 2012, J ANESTH, V26, P381, DOI 10.1007/s00540-011-1317-y; Loboda A, 2011, BMC MED GENOMICS, V4, DOI 10.1186/1755-8794-4-9; Lucchinetti E, 2009, ANESTH ANALG, V109, P1117, DOI 10.1213/ANE.0b013e3181b5a277; MITSUHATA H, 1995, INT J IMMUNOPHARMACO, V17, P529, DOI 10.1016/0192-0561(95)00026-X; Moradkhani MR, 2018, DRUG RES, V68, P125, DOI 10.1055/s-0043-119071; Nishiwada T, 2015, J ANESTH, V29, P805, DOI 10.1007/s00540-015-2025-9; Norris JL, 1999, J BIOL CHEM, V274, P13841, DOI 10.1074/jbc.274.20.13841; Pape M, 2006, ANESTH ANALG, V103, P173, DOI 10.1213/01.ane.0000222634.51192.a4; Peng J, 2017, GUT, V66, P984, DOI 10.1136/gutjnl-2016-312986; Ribatti D, 2017, EXP CELL RES, V353, P1, DOI 10.1016/j.yexcr.2017.02.041; Roberts AW, 2016, NEW ENGL J MED, V374, P311, DOI 10.1056/NEJMoa1513257; Robles-Escajeda E, 2016, CELL ONCOL, V39, P265, DOI 10.1007/s13402-016-0272-x; Saini KS, 2013, CANCER TREAT REV, V39, P935, DOI 10.1016/j.ctrv.2013.03.009; Santra MK, 2009, NATURE, V459, P722, DOI 10.1038/nature08011; Schmukler E, 2013, ONCOTARGET, V4, P145; Shi QY, 2015, BRIT J ANAESTH, V114, P825, DOI 10.1093/bja/aeu402; Siekmann W, 2017, COLORECTAL DIS, V19, pO186, DOI 10.1111/codi.13643; Sivaprasad U, 2008, J CELL MOL MED, V12, P1265, DOI 10.1111/j.1582-4934.2008.00282.x; Smith BN, 2016, J CLIN MED, V5, DOI 10.3390/jcm5020017; Sun HZ, 2016, J CLIN LAB ANAL, V30, P1175, DOI 10.1002/jcla.22000; Suter D, 2007, ANESTH ANALG, V104, P638, DOI 10.1213/01.ane.0000255046.06058.58; Tanida Isei, 2008, V445, P77, DOI 10.1007/978-1-59745-157-4_4; Tavare AN, 2012, INT J CANCER, V130, P1237, DOI 10.1002/ijc.26448; von Gise A, 2001, MOL CELL BIOL, V21, P2324, DOI 10.1128/MCB.21.7.2324-2336.2001; Wang J.Y., 2012, INT J ANESTHESIOL RE, V33, P314; Wang J, 2016, GENES DIS, V3, P3, DOI 10.1016/j.gendis.2016.01.002; Watanabe K, 2013, BRIT J ANAESTH, V110, P637, DOI 10.1093/bja/aes469; Williams CS, 2011, J CLIN INVEST, V121, P4056, DOI 10.1172/JCI44228; Wu AB, 2016, BIOMED PHARMACOTHER, V82, P290, DOI 10.1016/j.biopha.2016.04.008; Xu HM, 2018, AM J TRANSL RES, V10, P1703; Xu Y, 2017, MOL MED REP, V16, P7829, DOI 10.3892/mmr.2017.7519; Xu ZH, 2014, J BUON, V19, P466; Yang SF, 2017, ONCOL LETT, V13, P1041, DOI 10.3892/ol.2017.5557; Yilmaz M, 2009, CANCER METAST REV, V28, P15, DOI 10.1007/s10555-008-9169-0; Zhang L, 2015, INT J CLIN EXP MED, V8, P19412; Zhang XX, 2018, J CELL BIOCHEM, V119, P2864, DOI 10.1002/jcb.26461; Zhou X, 2015, EUR REV MED PHARMACO, V19, P4087; Zhuo WL, 2008, BIOCHEM BIOPH RES CO, V369, P1098, DOI 10.1016/j.bbrc.2008.02.143	65	23	24	2	5	PERGAMON-ELSEVIER SCIENCE LTD	OXFORD	THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND	0024-3205	1879-0631		LIFE SCI	Life Sci.	DEC 15	2019	239								116916	10.1016/j.lfs.2019.116916			13	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	JU0IH	WOS:000501363000029	31626792				2022-04-25	
J	Pan, ZP; Li, X; Wang, YJ; Jiang, QL; Jiang, L; Zhang, M; Zhang, N; Wu, FB; Liu, B; He, G				Pan, Zhaoping; Li, Xiang; Wang, Yujia; Jiang, Qinglin; Jiang, Li; Zhang, Min; Zhang, Nan; Wu, Fengbo; Liu, Bo; He, Gu			Discovery of Thieno[2,3-d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells	JOURNAL OF MEDICINAL CHEMISTRY			English	Article							BET BROMODOMAIN; HDAC INHIBITORS; SMALL-MOLECULE; IN-VITRO; PRELIMINARY BIOACTIVITY; CANCER STATISTICS; BRD4; DESIGN; POTENT; LEUKEMIA	Bromodomain-containing protein 4 (BRD4) and histone deacetylases (HDAC) are both attractive epigenetic targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, and in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4-HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC50 values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma (CRC) cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest that the BRD4-HDAC dual inhibition might be an attractive therapeutic strategy for CRC.	[Jiang, Qinglin; Jiang, Li; Zhang, Min] Chengdu Med Coll, Sch Pharm, Chengdu 610500, Peoples R China; [Jiang, Qinglin; Jiang, Li; Zhang, Min] Chengdu Med Coll, Sichuan Prov Coll Key Lab Struct Specif Small Mol, Chengdu 610500, Peoples R China; [Pan, Zhaoping; Li, Xiang; Wang, Yujia; Zhang, Nan; Wu, Fengbo; Liu, Bo; He, Gu] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China; [Pan, Zhaoping; Li, Xiang; Wang, Yujia; Zhang, Nan; Wu, Fengbo; Liu, Bo; He, Gu] Sichuan Univ, West China Hosp, Dept Urol, Chengdu 610041, Sichuan, Peoples R China; [Zhang, Nan; Liu, Bo; He, Gu] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China		Jiang, QL (corresponding author), Chengdu Med Coll, Sch Pharm, Chengdu 610500, Peoples R China.; Jiang, QL (corresponding author), Chengdu Med Coll, Sichuan Prov Coll Key Lab Struct Specif Small Mol, Chengdu 610500, Peoples R China.; Liu, B; He, G (corresponding author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China.; Liu, B; He, G (corresponding author), Sichuan Univ, West China Hosp, Dept Urol, Chengdu 610041, Sichuan, Peoples R China.; Liu, B; He, G (corresponding author), Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China.	jpl_cmc@163.com; liubo2400@163.com; hegu@scu.e.cu	He, Gu/G-5446-2015	He, Gu/0000-0002-1536-8882	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21772131, 81603065, 81673455]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2016M602696, 2016M592679]; National Science and Technology Major Project of the Ministry of Science and Technology of China [2018ZX09735005]; Fundamental Research Funds for the Science & Technology department of Sichuan Province [2019YFSY0004]	This work was supported by grants from National Natural Science Foundation of China (grant nos. 21772131, 81603065 and 81673455), China Postdoctoral Science Foundation (nos 2016M602696 and 2016M592679), National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2018ZX09735005) and the Fundamental Research Funds for the Science & Technology department of Sichuan Province (2019YFSY0004).	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Med. Chem.	APR 9	2020	63	7					3678	3700		10.1021/acs.jmedchem.9b02178			23	Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED); Index Chemicus (IC)	Pharmacology & Pharmacy	LE0HG	WOS:000526405300018	32153186				2022-04-25	
J	Cheng, KW; Wong, CC; Alston, N; Mackenzie, GG; Huang, LQ; Ouyang, NT; Xie, G; Wiedmann, T; Rigas, B				Cheng, Ka Wing; Wong, Chi C.; Alston, Ninche; Mackenzie, Gerardo G.; Huang, Liqun; Ouyang, Nengtai; Xie, Gang; Wiedmann, Timothy; Rigas, Basil			Aerosol Administration of Phospho-Sulindac Inhibits Lung Tumorigenesis	MOLECULAR CANCER THERAPEUTICS			English	Article							NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ACTIVATED PROTEIN-KINASE; COLON-CANCER; IBUPROFEN MDC-917; OXIDATIVE STRESS; AUTOPHAGY; SURVIVAL; GROWTH; APOPTOSIS; OXT-328	Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation. (C)2013 AACR.	[Cheng, Ka Wing; Wong, Chi C.; Alston, Ninche; Mackenzie, Gerardo G.; Huang, Liqun; Ouyang, Nengtai; Xie, Gang; Rigas, Basil] SUNY Stony Brook, Canc Prevent Div, Stony Brook, NY 11794 USA; [Ouyang, Nengtai] Medicon Pharmaceut Inc, Stony Brook, NY USA; [Wiedmann, Timothy] Univ Minnesota, Dept Pharmaceut, Minneapolis, MN 55455 USA		Rigas, B (corresponding author), SUNY Stony Brook, Canc Prevent Div, HSC, T-17 Room 080, Stony Brook, NY 11794 USA.	basil.rigas@stonybrookmedicine.edu	Cheng, Ka Wing/V-9433-2019; Mackenzie, Gerardo G/AAW-5114-2020; Wong, Chi Chun/C-4636-2016		NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA139454, R41CA162683]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA139454, R43CA165448] Funding Source: NIH RePORTER	This work was supported by NIH grants R01CA139454 and R41CA162683.	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Cancer Ther.	AUG	2013	12	8					1417	1428		10.1158/1535-7163.MCT-13-0006-T			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	198FU	WOS:000322908400004	23645590	Green Accepted, Bronze			2022-04-25	
J	Belovejdov, V; Dikov, D; Auriault, M; Copie-Bergman, C; Sarafian, V				Belovejdov, Veselin T.; Dikov, Dorian I.; Auriault, Marie L.; Copie-Bergman, Christiane; Sarafian, Victoria S.			Uterine leiomyoma with massive lymphoid infiltrate after colon cancer chemotherapy: an immunohistochemical investigation with special reference to lysosome-associated membrane protein expression	CENTRAL EUROPEAN JOURNAL OF MEDICINE			English	Article						Uterine leiomyoma with massive lymphoid infiltrate; Colon cancer; Immunohistochemistry; LAMPs	LYMPHOCYTIC INFILTRATION; SIMULATING LYMPHOMA; HORMONE AGONIST; CELL-DEATH; AUTOPHAGY	Uterine leiomyoma with massive lymphoid infiltration is a rare morphologic phenomenon. We describe the first case of uterine leiomyoma with lymphoid infiltration observed in a patient after chemotherapy for sigmoid cancer. We performed immunohistochemical analysis with a panel of antibodies to several markers. Detection of CD20, CD3, Ki67, CD68 and Epstein-Barr virus nuclear antigen assisted in the differential diagnosis and partial elucidation of the pathogenesis. In addition, we examined the lysosome-associated membrane proteins LAMP-1 and LAMP-2 for the first time in this lesion. Their expression was elevated, indicating enhanced autophagy, an indirect sign of degenerative changes in this benign tumor characterized by massive lymphoid infiltration.	[Belovejdov, Veselin T.] Med Univ Plovdiv, Dept Gen & Clin Pathol, Plovdiv 4002, Bulgaria; Ctr Hosp Lagny Marne La Vallee, Serv Anatom & Cytol Pathol, F-77405 Lagny Sur Marne, France; Hop Henri Mondor, Dept Pathol, F-94010 Creteil, France; Med Univ Plovdiv, Dept Biol, Plovdiv 4002, Bulgaria		Belovejdov, V (corresponding author), Med Univ Plovdiv, Dept Gen & Clin Pathol, Plovdiv 4002, Bulgaria.	vesbel@abv.bg					Bardsley V, 1998, HISTOPATHOLOGY, V33, P80, DOI 10.1046/j.1365-2559.1998.00451.x; Botsis D, 1999, EUR J GYNAECOL ONCOL, V20, P61; Bozzini N, 2003, ACTA OBSTET GYN SCAN, V82, P330, DOI 10.1034/j.1600-0412.2003.00049.x; Chuang SS, 2001, PATHOL RES PRACT, V197, P135, DOI 10.1078/0344-0338-5710024; COLGAN TJ, 1993, HUM PATHOL, V24, P1073, DOI 10.1016/0046-8177(93)90186-K; CROW J, 1995, INT J GYNECOL PATHOL, V14, P235, DOI 10.1097/00004347-199507000-00007; Cuervo AM, 2000, J CELL SCI, V113, P4441; FERRY JA, 1989, INT J GYNECOL PATHOL, V8, P263, DOI 10.1097/00004347-198909000-00010; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Huang J, 2007, CELL CYCLE, V6, P1837, DOI 10.4161/cc.6.15.4511; Ito F, 2001, FERTIL STERIL, V75, P125, DOI 10.1016/S0015-0282(00)01660-5; Laforga JBM, 1999, HISTOPATHOLOGY, V34, P471; McClean G, 2003, INT J SURG PATHOL, V11, P339, DOI 10.1177/106689690301100417; Ohmori T, 2002, HISTOPATHOLOGY, V41, P276; Paik SS, 2004, PATHOL INT, V54, P343, DOI 10.1111/j.1440-1827.2004.01629.x; Resta L, 2004, Pathologica, V96, P35; Saglam A, 2005, INT J GYNECOL CANCER, V15, P167; Sarafian VS, 2007, APMIS, V115, P701, DOI 10.1111/j.1600-0463.2007.apm_576.x; Ueda M, 1997, INT J CANCER, V71, P668, DOI 10.1002/(SICI)1097-0215(19970516)71:4<668::AID-IJC25>3.0.CO;2-6; Wei SZ, 2004, GYNECOL ONCOL, V95, P409, DOI 10.1016/j.ygyno.2004.07.058; Yoshimatsu K, 2008, ANTICANCER RES, V28, P373	21	0	0	0	1	SCIENDO	WARSAW	DE GRUYTER POLAND SP Z O O, BOGUMILA ZUGA 32A STR, 01-811 WARSAW, POLAND	1895-1058	1644-3640		CENT EUR J MED	Cent. Eur. J. Med.	MAR	2009	4	1					54	58		10.2478/s11536-009-0016-7			5	Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	General & Internal Medicine	406MP	WOS:000263299900008					2022-04-25	
J	Chen, J; Na, RS; Xiao, C; Wang, X; Wang, YP; Yan, DW; Song, GH; Liu, XI; Chen, JY; Lu, HJ; Chen, CY; Tang, HM; Zhuang, GH; Fan, GJ; Peng, ZH				Chen, Jian; Na, Risi; Xiao, Chao; Wang, Xiao; Wang, Yupeng; Yan, Dongwang; Song, Guohe; Liu, Xueni; Chen, Jiayi; Lu, Huijun; Chen, Chunyan; Tang, Huamei; Zhuang, Guohong; Fan, Guangjian; Peng, Zhihai			The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy	ONCOGENE			English	Article							GLYCINE; COLON; METABOLISM; METASTASIS; SERINE; CELLS; PKM2; RISK; GENE	5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2-p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.	[Chen, Jian] Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Thorac Surg, Shanghai, Peoples R China; [Na, Risi; Tang, Huamei; Peng, Zhihai] Xiamen Univ, Sch Med, Xiang An Hosp, Dept Gen Surg, Xiamen, Peoples R China; [Xiao, Chao] Fu Dan Univ, Sch Med, Hua Shan Hosp, Dept Gen Surg, Shanghai, Peoples R China; [Wang, Xiao] Sun Yat Sen Univ, Dept Gastrointestinal Surg, Affiliated Hosp 5, Zhuhai, Peoples R China; [Wang, Yupeng; Song, Guohe] Fu Dan Univ, Sch Med, Zhong Shan Hosp, Dept Gen Surg, Shanghai, Peoples R China; [Yan, Dongwang; Liu, Xueni; Chen, Jiayi; Fan, Guangjian] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Translat Med Ctr, Shanghai, Peoples R China; [Lu, Huijun] Guigang City Peoples Hosp, Dept Pathol, Guigang, Guangxi, Peoples R China; [Chen, Chunyan] Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Pathol, Shanghai, Peoples R China; [Tang, Huamei; Zhuang, Guohong; Peng, Zhihai] Xiamen Univ, Organ Transplantat Inst, Sch Med, Fujian Prov Key Lab Organ & Tissue Regenerat, Xiamen, Peoples R China		Tang, HM; Peng, ZH (corresponding author), Xiamen Univ, Sch Med, Xiang An Hosp, Dept Gen Surg, Xiamen, Peoples R China.; Fan, GJ (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Translat Med Ctr, Shanghai, Peoples R China.; Tang, HM; Zhuang, GH; Peng, ZH (corresponding author), Xiamen Univ, Organ Transplantat Inst, Sch Med, Fujian Prov Key Lab Organ & Tissue Regenerat, Xiamen, Peoples R China.	tanghuamei2014@163.com; zhgh@xmu.edu.cn; ytfan@126.com; pengzhihai1958@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81530044, 81802343, 81871931, 81602069, 81220108021, 81702337, 81602616]; Medical Guidance Project of Shanghai Science and Technology Commission [17411968200, 19QA1407100]; Natural Science Foundation of Shanghai MunicipalityNatural Science Foundation of Shanghai [16ZR1427700, 16CR2008A]; National Science and Technology Major Project of China [2017ZX10203206]	We acknowledge the National Natural Science Foundation of China (81530044, 81802343, 81871931, 81602069, 81220108021, 81702337, 81602616), the Medical Guidance Project of Shanghai Science and Technology Commission (17411968200, 19QA1407100), and the Natural Science Foundation of Shanghai Municipality (16ZR1427700). Shanghai 3-year action plan to promote the clinical skills and clinical innovation capacity of municipal hospitals (No. 16CR2008A). National Science and Technology Major Project of China Grant 2017ZX10203206.	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J	Jeong, S; Yun, HK; Jeong, YA; Jo, MJ; Kang, SH; Kim, JL; Kim, DY; Park, SH; Kim, BR; Na, YJ; Lee, SI; Kim, HD; Kim, DH; Oh, SC; Lee, DH				Jeong, Soyeon; Yun, Hye Kyeong; Jeong, Yoon A.; Jo, Min Jee; Kang, Sang Hee; Kim, Jung Lim; Kim, Dae Yeong; Park, Seong Hye; Kim, Bo Ram; Na, Yoo Jin; Lee, Sun Il; Kim, Han Do; Kim, Dae Hyun; Oh, Sang Cheul; Lee, Dae-Hee			Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells	CANCER LETTERS			English	Article						Marijuana extract; Bcl-2 protein family; ROS; Apoptotic cell death; Colon cancer	ENDOPLASMIC-RETICULUM STRESS; OXIDATIVE STRESS; ER STRESS; CANNABINOIDS; DEATH; MECHANISMS; ROS; AUTOPHAGY; PATHWAY	Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known. This study aimed to evaluate the apoptotic action of CBD in colorectal cancer (CRC) cells, and focused on its effects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway. CBD experiments were performed using the CRC cell lines HCT116 and DLD-1. CBD induced apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, Noxa levels were downregulated using siRNA, and the expression of apoptosis markers decreased. After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa, which along with ROS is a well-known pro-apoptotic signaling agents. As a result, CBD induced apoptosis in a Noxa-and-ROS-dependent manner. Taken together, the results obtained in this study re-demonstrated the effects of CBD treatment in vivo, thus confirming its role as a novel, reliable anticancer drug.	[Jeong, Soyeon; Kim, Jung Lim; Kim, Bo Ram; Oh, Sang Cheul; Lee, Dae-Hee] Korea Univ, Coll Med, Guro Hosp, Dept Oncol, Seoul, South Korea; [Yun, Hye Kyeong; Jeong, Yoon A.; Jo, Min Jee; Kim, Dae Yeong; Park, Seong Hye; Na, Yoo Jin; Oh, Sang Cheul; Lee, Dae-Hee] Korea Univ, Grad Sch Med, Coll Med, Seoul 08308, South Korea; [Kang, Sang Hee; Lee, Sun Il] Korea Univ, Coll Med, Guro Hosp, Dept Surg, Seoul, South Korea; [Kim, Han Do; Kim, Dae Hyun] Kaiyon Bio Tech Co Ltd, 226 Gamasan Ro, Seoul 08308, South Korea		Lee, DH (corresponding author), Korea Univ, Med Ctr, Dept Internal Med, Coll Med,Div Oncol Hematol, Seoul 08308, South Korea.; Oh, SC (corresponding author), Korea Univ, Guro Hosp, Dept Internal Med, Div Oncol Hematol, 148 Gurodong Gil, Seoul 08308, South Korea.	sachoh@korea.ac.kr; neogene@korea.ac.kr		Kang, Sanghee/0000-0002-6097-8831	National Research Foundation of Korea - Korea government (MSIP) [NRF-2017R1D1A1B03030703]; Business for Cooperative R & D between Industry, Academy, and Research Institute [C0566291]; Korea University Grant	This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIP) (NRF-2017R1D1A1B03030703) and supported by the Business for Cooperative R & D between Industry, Academy, and Research Institute funded Korea Small and Medium Business Administration in 20 (C0566291) and a Korea University Grant.	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J	Kwatra, D; Subramaniam, D; Ramamoorthy, P; Standing, D; Moran, E; Velayutham, R; Mitra, A; Umar, S; Anant, S				Kwatra, Deep; Subramaniam, Dharmalingam; Ramamoorthy, Prabhu; Standing, David; Moran, Elizabeth; Velayutham, Ravichandiran; Mitra, Ashim; Umar, Shahid; Anant, Shrikant			Methanolic Extracts of Bitter Melon Inhibit Colon Cancer Stem Cells by Affecting Energy Homeostasis and Autophagy	EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article							ACTIVATED PROTEIN-KINASE; MOMORDICA-CHARANTIA; ELEOSTEARIC ACID; STROMAL CELLS; IDENTIFICATION; APOPTOSIS; CURCUMIN; PROLIFERATION; NEOPLASIA; AGENTS	Bitter melon fruit is recommended in ancient Indian and Chinese medicine for prevention/treatment of diabetes. However its effects on cancer progression are not well understood. Here, we have determined the efficacy of methanolic extracts of bitter melon on colon cancer stem and progenitor cells. Both, whole fruit (BMW) and skin (BMSk) extracts showed significant inhibition of cell proliferation and colony formation, with BMW showing greater efficacy. In addition, the cells were arrested at the S phase of cell cycle. Moreover, BMW induced the cleavage of LC3B but not caspase 3/7, suggesting that the cells were undergoing autophagy and not apoptosis. Further confirmation of autophagy was obtained when western blots showed reduced Bcl-2 and increased Beclin-1, Atg 7 and 12 upon BMW treatment. BMW reduced cellular ATP levels coupled with activation of AMP activated protein kinase; on the other hand, exogenous additions of ATP lead to revival of cell proliferation. Finally, BMW treatment results in a dose-dependent reduction in the number and size of colonospheres. The extracts also decreased the expression of DCLK1 and Lgr5, markers of quiescent, and activated stem cells. Taken together, these results suggest that the extracts of bitter melon can be an effective preventive/therapeutic agent for colon cancer.	[Kwatra, Deep; Subramaniam, Dharmalingam; Ramamoorthy, Prabhu; Standing, David; Moran, Elizabeth; Umar, Shahid; Anant, Shrikant] Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, Kansas City, KS 66160 USA; [Subramaniam, Dharmalingam; Ramamoorthy, Prabhu; Standing, David; Umar, Shahid; Anant, Shrikant] Univ Kansas, Med Ctr, Ctr Canc, Kansas City, KS 66160 USA; [Velayutham, Ravichandiran] Vels Univ, Dept Pharmacognosy, Madras 600117, Tamil Nadu, India; [Mitra, Ashim] Univ Missouri, Dept Pharmaceut Sci, Kansas City, MO 64108 USA		Anant, S (corresponding author), Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, 3901 Rainbow Blvd MS 3040, Kansas City, KS 66160 USA.	sanant@kumc.edu	Anant, Shrikant/AAF-8020-2020	Pearsall, Elizabeth/0000-0003-1013-6238; Standing, David/0000-0003-3153-4374	NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK062265, CA109269, CA135559]; Thomas O'Sullivan Foundation; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA168524-01]; Cancer Center; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA109269, P30CA168524, R01CA135559] 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) [R01DK062265] Funding Source: NIH RePORTER	This work was supported by the NIH Grants DK062265, CA109269, and CA135559 to S. Anant and Grant support from the Thomas O'Sullivan Foundation and NCI-designated The University of Kansas Cancer Center (P30CA168524-01). S. Anant is an Eminent Scientist of the Kansas Biosciences Authority. The author would also like to acknowledge the Flow Cytometry Core Laboratory, which is sponsored in part by the Cancer Center. They also thank all members of the Anant Laboratory for their discussion during the course of this study.	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J	Sivaprasad, U; Basu, A				Sivaprasad, U.; Basu, A.			Inhibition of ERK attenuates autophagy and potentiates tumour necrosis factor-alpha-induced cell death in MCF-7 cells	JOURNAL OF CELLULAR AND MOLECULAR MEDICINE			English	Article						TNF; autophagy; ERK 1/2; U0126	PROTEIN-KINASE-C; COLON-CANCER CELLS; INDUCED APOPTOSIS; SIGNALING PATHWAYS; IN-VITRO; ACTIVATION; INDUCTION; MACROAUTOPHAGY; GROWTH; TRAIL	The role of autophagy in cell death is under considerable debate. The process of autophagy has been shown to lead to either cell survival or cell death depending on cell type and stimulus. In the present study, we determined the contribution of ERK1/2 signalling to autophagy and cell death induced by tumour necrosis factor-alpha (TNF) in MCF-7 breast cancer cells. Treatment of MCF-7 cells with TNF caused a time-dependent increase in ERK1/2 activity. There was an induction of autophagy and cleavage of caspase-7, -8, -9 and PARP. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 or PD98059 resulted in a decrease in TNF-induced autophagy that was accompanied by an increase in cleavage of caspase-7, -8, -9 and PARP Furthermore, inhibition of ERK1/2 signalling resulted in decreased clonogenic capacity of MCF-7 cells. These data suggest that TNF-induces autophagy through ERK1/2 and that inhibition of autophagy increases cellular sensitivity to TNF.	[Basu, A.] Univ N Texas, Hlth Sci Ctr, Dept Mol Biol & Immunol, Ft Worth, TX 76107 USA; Inst Canc Res, Ft Worth, TX USA		Basu, A (corresponding author), Univ N Texas, Hlth Sci Ctr, Dept Mol Biol & Immunol, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA.	abasu@hsc.unt.edu		Basu, Alakananda/0000-0002-1656-0788	NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA071727] Funding Source: NIH RePORTER; NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA71727, R01 CA071727] Funding Source: Medline		Aoki H, 2007, MOL PHARMACOL, V72, P29, DOI 10.1124/mol.106.033167; Basu A, 2002, J BIOL CHEM, V277, P41850, DOI 10.1074/jbc.M205997200; Basu A, 1999, BIOCHEMISTRY-US, V38, P4245, DOI 10.1021/bi982854q; Basu A, 2001, BIOCHEM BIOPH RES CO, V280, P883, DOI 10.1006/bbrc.2000.4209; Boya P, 2005, MOL CELL BIOL, V25, P1025, DOI 10.1128/MCB.25.3.1025-1040.2005; Broker LE, 2005, CLIN CANCER RES, V11, P3155, DOI 10.1158/1078-0432.CCR-04-2223; Canu N, 2005, J NEUROCHEM, V92, P1228, DOI 10.1111/j.1471-4159.2004.02956.x; Chang NS, 1997, AM J PHYSIOL-CELL PH, V273, pC1987, DOI 10.1152/ajpcell.1997.273.6.C1987; Corcelle E, 2006, CANCER RES, V66, P6861, DOI 10.1158/0008-5472.CAN-05-3557; Debnath J, 2005, AUTOPHAGY, V1, P66, DOI 10.4161/auto.1.2.1738; Djavaheri-Mergny M, 2006, J BIOL CHEM, V281, P30373, DOI 10.1074/jbc.M602097200; Ellington AA, 2006, CARCINOGENESIS, V27, P298, DOI 10.1093/carcin/bgi214; GHAVAMI S, 2007, J CELL MOL MED; Gonzalez-Polo RA, 2005, ONCOGENE, V24, P7503, DOI 10.1038/sj.onc.1208907; Gozuacik D, 2007, CURR TOP DEV BIOL, V78, P217, DOI 10.1016/S0070-2153(06)78006-1; Harhaji L, 2007, EUR J PHARMACOL, V568, P248, DOI 10.1016/j.ejphar.2007.04.029; Hetz CA, 2005, BIOCHEM CELL BIOL, V83, P579, DOI 10.1139/o05-065; Jaattela M, 2004, ONCOGENE, V23, P2746, DOI 10.1038/sj.onc.1207513; Jackson WT, 2005, PLOS BIOL, V3, P861, DOI 10.1371/journal.pbio.0030156; Jia GH, 2006, IMMUNOL CELL BIOL, V84, P448, DOI 10.1111/j.1440-1711.2006.01454.x; 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; Kim R, 2006, CANCER CHEMOTH PHARM, V57, P545, DOI 10.1007/s00280-005-0111-7; Kim R, 2006, J PATHOL, V208, P319, DOI 10.1002/path.1885; Kim R, 2005, ONCOL REP, V14, P595; Klionsky DJ, 2005, AUTOPHAGY, V1, P59, DOI 10.4161/auto.1.1.1536; Kuribayashi K, 2006, CANCER BIOL THER, V5, P763, DOI 10.4161/cbt.5.7.3228; Lee CY, 2001, DEVELOPMENT, V128, P1443; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Liu Y, 2005, CELL, V121, P567, DOI 10.1016/j.cell.2005.03.007; Lockshin RA, 2007, J CELL MOL MED, V11, P1214, DOI 10.1111/j.1582-4934.2007.00150.x; Lu DM, 2006, J BIOL CHEM, V281, P22799, DOI 10.1074/jbc.M603390200; Lum JJ, 2005, CELL, V120, P237, DOI 10.1016/j.cell.2004.11.046; Martin DN, 2004, DEVELOPMENT, V131, P275, DOI 10.1242/dev.00933; Martinet W, 2005, BIOTECHNOL LETT, V27, P1157, DOI 10.1007/s10529-005-0007-y; Mills KR, 2004, P NATL ACAD SCI USA, V101, P3438, DOI 10.1073/pnas.0400443101; Mizushima N, 2004, INT J BIOCHEM CELL B, V36, P2491, DOI 10.1016/j.biocel.2004.02.005; Ogier-Denis E, 2000, J BIOL CHEM, V275, P39090, DOI 10.1074/jbc.M006198200; Park KJ, 2007, CANCER RES, V67, P7327, DOI 10.1158/0008-5472.CAN-06-4766; Pattingre S, 2003, J BIOL CHEM, V278, P16667, DOI 10.1074/jbc.M210998200; Prins JB, 1998, BIOSCIENCE REP, V18, P329, DOI 10.1023/A:1020261316486; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Shinojima N, 2007, AUTOPHAGY, V3, P635, DOI 10.4161/auto.4916; Sivaprasad U, 2007, CELL DEATH DIFFER, V14, P851, DOI 10.1038/sj.cdd.4402077; Tanida I, 2004, J BIOL CHEM, V279, P47704, DOI 10.1074/jbc.M407016200; Tanida I, 2004, INT J BIOCHEM CELL B, V36, P2503, DOI 10.1016/j.biocel.2004.05.009; Tassa A, 2003, BIOCHEM J, V376, P577, DOI 10.1042/BJ20030826; Thorburn J, 2005, MOL BIOL CELL, V16, P1189, DOI 10.1091/mbc.E04-10-0906; Wang XJ, 2004, J BIOL CHEM, V279, P45855, DOI 10.1074/jbc.M405147200; Xue LZ, 1999, MOL CELL NEUROSCI, V14, P180, DOI 10.1006/mcne.1999.0780; Yu L, 2004, SCIENCE, V304, P1500, DOI 10.1126/science.1096645	51	107	112	0	4	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA		1582-4934		J CELL MOL MED	J. Cell. Mol. Med.	AUG	2008	12	4					1265	1271		10.1111/j.1582-4934.2008.00282.x			7	Cell Biology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Research & Experimental Medicine	336IU	WOS:000258358300024	18266953	Green Published			2022-04-25	
J	Wang, Y; Li, YZ; Yang, L; Yin, DX				Wang, Yang; Li, Yezhou; Yang, Li; Yin, Dexin			Intermittent low dose irradiation enhances the effectiveness of radio- and chemo-therapy for human colorectal adenocarcinoma cell line HT-29	ONCOLOGY REPORTS			English	Article						low dose irradiation; colorectal adenocarcinoma; chemotherapy; radiotherapy; cell signaling	COLON-CANCER CELLS; 5-FLUOROURACIL RESISTANCE; IONIZING-RADIATION; LEVEL; RADIORESISTANCE; PERSPECTIVES; MECHANISMS; AUTOPHAGY; HORMESIS; P53	Low dose irradiation (LDIR) induces hormesis and adaptive response in organism and mammalian cell lines. Notably, LDIR generates distinct biological effects in cancer cells from normal cells, e.g., it may affect the growth of cancer cells via the activation of certain cell signaling pathway, which does not exist in normal cells. Therefore, LDIR is considered as a promising assistant method of clinical cancer therapy. In this study, we chose human colorectal adenocarcinoma cell line HT-29 as the experimental model, and investigated the differential biological effects between 250 mGy single dose LDIR and 250 mGy intermittent LDIR pretreatments in high dose irradiation (HDIR) radiotherapy and 5-fluorouracil (5-FU) based chemotherapy. Through the cell growth assays, we observed that 250 mGy intermittent LDIR pretreatment significantly increased the killing effect of both radiotherapy and chemotherapy. Western blotting results showed that intermittent LDIR pretreatment apparently activated the ATM/p53 (ataxia telangiectasia mutated, ATM) pathway in radiotherapy; it also activated ERK and p38MAPK pathways in chemotherapy. When we used chemical inhibitors to block the ATM/p53 or p38MAPK pathways, the intermittent LDIR induced cell growth inhibitions were reversed. However, blockage of ERK pathway could not affect the cell growth inhibiton in chemotherapy. Taken together, our findings evaluated the intermittent LDIR as a potential valuable method that can enhance the effectiveness of radiotherapy and chemotherapy, especially in the radio- or chemo-resistant tumor types.	[Wang, Yang; Yang, Li] FAW Gen Hosp, Dept Gastroenterol, Changchun 130011, Jilin, Peoples R China; [Li, Yezhou; Yin, Dexin] Jilin Univ, Dept Vasc Surg, China Japan Union Hosp, 126 Xiantai St, Changchun 130033, Jilin, Peoples R China		Yin, DX (corresponding author), Jilin Univ, Dept Vasc Surg, China Japan Union Hosp, 126 Xiantai St, Changchun 130033, Jilin, Peoples R China.	jlucjuhyd@163.com					Brazina J, 2015, CELL CYCLE, V14, P375, DOI 10.4161/15384101.2014.988019; de la Cruz-Morcillo MA, 2012, ONCOGENE, V31, P1073, DOI 10.1038/onc.2011.321; Feinendegen LE, 2005, BRIT J RADIOL, V78, P3, DOI 10.1259/bjr/63353075; Grem JL, 2000, INVEST NEW DRUG, V18, P299, DOI 10.1023/A:1006416410198; Guo M, 2015, BIOMED PHARMACOTHER, V76, P107, DOI 10.1016/j.biopha.2015.10.027; Hafner MF, 2016, VISC MED, V32, P172, DOI 10.1159/000446486; Liang XY, 2016, DOSE-RESPONSE, V14, DOI 10.1177/1559325815622174; Lin K, 2012, CLIN CANCER RES, V18, P4191, DOI 10.1158/1078-0432.CCR-11-2936; Longley DB, 2003, NAT REV CANCER, V3, P330, DOI 10.1038/nrc1074; LUCKEY TD, 1982, HEALTH PHYS, V43, P771, DOI 10.1097/00004032-198212000-00001; OLIVIERI G, 1984, SCIENCE, V223, P594, DOI 10.1126/science.6695170; Shin YK, 2009, ELECTROPHORESIS, V30, P2182, DOI 10.1002/elps.200800806; Su XL, 2014, GENET MOL RES, V13, P2513, DOI 10.4238/2014.January.17.5; Sui XB, 2014, SCI REP-UK, V4, DOI 10.1038/srep04694; Tang FR, 2015, INT J RADIAT BIOL, V91, P13, DOI 10.3109/09553002.2014.937510; Violette S, 2002, INT J CANCER, V98, P498, DOI 10.1002/ijc.10146; Wei MF, 2014, AUTOPHAGY, V10, P1179, DOI 10.4161/auto.28679; Yang GZ, 2016, ONCOTARGET, V7, P71856, DOI 10.18632/oncotarget.12379; Yang GZ, 2016, INT J CANCER, V139, P2157, DOI 10.1002/ijc.30235; Yang XD, 2015, AM J CANCER RES, V5, P545	20	4	4	1	12	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	JUL	2017	38	1					591	597		10.3892/or.2017.5679			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	EY6JR	WOS:000404089500068	28560404	Bronze			2022-04-25	
J	Fuel, M; Mesas, C; Martinez, R; Ortiz, R; Quinonero, F; Prados, J; Porres, JM; Melguizo, C				Fuel, Marco; Mesas, Cristina; Martinez, Rosario; Ortiz, Raul; Quinonero, Francisco; Prados, Jose; Porres, Jesus M.; Melguizo, Consolacion			Antioxidant and antiproliferative potential of ethanolic extracts from Moringa oleifera, Tropaeolum tuberosum and Annona cherimola in colorrectal cancer cells	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Moringa oleifera; Tropaeolum tuberosum; Annona cherimola; Ethanolic extract; Colon cancer; 5-Fluorouracil	IN-VITRO; OXIDATIVE DAMAGE; CONSTITUENTS; ACETOGENINS; MECHANISMS; RESISTANCE; INHIBITORS; MURICATA; LEAVES; GREEN	Moringa oleifera, Tropaeolum tuberosum and Annona cherimola are medicinal plants traditionally used in Ecuador. However, their therapeutic properties are not completely known. We analyzed chromatographically ethanolic extracts of the seeds of M. oleifera, A. cherimola and the tubers of T. tuberosum; all presented a high content of polyphenols. The extract of A. cherimola showed the highest antioxidant activity and M. oleifera had the highest capacity to enhance the activity of detoxifying enzymes such as glutathione S-transferase and quinone oxidoreductase. The antitumor effect of these extracts was evaluated in vitro with colorectal cancer (CRC) cell lines T84, HCT-15, SW480 and HT-29, as well as with cancer stem cells (CSCs). A. cherimola and M. oleifera extracts presented the lowest IC50 in T-84 and HCT-15 (resistant) cells, respectively, as well as the highest level of inhibition of proliferation in multicellular tumor spheroids of HCT-15 cells. The inhibitory effect on CSCs is noteworthy because in vivo, these cells are often responsible for cancer recurrences and resistance to chemotherapy. Moreover, all extracts showed a synergistic activity with 5-Fu. The antiproliferative mechanism of the extracts was related to overexpression of caspases 9, 8 and 3 and increased production of reactive oxygen species. In addition, we observed cell death by autophagy in M. oleifera and T. tuberosum extracts. Therefore, these ethanolic extracts are excellent candidates for future molecular analysis of the presence of bioactive compounds and in vivo studies which could improve colon cancer therapy.	[Fuel, Marco; Mesas, Cristina; Ortiz, Raul; Quinonero, Francisco; Prados, Jose; Melguizo, Consolacion] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain; [Mesas, Cristina; Ortiz, Raul; Quinonero, Francisco; Prados, Jose; Melguizo, Consolacion] Univ Granada, Fac Med, Dept Anat & Embryol, Granada 18071, Spain; [Mesas, Cristina; Ortiz, Raul; Quinonero, Francisco; Prados, Jose; Melguizo, Consolacion] Inst Biosanitario Granada Ibs GRANADA, Granada 18014, Spain; [Martinez, Rosario; Porres, Jesus M.] Univ Almeria, NIF B04847216, Cellbitec SL, Sci Headquarters Almeria Technol Pk, Almeria 04128, Spain; [Martinez, Rosario; Porres, Jesus M.] Univ Granada, Biomed Res Ctr CIBM, Inst Nutr & Food Technol INyTA, Dept Physiol, Granada 18100, Spain		Prados, J (corresponding author), Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain.	jcprados@ugr.es	Herrera, Marco Fuel/AAG-9237-2020; Quiñonero, Francisco/T-3165-2018; Melguizo Alonso, Consolacion/E-9842-2016	Herrera, Marco Fuel/0000-0002-4170-2899; Quiñonero, Francisco/0000-0002-9087-8161; Mesas, Cristina/0000-0001-6369-5485; Melguizo Alonso, Consolacion/0000-0003-3990-806X	Granada Universit [CTS-107, AGR145]; 2018 Research Initiation Grants Program for Master Students of the Vice-Rectorate for Research and Knowledge Transfer of the University of Granada	This research was funded by the CTS-107 and AGR145 Groups from the Granada University. M. Fuel obtained all plants of the study from Ecuador. A part of this study has been funded by the 2018 Research Initiation Grants Program for Master Students of the Vice-Rectorate for Research and Knowledge Transfer of the University of Granada.	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Pharmacother.	NOV	2021	143								112248	10.1016/j.biopha.2021.112248		SEP 2021	15	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	WD4HD	WOS:000704903000004	34649364	Green Published, gold			2022-04-25	
J	Chang, HW; Liu, PF; Tsai, WL; Hu, WH; Hu, YC; Yang, HC; Lin, WY; Weng, JR; Shu, CW				Chang, Hsueh-Wei; Liu, Pei-Feng; Tsai, Wei-Lun; Hu, Wan-Hsiang; Hu, Yu-Chang; Yang, Hsiu-Chen; Lin, Wei-Yu; Weng, Jing-Ru; Shu, Chih-Wen			Xanthium strumarium Fruit Extract Inhibits ATG4B and Diminishes the Proliferation and Metastatic Characteristics of Colorectal Cancer Cells	TOXINS			English	Article						medicinal plant; autophagy; ATG4B; colorectal cancer	PROTECTIVE AUTOPHAGY; PROMOTES; GEMCITABINE; PROGRESSION; MECHANISMS; MIGRATION; AKT/MTOR; INVASION; DEATH	Autophagy is an evolutionarily conserved pathway to degrade damaged proteins and organelles for subsequent recycling in cells during times of nutrient deprivation. This process plays an important role in tumor development and progression, allowing cancer cells to survive in nutrient-poor environments. The plant kingdom provides a powerful source for new drug development to treat cancer. Several plant extracts induce autophagy in cancer cells. However, little is known about the role of plant extracts in autophagy inhibition, particularly autophagy-related (ATG) proteins. In this study, we employed S-tagged gamma-aminobutyric acid receptor associated protein like 2 (GABARAPL2) as a reporter to screen 48 plant extracts for their effects on the activity of autophagy protease ATG4B. Xanthium strumarium and Tribulus terrestris fruit extracts were validated as potential ATG4B inhibitors by another reporter substrate MAP1LC3B-PLA(2). The inhibitory effects of the extracts on cellular ATG4B and autophagic flux were further confirmed. Moreover, the plant extracts significantly reduced colorectal cancer cell viability and sensitized cancer cells to starvation conditions. The fruit extract of X. strumarium consistently diminished cancer cell migration and invasion. Taken together, the results showed that the fruit of X. strumarium may have an active ingredient to inhibit ATG4B and suppress the proliferation and metastatic characteristics of colorectal cancer cells.	[Chang, Hsueh-Wei] Kaohsiung Med Univ, Dept Biomed Sci & Environm Biol, Kaohsiung 80708, Taiwan; [Chang, Hsueh-Wei] Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung 80708, Taiwan; [Chang, Hsueh-Wei] Kaohsiung Med Univ, Drug Dev & Value Creat Res Ctr, Kaohsiung 80708, Taiwan; [Liu, Pei-Feng; Yang, Hsiu-Chen] Kaohsiung Vet Gen Hosp, Dept Med Educ & Res, Kaohsiung 81362, Taiwan; [Tsai, Wei-Lun] Kaohsiung Vet Gen Hosp, Div Gastroenterol, Dept Internal Med, Kaohsiung 813, Taiwan; [Hu, Wan-Hsiang] Kaohsiung Chang Gung Mem Hosp, Dept Colorectal Surg, Kaohsiung 83341, Taiwan; [Hu, Wan-Hsiang] Chang Gung Univ, Coll Med, Kaohsiung 83341, Taiwan; [Hu, Yu-Chang] Kaohsiung Vet Gen Hosp, Dept Radiat Oncol, Kaohsiung 81362, Taiwan; [Lin, Wei-Yu] Kinmen Hosp, Dept Pharm, Kinmen 89142, Taiwan; [Weng, Jing-Ru] Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 80424, Taiwan; [Shu, Chih-Wen] I Shou Univ, Sch Med Int Students, Kaohsiung 82445, Taiwan		Weng, JR (corresponding author), Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 80424, Taiwan.; Shu, CW (corresponding author), I Shou Univ, Sch Med Int Students, Kaohsiung 82445, Taiwan.	changhw@kmu.edu.tw; pfliu@vghks.gov.tw; tsaiwl@yahoo.com.tw; gary.hu0805@msa.hinet.net; ychu81@gmail.com; mini16610@gmail.com; u8557006@gmail.com; jrweng@mail.nsysu.edu.tw; cwshu@isu.edu.tw	Shu, Chih-Wen/AAE-9652-2019	Liu, Pei-Feng/0000-0002-7849-8940; Chang, Hsueh-Wei/0000-0003-0068-2366; Shu, Chih-Wen/0000-0002-7774-0002	Ministry of Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [106-2311-B-075B-001, 106-2320-B-110-003-MY3, 107-2311-B-214-003]; Kaohsiung Veterans General Hospital [VGHNSU108-006]; Kaohsiung Medical University Research Center [KMU-TC108A03]	Ministry of Science and Technology: 106-2311-B-075B-001, 106-2320-B-110-003-MY3, and 107-2311-B-214-003; Kaohsiung Veterans General Hospital: VGHNSU108-006; the Kaohsiung Medical University Research Center (KMU-TC108A03).	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J	Dey, DK; Chang, SN; Vadlamudi, Y; Park, JG; Kang, SC				Dey, Debasish Kumar; Chang, Sukkum Ngullie; Vadlamudi, Yellamandayya; Park, Jae Gyu; Kang, Sun Chul			Synergistic therapy with tangeretin and 5-fluorouracil accelerates the ROS/JNK mediated apoptotic pathway in human colorectal cancer cell	FOOD AND CHEMICAL TOXICOLOGY			English	Article						Oxidative stress; Mitochondria; DNA damage; Apoptosis; Colon cancer	WEISSELLA-CONFUSA DD-A7; HUMAN BREAST; IN-VITRO; COLON; PROLIFERATION; MECHANISMS; ARREST; DAMAGE; ACID	Synergistic therapy is emerging as a promising strategy for improving the chemotherapeutic efficacy of anticancer drugs. Addition of adjuvants with standard anticancer drugs has shown successful reduction of adverse side effects. The synthetic drug 5-Fluorouracil (5-FU) shows several side effects upon prolonged chemotherapy, thereby restricting its long-term clinical application. Several studies have reported anticancer potential and anti-inflammatory activity of tangeretin (TAN) towards mammalian cells. Therefore, we investigate whether the combination of TAN with 5-FU increases their anticancer potential against colorectal cancer. In this study, we examined the synergistic activity of TAN and 5-FU on the viability of several human cancer and normal cells. Several possible mechanistic pathways were screened, and found that co-exposure of TAN and 5-FU accelerates oxidative-stress and increases endogenous-ROS generation, which sequentially triggers the DNA damage response and activates the apoptotic pathway, by down-regulating autophagy and DNA repair system in HCT-116 cells. TAN and 5-FU co-treatment also remarkably reduces the mitochondrial membrane potential, and sequentially decreases ATPase activity. Collectively, results indicate that combination of TAN and 5-FU significantly accelerates apoptosis via JNK mediated pathway. To our knowledge gained from literature, this study is the first to describe synergistic activity of TAN and 5-FU against colorectal cancer cells.	[Dey, Debasish Kumar; Chang, Sukkum Ngullie; Vadlamudi, Yellamandayya; Kang, Sun Chul] Daegu Univ, Dept Biotechnol, Gyongsan 38453, South Korea; [Park, Jae Gyu] Pohang Technopk Fdn, Adv Bio Convergence Ctr, Pohang 37668, Gyeongbuk, South Korea		Kang, SC (corresponding author), Daegu Univ, Dept Biotechnol, Gyongsan 38453, South Korea.; Park, JG (corresponding author), Pohang Technopk Fdn, Adv Bio Convergence Ctr, Pohang 37668, Gyeongbuk, South Korea.	jaegpark@gmail.com; sckang@daegu.ac.kr	Dey, Debasish/AAP-6607-2020	Dey, Debasish/0000-0001-5429-0216; Chang, Sukkum Ngullie/0000-0001-8391-8041	National Research Foundation of KoreaNational Research Foundation of Korea [NRF2019R1A2B501070543, 2019H1D3A1A01103012]	This research was supported by the National Research Foundation of Korea grant, NRF2019R1A2B501070543 and 2019H1D3A1A01103012.	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Toxicol.	SEP	2020	143								111529	10.1016/j.fct.2020.111529			14	Food Science & Technology; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology; Toxicology	NE6SV	WOS:000562731900021	32619557				2022-04-25	
J	Luo, W; Liu, QA; Chen, XW; Liu, HJ; Quan, B; Lu, JL; Zhang, K; Wang, XL				Luo, Wen; Liu, Qingan; Chen, Xinwen; Liu, Haijun; Quan, Bin; Lu, Jinli; Zhang, Ke; Wang, Xiangling			FXYD6 Regulates Chemosensitivity by Mediating the Expression of Na plus /K plus -ATPase alpha 1 and Affecting Cell Autophagy and Apoptosis in Colorectal Cancer	BIOMED RESEARCH INTERNATIONAL			English	Article							III COLON-CANCER; NA+/K+-ATPASE; CARDIOTONIC STEROIDS; IRINOTECAN; SIGNATURE; IDENTIFICATION; ESTABLISHMENT; FLUOROURACIL; CHEMOTHERAPY; OXALIPLATIN	Purpose. Chemoresistance is a challenge of improving chemotherapeutic efficacy and prolonging survival time for patients with colorectal cancer (CRC); it is the major cause of frequent recurrence, rapid metastasis, and poor prognosis for CRC patients. FXYD6 is a regulator of Na+/K+-ATPase which is depressed in chemoresistant CRC patients. However, the biological roles of FXYD6 on regulating chemoresistance in CRC are still unclear. Methods. GSE3964 and GSE69657 from GEO DataSets were used to analyze the relationship of genes and chemoresistance. The FXYD6 expression level was detected by western blotting and real-time PCR and also analyzed from TCGA DataSet. To investigate the functional role of FXYD6 and ATP-alpha 1, FXYD6 and ATP-alpha 1 functional cell models were constructed. Drug sensitivity and cell proliferation were performed by MTT assay. Autophagy and apoptosis were conducted by autophagy fluorescence analysis and flow cytometric analysis, respectively. Autophagy and apoptosis markers were tested by western blotting. Results. FXYD6 was downregulated in CRC resistant patients and irinotecan- (Iri-) resistant SW620 cells (SW620/Iri). FXYD6 silence inhibited cell apoptosis and enhanced prosurvival autophagy, whereas FXYD6 overexpression produced the opposite effect which alleviated the drug resistance to irinotecan and oxaliplatin of CRC cells. FXYD6 regulates chemosensitivity by mediating the expression of Na+/K+-ATPase alpha 1 and affecting cell autophagy and apoptosis in colorectal cancer. Conclusion. FXYD6 functions as a chemosensitivity regulator which may predict the curative effect of chemotherapy in colorectal cancer.	[Luo, Wen; Liu, Qingan; Chen, Xinwen; Liu, Haijun; Quan, Bin; Lu, Jinli; Zhang, Ke; Wang, Xiangling] Changde First Peoples Hosp, Dept Gen Surg, Changde 415000, Hunan, Peoples R China		Liu, QA (corresponding author), Changde First Peoples Hosp, Dept Gen Surg, Changde 415000, Hunan, Peoples R China.	ji17483chundu@163.com; lqapwas98@163.com; chuang864676qic@163.com; huiyi352148ship@163.com; pu500351bozhang@163.com; ao5014703laotunfe@163.com; zhihuan0433811y@163.com; huan64376xiongha@163.com			Project of Changde Science and Technology Bureau of Hunan Province in China [2017S040]	This work was supported by the Project of Changde Science and Technology Bureau of Hunan Province in China (2017S040).	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Int.	JUN 9	2021	2021								9986376	10.1155/2021/9986376			15	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	SX0PE	WOS:000664913500005	34212047	gold, Green Published			2022-04-25	
J	Sharma, N; Kumar, A; Sharma, PR; Qayum, A; Singh, SK; Dutt, P; Paul, S; Gupta, V; Verma, MK; Satti, NK; Vishwakarma, R				Sharma, Neha; Kumar, Ashok; Sharma, P. R.; Qayum, Arem; Singh, Shashank K.; Dutt, Prabhu; Paul, Satya; Gupta, Vivek; Verma, M. K.; Satti, N. K.; Vishwakarma, R.			A new clerodane furano diterpene glycoside from Tinospora cordifolia triggers autophagy and apoptosis in HCT-116 colon cancer cells	JOURNAL OF ETHNOPHARMACOLOGY			English	Article						Tinospora cordifolia; DAPI (4 '-6-Diamidino-2-phenylindole); Apoptosis; HCT116; MMP potential; ROS	EXTRACT INDUCES APOPTOSIS; EX HOOK F; ANTIPROLIFERATIVE ACTIVITY; ANTITUMOR-ACTIVITY; MEDICINAL-PLANTS; MCF-7 CELLS; DEATH; BERBERINE; PATHWAY; LINES	Ethnophatmacological relevance: Tinospora cordifolia is a miraculous ayurvedic herb used in the treatment of innumerable diseases such as diabetes, gonorrhea, secondary syphilis, anaemia, rheumatoid arthritis, dermatological diseases, cancer, gout, jaundice, asthma, leprosy, in the treatment of bone fractures, liver & intestinal disorders, purifies the blood, gives new life to the whole body; (rejuvenating herb) and many more. Recent studies have revealed the anticancer potential of this plant but not much work has been done on the anticancer chemical constituents actually responsible for its amazing anticancer effects. This prompted us to investigate this plant further for new potent anticancer molecules. Aim of the study: The present study was designed to isolate and identify new promising anticancer candidates from the aqueous alcoholic extract of T. cordifolia using bioassay-guided fractionation. Materials and methods: The structures of the isolated compounds were determined on the basis of spectroscopic data interpretation and that of new potent anticancer molecule, TC-2 was confirmed by a single-crystal X-ray crystallographic analysis of its corresponding acetate. The in vitro anti-cancer activity of TC-2 was evaluated by SRB assay and the autophagic activity was investigated by immunofluorescence microscopy. Annexin-V FITC and PI dual staining was applied for the detection of apoptosis. The studies on Mitochondrial Membrane potential and ROS (Reactive oxygen species) production were also done. Results: Bioassay guided fractionation and purification of the aqueous alcoholic stem extract of Tinospora cordifolia led to the isolation of a new clerodane furano diterpene glycoside (TC-2) along with five known compounds i.e. cordifolioside A (beta-D-Glucopyranoside,4-(3-hydroxy-l-propeny1)- 2,6-dimethoxyphenyl 3-O-D-apio-beta-D-furanosyl) (TC-1), beta-Sitosterol(TC-3), 2 beta,3 beta:15,16-Diepoxy- 4 alpha, 6 beta-dihydroxy-13(16),14-clerodadiene-17,12:18,1-diolide (TC-4), ecdysterone(TC-5) and tinosporoside(TC-6). TC-2 emerged as a potential candidate for the treatment of colon cancer. Conclusion: The overall study on the bioassay guided isolation of T.cordifolia identified and isolated a new clerodane furano diterpenoid that exhibited anticancer activity via induction of mitochondria mediated apoptosis and autophagy in HCT116 cells. We have reported a promising future candidate for treating colon cancer.	[Sharma, Neha; Dutt, Prabhu; Satti, N. K.; Vishwakarma, R.] CSIR, Indian Inst Integrat Med, Nat Prod Chem Div, Jammu 180001, India; [Sharma, Neha; Verma, M. K.] CSIR, Indian Inst Integrat Med, Analyt Chem Div Instrumentat, Jammu 180001, India; [Kumar, Ashok; Sharma, P. R.; Qayum, Arem; Singh, Shashank K.] CSIR, Indian Inst Integrat Med, Canc Pharmacol Div, Jammu 180001, India; [Paul, Satya] Univ Jammu, Dept Chem, Jammu 180006, India; [Gupta, Vivek] Univ Jammu, Postgrad Dept Phys, Jammu 180006, India; [Kumar, Ashok; Sharma, P. R.; Qayum, Arem; Singh, Shashank K.] AcSIR Acad Sci & Innovat Res, Jammu Campus, Jammu, India		Satti, NK (corresponding author), CSIR, Indian Inst Integrat Med, Nat Prod Chem Div, Jammu 180001, India.	nksatti@rediffmail.com	Sharma, Neha/AAN-2750-2021; Jani, Arpit/B-5376-2017; Clark, James/C-2064-2012	Sharma, Neha/0000-0001-9771-3549; Clark, James/0000-0002-5860-2480; Paul, Satya/0000-0002-9859-3371; singh, shashank/0000-0001-8532-7421	Department of Science and Technology, New DelhiDepartment of Science & Technology (India) [GAP-1168]	This work was supported by the Department of Science and Technology (GAP-1168), New Delhi.	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JAN 30	2018	211						295	310		10.1016/j.jep.2017.09.034			16	Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine	FN9XJ	WOS:000416395900027	28962889				2022-04-25	
J	Oliveira, I; Nunes, A; Lima, A; Borralho, P; Rodrigues, C; Ferreira, RB; Ribeiro, AC				Oliveira, Isabel; Nunes, Antonio; Lima, Ana; Borralho, Pedro; Rodrigues, Cecilia; Ferreira, Ricardo Boavida; Ribeiro, Ana Cristina			New Lectins from Mediterranean Flora. Activity against HT29 Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						lectins; glycosylated receptors; HT29 colon cancer cells; antitumor activity	CONCANAVALIN-A; PLANT-PROTEINS; IN-VITRO; AUTOPHAGY; INDUCTION; APOPTOSIS; DEATH; MMP-9	Experiments conducted in vitro and in vivo, as well as some preclinical trials for cancer therapeutics, support the antineoplastic properties of lectins. A screening of antitumoral activity on HT29 colon cancer cells, based on polypeptide characterization and specific lectin binding to HT29 cells membrane receptors, was performed in order to assess the bioactivities present in four Mediterranean plant species: Juniperus oxycedrus subsp. oxycedrus, Juniperus oxycedrus subsp. badia, Arbutus unedo and Corema album. Total leaf proteins from each species were evaluated with respect to cell viability and inhibitory activities on HT29 cells (cell migration, matrix metalloproteinase -MMP proteolytic activities). A discussion is presented on a possible mechanism justifying the specific binding of lectins to HT29 cell receptors. All species revealed the presence of proteins with affinity to HT29 cell glycosylated receptors, possibly explaining the differential antitumor activity exhibited by the two most promising species, Juniperus oxycedrus subsp. badia and Arbutus unedo.	[Oliveira, Isabel; Nunes, Antonio; Ribeiro, Ana Cristina] Univ Lisbon, Fac Pharm, Dept Toxicol & Bromatol Sci DCTB, P-1649003 Lisbon, Portugal; [Oliveira, Isabel; Nunes, Antonio; Lima, Ana; Ferreira, Ricardo Boavida; Ribeiro, Ana Cristina] Univ Lisbon, Inst Super Agron, Linking Landscape Environm Agr & Food LEAF, P-1349017 Lisbon, Portugal; [Borralho, Pedro; Rodrigues, Cecilia] Univ Lisbon, Fac Pharm, Res Inst Med iMed ULisboa, P-1649003 Lisbon, Portugal		Ribeiro, AC (corresponding author), Univ Lisbon, Fac Pharm, Dept Toxicol & Bromatol Sci DCTB, P-1649003 Lisbon, Portugal.; Ribeiro, AC (corresponding author), Univ Lisbon, Inst Super Agron, Linking Landscape Environm Agr & Food LEAF, P-1349017 Lisbon, Portugal.	ioliveira2@campus.ul.pt; filipe_estesl@yahoo.com; agusmaolima@gmail.com; borralhopm@gmail.com; cmprodrigues@ff.ulisboa.pt; rbferreira@isa.ulisboa.pt; acribeiro@ff.ulisboa.pt	Ribeiro, Ana Cristina/AAA-6457-2020; Borralho, Pedro/AAJ-2829-2021; Rodrigues, Cecilia MP/M-3572-2013; Ribeiro, Ana Cristina/A-6769-2017; Borralho, Pedro/C-2727-2011	Rodrigues, Cecilia MP/0000-0002-4829-754X; Lima, Ana/0000-0001-8251-6286; Ribeiro, Ana Cristina/0000-0001-9555-5735; Borralho, Pedro/0000-0003-4488-7240; Ferreira, Ricardo Boavida/0000-0002-5027-7564	Fundacao para a Ciencia e a TecnologiaPortuguese Foundation for Science and TechnologyEuropean Commission [UID/AGR/4129]	Fundacao para a Ciencia e a Tecnologia, UID/AGR/4129.	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J. Mol. Sci.	JUN 2	2019	20	12							3059	10.3390/ijms20123059			21	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	IG4ED	WOS:000473756000209	31234551	Green Published, Green Submitted, gold			2022-04-25	
J	Bai, LY; Weng, JR; Chiu, CF; Wu, CY; Yeh, SP; Sargeant, AM; Lin, PH; Liao, YM				Bai, Li-Yuan; Weng, Jing-Ru; Chiu, Chang-Fang; Wu, Chia-Yung; Yeh, Su-Peng; Sargeant, Aaron M.; Lin, Po-Han; Liao, Yu-Min			OSU-A9, an indole-3-carbinol derivative, induces cytotoxicity in acute myeloid leukemia through reactive oxygen species-mediated apoptosis	BIOCHEMICAL PHARMACOLOGY			English	Article						OSU-A9; Indole-3-carbinol; Acute myeloid leukemia; Reactive oxygen species; Glutathione	PROSTATE-CANCER CELLS; DIETARY INDOLE-3-CARBINOL; MECHANISMS; AUTOPHAGY; PROTEIN; AGENT; DEATH	Indole-3-carbinol (I3C) is a broadly targeted phytochemical shown to prevent carcinogenesis in animal studies and to suppress the proliferation of cancer cells of human breast, colon, prostate, and endometrium. Here we demonstrate that OSU-A9, an I3C derivative with improved anticancer potency, induces cytotoxicity in acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells were less sensitive to OSU-A9 than leukemia cells. OSU-A9 induces caspase activation, PARP cleavage, and autophagy but not autophagic cell death. Interestingly, pretreatment of AML cell lines and primary AML cells with N-acetylcysteine or glutathione rescues them from apoptosis (and concomitant PARP cleavage) and Akt hypophosphorylation, implicating a key role of reactive oxygen species (ROS) in OSU-A9-related cytotoxicity. Importantly, the anticancer utility of OSU-A9 is extended in vivo as it, administered intraperitoneally, suppresses the growth of THP-1 xenograft tumors in athymic nude mice without obvious toxicity. This study shows that ROS-mediated apoptosis contributes to the anticancer activity of OSU-A9 in AML cell lines and primary AML cells, and thus should be considered in the future assessment of its translational value in AML therapy. (C) 2013 Elsevier Inc. All rights reserved.	[Bai, Li-Yuan; Chiu, Chang-Fang; Yeh, Su-Peng; Lin, Po-Han; Liao, Yu-Min] China Med Univ Hosp, Dept Internal Med, Div Hematol & Oncol, Taichung 40402, Taiwan; [Chiu, Chang-Fang] China Med Univ Hosp, Ctr Canc, Taichung 40402, Taiwan; [Bai, Li-Yuan; Chiu, Chang-Fang; Yeh, Su-Peng] China Med Univ, Sch Med, Coll Med, Taichung 40402, Taiwan; [Weng, Jing-Ru; Wu, Chia-Yung] China Med Univ, Dept Biol Sci & Technol, Taichung 40402, Taiwan; [Sargeant, Aaron M.] Charles River Labs, Preclin Serv, Spencerville, OH 45887 USA		Bai, LY (corresponding author), China Med Univ Hosp, Dept Med, Div Hematol & Oncol, 2 Yude Rd, Taichung 40402, Taiwan.	lybai6@gmail.com	Lin, Po-Han/AEU-8550-2022; Weng, Jing-Ru/L-1743-2013	Lin, Po-Han/0000-0001-6066-398X; 	Taiwan Department of Health, China Medical University Hospital Cancer Research of Excellence [DOH102-TD-C-111-005]; National Science CouncilMinistry of Science and Technology, Taiwan [NSC 101-2314-B-039-021-MY2, NSC 101-2320-B-039-029-MY2]; China Medical University Hospital [DMR-99-304, DMR-101-008]	We thank Dr. Chun-Ru Chien of China Medical University Hospital for the statistical assistance. This work was supported in part by grants from the Taiwan Department of Health, China Medical University Hospital Cancer Research of Excellence (DOH102-TD-C-111-005), National Science Council grants (NSC 101-2314-B-039-021-MY2, NSC 101-2320-B-039-029-MY2) and China Medical University Hospital (DMR-99-304, DMR-101-008).	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Pharmacol.	NOV 15	2013	86	10					1430	1440		10.1016/j.bcp.2013.09.002			11	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	245AZ	WOS:000326432600004	24041743				2022-04-25	
J	Tao, FF; Zhang, YR; Zhang, ZQ				Tao, Fangfang; Zhang, Yanrong; Zhang, Zhiqian			The Role of Herbal Bioactive Components in Mitochondria Function and Cancer Therapy	EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Review							GANODERMA-ATRUM POLYSACCHARIDE; THYMOQUINONE INDUCES APOPTOSIS; INDUCED OXIDATIVE STRESS; AUTOPHAGIC CELL-DEATH; INHIBITS TUMOR-GROWTH; MEDIATED APOPTOSIS; COLON-CANCER; IN-VITRO; ANTITUMOR-ACTIVITY; GINSENOSIDE RB1	Mitochondria are highly dynamic double-membrane organelles which play a well-recognized role in ATP production, calcium homeostasis, oxidation-reduction (redox) status, apoptotic cell death, and inflammation. Dysfunction of mitochondria has long been observed in a number of human diseases, including cancer. Targeting mitochondria metabolism in tumors as a cancer therapeutic strategy has attracted much attention for researchers in recent years due to the essential role of mitochondria in cancer cell growth, apoptosis, and progression. On the other hand, a series of studies have indicated that traditional medicinal herbs, including traditional Chinese medicines (TCM), exert their potential anticancer effects as an effective adjunct treatment for alleviating the systemic side effects of conventional cancer therapies, for reducing the risk of recurrence and cancer mortality and for improving the quality of patients' life. An amazing feature of these structurally diverse bioactive components is that majority of them target mitochondria to provoke cancer cell-specific death program. The aim of this review is to summarize the in vitro and in vivo studies about the role of these herbs, especially their bioactive compounds in the modulation of the disturbed mitochondrial function for cancer therapy.	[Tao, Fangfang] Zhejiang Chinese Med Univ, Basic Med Coll, Dept Immunol & Microbiol, Hangzhou 310053, Zhejiang, Peoples R China; [Zhang, Yanrong] Hebei Med Univ, Hosp 3, Dept Vasc Surg, Shijiazhuang, Hebei, Peoples R China; [Zhang, Zhiqian] Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Guangdong, Peoples R China		Zhang, YR (corresponding author), Hebei Med Univ, Hosp 3, Dept Vasc Surg, Shijiazhuang, Hebei, Peoples R China.; Zhang, ZQ (corresponding author), Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Guangdong, Peoples R China.	zhangyanrong@hebmu.edu.cn; zhangzq@sustech.edu.cn	Zhang, Zhiqian/P-7746-2018	Zhang, Zhiqian/0000-0003-1226-4807; tao, fang fang/0000-0002-2090-2701	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81302896]; Zhejiang TCM Science and Technology Program [2019ZQ013]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2015M581292]	This work was supported by National Natural Science Foundation of China (no. 81302896), Zhejiang TCM Science and Technology Program (no. 2019ZQ013), and China Postdoctoral Science Foundation grant (no. 2015M581292).	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Med.		2019	2019								3868354	10.1155/2019/3868354			12	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	IF3RQ	WOS:000473001000001	31308852	Green Published, Green Submitted, gold			2022-04-25	
J	Brachtendorf, S; Wanger, RA; Birod, K; Thomas, D; Trautmann, S; Wegner, MS; Fuhrmann, DC; Brune, B; Geisslinger, G; Grosch, S				Brachtendorf, Sebastian; Wanger, Ruth Anna; Birod, Kerstin; Thomas, Dominique; Trautmann, Sandra; Wegner, Marthe-Susanna; Fuhrmann, Dominik C.; Bruene, Bernhard; Geisslinger, Gerd; Groesch, Sabine			Chemosensitivity of human colon cancer cells is influenced by a p53-dependent enhancement of ceramide synthase 5 and induction of autophagy	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS			English	Article						Sphingolipid; Chemoresistance; shRNA; Oxaliplatin; 5-Fluorouracil	LONG-CHAIN CERAMIDES; UP-REGULATION; CARCINOMA CELLS; MESSENGER-RNA; HUMAN BREAST; DNA-DAMAGE; P53; APOPTOSIS; ACTIVATION; PROTEIN	Resistance against chemotherapy is a life-threatening complication in colon cancer therapy. To increase response rate, new additional targets that contribute to chemoresistance are still needed to be explored. Ceramides, which belong to the group of sphingolipids, are well-known regulators of cell death and survival, respectively. Here, we show that in human wild-type ((wt)) p53 HCT-116 colon cancer cells treatment with oxaliplatin or 5-fluorouracil (5-FU) leads to a strong increase in ceramide synthase 5 (CerS5) expression and C-16:0-ceramide levels, which was not shown in HCT-116 lacking p53 expression (HCT-116 p53(-/-)). The increase in CerS5 expression occurs by stabilizing CerS5 mRNA at the 3'-UTR. By contrast, in the p53-deficient cells CerS2 expression and CerS2-related C-24:0- and C-24:1-ceramide levels were elevated which is possibly related to enhanced polyadenylation of the CerS2 transcript in these cells. Stable knockdown of CerS5 expression using CerS5-targeting shRNA led to an increased sensitivity of HCT-116 p53(wt) cells, but not of p53(-/-) cells, to oxaliplatin and 5-FU. Enhanced sensitivity was accompanied by an inhibition of autophagy and inhibition of mitochondrial respiration in these cells. However, knockdown of CerS2 had no significant effects on chemosensitivity of both cell lines. In conclusion, in p53(wt) colon cancer cells chemosensitivity against oxaliplatin or 5-FU could be enhanced by downregulation of CerS5 expression leading to reduced autophagy and mitochondrial respiration.	[Brachtendorf, Sebastian; Wanger, Ruth Anna; Birod, Kerstin; Thomas, Dominique; Trautmann, Sandra; Wegner, Marthe-Susanna; Geisslinger, Gerd; Groesch, Sabine] Goethe Univ Frankfurt, Fac Med, Inst Clin Pharmacol, Frankfurt, Germany; [Geisslinger, Gerd] Fraunhofer Inst Mol Biol & Appl Ecol IME, Project Grp Translat Med & Pharmacol TMP, Frankfurt, Germany; [Fuhrmann, Dominik C.; Bruene, Bernhard] Goethe Univ Frankfurt, Inst Biochem 1, Fac Med, Frankfurt, Germany		Grosch, S (corresponding author), Goethe Univ, Inst Clin Pharmacol, Theodor Stern Kai 7, D-60590 Frankfurt, Germany.	groesch@em.uni-frankfurt.de	Fuhrmann, Dominik/AAG-2145-2022	Fuhrmann, Dominik/0000-0002-4902-9387	Deutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [SFB 1039/2]; DFGGerman Research Foundation (DFG)European Commission [GR2011/3-2, WE 5825/1-1]; August Scheidel- and Heinrich and Fritz Riese-Stiftung	This work was supported by the Deutsche Forschungsgemeinschaft (DFG) [SFB 1039/2]; DFG project [GR2011/3-2]; DFG project [WE 5825/1-1] and the August Scheidel- and Heinrich and Fritz Riese-Stiftung.	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Biophys. Acta Mol. Cell Biol. Lipids	OCT	2018	1863	10					1214	1227		10.1016/j.bbalip.2018.07.011			14	Biochemistry & Molecular Biology; Biophysics; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics; Cell Biology	GU5EY	WOS:000445310000006	30059758				2022-04-25	
J	Psahoulia, FH; Moumtzi, S; Roberts, ML; Sasazuki, T; Shirasawa, S; Pintzas, A				Psahoulia, Faiy H.; Moumtzi, Sophy; Roberts, Michael L.; Sasazuki, Takehiko; Shirasawa, Senji; Pintzas, Alexander			Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha-RAS-transformed human colon cells	CARCINOGENESIS			English	Article							HUMAN CANCER; K-RAS; N-RAS; GROWTH; ACTIVATION; PROTEIN; CARCINOMA; KINASE; LINES; MACROAUTOPHAGY	Several food polyphenols act as chemopreventers by reducing the incidence of many types of cancer, especially in colon epithelia. In this study, we have investigated whether the flavonoid quercetin can modulate cell proliferation and survival by targeting key molecules and/or biological processes responsible for tumor cell properties. The effect of quercetin on the expression of Ras oncoproteins was specifically studied using systems of either constitutive or conditional expression of oncogenic RAS in human epithelial cells. Our findings suggest that quercetin inhibits cell viability as well as cancer cell properties like anchorage-independent growth. These findings were further supported at the molecular level, since quercetin treatment resulted in a preferential reduction of Ras protein levels in cell lines expressing oncogenic Ras proteins. Notably, in cells that only express wild-type Ras or in those where the oncogenic Ras allele was knocked out, quercetin had no evident effects upon Ras levels. We have shown that quercetin drastically reduces half-life of oncogenic Ras but has no effect when the cells are treated with a proteasome inhibitor. Moreover, in Ha-RAS-transformed cells, quercetin induces autophagic processes. Since quercetin downregulates the levels of oncogenic Ras in cancer cells, we propose that this flavonoid could act as a chemopreventive agent for cancers with frequent mutations of RAS genes.	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J	Choi, EJ; Lee, JH; Kim, MS; Song, SY; Yoo, NJ; Lee, SH				Choi, Eun Ji; Lee, Ju Hwa; Kim, Min Sung; Song, Sang Yong; Yoo, Nam Jin; Lee, Sug Hyung			Intratumoral Heterogeneity of Somatic Mutations for NRIP1, DOK1, ULK1, ULK2, DLGAP3, PARD3 and PRKCI in Colon Cancers	PATHOLOGY & ONCOLOGY RESEARCH			English	Article						Tumor suppressor gene; Frameshift mutation; Colon cancer; Microsatellite instability	PROTEIN-KINASE-C; MICROSATELLITE INSTABILITY; FRAMESHIFT MUTATIONS; EXPRESSION; GENE; SYSTEM	Both NRIP1 and DOK1 genes are considered candidate tumor suppressor genes (TSGs). Also, cell polarity-related genes PARD3, PRKCI and DLGAP3, and autophagy-related genes ULK1 and ULK2 genes are considered to play crucial roles in tumorigenesis. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 harbored 18 (22.8%), 2 (2.5%), 2 (2.5%), 2 (2.5%), 5 (6.3%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. We also studied ITH for the frameshift mutations in 16 cases of CRCs and detected that the frameshift mutations of NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 showed regional ITH in 5 (31.3%), 2 (12.5%), 0 (0%), 0 (0%), 1 (6.3%), 1 (6.3%) and 3 (18.8%) cases, respectively. Our data exhibit that candidate cancer-related genes NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.	[Choi, Eun Ji; Lee, Ju Hwa; Kim, Min Sung; Yoo, Nam Jin; Lee, Sug Hyung] Catholic Univ Korea, Coll Med, Dept Pathol, 505 Banpo Dong, Seoul 137701, South Korea; [Song, Sang Yong] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol & Translat Genom, Seoul, South Korea		Lee, SH (corresponding author), Catholic Univ Korea, Coll Med, Dept Pathol, 505 Banpo Dong, Seoul 137701, South Korea.	suhulee@catholic.ac.kr			National Research Foundation of KoreaNational Research Foundation of Korea [2012R1A5A2047939, 2016R1D1A1B01007490]	This study was supported by grants from National Research Foundation of Korea (2012R1A5A2047939and 2016R1D1A1B01007490).	Berger AH, 2010, NAT GENET, V42, P216, DOI 10.1038/ng.527; Calin GA, 2000, INT J CANCER, V89, P230, DOI 10.1002/1097-0215(20000520)89:3<230::AID-IJC4>3.0.CO;2-J; Choi EJ, 2017, PATHOL ONCOL RES, V23, P145, DOI 10.1007/s12253-016-0112-3; Choi YJ, 2017, J PATHOL, V241, P57, DOI 10.1002/path.4819; Choi YJ, 2014, PATHOL ONCOL RES, V20, P965, DOI 10.1007/s12253-014-9781-y; Di Cristofano A, 1998, J BIOL CHEM, V273, P4827, DOI 10.1074/jbc.273.9.4827; Docquier A, 2010, CLIN CANCER RES, V16, P2959, DOI 10.1158/1078-0432.CCR-09-3153; Ebnet K, 2001, EMBO J, V20, P3738, DOI 10.1093/emboj/20.14.3738; Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013; Imai K, 2008, CARCINOGENESIS, V29, P673, DOI 10.1093/carcin/bgm228; Jiang XJ, 2015, J CLIN INVEST, V125, P47, DOI 10.1172/JCI73942; Jo YS, 2016, PATHOL ONCOL RES, V22, P769, DOI 10.1007/s12253-016-0070-9; Jung SH, 2016, P NATL ACAD SCI USA, V113, P10672, DOI 10.1073/pnas.1606946113; Lapierre M, 2014, J CLIN INVEST, V124, P1899, DOI 10.1172/JCI65178; Marusyk A, 2012, NAT REV CANCER, V12, P323, DOI 10.1038/nrc3261; MAZZARELLA R, 1995, GENOMICS, V26, P629, DOI 10.1016/0888-7543(95)80190-W; McGranahan N, 2015, CANCER CELL, V27, P15, DOI 10.1016/j.ccell.2014.12.001; Murphy KM, 2006, J MOL DIAGN, V8, P305, DOI 10.2353/jmoldx.2006.050092; Suzuki A, 2001, J CELL BIOL, V152, P1183, DOI 10.1083/jcb.152.6.1183; Welch JM, 2004, J COMP NEUROL, V472, P24, DOI 10.1002/cne.20060; Zen K, 2009, ONCOGENE, V28, P2910, DOI 10.1038/onc.2009.148	21	10	10	1	9	SPRINGER	DORDRECHT	VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS	1219-4956	1532-2807		PATHOL ONCOL RES	Pathol. Oncol. Res.	OCT	2018	24	4					827	832		10.1007/s12253-017-0297-0			6	Oncology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pathology	GS8QP	WOS:000443977800014	28844109				2022-04-25	
J	Pattingre, S; Bauvy, C; Codogno, P				Pattingre, S; Bauvy, C; Codogno, P			Amino acids interfere with the ERK1/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells	JOURNAL OF BIOLOGICAL CHEMISTRY			English	Article							CONTROLS AUTOPHAGIC SEQUESTRATION; ALPHA-INTERACTING PROTEIN; ISOLATED RAT HEPATOCYTES; EPIDERMAL GROWTH-FACTOR; OKADAIC ACID; KINASE ACTIVATION; PHOSPHATASE 2A; IN-VIVO; PHOSPHORYLATION; INHIBITION	Activation of ERK1/2 stimulates macroautophagy in the human colon cancer cell line HT-29 by favoring the phosphorylation of the Galpha-interacting protein (GAIP) in an amino acid-dependent manner (Ogier-Denis, E., Pattingre, S., El Benna, J., and Codogno, P. (2000) J. Biol. Chem. 275, 39090-39095). Here we show that ERK1/2 activation by aurintricarboxylic acid (ATA) treatment induces the phosphorylation of GAIP in an amino acid-dependent manner. Accordingly, ATA challenge increased the rate of macroautophagy, whereas epidermal growth factor did not significantly affect macroautophagy and GAIP phosphorylation status. In fact, ATA activated the ERK1/2 signaling pathway, whereas epidermal growth factor stimulated both the ERK1/2 pathway and the class I phosphoinositide 3-kinase pathway, known to decrease the rate of macroautophagy. Amino acids interfered with the ATA-induced macroautophagy by inhibiting the activation of the kinase Raf-1. The role of the Ras/Raf-1/ERK1/2 signaling pathway in the GAIP- and amino acid-dependent control of macroautophagy was confirmed in HT-29 cells expressing the Ras(G12V, T35S) mutant. Similar to the protein phosphatase 2A inhibitor okadaic acid, amino acids sustained the phosphorylation of Ser(259), which is involved in the negative regulation of Raf-1. In conclusion, these results add a novel target to the amino acid signaling-dependent control of macroautophagy in intestinal cells.	INSERM, U504, F-94807 Villejuif, France		Codogno, P (corresponding author), INSERM, U504, 16 Ave Paul Vaillant Couturier, F-94807 Villejuif, France.		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J	Chen, H; Tang, XC; Liu, T; Jing, L; Wu, JH				Chen, Hai; Tang, Xiaocheng; Liu, Ting; Jing, Liang; Wu, Junhui			Zingiberene inhibits in vitro and in vivo human colon cancer cell growth via autophagy induction, suppression of PI3K/AKT/mTOR Pathway and caspase 2 deactivation	JOURNAL OF BUON			English	Article						colon cancer; zingiberene; autophagy; caspases proliferation	NATURAL-PRODUCTS; DRUGS; SESQUITERPENE; AGENTS	Purpose: Colon cancer (CC) 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 form a serious obstacle in the treatment of CC. Herein, the anticancer potential of Zingiberene was examined against the CC cells. Methods: The proliferation rate of the CC cells was assessed by cell counting assay. Autophagy was detected by transmission electron microscopy (TEM). The transfected cells were then treated with varied concentrations of Zingiberene (0, 10, 20 and 40 mu M) for 24 h and monitored by fluorescent microscopy. Cell cycle analysis was performed by flow cytometry. Protein expression was determined by immunoblotting. Results: Zingiberene could considerably inhibit the proliferation of CC cells. The anticancer activity of Zingiberene against the HT-29 CC cells was found to be due to induction of autophagy. The Zingiberene triggered autophagy was also linked with increase in the expression of LC3-II and decrease in p62 expression. However, no apparent effects were observed on the LC3-I expression. Moreover, it was found that zingiberine also caused activation of autophagy-related caspases in the HT-29 cells. Further, it was found that Zingiberene could inhibit the mTOR/PI3K/AKT signalling pathway in the CC cells. Zingiberene also suppressed the weight and volume of the xenografted tumors concentration-dependently. Conclusions: These results indicate that Zingiberene may inhibit the growth of CC in vitro and in vivo and may be used for the development of systemic therapy against CC.	[Chen, Hai; Tang, Xiaocheng; Liu, Ting; Jing, Liang; Wu, Junhui] Cent S Univ, Xiangya Hosp 3, Dept Gastrointestinal Surg, Changsha 410000, Hunan, Peoples R China		Wu, JH (corresponding author), Cent S Univ, Xiangya Hosp 3, Dept Gastrointestinal Surg, Changsha 410000, Hunan, Peoples R China.	howyver@yahoo.com					Arnold M, 2017, GUT, V66, P683, DOI 10.1136/gutjnl-2015-310912; BALANDRIN MF, 1985, SCIENCE, V228, P1154, DOI 10.1126/science.3890182; BRUCE WR, 1966, JNCI-J NATL CANCER I, V37, P233; Butler MS, 2008, NAT PROD REP, V25, P475, DOI 10.1039/b514294f; Chan ML, 2015, N-S ARCH PHARMACOL, V388, P1223, DOI 10.1007/s00210-015-1152-z; Chen MH, 2019, CHEM-BIOL INTERACT, V299, P1, DOI 10.1016/j.cbi.2018.11.009; Cragg GM, 2000, EXPERT OPIN INV DRUG, V9, P2783, DOI 10.1517/13543784.9.12.2783; Cudjoe E.K., 2019, TARGETING CELL SURVI, P259; Ghantous A, 2010, DRUG DISCOV TODAY, V15, P668, DOI 10.1016/j.drudis.2010.06.002; Guinney J, 2015, NAT MED, V21, P1350, DOI 10.1038/nm.3967; Habib SHM, 2008, CLINICS, V63, P807, DOI 10.1590/S1807-59322008000600017; Millar JG, 1998, J NAT PROD, V61, P1025, DOI 10.1021/np9800699; Morgensztern D, 2005, ANTI-CANCER DRUG, V16, P797, DOI 10.1097/01.cad.0000173476.67239.3b; Newman DJ, 2007, J NAT PROD, V70, P461, DOI 10.1021/np068054v; O'Brien CA, 2007, NATURE, V445, P106, DOI 10.1038/nature05372; Kreuger MRO, 2012, ANTI-CANCER DRUG, V23, P883, DOI 10.1097/CAD.0b013e328356cad9; Ramakrishnan R., 2013, IJMPS, V3, P11; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Van Cutsem E, 2016, ANN ONCOL, V27, P1386, DOI 10.1093/annonc/mdw235; Wang B, 2018, BIOCHEM BIOPH RES CO, V499, P156, DOI 10.1016/j.bbrc.2018.03.091; Zhang Siyuan, 2005, Current Medicinal Chemistry - Anti-Cancer Agents, V5, P239, DOI 10.2174/1568011053765976	21	7	8	1	6	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	JUL-AUG	2019	24	4					1470	1475					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	IR7BT	WOS:000481595900020	31646793				2022-04-25	
J	Zheng, XJ; Xie, GX; Jia, W				Zheng, Xiaojiao; Xie, Guoxiang; Jia, Wei			Metabolomic profiling in colorectal cancer: opportunities for personalized medicine	PERSONALIZED MEDICINE			English	Review						biomarkers; colorectal cancer; drug discovery; early diagnosis; metabolomic profiling; personalized medicine; staging; treatment	CHAIN FATTY-ACIDS; MAS NMR-SPECTROSCOPY; COLON-CANCER; CELL-PROLIFERATION; PROSTATE-CANCER; GENE-EXPRESSION; SERUM; IDENTIFICATION; PROTEOMICS; AUTOPHAGY	Colorectal cancer (CRC) is one of the most common types of cancer in the world, with high prevalence and mortality. Understanding the alterations of cancer metabolism and identifying reliable biomarkers would facilitate the development of novel technologies of CRC screening and early diagnosis, as well as new approaches to providing personalized medicine. Metabolomics, as an emerging molecular phenotyping approach, provides a clinical platform technology with an unprecedented amount of metabolic readout information, which is ideal for theranostic biomarker discovery. Metabolic signatures can link the unique pathophysiological states of patients to personalized health monitoring and intervention strategies. This article presents an overview of the metabolomic studies of CRC with a focus on recent advances in the biomarker discovery in serum, urine, fecal water and tissue samples for cancer diagnosis. The development and application of metabolomics towards personalized medicine, including early diagnosis, cancer staging, treatment and drug discovery are also discussed.	[Zheng, Xiaojiao; Jia, Wei] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Ctr Translat Med, Shanghai 200233, Peoples R China; [Zheng, Xiaojiao; Jia, Wei] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Key Lab Diabet Mellitus, Dept Endocrinol & Metab, Shanghai 200233, Peoples R China; [Xie, Guoxiang; Jia, Wei] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA; [Jia, Wei] Shanghai Univ Tradit Chinese Med, E Inst Shanghai Municipal Educ Comm, Shanghai 201203, Peoples R China		Jia, W (corresponding author), Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Ctr Translat Med, Shanghai 200233, Peoples R China.	wjia@cc.hawaii.edu	Xie, Guoxiang/F-3022-2016; Jia, Wei/AAN-5102-2020	Xie, Guoxiang/0000-0002-0951-4150; Jia, Wei/0000-0002-3739-8994	Metabolic Disease Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital; E-institutes of Shanghai Municipal Education Commission [E03008]; Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [2011-50, 085ZY1205]; Shanghai Science and Technology funds [12DZ2295004]	The authors are thankful for the support of the Metabolic Disease Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital. This work was funded in part by E-institutes of Shanghai Municipal Education Commission (E03008), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (No. 2011-50), 085ZY1205 and Shanghai Science and Technology funds (12DZ2295004). 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	Sundaramoorthy, P; Baskaran, R; Mishra, SK; Jeong, KY; Oh, SH; Yoo, BK; Kim, HM				Sundaramoorthy, Pasupathi; Baskaran, Rengarajan; Mishra, Siddhartha Kumar; Jeong, Keun-Yeong; Oh, Seung Hyun; Yoo, Bong Kyu; Kim, Hwan Mook			Novel self-micellizing anticancer lipid nanoparticles induce cell death of colorectal cancer cells	COLLOIDS AND SURFACES B-BIOINTERFACES			English	Article						Nanoparticle; Self-micellizing anticancer lipid; Apoptosis; Autophagy; Colorectal cancer	LIPOSOMAL NANOPARTICLES; ANTITUMOR EFFICACY; DELIVERY; THERAPY; CHEMOTHERAPY; PLATFORM; SPHINGOLIPIDS; IRINOTECAN; RESISTANCE; APOPTOSIS	In the present study, we developed a novel drug-like self-micellizing anticancer lipid (SMAL), and investigated its anticancer activity and effects on cell death pathways in human colorectal cancer (CRC) cell lines.-Three self-assembled nanoparticles were prepared, namely, SMAL102 (lauramide derivative), SMAL104 (palmitamide derivative), and SMAL108 (stearamide derivative) by a thin-film hydration technique, and were characterized for physicochemical and biological parameters. SMAL102 were nanosized (160.23 +/- 8.11 nm) with uniform spherical shape, while SMAL104 and SMAL108 did not form spherical shape but formed large size nanoparticles and irregular in shape. Importantly, SMAL102 showed a cytotoxic effect towards CRC cell lines (HCT116 and HT-29), and less toxicity to a normal colon fibroblast cell line (CCD-18Co). Conversely, SMAL104 and SMAL108 did not have an anti-proliferative effect on CRC cell lines. SMAL102 nanoparticles were actively taken up by CRC cell lines, localized in the cell membrane, and exhibited remarkable cytotoxicity in a concentration-dependent manner. The normal colon cell line showed significantly less cellular uptake and non-cytotoxicity as compared with the CRC cell lines. SMAL102 nanoparticles induced caspase-3, caspase-9, and PARP cleavage in HT-29 cells, indicating the induction of apoptosis; whereas LOB was activated in HCT116 cells, indicating autophagy-induced cell death. Collectively, these results demonstrate that SMAL102 induced cell death via activation of apoptosis and autophagy in CRC cell lines. The present study could be a pioneer for further preclinical and clinical development of such compounds. (c) 2015 Elsevier B.V. All rights reserved.	[Sundaramoorthy, Pasupathi; Baskaran, Rengarajan; Mishra, Siddhartha Kumar; Jeong, Keun-Yeong; Oh, Seung Hyun; Yoo, Bong Kyu; Kim, Hwan Mook] Gachon Univ, Gachon Inst Pharmaceut Sci, Inchon 406840, South Korea; [Mishra, Siddhartha Kumar] Dr Harisingh Gour Cent Univ, Sch Biol Sci, Dept Zool, Sagar 470003, India		Kim, HM (corresponding author), Gachon Univ, Gachon Inst Pharmaceut Sci, Inchon 406840, South Korea.	hwanmook@gachon.ac.kr	Mishra, Siddhartha Kumar/A-4344-2016; Jeong, Keun-Yeong/B-8845-2015; Sundaramoorthy, Pasupathi/I-4307-2019; Oh, Seung/AAN-6744-2021	Mishra, Siddhartha Kumar/0000-0003-1627-1377; Jeong, Keun-Yeong/0000-0002-4933-3493; Sundaramoorthy, Pasupathi/0000-0003-1045-093X; 	Gachon Institute of Pharmaceutical Sciences Research Fund, Gachon University, Republic of Korea	This research was supported by the Gachon Institute of Pharmaceutical Sciences Research Fund 2014, Gachon University and the Republic of Korea. We thank Dr. Thiruganesh Ramasamy (Yeungnam University, South Korea) for his valuable help in proofreading the manuscript.	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J	Mainz, L; Rosenfeldt, MT				Mainz, Laura; Rosenfeldt, Mathias T.			Autophagy and cancer - insights from mouse models	FEBS JOURNAL			English	Review						autophagy; cancer; chloroquine; mouse models; treatment	DOUBLE-EDGED-SWORD; PANCREATIC-CANCER; AKT INHIBITION; COLON-CANCER; CELL-DEATH; PTEN LOSS; IN-VITRO; CHLOROQUINE; TUMORIGENESIS; MUTANTS	(Macro-)autophagy is an evolutionary conserved self-digestion program' that serves to maintain cellular metabolism and is implicated in many pathological processes such as cancer. In recent years, an increasing number of studies in murine cancer models have provided a plethora of sometimes conflicting results about the role of autophagy in cancer biology. This review summarizes these studies and raises awareness that there are situations in which autophagy blockage might indeed reduce tumor growth, but that sometimes the exact opposite is the case. It is therefore vital to mimic patient conditions in preclinical mouse experiments as thoroughly as possible before commencing clinical trials.	[Rosenfeldt, Mathias T.] Univ Wurzburg, Inst Pathol, Josef Schneider Str 2, D-97080 Wurzburg, Germany; Univ Wurzburg, Germany & Comprehens Canc Ctr Mainfranken, Wurzburg, Germany		Rosenfeldt, MT (corresponding author), Univ Wurzburg, Inst Pathol, Josef Schneider Str 2, D-97080 Wurzburg, Germany.	mathias.rosenfeldt@uni-wuerzburg.de	Rosenfeldt, Mathias/ABE-4736-2022	Rosenfeldt, Mathias/0000-0001-7650-8458	German Research FoundationGerman Research Foundation (DFG) [FOR2314]	This work was supported by a grant of the German Research Foundation to MTR as part of FOR2314.	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MAR	2018	285	5					792	808		10.1111/febs.14274			17	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	FY8VL	WOS:000427143000001	28921866	Bronze			2022-04-25	
J	Gong, YZ; Ma, H; Ruan, GT; Zhu, LC; Liao, XW; Wang, S; Yan, L; Huang, W; Huang, KT; Xie, HL; Zhu, GZ; Wang, XK; Liao, C; Gao, F				Gong, Yi-Zhen; Ma, Hui; Ruan, Guo-Tian; Zhu, Li-Chen; Liao, Xi-Wen; Wang, Shuai; Yan, Ling; Huang, Wei; Huang, Ke-Tuan; Xie, Hailun; Zhu, Guang-Zhi; Wang, Xiang-Kun; Liao, Cun; Gao, Feng			Diagnosis and prognostic value of C-X-C motif chemokine ligand 1 in colon adenocarcinoma based on The Cancer Genome Atlas and Guangxi cohort	JOURNAL OF CANCER			English	Article						CXCL1; COAD; Diagnosis; Prognosis; Biomarker; GSEA	FALSE DISCOVERY RATE; COLORECTAL-CANCER; GRO-ALPHA; STAGE-II; EXPRESSION; CXCL1; ANGIOGENESIS; BIOMARKER; BETA; SET	Objective: The objective was to identify and validate C-X-C motif chemokine ligand 1(CXCL1) for diagnosis and prognosis in colon adenocarcinoma (COAD). Methods: Our current study had enrolled one The Cancer Genome Atlas (TCGA) cohort and two Guangxi cohorts to identify and verify the diagnostic and prognostic values of CXCL1 in COAD. Functional enrichment was performed by gene set enrichment analysis (GSEA). Results: In TCGA cohort, the expression of CXCL1 was significantly up-regulated in tumor tissues and decreased as the tumor stage developed. The receiver operating characteristic (ROC) curve showed that CXCL1 had a high diagnostic value for COAD. The result of Kaplan-Meier survival analysis showed that CXCL1 gene expression (P=0.045) was significantly correlated with overall survival (OS) of COAD. Results of Guangxi cohort also verified the diagnostic value of CXCL1 in COAD, and sub-group survival analyses also suggested that patients with high CXCL1 expression were related to a favorable OS (Corrected P=0.005). GSEA revealed that CXCL1 high expression phenotype was related to cytokine activity, cell apoptosis, P53 regulation pathway, and regulation of autophagy in COAD. Conclusions: In this study, we found that CXCL1 gene might be a potential diagnostic biomarker for COAD, and might serve as a prognostic biomarker for specific subgroup of COAD.	[Gong, Yi-Zhen; Ma, Hui; Ruan, Guo-Tian; Wang, Shuai; Yan, Ling; Huang, Wei; Xie, Hailun; Liao, Cun; Gao, Feng] Guangxi Med Univ, Dept Colorectal & Anal Surg, Affiliated Hosp 1, 6 ShuangYong Rd, Nanning 530021, Guangxi Zhuang, Peoples R China; [Zhu, Li-Chen] Guangxi Med Univ, Sch Preclin Med, Dept Immunol, Nanning, Guangxi Zhuang, Peoples R China; [Liao, Xi-Wen; Huang, Ke-Tuan; Zhu, Guang-Zhi; Wang, Xiang-Kun] Guangxi Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Nanning, Guangxi Zhuang, Peoples R China		Gao, F (corresponding author), Guangxi Med Univ, Dept Colorectal & Anal Surg, Affiliated Hosp 1, 6 ShuangYong Rd, Nanning 530021, Guangxi Zhuang, Peoples R China.	gaofeng@gxmu.edu.cn			Innovation Project of Guangxi Graduate Education [YCBZ2020048]; Basic Ability Improvement Project for Middle-aged and Young Teachers in Colleges and Universities in Guangxi [2020KY12026]	The present study was supported by the Innovation Project of Guangxi Graduate Education (YCBZ2018036), The Basic Ability Improvement Project for Middle-aged and Young Teachers in Colleges and Universities in Guangxi (2020KY12026) and Innovation Project of Guangxi Graduate Education (YCBZ2020048).	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Cancer		2021	12	18					5506	5518		10.7150/jca.51524			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	XA7YV	WOS:000720858900003	34405013	gold, Green Published			2022-04-25	
J	Lee, SJ; Lee, HJ; Jung, YH; Kim, JS; Choi, SH; Han, HJ				Lee, Sei-Jung; Lee, Hyun Jik; Jung, Young Hyun; Kim, Jun Sung; Choi, Sang Ho; Han, Ho Jae			Melatonin inhibits apoptotic cell death induced by Vibrio vulnificus VvhA via melatonin receptor 2 coupling with NCF-1	CELL DEATH & DISEASE			English	Article							COLON-CANCER CELLS; JNK1-MEDIATED PHOSPHORYLATION; EXTRACELLULAR CYTOLYSIN; SIGNALING PATHWAY; EPITHELIAL-CELLS; JNK ACTIVATION; NADPH OXIDASES; PROTEIN-KINASE; NOX FAMILY; AUTOPHAGY	Melatonin, an endogenous hormone molecule, has a variety of biological functions, but a functional role of melatonin in the infection of Gram-negative bacterium Vibrio vulnificus has yet to be described. In this study, we investigated the molecular mechanism of melatonin in the apoptosis of human intestinal epithelial (HCT116) cells induced by the hemolysin (VvhA) produced by V. vulnificus. Melatonin (1 mu M) significantly inhibited apoptosis induced by the recombinant protein (r) VvhA, which had been inhibited by the knockdown of MT2. The rVvhA recruited caveolin-1, NCF-1, and Rac1 into lipid rafts to facilitate the production of ROS responsible for the phosphorylation of PKC and JNK. Interestingly, melatonin recruited NCF-1 into non-lipid rafts to prevent ROS production via MT2 coupling with Gaq. Melatonin inhibited the JNK-mediated phosphorylation of c-Jun responsible for Bax expression, the release of mitochondrial cytochrome c, and caspase-3/-9 activation during its promotion of rVvhA-induced apoptotic cell death. In addition, melatonin inhibited JNK-mediated phosphorylation of Bcl-2 responsible for the release of Beclin-1 and Atg5 expression during its promotion of rVvhA-induced autophagic cell death. These results demonstrate that melatonin signaling via MT2 triggers recruitment of NCF-1 into non-lipid rafts to block ROS production and JNK-mediated apoptotic and autophagic cell deaths induced by rVvhA in intestinal epithelial cells.	[Lee, Sei-Jung] Daegu Haany Univ, Dept Pharmaceut Engn, Gyongsan 38610, South Korea; [Lee, Hyun Jik; Jung, Young Hyun; Kim, Jun Sung; Han, Ho Jae] Seoul Natl Univ, Dept Vet Physiol, Coll Vet Med, Res Inst Vet Sci, Seoul 08826, South Korea; [Lee, Hyun Jik; Jung, Young Hyun; Kim, Jun Sung; Han, Ho Jae] Seoul Natl Univ, PLUS Program Creat Vet Sci Res BK21, Seoul 08826, South Korea; [Choi, Sang Ho] Seoul Natl Univ, Natl Res Lab Mol Microbiol & Toxicol, Dept Agr Biotechnol, Seoul 08826, South Korea; [Choi, Sang Ho] Seoul Natl Univ, Ctr Food Safety & Toxicol, Seoul 08826, South Korea		Han, HJ (corresponding author), Seoul Natl Univ, Dept Vet Physiol, Coll Vet Med, Res Inst Vet Sci, Seoul 08826, South Korea.; Han, HJ (corresponding author), Seoul Natl Univ, PLUS Program Creat Vet Sci Res BK21, Seoul 08826, South Korea.	hjhan@snu.ac.kr	Lee, Sei-Jung/V-8772-2019	Choi, Sang Ho/0000-0003-3865-1039	National R&D Program through the National Research Foundation of Korea (NRF) - Ministry of Science and ICT [NRF-2017M3A9F3047062]; Basic Science Research Program through the NRF - Ministry of Education [NRF-2016R1D1A1B03930458]; Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through Agriculture, Food and Rural Affairs Research Center Support Program - Ministry of Agriculture, Food and Rural Affairs (MAFRA), Republic of Korea [710012-03-1-SB110]	This research was supported by National R&D Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017M3A9F3047062) and Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2016R1D1A1B03930458); and Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through Agriculture, Food and Rural Affairs Research Center Support Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA)(710012-03-1-SB110), Republic of Korea.	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JAN 19	2018	9								48	10.1038/s41419-017-0083-7			14	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	FZ1PO	WOS:000427349600007	29352110	Green Published, gold			2022-04-25	
J	Fu, Q; Cheng, J; Zhang, JD; Zhang, YL; Chen, XB; Xie, JG; Luo, SX				Fu, Qiang; Cheng, Jing; Zhang, Jindai; Zhang, Yonglei; Chen, Xiaobing; Xie, Jianguo; Luo, Suxia			Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy	ONCOLOGY REPORTS			English	Article						miR-218; YEATS4; colorectal cancer; chemosensitivity; autophagy; cell apoptosis	TUMOR-SUPPRESSIVE MICRORNA-218; DRUG-RESISTANCE; HMGB1-MEDIATED AUTOPHAGY; MULTIDRUG-RESISTANCE; LUNG-CANCER; EXPRESSION; CARCINOMA; PATHWAY; OXALIPLATIN; SURVIVIN	Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Deregulation of microRNAs (miRNAs) has been reported to participate in CRC progression. In the present study, we observed downregulation of miR-218 and upregulation of YEATS domain containing 4 (YEATS4) in CRC tissues and in multidrug-resistant HCT-116/L-OHP cells compared with these levels in normal tissues and parental HCT-116 cells, respectively. The results indicated that miR-218 overexpression significantly decreased the IC50 value of oxaliplatin (L-OHP) in the HCT-116/L-OHP cells, and suppression of miR-218 significantly enhanced the IC50 of L-OHP in the HCT-116 cells. Flow cytometric analysis showed that miR-218 overexpression alone promoted cell apoptosis in the HCT-116/L-OHP cells, which was further enhanced in response to L-OHP, and miR-218 inhibition decreased cell apoptosis in the HCT-116 cells following treatment with L-OHP. Western blot analysis indicated that, compared with the small increase observed in HCT-116 cells, the relative LC3 II level in HCT-116/L-OHP cells after lysosome inhibition via chloroquine (CQ) was markedly upregulated following L-OHP treatment, suggesting induction of autophagy. Exposure of HCT-116/L-OHP cells to L-OHP after control mimic transfection increased autophagic flux, as reflected by increased LC3 II levels, while miR-218 overexpression partly reversed L-OHP-mediated LC3 II accumulation. Additionally, both miR-218 overexpression and CQ treatment promoted L-OHP-induced HCT-116/L-OHP cell apoptosis. Molecularly, our results confirmed that miR-218 directly targets the YEATS4 gene and inhibits YEATS4 expression. Furthermore, YEATS4 overexpression without the 3'-untranslated region (3'-UTR) restored miR-218-inhibited YEATS4 and LC3 II expression, and abolished miR-218-stimulated cell viability loss and cell apoptosis increase in response to L-OHP. In conclusion, miR-218 sensitized HCT-116/L-OHP cells to L-OHP-induced cell apoptosis via inhibition of cytoprotective autophagy by targeting YEATS4 expression.	[Fu, Qiang; Zhang, Jindai; Zhang, Yonglei; Xie, Jianguo] Zhengzhou Univ, Affiliated Tumor Hosp, Tumor Hosp Henan Prov, Dept Gastrointestinal Surg, 127 Dongming Rd, Zhengzhou 450008, Henan, Peoples R China; [Chen, Xiaobing; Luo, Suxia] Zhengzhou Univ, Affiliated Tumor Hosp, Tumor Hosp Henan Prov, Dept Digest Oncol, Zhengzhou 450008, Henan, Peoples R China; [Cheng, Jing] Zhengzhou Univ, Affiliated Cent Hosp, Zhengzhou Cent Hosp, Dept Med Oncol, Zhengzhou 450007, Henan, Peoples R China		Xie, JG (corresponding author), Zhengzhou Univ, Affiliated Tumor Hosp, Tumor Hosp Henan Prov, Dept Gastrointestinal Surg, 127 Dongming Rd, Zhengzhou 450008, Henan, Peoples R China.	jianguo_xie@126.com					Alajez NM, 2011, CANCER RES, V71, P2381, DOI 10.1158/0008-5472.CAN-10-2754; Barretina J, 2010, NAT GENET, V42, P715, DOI 10.1038/ng.619; Carro MS, 2010, NATURE, V463, P318, DOI 10.1038/nature08712; Faltejskova P, 2012, INT J COLORECTAL DIS, V27, P1401, DOI 10.1007/s00384-012-1461-3; Fang LK, 2014, ONCOTARGET, V5, P2974, DOI 10.18632/oncotarget.1614; Fischer U, 1997, HUM MOL GENET, V6, P1817, DOI 10.1093/hmg/6.11.1817; Fischer U, 1996, HUM GENET, V98, P625, DOI 10.1007/s004390050271; Gao XC, 2014, CANCER LETT, V353, P25, DOI 10.1016/j.canlet.2014.07.011; He XQ, 2012, MOL MED, V18, P1491, DOI 10.2119/molmed.2012.00304; Hu YH, 2015, BREAST CANCER RES TR, V151, P269, DOI 10.1007/s10549-015-3372-9; Kim YR, 2015, ONCOTARGET, V6, P31030, DOI 10.18632/oncotarget.5208; Li PL, 2015, CARCINOGENESIS, V36, P1484, DOI 10.1093/carcin/bgv145; Liu WJ, 2015, CANCER BIOL THER, V16, P511, DOI 10.1080/15384047.2015.1017691; Longley DB, 2005, J PATHOL, V205, P275, DOI 10.1002/path.1706; Mikhaylova O, 2012, CANCER CELL, V21, P532, DOI 10.1016/j.ccr.2012.02.019; Mizushima N, 2010, CELL, V140, P313, DOI 10.1016/j.cell.2010.01.028; Park JH, 2006, MOL CELL BIOL, V26, P4006, DOI 10.1128/MCB.02185-05; Pikor LA, 2013, CANCER RES, V73, P7301, DOI 10.1158/0008-5472.CAN-13-1897; Ran XM, 2015, INT J CLIN EXP PATHO, V8, P6617; Sakitani K, 2015, BMC CANCER, V15, DOI 10.1186/s12885-015-1789-5; Shi Y, 2015, J CELL MOL MED, V19, P535, DOI 10.1111/jcmm.12435; Stanton MJ, 2013, CANCER RES, V73, P160, DOI 10.1158/0008-5472.CAN-11-3635; Stiegelbauer V, 2014, WORLD J GASTROENTERO, V20, P11727, DOI 10.3748/wjg.v20.i33.11727; Sui X, 2013, CELL DEATH DIS, V4, DOI 10.1038/cddis.2013.350; Taniguchi K, 2015, CANCER LETT, V363, P17, DOI 10.1016/j.canlet.2015.03.026; Tao K, 2015, AM J TRANSL RES, V7, P616; Wang KY, 2014, IUBMB LIFE, V66, P645, DOI 10.1002/iub.1317; Wei MF, 2014, AUTOPHAGY, V10, P1179, DOI 10.4161/auto.28679; Xie LL, 2015, BLOOD REV, V29, P33, DOI 10.1016/j.blre.2014.09.005; Xu K, 2012, EXP CELL RES, V318, P2168, DOI 10.1016/j.yexcr.2012.04.014; Yamamoto N, 2013, INT J ONCOL, V42, P1523, DOI 10.3892/ijo.2013.1851; Yang HZ, 2015, CANCER LETT, V361, P128, DOI 10.1016/j.canlet.2015.02.045; Yang ZNJ, 2011, MOL CANCER THER, V10, P1533, DOI 10.1158/1535-7163.MCT-11-0047; Yu H, 2013, INT J CLIN EXP PATHO, V6, P2904; Zarogoulidis P, 2015, CELL SIGNAL, V27, P1576, DOI 10.1016/j.cellsig.2015.04.009; Zhang XL, 2015, INT J CLIN EXP PATHO, V8, P6397; Zhong XH, 2015, BIOCHEM BIOPH RES CO, V466, P206, DOI 10.1016/j.bbrc.2015.09.008	37	21	22	0	13	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	DEC	2016	36	6					3682	3690		10.3892/or.2016.5195			9	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	ED2DG	WOS:000388653200072	27779719	Bronze			2022-04-25	
J	Muzes, G; Kiss, AL; Tulassay, Z; Sipos, F				Muzes, Gyorgyi; Kiss, Anna L.; Tulassay, Zsolt; Sipos, Ferenc			Cell-free DNA-induced alteration of autophagy response and TLR9-signaling: Their relation to amelioration of DSS-colitis	COMPARATIVE IMMUNOLOGY MICROBIOLOGY AND INFECTIOUS DISEASES			English	Article						Cell-free DNA; DSS-colitis; TLR9; Beclin1; ATG16L1; LC3B; Autophagy; Inflammation; Spleen index	TOLL-LIKE RECEPTORS; DOUBLE-EDGED SWORDS; NUCLEIC-ACIDS; ULCERATIVE-COLITIS; IMMUNE ACTIVATION; OXIDATIVE STRESS; DENDRITIC CELLS; INNATE; CANCER; MECHANISMS	Background: The influence of cell-free DNA (fDNA) administration on the TLR9-autophagy regulatory crosstalk within inflammatory circumstances remains unclear. Aims: To examine the immunobiologic effects of iv. fDNA injection on the TLR9-mediated autophagy response in murine DSS-colitis. Methods: Different types of modified fDNAs were administered to DSS-colitic mice. Disease and histological activities, spleen index were measured. Changes of the TLR9-associated and autophagy-related gene expression profiles of lamina proprial cells and splenocytes were assayed by quantitative real-time PCR, and validated by immunohistochemistries. Ultrastructural changes of the colon were examined by transmission electron microscopy (TEM). Results: A single intravenous injection of colitic fDNA (C-DNA) exhibited beneficial clinical and histological effects on DSS-colitis, compared to normal (N-DNA). C-DNA administration displayed a more prominent impact on the outcome of the TLR9-autophagy response than N-DNA. C-DNA resulted in a decreased spleen index in DSS-colitic mice. C-DNA treatment of normal mice resulted in a downregulation of Beclin1 and ATG16L1 mRNA and protein expression in the colon. These as well as LC3B were downregulated in the spleen. In contrast, the Beclin1, ATG16L1 and LC3B gene and protein expressions were upregulated in both the colon and the spleen by C-DNA injection. Moreover, C-DNA administration to DSS-colitic mice resulted in a remarkable increase of epithelial autophagic vacuoles representing an intensified macroautophagy. Conclusions: The effect of intravenously administered fDNA on the TLR9-mediated autophagy response is expressly dependent on the origin of fDNA (i.e. inflammatory or not) and on the characteristics of the local immunobiologic milieu (i.e. inflammatory or not, as well).	[Muzes, Gyorgyi; Tulassay, Zsolt; Sipos, Ferenc] Semmelweis Univ, Dept Internal Med 2, H-1088 Budapest, Hungary; [Tulassay, Zsolt] Hungarian Acad Sci, Mol Med Res Unit, H-1051 Budapest, Hungary; Semmelweis Univ, Dept Human Morphol & Dev Biol, H-1094 Budapest, Hungary		Muzes, G (corresponding author), Semmelweis Univ, Dept Internal Med 2, Immunol & Internal Med, Szentkiralyi St 46, H-1088 Budapest, Hungary.	muzes.gyorgyi@med.semmelweis-univ.hu		Sipos, Ferenc/0000-0002-2767-7746	Hungarian Scientific Research FundOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA-K111743]	This study was funded by the Hungarian Scientific Research Fund (OTKA-K111743 grant) to ZT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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Immunol. Microbiol. Infect. Dis.	JUN	2017	52						48	57		10.1016/j.cimid.2017.06.005			10	Immunology; Microbiology; Veterinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Microbiology; Veterinary Sciences	FA2MJ	WOS:000405275200009	28673462				2022-04-25	
J	Zhao, MN; Liu, Q; Gong, YC; Xu, XH; Zhang, C; Liu, XJ; Zhang, CB; Guo, HY; Zhang, XY; Gong, YQ; Shao, CS				Zhao, Minnan; Liu, Qiao; Gong, Yanchao; Xu, Xiuhua; Zhang, Chen; Liu, Xiaojie; Zhang, Caibo; Guo, Haiyang; Zhang, Xiyu; Gong, Yaoqin; Shao, Changshun			GSH-dependent antioxidant defense contributes to the acclimation of colon cancer cells to acidic microenvironment	CELL CYCLE			English	Article						acidic microenvironment; antioxidant defense; CD44; colorectal cancer; GSH; GSR	HUMAN-MELANOMA CELLS; CELLULAR ADAPTATION; OXIDATIVE STRESS; MAMMALIAN-CELLS; HUMAN-TUMORS; PH; PROGRESSION; PROMOTES; SENESCENCE; AUTOPHAGY	Due to increased glycolysis and poor local perfusion, solid tumors are usually immersed in an acidic microenvironment. While extracellular acidosis is cytotoxic, cancer cells eventually become acclimated to it. While previous studies have addressed the acute effect of acidosis on cancer cells, little is known about how cancer cells survive chronic acidosis. In this study we exposed colorectal cancer (CRC) cells (HCT15, HCT116 and LoVo) to acidic pH (pH 6.5) continuously for over three months and obtained CRC cells that become acclimated to acidic pH, designated as CRC-acidosis-acclimated or CRC-AA. We unexpectedly found that while acute exposure to low pH resulted in an increase in the level of intracellular reactive oxygen species (ROS), CRC-AA cells exhibited a significantly reduced level of ROS when compared to ancestor cells. CRC-AA cells were found to maintain a higher level of reduced glutathione, via the upregulation of CD44 and glutathione reductase (GSR), among others, than their ancestor cells. Importantly, CRC-AA cells were more sensitive to agents that deplete GSH. Moreover, downregulation of GSR by RNA interference was more deleterious to CRC-AA cells than to control cells. Together, our results demonstrate a critical role of glutathione-dependent antioxidant defense in acclimation of CRC cells to acidic extracellular pH.	[Zhao, Minnan; Liu, Qiao; Gong, Yanchao; Xu, Xiuhua; Zhang, Chen; Liu, Xiaojie; Zhang, Caibo; Guo, Haiyang; Zhang, Xiyu; Gong, Yaoqin; Shao, Changshun] Shandong Univ, Sch Med, Key Lab Expt Teratol, Minist Educ, 44 W Wenhua Rd, Jinan 250012, Shandong, Peoples R China; [Zhao, Minnan; Liu, Qiao; Gong, Yanchao; Xu, Xiuhua; Zhang, Chen; Liu, Xiaojie; Zhang, Caibo; Guo, Haiyang; Zhang, Xiyu; Gong, Yaoqin; Shao, Changshun] Shandong Univ, Sch Med, Dept Mol Med & Genet, 44 W Wenhua Rd, Jinan 250012, Shandong, Peoples R China; [Shao, Changshun] Rutgers State Univ, Human Genet Inst New Jersey, Dept Genet, Piscataway, NJ USA		Shao, CS (corresponding author), Shandong Univ, Sch Med, Dept Mol Med & Genet, 44 W Wenhua Rd, Jinan 250012, Shandong, Peoples R China.	changshun.shao@gmail.com	Shao, Changshun/AAD-8977-2022	Shao, Changshun/0000-0003-2618-9342; guo, haiyang/0000-0001-5503-6922	National Basic Research Program of China (973 Program)National Basic Research Program of China [2011CB966200]; National Natural Science Foundation Research Grants [81372241, 81572785, 81330050]; State Program of National Natural Science Foundation of China for Innovative Research GroupNational Natural Science Foundation of China (NSFC) [81321061]	This study was supported by National Basic Research Program of China (973 Program) grant (2011CB966200), National Natural Science Foundation Research Grants (81372241,81572785 and 81330050), and State Program of National Natural Science Foundation of China for Innovative Research Group (81321061).	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J	Chen, L; Meng, Y; Sun, Q; Zhang, ZY; Guo, XQ; Sheng, XT; Tai, GH; Cheng, HR; Zhou, YF				Chen, Lei; Meng, Yue; Sun, Qi; Zhang, Zhongyu; Guo, Xiaoqing; Sheng, Xiaotong; Tai, Guihua; Cheng, Hairong; Zhou, Yifa			Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation	CELL DEATH & DISEASE			English	Article							DEATH RECEPTOR 5; NF-KAPPA-B; CCAAT/ENHANCER-BINDING-PROTEIN; LIGAND TRAIL; HOMOLOGOUS PROTEIN; MEDIATED APOPTOSIS; DOWN-REGULATION; MELANOMA-CELLS; IN-VIVO; METABOLITE	Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. However, acquired resistance of cancer cells to TRAIL is a roadblock. Agents that can either potentiate the effect of TRAIL or overcome resistance to TRAIL are urgently needed. This article reports that ginsenoside compound K (CK) potentiates TRAIL-induced apoptosis in HCT116 colon cancer cells and sensitizes TRAIL-resistant colon cancer HT-29 cells to TRAIL. On a cellular mechanistic level, CK downregulated cell survival proteins including Mcl-1, Bcl-2, surviving, X-linked inhibitor of apoptosis protein and Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein, upregulated cell pro-apoptotic proteins including Bax, tBid and cytochrome c, and induced the cell surface expression of TRAIL death receptor DR5. Reduction of DR5 levels by siRNAs significantly decreases CK-and TRAIL-mediated apoptosis. Importantly, our results indicate, for the first time, that DR5 upregulation is mediated by autophagy, as blockade of CK-induced autophagy by 3-MA, LY294002 or Atg7 siRNAs substantially decreases DR5 upregulation and reduces the synergistic effect. Furthermore, CK-stimulated autophagy is mediated by the reactive oxygen species-c-Jun NH2-terminal kinase pathway. Moreover, we found that p53 and the C/EBP homologous (CHOP) protein is also required for DR5 upregulation but not related with autophagy. Our findings contribute significantly to the understanding of the mechanism accounted for the synergistic anticancer activity of CK and TRAIL, and showed a novel mechanism related with DR5 upregulation.	[Chen, Lei; Meng, Yue; Sun, Qi; Zhang, Zhongyu; Guo, Xiaoqing; Sheng, Xiaotong; Tai, Guihua; Cheng, Hairong; Zhou, Yifa] Northeast Normal Univ, Sch Life Sci, Jilin Prov Key Lab Chem & Biol Changbai Mt Nat Dr, 5268 Renmin St, Changchun 130024, Peoples R China		Cheng, HR; Zhou, YF (corresponding author), Northeast Normal Univ, Sch Life Sci, Jilin Prov Key Lab Chem & Biol Changbai Mt Nat Dr, 5268 Renmin St, Changchun 130024, Peoples R China.	chenghr893@nenu.edu.cn; zhouyf383@nenu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81302172, 31170770]; Doctoral Fund of Ministry of Education of ChinaMinistry of Education, China [20120043130001]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2014T70270]; Key Scientific Program of Jilin Province [20140101122JC]	This work was supported by the National Natural Science Foundation of China (no. 81302172 and no. 31170770), the Doctoral Fund of Ministry of Education of China (no. 20120043130001), the China Postdoctoral Science Foundation (no. 2014T70270) and the Key Scientific Program of Jilin Province (no. 20140101122JC).	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AUG	2016	7								e2334	10.1038/cddis.2016.234			13	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	DU2YP	WOS:000382077800013	27512955	Green Published, gold			2022-04-25	
J	Mohamed, A; Ayman, A; Deniece, J; Wang, TT; Kovach, C; Siddiqui, MT; Cohen, C				Mohamed, Amr; Ayman, Alkhoder; Deniece, Johnson; Wang, Tengteng; Kovach, Charles; Siddiqui, Momin T.; Cohen, Cynthia			P62/Ubiquitin IHC expression correla ec with clinicopathologic parameters and outcome in gastrointestinal carcinomas	FRONTIERS IN ONCOLOGY			English	Article						P62; ubiquitin; immunohistochemical expression; GI carcinoma	E3 UBIQUITIN LIGASES; BINDING PROTEIN P62; CANCER; PATHWAY	P62 and ubiquitin are small regulatory proteins demonstrated to have implications in the prognosis and survival of various malignancies including: hepatocellular, breast, ovarian, and some gastrointestinal carcinomas. Several trials studied the link of their activity to the extrinsic apoptosis pathway and showed that their autophagy modification has a critical stand point in tumorigenesis.These findings explain their vital role in controlling the process of cell death and survival. It has been shown recently that p62 and ubiquitin overexpression in different types of cancers, such as triple negative breast and ovarian cancers, have directly correlated with incidence of distant metastases. We aim to evaluate p62/ubiquitin expression in gastrointestinal carcinomas of gastric, colonic, and pancreatic origin, and correlate with annotated clinicopathologic data. In gastric carcinoma (61), positive p62 nuclear expression was noted in 57% and cytoplasmic in 61%, while positive ubiquitin was nuclear expressed in 68.8%, and cytoplasmic in 29.5%. In colon carcinoma (45), positive p62 nuclear expression was noted in 29% and cytoplasmic in 71%, while positive ubiquitin was nuclear in 58% and cytoplasmic in 44%. In pancreatic cancer (18), positive p62 nuclear expression was noted in 78% and cytoplasmic in 56%, while positive ubiquitin was nuclear in 83% and cytoplasmic in 72%. Normal gastric (6), colon (4), and pancreatic (4) tissues were negative for both P62 and ubiquitin (nuclear and cytoplasmic staining <20%). Ubiquitin high expression was associated with more lymph node metastases in colon (4.14 vs 1.70, P=0.04), and pancreatic adenocarcinomas (3.07 vs 0.33, P= 0.03). Also, ubiquitin high expression was associated with worse pancreatic adenocarcinoma overall survival (1.37 vs 2.26 mos, P= 0.04). In addition, gastric cancer patients with high p62 expression tend to have more poorly differentiated grade when compared to those with low expression (21 vs 17, P= 0.04) but less lymph node metastases (2.77 vs 5.73, P=0.01). P62 and ubiquitin expression did not correlate with other clinicopathologic parameters in gastric, colon or pancreatic denocarcinomas. The results suggest that p62 and ubiquitin are highly expressed in gastric, colonic, and pancreatic carcinomas. High ubiquitin expression was noted to have an impact on number of lymph node metastases in patients with colon and pancreatic adenocarcinomas, but on overall survival only in patients with pancreatic adenocarcinoma. Also, P62 high expression is correlated with poor differentiation, but less lymph node metastases, in gastric carcinoma.	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Oncol.	MAR 30	2015	5								70	10.1158/1541-7786.MCR-06-0182; 10.3389/fonc.2015.00070			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CO3UD	WOS:000359084600001	25870850				2022-04-25	
J	Robertson, H; Dinkova-Kostova, AT; Hayes, JD				Robertson, Holly; Dinkova-Kostova, Albena T.; Hayes, John D.			NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis	CANCERS			English	Review						NRF2; KEAP1; Cullin 3; ATF4; oxidative stress; reactive oxygen species; antioxidant; adaptation; glutathione; thioredoxin; NADPH generation; pentose phosphate pathway; proteasome; autophagy; drug metabolism; chemoprevention; chemotherapy; bioactivation; quinone-containing drugs; drug resistance; oncogene; tumour suppressor; initiation; progression; metastasis; recurrent disease; lung; oesophagus; liver; head and neck; stomach; bladder; colon; rectum	GLUTATHIONE-S-TRANSFERASE; TRANSCRIPTION FACTOR NRF2; COMPREHENSIVE MOLECULAR CHARACTERIZATION; INDUCED LUNG CARCINOGENESIS; HIGH CATALYTIC-ACTIVITY; CUL3-BASED E3 LIGASE; ALDO-KETO REDUCTASES; OXIDATIVE STRESS; NAD(P)H-QUINONE OXIDOREDUCTASE; GENOMIC CHARACTERIZATION	Simple Summary Transcription factor NRF2 controls expression of antioxidant and detoxification genes. Normally, the activity of NRF2 is tightly controlled in the cell, and is continuously adjusted to ensure that cells are protected against endogenous chemicals and environmental agents that perturb the intracellular antioxidant/pro-oxidant balance (i.e., redox) that must be maintained for them to grow and survive in an appropriate manner. This tight control of NRF2 is achieved by a repressor protein called KEAP1 that perpetually targets NRF2 protein for degradation under normal conditions, but is unable to do so when challenged with oxidants or thiol-reactive chemicals. In the context of cancer, it is well known that drugs that stimulate short-term and reversible activation of NRF2 can provide protection for a limited period against exposure to chemicals that cause cancer. However, it is also becoming widely recognised that permanent hyper-activation of NRF2 resulting from somatic mutations in the gene that encodes NRF2, or in genes associated with its degradation, is frequently observed in certain cancers and associated with poor outcome. In this article, we provide a critical overview of the literature describing the seemingly ambiguous contributions that NRF2 makes to the development of cancer. In particular, we describe the range of genetic and other mechanisms that are responsible for the upregulation of NRF2 in tumours, and highlight shortcomings in our knowledge of how frequently this occurs in different types of cancer. Moreover, we discuss how upregulation of NRF2 might aid the growth and survival of tumours, whether NRF2 upregulation in particular types of cancer is associated with mutations in specific oncogenes, and at what stage of cancer development this is likely to occur. Lastly, we discuss therapeutic strategies that have been proposed that selectively target tumours in which NRF2 is permanently activated with a view to overcoming NRF2-associated drug resistance. NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.	[Robertson, Holly; Dinkova-Kostova, Albena T.; Hayes, John D.] Univ Dundee, Ninewells Hosp & Med Sch, Jacqui Wood Canc Ctr, Div Cellular Med, Dundee DD1 9SY, Scotland; [Robertson, Holly] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England		Hayes, JD (corresponding author), Univ Dundee, Ninewells Hosp & Med Sch, Jacqui Wood Canc Ctr, Div Cellular Med, Dundee DD1 9SY, Scotland.	hr6@sanger.ac.uk; A.DinkovaKostova@dundee.ac.uk; j.d.hayes@dundee.ac.uk		Dinkova-Kostova, Albena/0000-0003-0316-9859	Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [MR/N009851/1, MR/T014644/1]; Biotechnology and Biological Sciences Research CouncilUK Research & Innovation (UKRI)Biotechnology and Biological Sciences Research Council (BBSRC) [BB/L01405X/1]; Cancer Research UKCancer Research UK [C20953/A18644]; MRCUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [MR/T014644/1, MR/N009851/1] Funding Source: UKRI	Our work was supported by the Medical Research Council (MR/N009851/1 and MR/T014644/1, awarded to ATD-K and J.D.H.), the Biotechnology and Biological Sciences Research Council (Industrial CASE PhD studentship BB/L01405X/1, awarded to J.D.H.) and Cancer Research UK (C20953/A18644, awarded to ATD-K).	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J	Asghari, MH; Ghobadi, E; Moloudizargari, M; Fallah, M; Abdollahi, M				Asghari, Mohammad Hossein; Ghobadi, Emad; Moloudizargari, Milad; Fallah, Marjan; Abdollahi, Mohammad			Does the use of melatonin overcome drug resistance in cancer chemotherapy?	LIFE SCIENCES			English	Review						Cancer; Chemotherapy; Drug resistance; Melatonin	HUMAN HEPATOCELLULAR-CARCINOMA; NIGHT-SHIFT WORK; ENDOPLASMIC-RETICULUM STRESS; EPIDERMAL-GROWTH-FACTOR; BREAST-CANCER; MULTIDRUG-RESISTANCE; ANTITUMOR-ACTIVITY; INDUCED APOPTOSIS; OXIDATIVE STRESS; COLORECTAL-CANCER	Our knowledge regarding the implications of melatonin in the therapy of numerous medical conditions, including cancer is constantly expanding. Melatonin can variably affect cancer pathology via targeting several key aspects of any neoplastic condition, including the very onset of carcinogenesis as well as tumor growth, differentiation, and dissemination. Numerous studies have examined the effects of melatonin in the context of various cancers reporting the enhanced efficacy of chemo/radiotherapy in combination with this compound. Reduced sensitivity and also resistance of cancer cells to antineoplastic agents are common events which might arise as a result of genomic instability of the malignant cells. Genetic mutations provide numerous mechanisms for these cells to resist cytotoxic therapies. Melatonin, due to its pleitropic effects, is able to correct these alterations in favour of sensitization to antineoplastic agents as evident by increased response to treatment via modulating the expression and phosphorylation status of drug targets, the reduced clearance of drugs by affecting their metabolism and transport within the body, decreased survival of malignant cells via altering DNA repair and telomerase activity, and enhanced responsiveness to cell death-associated mechanisms such as apoptosis and autophagy. These effects are presumably governed by melatonin's interventions in the main signal transduction pathways such as Akt and MAPK, independent of its antioxidant properties. Possessing such a signaling altering nature, melatonin can considerably affect the drug-resistance mechanisms employed by the malignant cells in breast, lung, hepatic, and colon cancers as well as different types of leukemia which are the subject of the current review.	[Asghari, Mohammad Hossein] Babol Univ Med Sci, Dept Pharmacol, Fac Med, Babol Sar, Iran; [Ghobadi, Emad] Univ Tehran Med Sci, Dept Toxicol & Pharmacol, Fac Pharm, Tehran, Iran; [Moloudizargari, Milad] Shahid Beheshti Univ Med Sci, Sch Med, Dept Immunol, Student Res Comm, Tehran, Iran; [Fallah, Marjan] Mazandaran Univ Med Sci, Dept Pharmacol & Toxicol, Student Res Comm, Fac Pharm, Sari, Iran; [Abdollahi, Mohammad] Univ Tehran Med Sci, Toxicol & Dis Grp, Pharmaceut Sci Res Ctr, Tehran, Iran		Abdollahi, M (corresponding author), Univ Tehran Med Sci, Fac Pharm, Tehran 1417614411, Iran.; Abdollahi, M (corresponding author), Univ Tehran Med Sci, Pharmaceut Sci Res Ctr, Tehran 1417614411, Iran.	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MAR 1	2018	196						143	155		10.1016/j.lfs.2018.01.024			13	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	FX1YG	WOS:000425851500018	29374563				2022-04-25	
J	Kim, DH; Shin, EA; Kim, B; Shim, BS; Kim, SH				Kim, Dong Hee; Shin, Eun Ah; Kim, Bonglee; Shim, Bum Sang; Kim, Sung-Hoon			Reactive oxygen species-mediated phosphorylation of p38 signaling is critically involved in apoptotic effect of Tanshinone I in colon cancer cells	PHYTOTHERAPY RESEARCH			English	Article						caspase-3; colon cancer; p38; reactive oxygen species; Tanshinone I	MAPK ACTIVATION; ADJUVANT CHEMOTHERAPY; ROS GENERATION; PATHWAY; AUTOPHAGY; ROLES; DEATH	Though Tanshinone I (Tan I), a phenolic compound from Salvia miltiorrhiza, is known to have anticancer activity in several cancers, its anticancer mechanisms are not fully understood in colon cancer cells. Thus, in the present study, the underlying molecular mechanism of Tan I was explored in HCT116 and HT29 colorectal cancer cells (CRCs). Here, Tan I suppressed viability in HCT116 and HT29 cells in a time- and dose-dependent manner. Also, Tan I increased the number of terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and sub-G1 population in HCT116 and HT29 cells. Consistently, Tan I cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) and caspase-8, caspase-3, attenuated the expression of Bid and activated tBid as a caspase-8 substrate and activated phosphorylation of p38 MAPK in HCT116and HT29 cells. Of note, Tan I generated reactive oxygen species (ROS) and conversely an ROS scavenger, N-acetyl-(L)-cysteine, reversed ROS production, PARP cleavage, caspase-3 activation, and p38 MAPK phosphorylation induced by Tan I in HCT116 cells. Furthermore, p38 MAPK inhibitor SB203580 reduced cytotoxicity, increase of TUNEL-positive cells, cleavages of PARP and caspase-3 induced by Tan I in HCT116 cells. Overall, our findings for the first time suggest that ROS-dependent activation of p38 MAPK and caspase-3 is critically involved in Tan I induced apoptosis in CRCs as a potent anticancer agent.	[Kim, Dong Hee; Shin, Eun Ah; Kim, Bonglee; Shim, Bum Sang; Kim, Sung-Hoon] Kyung Hee Univ, Coll Korean Med, Seoul, South Korea		Kim, SH (corresponding author), Kyung Hee Univ, Canc Mol Targeted Herbal Res Ctr, Coll Korean Med, 1 Hoegi Dong, Seoul 02447, South Korea.	sungkim7@khu.ac.kr	Kim, Bonglee/AAH-9077-2020; Shim, Bum-sang/AAH-9081-2020	Kim, Bonglee/0000-0002-8678-156X; kim, sunghoon/0000-0003-2423-1973	Cooperative Research Program for Agriculture Science and Technology DevelopmentRural Development Administration (RDA) [PJ01317002]; National Research Foundation of KoreaNational Research Foundation of Korea [2017R1A2A1A17069297]	Cooperative Research Program for Agriculture Science and Technology Development, Grant/Award Number: PJ01317002; National Research Foundation of Korea, Grant/Award Number: 2017R1A2A1A17069297	Bonjer HJ, 2005, LANCET ONCOL, V6, P477, DOI 10.1016/S1470-2045(05)70221-7; Boutros T, 2008, PHARMACOL REV, V60, P261, DOI 10.1124/pr.107.00106; Bragado P, 2007, APOPTOSIS, V12, P1733, DOI 10.1007/s10495-007-0082-8; Burz C, 2009, ACTA ONCOL, V48, P811, DOI 10.1080/02841860902974175; Chang ZQ, 2014, TUMOR BIOL, V35, P753, DOI 10.1007/s13277-013-1102-7; Chawla-Sarkar M, 2003, APOPTOSIS, V8, P237, DOI 10.1023/A:1023668705040; Fang SH, 2011, MOL CELL BIOCHEM, V347, P175, DOI 10.1007/s11010-010-0626-z; Hua X, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-09636-w; Jemal A, 2008, CA-CANCER J CLIN, V58, P71, DOI 10.3322/CA.2007.0010; Jing XP, 2016, CANCER CHEMOTH PHARM, V77, P1171, DOI 10.1007/s00280-016-3034-6; Kasibhatla S., 2006, COLD SPRING HARBOR P, V2006, DOI [10. 1101/pdb. prot4463, DOI 10.1101/PDB.PR0T4463]; Kim BM, 2007, BIOCHEM BIOPH RES CO, V363, P745, DOI 10.1016/j.bbrc.2007.09.024; Kim EJ, 2016, BIOMOL THER, V24, P623, DOI 10.4062/biomolther.2016.023; Kim HS, 2015, PHARM BIOL, V53, P212, DOI 10.3109/13880209.2014.913297; Lee DS, 1999, BIOSCI BIOTECH BIOCH, V63, P2236, DOI 10.1271/bbb.63.2236; Lee WYW, 2009, CANCER LETT, V285, P46, DOI 10.1016/j.canlet.2009.04.040; Liu B, 2009, CANCER LETT, V275, P54, DOI 10.1016/j.canlet.2008.09.042; Liu L, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0097245; Lu MJ, 2016, INT J ONCOL, V49, P603, DOI 10.3892/ijo.2016.3565; Martenson JA, 2004, J CLIN ONCOL, V22, P3277, DOI 10.1200/JCO.2004.01.029; Milone MR, 2013, CELL DEATH DIS, V4, DOI 10.1038/cddis.2013.165; Nizamutdinova IT, 2008, INT J ONCOL, V33, P485, DOI 10.3892/ijo_00000031; Park JH, 2014, NEUROCHEM RES, V39, P1300, DOI 10.1007/s11064-014-1312-4; Probin V, 2007, FREE RADICAL BIO MED, V42, P1858, DOI 10.1016/j.freeradbiomed.2007.03.020; Ribic CM, 2003, NEW ENGL J MED, V349, P247, DOI 10.1056/NEJMoa022289; Shin EA, 2014, ONCOTARGET, V5, P5624, DOI 10.18632/oncotarget.2152; Son Yong, 2011, J Signal Transduct, V2011, P792639, DOI 10.1155/2011/792639; Valko M, 2007, INT J BIOCHEM CELL B, V39, P44, DOI 10.1016/j.biocel.2006.07.001; Weh KM, 2015, CANCER RES, V75, DOI 10.1158/1538-7445.AM2015-1898; Woo KS, 2013, EVID-BASED COMPL ALT, V2013, P1; Xing HM, 2000, EMBO J, V19, P349, DOI 10.1093/emboj/19.3.349; Yamaguchi K, 2017, METHODS MOL BIOL, V1578, P309, DOI 10.1007/978-1-4939-6859-6_26; Yang L, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0080464; Zhang Q, 2016, SCI REP-UK, V6, DOI 10.1038/srep30146; Zhong YJ, 2017, TOXICON, V137, P106, DOI 10.1016/j.toxicon.2017.07.018; Zhou L, 2017, INT J IMMUNOPATH PH, V30, P123, DOI 10.1177/0394632017703274; Zhu J, 2017, CELL DEATH DIS, V8, DOI 10.1038/cddis.2017.488; Zhu YY, 2017, BIOMED PHARMACOTHER, V87, P527, DOI 10.1016/j.biopha.2016.12.095	38	9	9	3	12	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0951-418X	1099-1573		PHYTOTHER RES	Phytother. Res.	OCT	2018	32	10					1975	1982		10.1002/ptr.6126			8	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	GW0NW	WOS:000446565300010	29876988				2022-04-25	
J	Li, S; Liu, JY; Zheng, XJ; Ren, LW; Yang, YH; Li, W; Fu, WQ; Wang, JH; Du, GH				Li, Sha; Liu, Jinyi; Zheng, Xiangjin; Ren, Liwen; Yang, Yihui; Li, Wan; Fu, Weiqi; Wang, Jinhua; Du, Guanhua			Tumorigenic bacteria in colorectal cancer: mechanisms and treatments	CANCER BIOLOGY & MEDICINE			English	Review						Colorectal cancer; microbiota; tumorigenic mechanism; genotoxicity; cancer pathways; tumor immunity	DOUBLE-STRAND BREAKS; FACTOR-KAPPA-B; FUSOBACTERIUM-NUCLEATUM; GENOTOXIN COLIBACTIN; COLON TUMORIGENESIS; EPITHELIAL-CELLS; GUT MICROBIOTA; UP-REGULATION; EXPRESSION; PROTEIN	Colorectal cancer (CRC) is the third most common and the second most fatal cancer. In recent years, more attention has been directed toward the role of gut microbiota in the initiation and development of CRC. Some bacterial species, such as Fusobacterium nucleatum, Escherichia colt, Bacteroides fragilis, Enterococcus faecalis, and Salmonella sp. have been associated with CRC, based upon sequencing studies in CRC patients and functional studies in cell culture and animal models. These bacteria can cause host DNA damage by genotoxic substances, including colibactin secreted by pks + Escherichia coli, B. fragilis toxin (BFT) produced by Bacteroides and typhoid toxin (TT) from Salmonella. These bacteria can also indirectly promote CRC by influencing host-signaling pathways, such as E-cadherin/beta-catenin, TLR4/MYD88/NF-kappa B, and SMO/RAS/p38 MAPK. Moreover, some of these bacteria can contribute to CRC progression by helping tumor cells to evade the immune response by suppressing immune cell function, creating a proinflammatory environment, or influencing the autophagy process. Treatments with the classical antibacterial drugs, metronidazole or erythromycin, the antibacterial active ingredients, M13@ Ag (electrostatically assembled from inorganic silver nanoparticles and the protein capsid of bacteriophage M13), berberine, and zerumbone, were found to inhibit tumorigenic bacteria to different degrees. In this review, we described progress in elucidating the tumorigenic mechanisms of several CRC-associated bacteria, as well as progress in developing effective antibacterial therapies. Specific bacteria have been shown to be active in the oncogenesis and progression of CRC, and some antibacterial compounds have shown therapeutic potential in bacteria-induced CRC. These bacteria may be useful as biomarkers or therapeutic targets for CRC.	[Li, Sha; Liu, Jinyi; Zheng, Xiangjin; Ren, Liwen; Yang, Yihui; Li, Wan; Fu, Weiqi; Wang, Jinhua; Du, Guanhua] State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China; [Li, Sha; Liu, Jinyi; Zheng, Xiangjin; Ren, Liwen; Yang, Yihui; Li, Wan; Fu, Weiqi; Wang, Jinhua; Du, Guanhua] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Key Lab Drug Target Res & Drug Screen, Beijing 100050, Peoples R China		Wang, JH; Du, GH (corresponding author), State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.; Wang, JH; Du, GH (corresponding author), Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Key Lab Drug Target Res & Drug Screen, Beijing 100050, Peoples R China.	wjh@imm.ac.cn; dugh@imm.ac.cn			CAMS Innovation Fund for Medical Sciences [2016-I2M-3-007]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81803584]; Technology Major Projects for "Major New Drugs Innovation and Development" [2018ZX09711001005-025, 2018ZX09711001-012]; Inner Mongolian Natural Science Foundation [2018LH08032]	This work was supported by the CAMS Innovation Fund for Medical Sciences (Grant No. 2016-I2M-3-007), the National Natural Science Foundation of China (Grant No. 81803584), the Technology Major Projects for "Major New Drugs Innovation and Development" (Grant Nos. 2018ZX09711001005-025 and 2018ZX09711001-012), and the Inner Mongolian Natural Science Foundation (Grant No. 2018LH08032)	Abed J, 2016, CELL HOST MICROBE, V20, P215, DOI 10.1016/j.chom.2016.07.006; Aleksandrov R, 2020, CELLS-BASEL, V9, DOI 10.3390/cells9081853; Arnold M, 2017, GUT, V66, P683, DOI 10.1136/gutjnl-2015-310912; Arthur JC, 2012, SCIENCE, V338, P120, DOI 10.1126/science.1224820; Bai F, 2020, J IMMUNOTHER CANCER, V8, DOI 10.1136/jitc-2019-000169; Baxter NT, 2016, GENOME MED, V8, DOI 10.1186/s13073-016-0290-3; Boleij A, 2011, CLIN INFECT DIS, V53, P870, DOI 10.1093/cid/cir609; Bossuet-Greif N, 2018, MBIO, V9, DOI 10.1128/mBio.02393-17; Bossuet-Greif N, 2016, MOL MICROBIOL, V99, P897, DOI 10.1111/mmi.13272; 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Med.	FEB	2022	19	2					147	162		10.20892/j.issn.2095-3941.2020.0651		SEP 2021	16	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	YR4LH	WOS:000729398400001	34586760	gold			2022-04-25	
J	Valdes, A; Artemenko, KA; Bergquist, J; Garcia-Canas, V; Cifuentes, A				Valdes, Alberto; Artemenko, Konstantin A.; Bergquist, Jonas; Garcia-Canas, Virginia; Cifuentes, Alejandro			Comprehensive Proteomic Study of the Antiproliferative Activity of a Polyphenol-Enriched Rosemary Extract on Colon Cancer Cells Using Nanoliquid Chromatography-Orbitrap MS/MS	JOURNAL OF PROTEOME RESEARCH			English	Article						antiproliferative activity; foodomics; colon cancer; dimethyl labeling; HT-29 cells; mass spectrometry; quantitative proteomics; rosemary extract	ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; ER-STRESS; CARNOSIC ACID; TRANSCRIPTION FACTOR; IN-VITRO; AUTOPHAGY; PATHWAY; P62; NRF2	In this work, a proteomics strategy based on nanoliquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) using an Orbitrap high-resolution mass spectrometer together with stable isotope dimethyl labeling (DML) is applied to quantitatively examine relative changes in the protein fraction of HT-29 human colon cancer cells treated with different concentrations of a polyphenol-enriched rosemary extract over the time. The major objective of this study was to gain insights into the antiproliferative mechanisms induced by rosemary polyphenols. Using this methodology, 1909 and 698 proteins were identified and quantified in cell extracts. The polyphenol-enriched rosemary extract treatment changed the expression of several proteins in a time- and concentration-dependent manner. Most of the altered proteins are implicated, in the activation of Nrf2 transcription factor and the unfolded protein response. In conclusion, rosemary polyphenols induced proteomic changes that were related to the attenuation of aggresome formation and activation of autophagy to alleviate cellular stress..	[Valdes, Alberto; Garcia-Canas, Virginia; Cifuentes, Alejandro] CSIC, Inst Food Sci Res CIAL, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain; [Artemenko, Konstantin A.; Bergquist, Jonas] Uppsala Univ, Dept Chem BMC, Analyt Chem, Husargatan 3, S-75124 Uppsala, Sweden; [Artemenko, Konstantin A.; Bergquist, Jonas] Uppsala Univ, SciLifeLab, Husargatan 3, S-75124 Uppsala, Sweden		Garcia-Canas, V (corresponding author), CSIC, Inst Food Sci Res CIAL, Lab Food, Calle Nicolas Cabrera 9, Madrid 28049, Spain.; Bergquist, J (corresponding author), Uppsala Univ, Dept Chem BMC, Analyt Chem, Husargatan 3, S-75124 Uppsala, Sweden.; Bergquist, J (corresponding author), Uppsala Univ, SciLifeLab, Husargatan 3, S-75124 Uppsala, Sweden.	jonas.bergquist@kemi.uu.se; virginia.garcia@csic.es	Cifuentes, Alejandro/B-4715-2011; Garcia-Cañas, Virginia/H-4037-2012; Valdés, Alberto/C-3454-2019	Cifuentes, Alejandro/0000-0002-7464-0217; Garcia-Cañas, Virginia/0000-0001-6728-4325; Valdés, Alberto/0000-0002-7901-5816; Bergquist, Jonas/0000-0002-4597-041X	Ministerio de Economia y Competitividad, SpainSpanish Government [AGL2014-53609-P]; Comunidad de MadridComunidad de Madrid [S2013/ABI-2728]; Ministerio de Economia y CompetitividadSpanish Government [BES-2012-057014]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2011-4423, 2015-4870]	This work was supported by the projects AGL2014-53609-P (Ministerio de Economia y Competitividad, Spain) and S2013/ABI-2728 (Comunidad de Madrid). A.V. thanks the Ministerio de Economia y Competitividad for his FPI predoctoral fellowship (BES-2012-057014). The Swedish Research Council (2011-4423 and 2015-4870; J.B.) is acknowledged for financial support.	Arlt A, 2009, ONCOGENE, V28, P3983, DOI 10.1038/onc.2009.264; Barni MV, 2012, ONCOL REP, V27, P1041, DOI 10.3892/or.2012.1630; Benbrook D. 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J	Kumar, A; Singh, B; Sharma, PR; Bharate, SB; Saxena, AK; Mondhe, DM				Kumar, Ashok; Singh, Baljinder; Sharma, Parduman R.; Bharate, Sandip B.; Saxena, Ajit K.; Mondhe, D. M.			A novel microtubule depolymerizing colchicine analogue triggers apoptosis and autophagy in HCT-116 colon cancer cells	CELL BIOCHEMISTRY AND FUNCTION			English	Article						colchicine analogue; cytotoxicity; tubulin; reactive oxygen species; apoptosis; autophagy	VASCULAR-TARGETING AGENT; DEATH; INDUCTION; DERIVATIVES; PROGRESSION; ZD6126	Colchicine is a tubulin-binding natural product isolated from Colchicum autumnale. Here we report the in vitro anticancer activity of C-ring modified semi-synthetic derivative of colchicine; N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(4-phenyl-piperidin-1-yl)-5,6,7,9 tetrahydrobenzo[a]heptalen-7-yl]acetamide (4h) on colon cancer HCT-116 cell line. The compound 4h was screened for anti-proliferative activity against different human cancer cell lines and was found to exhibit higher cytotoxicity against colon cancer cell lines HCT-116 and Colo-205 with IC50 of 1 and 0.8M respectively. Cytotoxicity of the compound to the normal fR2 breast epithelial cells and normal HEK293 human embryonic kidney cells was evaluated in concentration and time-dependent manner to estimate its selectivity for cancer cells which showed much better selectivity than that of colchicine. Compound 4h induced cell death in HCT-116 cells by activating apoptosis and autophagy pathways. Autophagy inhibitor 3-MA blocked the production of LC3-II and reduced the cytotoxicity in response to 4h, but did not affect apoptosis, suggesting thereby that these two were independent events. Reactive oxygen species scavenger ascorbic acid pretreatment not only decreased the reactive oxygen species level but also reversed 4h induced cytotoxicity. Treatment with compound 4h depolymerized microtubules and the majority of cells arrested at the G2/M transition. Together, these data suggest that 4h has better selectivity and is a microtubule depolymerizer, which activates dual cell-death machineries, and thus, it could be a potential novel therapeutic agent in cancer therapy. Copyright (c) 2016 John Wiley & Sons, Ltd.	[Kumar, Ashok; Sharma, Parduman R.; Mondhe, D. M.] Indian Inst Integrat Med, CSIR, Canc Pharmacol Div, Jammu 180001, India; [Kumar, Ashok; Singh, Baljinder; Sharma, Parduman R.; Bharate, Sandip B.; Mondhe, D. M.] Indian Inst Integrat Med, CSIR, Acad Sci & Innovat Res AcSIR, Jammu 180001, India; [Singh, Baljinder] Indian Inst Integrat Med, CSIR, Nat Prod Chem Div, Jammu 180001, India; [Bharate, Sandip B.] Indian Inst Integrat Med, CSIR, Med Chem Div, Jammu 180001, India; [Saxena, Ajit K.] Amity Univ, Lucknow, Uttar Pradesh, India		Sharma, PR; Mondhe, DM (corresponding author), Indian Inst Integrat Med, CSIR, Canc Pharmacol Div, Jammu 180001, India.	prsharma@iiim.ac.in; dmmondhe@iiim.res.in	Bharate, Sandip B/B-7104-2018; Singh, Baljinder/W-6314-2018	Singh, Baljinder/0000-0003-2828-5768	Department of Science and Technology, Government of IndiaDepartment of Science & Technology (India); CSIRCouncil of Scientific & Industrial Research (CSIR) - India	We thank our Director Dr. Ram A. Vishwakarma for encouraging us to complete this work. Ashok Kumar is thankful to Department of Science and Technology, Government of India for INSPIRE fellowship. Baljinder Singh thanks the CSIR 12th FYP project for fellowship.	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Funct.	MAR	2016	34	2					69	81		10.1002/cbf.3166			13	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	DF5YI	WOS:000371428500003	26919061				2022-04-25	
J	Lee, JW; Jeong, EG; Lee, SH; Yoo, NJ; Lee, SH				Lee, Jong Woo; Jeong, Eun Goo; Lee, Sung Hak; Yoo, Nam Jin; Lee, Sug Hyung			Somatic mutations of BECN1, an autophagy-related gene, in human cancers	APMIS			English	Article						BECN1; autophagy; mutation; cancer	TUMOR-SUPPRESSOR; INACTIVATING MUTATIONS; BECLIN-1; TUMORIGENESIS; APOPTOSIS; PROTEIN; DEATH	Evasion of programmed cell death (PCD) is one of the hallmarks of human cancers. It is well known that not only apoptosis, but also autophagy, acts as an action mechanism of PCD. BECN1 protein is a key regulator of autophagic PCD. The BECN1 gene that encodes BECN1 protein acts as a haploinsufficient tumor-suppressor gene. However, to date, data on BECN1 mutation in human cancer tissues are lacking. To explore the possibility that somatic mutation of the BECN1 gene might contribute to the development of human cancers, we analyzed the entire coding region and all splice sites of the human BECN1 gene for detection of somatic mutations in 180 gastric carcinomas, 94 breast carcinomas, 50 acute leukemias, 50 colorectal carcinomas, 50 hepatocellular carcinomas, and 124 non-small cell lung cancers by single-strand conformation polymorphism (SSCP) and DNA sequencing. Overall, we detected 11 somatic mutations of the BECN1 gene, including 3 missense mutations (N8K, P350R and R389C) in coding sequences and 8 mutations in introns. The mutations were observed in five gastric, three colorectal, one lung and one breast carcinoma (s). We expressed the three mutations (N8K, P350R and R389C) in HT1080 cells, and found that two (P350R and R389C) of them showed only slightly decreased cell death activities compared to the wild-type BECN1. This is the first report on BECN1 gene mutations in human cancer tissues, and the data suggest that point mutations are a rare event in common human cancers and probably do not play a major role in cancer pathogenesis.	Catholic Univ Korea, Coll Med, Dept Pathol, Seoul 137701, South Korea		Lee, SH (corresponding author), Catholic Univ Korea, 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; BERG JM, 2002, BIOCHEMISTRY-US, P18; Edinger AL, 2004, CURR OPIN CELL BIOL, V16, P663, DOI 10.1016/j.ceb.2004.09.011; EDMONDSON HA, 1954, CANCER-AM CANCER SOC, V7, P462, DOI 10.1002/1097-0142(195405)7:3<462::AID-CNCR2820070308>3.0.CO;2-E; Futreal PA, 2004, NAT REV CANCER, V4, P177, DOI 10.1038/nrc1299; 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; KRAWCZAK M, 1992, HUM GENET, V90, P41; Lee JW, 2004, CARCINOGENESIS, V25, P1371, DOI 10.1093/carcin/bgh145; 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; 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; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	22	30	32	0	5	WILEY-BLACKWELL	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0903-4641			APMIS	APMIS	JUN	2007	115	6					750	756		10.1111/j.1600-0463.2007.apm_640.x			7	Immunology; Microbiology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Microbiology; Pathology	173ZJ	WOS:000246910700009	17550384				2022-04-25	
J	Ma, XK; Wang, MH; Zheng, N; Wang, GY; Zhuang, JH; Ye, Y; Xia, W				Ma, Xiaokun; Wang, Menghan; Zheng, Ni; Wang, Guoyu; Zhuang, Juhua; Ye, Ying; Xia, Wei			Apatinib inhibits the proliferation of colon cancer cells by down-regulating the VEGFR2-PLC-ERK1/2 pathway	INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE			English	Article						Colon cancer; apatinib; apoptosis; VEGFR2-PLC-ERK1/2 pathway	CYCLE ARREST; APOPTOSIS; AUTOPHAGY; TRIAL	Objective: To analyze the effect of apatinib on colon cancer cells via the VEGFR2-PLC-ERK1/2 pathway. Methods: Human colon cancer cell line LS174T in the logarithmic phase of growth were treated with apatinib solution at concentrations of 0, 25, 50, and 100 mol/L for 24, 48, and 72 hours, respectively. CCK-8 detected cell proliferation, flow cytometry evaluated the cell apoptosis and cell cycle. Western blot was used to detect the phosphorylation of key enzymes in VEGFR2-PLC-ERK1/2 pathway and expression of related apoptotic proteins. Results: Compared with 0 mol/L, the absorbance of LS174T cells at 25, 50, and 100 mol/L decreased significantly after 24, 48, and 72 h of cell culture (P < 0.05); and the inhibitory effect of apatinib on colon cancer cells was increased in a dose/time-dependent manner. The apoptosis rate of the control group was (6.55 +/- 1.08)% which is significantly different from (12.58 +/- 1.36)% (24 h), (18.85 +/- 1.37)% (48 h) and (25.74 +/- 143)% (72 h) in the 100 mol/L apatinib group (P < 0.05). Apatinib-induced apoptosis exhibited a time-dependent relationship. Compared with the control group, the 100 mol/L apatinib group showed a decrease in S-phase and G2/M-phase cells and an increase in G0/G1-phase cells (P < 0.05), while the expression of pPCL and pERK1/2 proteins in the 100 mol/L apatinib group decreased at 24, 48, and 72 h (P < 0.05). Conclusion: Apatinib can inhibit the proliferation of colon cancer cells and accelerate apoptosis, which was related to the inhibition of phosphorylation of key proteases in the VEGFR2-PLC-ERK1/2 pathway.	[Ma, Xiaokun; Wang, Menghan; Zheng, Ni; Wang, Guoyu; Zhuang, Juhua; Xia, Wei] Shanghai Univ Tradit Chinese Med, Peoples Hosp 7, Dept Nucl Med, 358 Datong Rd, Shanghai 200120, Peoples R China; [Ye, Ying] Shanghai Univ Tradit Chinese Med, Peoples Hosp 7, Cent Lab, 358 Datong Rd, Shanghai 200120, Peoples R China		Xia, W (corresponding author), Shanghai Univ Tradit Chinese Med, Peoples Hosp 7, Dept Nucl Med, 358 Datong Rd, Shanghai 200120, Peoples R China.; Ye, Y (corresponding author), Shanghai Univ Tradit Chinese Med, Peoples Hosp 7, Cent Lab, 358 Datong Rd, Shanghai 200120, Peoples R China.	yy49453324@163.com; wxeiia00@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81873178, 81904036]; Science and Technology Development Fund of Shanghai Pudong New Area [PKJ2017-Y14]; Special Fund for Health of Pudong Health and Family Planning Commission of Shanghai [PW2018E-02]	This study was supported by grants from National Natural Science Foundation of China (No. 81873178 and No. 81904036), Science and Technology Development Fund of Shanghai Pudong New Area (PKJ2017-Y14), Special Fund for Health of Pudong Health and Family Planning Commission of Shanghai (PW2018E-02), Science and Technology Development Fund of Shanghai Pudong New Area (No. PKJ2017-Y14).	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J	Kaluderovic, MR; Mojic, M; Gomez-Ruiz, S; Mijatovic, S; Maksimovic-Ivanic, D				Kaluderovic, Milena R.; Mojic, Marija; Gomez-Ruiz, Santiago; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela			Anticancer Activity of Organogallium(III) Complexes in Colon Cancer Cells	ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY			English	Article						Apoptosis; autophagy; cell division; cisplatin; cytotoxic activity; organogallium(III) complexes	GALLIUM(III) COMPLEXES; INSIGHT; DEATH	In vitro antitumor activity of various organogallium(III) complexes (1-8) has been tested against CT26CL25, HCT116, SW480 colon cancer cell lines. CV and MTT assays were used to assess on the antiproliferative effect of investigated organogallium(III) complexes. From the investigated complexes, the most active was found to be tetranuclear compound 8 against CT26CL25 cells. Flow cytometric analysis of the CT26CL25 cells upon the treatment with 8 was performed in order to determine the role of apoptosis, caspase activation, autophagy and proliferation rate on the cell death caused with this compound. Results indicate cytotoxic potential of the tetranuclear complex 8 by inducing caspase independent apoptosis and blocking most of the cells before first division.	[Kaluderovic, Milena R.] Univ Hosp Leipzig, Dept Oral Maxillary Facial & Reconstruct Plast Su, D-04103 Leipzig, Germany; [Mojic, Marija; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela] Univ Belgrade, Inst Biol Res Sinisa Stankovic, Dept Immunol, Bulevar Despota Stefana 142, Belgrade 11060, Serbia; [Gomez-Ruiz, Santiago] Univ Rey Juan Carlos, ESCET, Dept Biol & Geol Fis & Quim Inorgan, Calle Tulipan S-N, Mostoles 28933, Madrid, Spain		Kaluderovic, MR (corresponding author), Univ Hosp Leipzig, Dept Oral Maxillary Facial & Reconstruct Plast Su, D-04103 Leipzig, Germany.	milena.kaluderovic@medizin.uni-leipzig.de	Gómez-Ruiz, Santiago/E-4863-2012; Mojic, Marija/E-8729-2015	Gómez-Ruiz, Santiago/0000-0001-9538-8359; Mojic, Marija/0000-0002-4906-9880	Ministry of Education, Science and Technological Development, Republic of Serbia [173013]; Ministerio de Economia y Competitividad, Spain [CTQ2012-30762]; Universidad Rey Juan Carlos-Banco de Santander (Excellence group QUINANOAP, Convocatoria de ayudas a la Actividad de Grupos de Excelencia Investigadora)	We gratefully acknowledge financial support from the Ministry of Education, Science and Technological Development, Republic of Serbia (#173013) and Ministerio de Economia y Competitividad, Spain (Grant no. CTQ2012-30762) and of Universidad Rey Juan Carlos-Banco de Santander (Excellence group QUINANOAP, Convocatoria de ayudas a la Actividad de Grupos de Excelencia Investigadora).	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Chem.		2016	16	3					359	364		10.2174/1871520615666151007160319			6	Oncology; Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	DI4UG	WOS:000373494300008	26443026				2022-04-25	
J	Sousa, ML; Preto, M; Vasconcelos, V; Linder, S; Urbatzka, R				Sousa, Maria Ligia; Preto, Marco; Vasconcelos, Vitor; Linder, Stig; Urbatzka, Ralph			Antiproliferative Effects of the Natural Oxadiazine Nocuolin A Are Associated With Impairment of Mitochondrial Oxidative Phosphorylation	FRONTIERS IN ONCOLOGY			English	Article						natural products; cyanobacteria; spheroids; colon cancer; ant-cancer drugs; mitochondria; autophagy	CONNECTIVITY MAP; TUMOR-CELLS; ANTICARCINOMA ACTIVITY; BRENTUXIMAB VEDOTIN; CYANOBACTERIA; MARINE; DRUG; TARGET; EXPRESSION; INHIBITOR	Natural products are interesting sources for drug discovery. The natural product oxadiazine Nocuolin A (NocA) was previously isolated from the cyanobacterial strain Nodularia sp. LEGE 06071 and here we examined its cytotoxic effects against different strains of the colon cancer cell line HCT116 and the immortalized epithelial cell line hTERT RPE-1. NocA was cytotoxic against colon cancer cells and immortalized cells under conditions of exponential growth but was only weakly active against non-proliferating immortalized cells. NocA induced apoptosis by mechanism(s) resistant to overexpression of BCL family members. Interestingly, NocA affected viability and induced apoptosis of HCT116 cells grown as multicellular spheroids. Analysis of transcriptome profiles did not match signatures to any known compounds in CMap but indicated stress responses and induction of cell starvation. Evidence for autophagy was observed, and a decrease in various mitochondrial respiration parameter within 1 h of treatment. These results are consistent with previous findings showing that nutritionally compromised cells in spheroids are sensitive to impairment of mitochondrial energy production due to limited metabolic plasticity. We conclude that the antiproliferative effects of NocA are associated with effects on mitochondrial oxidative phosphorylation.	[Sousa, Maria Ligia; Vasconcelos, Vitor] Univ Porto, Fac Sci, Porto, Portugal; [Sousa, Maria Ligia; Preto, Marco; Vasconcelos, Vitor; Urbatzka, Ralph] Interdisciplinary Ctr Marine & Environm Res, Porto, Portugal; [Linder, Stig] Karolinska Inst, Dept Oncol & Pathol, Canc Ctr Karolinska, Stockholm, Sweden; [Linder, Stig] Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden		Urbatzka, R (corresponding author), Interdisciplinary Ctr Marine & Environm Res, Porto, Portugal.	rurbatzka@ciimar.up.pt	Sousa, Maria Lígia/AAC-9071-2020; Vasconcelos, Vitor/A-8933-2008; Urbatzka, Ralph/G-8907-2013	Sousa, Maria Lígia/0000-0003-0012-7493; Vasconcelos, Vitor/0000-0003-3585-2417; Urbatzka, Ralph/0000-0001-7476-9195; Correia Preto, Marco Aurelio/0000-0002-9697-5579	Structured Program of R&D&I INNOVMAR-Innovation and Sustainability in the Management and Exploitation of Marine Resources - Northern Regional Operational Program (NORTE2020) through the European Regional Development Fund (ERDF) [NORTE-01-0145-FEDER-000035]; project CYANCAN-Uncovering the cyanobacterial chemical diversity: the search for novel anticancer compounds - NORTE 2020, Portugal 2020 [PTDC/MEDQUI/30944/2017]; European Union through the ERDF; Foundation for Science and Technology; FCTPortuguese Foundation for Science and TechnologyEuropean Commission [SFRH/BPD/112287/2015, SFRH/BD/108314/2015]	This research was supported by the Structured Program of R&D&I INNOVMAR-Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR), funded by the Northern Regional Operational Program (NORTE2020) through the European Regional Development Fund (ERDF). The project was additionally supported the project CYANCAN-Uncovering the cyanobacterial chemical diversity: the search for novel anticancer compounds (reference PTDC/MEDQUI/30944/2017) co-financed by NORTE 2020, Portugal 2020, and the European Union through the ERDF, and by Foundation for Science and Technology through national funds. RU was supported by the FCT postdoc grant SFRH/BPD/112287/2015 and MS by the FCT PhD grant SFRH/BD/108314/2015.	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Oncol.	APR 3	2019	9								224	10.3389/fonc.2019.00224			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	HR8RP	WOS:000463427000001	31001482	Green Published, gold			2022-04-25	
J	Deng, J; Wang, Y; Lei, J; Lei, W; Xiong, JP				Deng, Jun; Wang, Yi; Lei, Jun; Lei, Wan; Xiong, Jian Ping			Insights into the involvement of noncoding RNAs in 5-fluorouracil drug resistance	TUMOR BIOLOGY			English	Review						microRNA; long noncoding RNA; 5-fluorouracil; drug resistance	COLON-CANCER CELLS; HEPATOCELLULAR-CARCINOMA CELLS; DIHYDROPYRIMIDINE DEHYDROGENASE EXPRESSION; EPITHELIAL-MESENCHYMAL TRANSITION; MICRORNA-21 INDUCES RESISTANCE; HUMAN COLORECTAL-CANCER; HUMAN GASTRIC-CANCER; DOWN-REGULATION; THYMIDYLATE SYNTHASE; TUMOR-SUPPRESSOR	5-Fluorouracil is a classic chemotherapeutic drug that is widely used to treat various cancers. However, patients often exhibit primary or acquired drug resistance during treatment with 5-fluorouracil chemotherapy. 5-Fluorouracil resistance is a multifactorial event that involves abnormal enzyme metabolism, transport deregulation, cell cycle disorders, apoptosis resistance, and mismatch repair deficiency. Despite advancements in bioresearch technologies in the past several decades, the molecular mechanisms of 5-fluorouracil resistance have not been completely clarified. Recently, microarray analyses have shown that noncoding RNAs (i.e. microRNAs and long noncoding RNAs) play a vital role in 5-fluorouracil resistance in multiple cancer cell lines. These noncoding RNAs can function as oncogenes or tumor suppressors, contributing to 5-fluorouracil drug resistance. In this review, we discuss the effects of microRNAs on 5-fluorouracil sensitivity via targeting of metabolic enzymes, the cell cycle, apoptosis, autophagy, the epithelial-mesenchymal transition, and cancer stem cells. In particular, we focus on summarizing current knowledge on the molecular mechanisms through which long noncoding RNAs mediate 5-fluorouracil drug resistance. Moreover, we describe the specific microRNAs that may function as markers for prediction of chemotherapeutic response to 5-fluorouracil. This review will help to improve the current understanding of how to reverse 5-fluorouracil resistance and may facilitate the establishment of new strategies for alleviating drug resistance in the future.	[Deng, Jun; Wang, Yi; Lei, Jun; Lei, Wan; Xiong, Jian Ping] Nanchang Univ, Affiliated Hosp 1, Dept Oncol, Nanchang 330006, Jiangxi, Peoples R China		Deng, J; Xiong, JP (corresponding author), Nanchang Univ, Affiliated Hosp 1, Dept Oncol, Nanchang 330006, Jiangxi, Peoples R China.	dengjun19871106@126.com; junjungege@outlook.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81160281, 81441083]; Jiangxi Province Talent 555 Project; National Natural Science Foundation of Jiangxi Province [20152ACB20024, 20151BBG70228]	This work was supported by the National Natural Science Foundation of China (grant nos 81160281 and 81441083), the Jiangxi Province Talent 555 Project, and the National Natural Science Foundation of Jiangxi Province (grant nos 20152ACB20024 and 20151BBG70228).	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APR	2017	39	4							697553	10.1177/1010428317697553			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	ET4QD	WOS:000400268800038	28381160	gold			2022-04-25	
J	Zeya, B; Nafees, S; Imtiyaz, K; Uroog, L; Fakhri, KU; Rizvi, MMA				Zeya, Bushra; Nafees, Sana; Imtiyaz, Khalid; Uroog, Laraib; Fakhri, Khalid Umar; Rizvi, M. Moshahid A.			Diosmin in combination with naringenin enhances apoptosis in colon cancer cells	ONCOLOGY REPORTS			English	Article						colon cancer; flavonoids; naringenin; diosmin; apoptosis; inflammatory pathway	NF-KAPPA-B; INFLAMMATION; ANTIOXIDANT; ACTIVATION; CARCINOMA; MECHANISMS; FLAVONOIDS; HALLMARKS; AUTOPHAGY; SYNERGISM	Colon cancer is one of the most commonly diagnosed malignancies, which begins as a polyp and grows to become cancer. Diosmin (DS) and naringenin (NR) are naturally occurring flavonoids that exhibit various pharmacological activities. Although several studies have illustrated the effectiveness of these flavonoids as anti-cancerous agents individually, the combinatorial impact of these compounds has not been explored. In the present study, the combined effect of DS and NR (DiNar) in colon cancer cell lines HCT116 and SW480 were assessed by targeting apoptosis and inflammatory pathways. The MTT assay was used to evaluate the effect of DiNar on cell proliferation, while Chou-Talalay analysis was employed to determine the combination index of DS and NR. Moreover, flow cytometry was used to monitor cell cycle arrest and population study. The onset of apoptosis was assessed by DAPI staining, DNA fragmentation, and Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI). The expression levels of apoptotic pathway markers, Bcl-2, Bax, caspase3, caspase8, caspase9 and p53, and inflammatory markers, NF-kappa beta, IKK-alpha and IKK-beta, were assessed using western blotting and reverse transcription-quantitative PCR. These results suggested that DiNar treatment acts synergistically and induces cytotoxicity with a concomitant increase in chromatin condensation, DNA fragmentation and cell cycle arrest in the G0/G1 phase. Annexin V-FITC/PI apoptosis assay also showed increased number of cells undergoing apoptosis in the DiNar treatment group. Furthermore, the expression of apoptosis and inflammatory markers was also more effectively regulated under the DiNar treatment. Thereby, these findings demonstrated that DiNar treatment could be a potential novel chemotherapeutic alternative in colon cancer.	[Zeya, Bushra; Nafees, Sana; Imtiyaz, Khalid; Uroog, Laraib; Fakhri, Khalid Umar; Rizvi, M. Moshahid A.] Jamia Millia Islamia, Genome Biol Lab, Dept Biosci, Ramanujan Block, Delhi 110025, India		Rizvi, MMA (corresponding author), Jamia Millia Islamia, Genome Biol Lab, Dept Biosci, Ramanujan Block, Delhi 110025, India.	rizvijmi@gmail.com					Ahamad MS, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0110003; Ahmad, 2014, J BIOL ACTIVE PRODUC, V4, P158, DOI DOI 10.1080/22311866.2014.933084; American Cancer Society, 2021, COL CANC FACTS FIG; Arul D, 2013, PATHOL ONCOL RES, V19, P763, DOI 10.1007/s12253-013-9641-1; Atreya I, 2008, J INTERN MED, V263, P591, DOI 10.1111/j.1365-2796.2008.01953.x; Attardi LD, 1999, CELL MOL LIFE SCI, V55, P48, DOI 10.1007/s000180050269; Bleiberg H, 2012, ACTA GASTRO-ENT BELG, V75, P14; Bodduluru LN, 2016, INT IMMUNOPHARMACOL, V30, P102, DOI 10.1016/j.intimp.2015.11.036; CHOU TC, 1984, ADV ENZYME REGUL, V22, P27, DOI 10.1016/0065-2571(84)90007-4; Chou TC, 2006, PHARMACOL REV, V58, P621, DOI 10.1124/pr.58.3.10; Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013; Hollman PCH, 1999, FOOD CHEM TOXICOL, V37, P937, DOI 10.1016/S0278-6915(99)00079-4; Huang YY, 2021, J CELL MOL MED, V25, P1480, DOI 10.1111/jcmm.16237; Jurisicova A, 1996, MOL HUM REPROD, V2, P93, DOI 10.1093/molehr/2.2.93; Kagan VE, 2000, FEBS LETT, V477, P1, DOI 10.1016/S0014-5793(00)01707-5; KERR JFR, 1972, BRIT J CANCER, V26, P239, DOI 10.1038/bjc.1972.33; Key TJ, 2011, BRIT J CANCER, V104, P6, DOI 10.1038/sj.bjc.6606032; Khan KH, 2014, CRIT REV ONCOL HEMAT, V90, P200, DOI 10.1016/j.critrevonc.2013.12.012; Khan N, 2019, INT J CANCER, V145, P3022, DOI 10.1002/ijc.32367; Kojima M, 2004, ANTICANCER RES, V24, P675; Lakatos PL, 2008, WORLD J GASTROENTERO, V14, P3937, DOI 10.3748/wjg.14.3937; Lee H, 2014, ANN SURG ONCOL, V21, P1641, DOI 10.1245/s10434-013-3477-5; Lewinska A, 2017, TOXICOL LETT, V265, P117, DOI 10.1016/j.toxlet.2016.11.018; Lewinska A, 2015, TOXICOL IN VITRO, V29, P417, DOI 10.1016/j.tiv.2014.12.005; Liu L, 2019, BIOL RES, V52, DOI 10.1186/s40659-019-0243-6; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Longley DB, 2003, NAT REV CANCER, V3, P330, DOI 10.1038/nrc1074; Lowe SW, 2000, CARCINOGENESIS, V21, P485, DOI 10.1093/carcin/21.3.485; Mills CC, 2018, CANCER RES, V78, P320, DOI 10.1158/0008-5472.CAN-17-2782; Mir IA, 2015, NUTR CANCER, V67, P27, DOI 10.1080/01635581.2015.976320; Mishra J, 2013, CRIT REV ONCOL HEMAT, V86, P232, DOI 10.1016/j.critrevonc.2012.09.014; Morgan D M, 1998, Methods Mol Biol, V79, P179; Nafees S, 2018, ARCH MED RES, V49, P226, DOI 10.1016/j.arcmed.2018.09.008; Naso L, 2016, BIOORGAN MED CHEM, V24, P4108, DOI 10.1016/j.bmc.2016.06.053; Naugler WE, 2008, CURR OPIN GENET DEV, V18, P19, DOI 10.1016/j.gde.2008.01.020; Park HJ, 2017, FOOD CHEM TOXICOL, V99, P1, DOI 10.1016/j.fct.2016.11.008; Park JH, 2008, FOOD CHEM TOXICOL, V46, P3684, DOI 10.1016/j.fct.2008.09.056; Patel K, 2018, CHIN J INTEGR MED, V24, P551, DOI 10.1007/s11655-014-1960-x; Ren WY, 2003, MED RES REV, V23, P519, DOI 10.1002/med.10033; Saraste A, 2000, CARDIOVASC RES, V45, P528, DOI 10.1016/S0008-6363(99)00384-3; Shi XY, 2021, J CELL MOL MED, V25, P2563, DOI 10.1111/jcmm.16226; Silambarasan T, 2012, EUR J PHARMACOL, V679, P81, DOI 10.1016/j.ejphar.2011.12.040; Stewart ZA, 2003, TRENDS PHARMACOL SCI, V24, P139, DOI 10.1016/S0165-6147(03)00026-9; Sung H, 2021, CA-CANCER J CLIN, V71, P209, DOI 10.3322/caac.21660; TERAO J, 1994, ARCH BIOCHEM BIOPHYS, V308, P278, DOI 10.1006/abbi.1994.1039; Terzic J, 2010, GASTROENTEROLOGY, V138, P2101, DOI 10.1053/j.gastro.2010.01.058; THOMPSON CB, 1995, SCIENCE, V267, P1456, DOI 10.1126/science.7878464; Totta P, 2004, IUBMB LIFE, V56, P491, DOI 10.1080/15216540400010792; Dung TD, 2012, FOOD CHEM, V132, P2065, DOI 10.1016/j.foodchem.2011.11.149; Verhoeyen ME, 2002, J EXP BOT, V53, P2099, DOI 10.1093/jxb/erf044; Wu M, 2015, PHYTOMEDICINE, V22, P902, DOI 10.1016/j.phymed.2015.06.008; Xu ZX, 2018, TOXICOLOGY, V410, P231, DOI 10.1016/j.tox.2018.08.013; Yu H, 2009, NAT REV CANCER, V9, P798, DOI 10.1038/nrc2734; Zhang N, 2009, CANCER SCI, V100, P2459, DOI 10.1111/j.1349-7006.2009.01340.x	54	0	0	6	6	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X	1791-2431		ONCOL REP	Oncol. Rep.	JAN	2022	47	1							4	10.3892/or.2021.8215			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	XA0NT	WOS:000720355800001	34738632				2022-04-25	
J	Zeng, XH; Yan, T; Schupp, JE; Seo, YJ; Kinsella, TJ				Zeng, Xuehuo; Yan, Tao; Schupp, Jane E.; Seo, Yuji; Kinsella, Timothy J.			DNA mismatch repair initiates 6-thioguanine-induced autophagy through p53 activation in human tumor cells	CLINICAL CANCER RESEARCH			English	Article							CANCER-CELLS; COLORECTAL-CANCER; DEATH; DAMAGE; CYTOTOXICITY; INSTABILITY; APOPTOSIS; MUTATION; ARREST; SYSTEM	Purpose: We investigate the roles of DNA mismatch repair (MMR) and p53 in mediating the induction of autophagy in human tumor cells after exposure to 6-thioguanine (6-TG), a chemotherapy drug recognized by MMR. We also examine how activation of autophagy affects apoptosis (type I cell death) after MMR processing of 6-TG. Experimental Design: Using isogenic pairs of MLH1(-)/MLH1(+) human colorectal cancer cells (HCT116) and MSH2(-)/MSH2(+) human endometrial cancer cells (HEC59), we initially measure activation of autophagy for up to 3 days after 6-TG treatment using LC3, a specific marker of autophagy. We then assess the role of p53 in autophagic signaling of 6-TG MMR processing using both pifithrin-alpha cotreatment to chemically inhibit p53 transcription and small hairpin RNA inhibition of p53 expression. Finally, we use Atg5 small hairpin RNA inhibition of autophagy to assess the effect on apoptosis after MMR processing of 6-TG. Results: We find that MMR is required for mediating autophagy in response to 6-TG treatment in these human tumor cells. We also show that p53 plays an essential role in signaling from MMR to the autophagic pathway. Finally, our results indicate that 6-TG-induced autophagy inhibits apoptosis after MMR processing of 6-TG. Conclusions: These data suggest a novel function of MMR in mediating autophagy after a chemical (6-TG) DNA mismatch damage through p53 activation. The resulting autophagy inhibits apoptosis after MMR processing of 6-TG.	Univ Hosp Cleveland, Dept Radiat Oncol, Case Integrat Canc BiolProgram, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA; Case Western Reserve Univ, Dept Radiat Oncol, Cleveland, OH 44106 USA		Kinsella, TJ (corresponding author), Univ Hosp Cleveland, Dept Radiat Oncol, Case Integrat Canc BiolProgram, Case Comprehens Canc Ctr, LTR6068,11100 Euclid Ave, Cleveland, OH 44106 USA.	timothy.kinsella@uhhospitals.org			NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA112963, CA050595] Funding Source: Medline; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA050595] Funding Source: NIH RePORTER		AQUILINA G, 1993, CARCINOGENESIS, V14, P2097, DOI 10.1093/carcin/14.10.2097; Brown KD, 2003, NAT GENET, V33, P80, DOI 10.1038/ng1052; Cejka P, 2003, EMBO J, V22, P2245, DOI 10.1093/emboj/cdg216; Clodfelter JE, 2005, NUCLEIC ACIDS RES, V33, P3323, DOI 10.1093/nar/gki646; 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; DUNN WA, 1990, J CELL BIOL, V110, P1935, DOI 10.1083/jcb.110.6.1935; ELDEIRY WS, 1993, CELL, V75, P817, DOI 10.1016/0092-8674(93)90500-P; Feng ZH, 2005, P NATL ACAD SCI USA, V102, P8204, DOI 10.1073/pnas.0502857102; Hait WN, 2006, CLIN CANCER RES, V12, P1961, DOI 10.1158/1078-0432.CCR-06-0011; Harfe BD, 2000, ANNU REV GENET, V34, P359, DOI 10.1146/annurev.genet.34.1.359; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; Jacob S, 2001, CANCER RES, V61, P6555; Jacob S, 2002, BIOCHIMIE, V84, P27, DOI 10.1016/S0300-9084(01)01362-1; Jiricny J, 2000, CURR OPIN GENET DEV, V10, P157, DOI 10.1016/S0959-437X(00)00066-6; 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; KAT A, 1993, P NATL ACAD SCI USA, V90, P6424, DOI 10.1073/pnas.90.14.6424; Komarov PG, 1999, SCIENCE, V285, P1733, DOI 10.1126/science.285.5434.1733; Levine B, 2005, J CLIN INVEST, V115, P2679, DOI 10.1172/JCI26390; Lum JJ, 2005, CELL, V120, P237, DOI 10.1016/j.cell.2004.11.046; Marti TM, 2002, J CELL PHYSIOL, V191, P28, DOI 10.1002/jcp.10077; Miyaki M, 1997, NAT GENET, V17, P271, DOI 10.1038/ng1197-271; Mizushima N, 2001, J CELL BIOL, V152, P657, DOI 10.1083/jcb.152.4.657; Mizushima N, 2004, INT J BIOCHEM CELL B, V36, P2491, DOI 10.1016/j.biocel.2004.02.005; Modrich P, 1996, ANNU REV BIOCHEM, V65, P101, DOI 10.1146/annurev.bi.65.070196.000533; O'Brien V, 2006, CARCINOGENESIS, V27, P682, DOI 10.1093/carcin/bgi298; Paglin S, 2001, CANCER RES, V61, P439; PAPADOPOULOS N, 1994, SCIENCE, V263, P1625, DOI 10.1126/science.8128251; Ravikumar B, 2006, HUM MOL GENET, V15, P1209, DOI 10.1093/hmg/ddl036; Shiloh Y, 2001, CURR OPIN GENET DEV, V11, P71, DOI 10.1016/S0959-437X(00)00159-3; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Shintani T, 2004, SCIENCE, V306, P990, DOI 10.1126/science.1099993; Stojic L, 2004, DNA REPAIR, V3, P1091, DOI 10.1016/j.dnarep.2004.06.006; TRAGANOS F, 1994, METHOD CELL BIOL, V41, P185; UMAR A, 1994, J BIOL CHEM, V269, P14367; Umar A, 1997, CANCER RES, V57, P3949; Vogelstein B, 2000, NATURE, V408, P307, DOI 10.1038/35042675; Yan T, 2003, CLIN CANCER RES, V9, P2327; Yu L, 2004, SCIENCE, V304, P1500, DOI 10.1126/science.1096645; Zeng XH, 2006, J CELL SCI, V119, P259, DOI 10.1242/jcs.02735; Zou L, 2003, SCIENCE, V300, P1542, DOI 10.1126/science.1083430	42	60	64	0	2	AMER ASSOC CANCER RESEARCH	PHILADELPHIA	615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA	1078-0432			CLIN CANCER RES	Clin. Cancer Res.	FEB 15	2007	13	4					1315	1321		10.1158/1078-0432.CCR-06-1517			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	140JO	WOS:000244501100033	17317843	Bronze			2022-04-25	
J	Manogaran, P; Beeraka, NM; Huang, CY; Padma, VV				Manogaran, Prasath; Beeraka, Narasimha Murthy; Huang, Chih-Yang; Padma, Viswanadha Vijaya			Neferine and isoliensinine enhance 'intracellular uptake of cisplatin' and induce 'ROS-mediated apoptosis' in colorectal cancer cells - A comparative study	FOOD AND CHEMICAL TOXICOLOGY			English	Article						Cisplatin; Neferine; Isoliensinine; Colon cancer HCT-15 cells	STRAWBERRY TREE HONEY; NELUMBO-NUCIFERA; SIGNALING PATHWAYS; AUTOPHAGY; PROLIFERATION; INHIBITION; ACTIVATION; GENERATION; KINASE	Cisplatin (CDDP) is a potent platinum-based chemotherapeutic agent used to treat solid tumors including colorectal cancer via inducing cytotoxicity. CDDP usage is limited due to the chemoresistance and associated adverse effects. A combinatorial regimen of phytochemicals with anticancer activity along with approved anticancer drugs seems to be a hopeful strategy against cancer treatment. Lotus-derived compounds such as neferine and isoliensinine have proven significant chemosensitizing activity in different cancer cells. Present study aims to compare chemosensitizing activity/anticancer potential of neferine/isoliensinine in combinatorial regimen with CDDP. Results documented that neferine/isoliensinine with CDDP augmented 'intracellular uptake of cisplatin' consequently apoptosis in HCT-15 cells exemplified by 'apoptotic morphological changes', 'S phase cell cycle arrest', 'ROS mediated oxidative stress' with the concomitant escalation in intracellular calcium & dissipation of MMP and activation of MAPK/PI3K/AKT pathway'. Furthermore, isoliensinine combination with CDDP exclusively enhanced CDDP uptake and induced more ROS-mediated apoptosis compared to other treatment regimens. Combination regimens induced downregulation of Bcl2 and upregulation of cytochrome c, caspase 3, 9, PARP cleavage indicating apoptosis induction through the intrinsic pathway. Thus, the results of the present study suggest that CDDP combination with neferine/isoliensinine augments the anticancer potential of CDDP in an additive manner and decrease CDDP dose requirement.	[Manogaran, Prasath; Beeraka, Narasimha Murthy; Padma, Viswanadha Vijaya] Bharathiar Univ, Translat Res Lab, Dept Biotechnol, Coimbatore, Tamil Nadu, India; [Huang, Chih-Yang; Padma, Viswanadha Vijaya] China Med Univ, Lifu Teaching Bldg 12F,91 Hsueh Shih Rd, Taichung 40402, Taiwan		Padma, VV (corresponding author), Bharathiar Univ, Dept Biotechnol, Coimbatore 641046, Tamil Nadu, India.	vvijayapadma@rediffmail.com	Manogaran, Prasath/AAX-3974-2020	Huang, Chih-Yang/0000-0003-2347-0411; Beeraka, Narasimha/0000-0001-6879-7835; Manogaran, Prasath/0000-0001-6105-7818	DST-SERB [SB/SO/HS/075/2013]; DST-FISTDepartment of Science & Technology (India); UGC-SAPUniversity Grants Commission, India	We acknowledge our sincere thanks to DST-SERB (Funding ref. no. SB/SO/HS/075/2013) for their financial support to this entire study and DST-FIST& UGC-SAP for supporting the Department.	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Toxicol.	OCT	2019	132								110652	10.1016/j.fct.2019.110652			9	Food Science & Technology; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology; Toxicology	IW0JB	WOS:000484647100002	31255669				2022-04-25	
S	Dudkowska, M; Staniak, K; Bojko, A; Sikora, E		Gewirtz, DA; Fisher, PB		Dudkowska, Magdalena; Staniak, Karolina; Bojko, Agnieszka; Sikora, Ewa			The role of autophagy in escaping therapy-induced polyploidy/senescence	AUTOPHAGY AND SENESCENCE IN CANCER THERAPY	Advances in Cancer Research		English	Review; Book Chapter							COLON-CANCER CELLS; CELLULAR SENESCENCE; DOWN-REGULATION; TUMOR-CELLS; IONIZING-RADIATION; PRO-SENESCENCE; STEM-LIKE; IN-VITRO; POLYPLOIDY; MTOR	Autophagy is an evolutionarily conserved process necessary to maintain cell homeostasis in response to various forms of stress such as nutrient deprivation and hypoxia as well as functioning to remove damaged molecules and organelles. The role of autophagy in cancer varies depending on the stage of cancer. Cancer therapeutics can also simultaneously evoke cancer cell senescence and ploidy increase. Both cancer cell senescence and polyploidization are reversible by depolyploidization giving rise to the progeny. Autophagy activation may be indispensable for cancer cell escape from senescence/polyploidy. As cancer cell polyploidy is proposed to be involved in cancer origin, the role of autophagy in polyploidization/depolyploidization of senescent cancer cells seems to be crucial. Accordingly, this review is an attempt to understand the complicated interrelationships between reversible cell senescence/polyploidy and autophagy.	[Dudkowska, Magdalena; Staniak, Karolina; Bojko, Agnieszka; Sikora, Ewa] Polish Acad Sci, Lab Mol Bases Aging, Nencki Inst Expt Biol, Warsaw, Poland		Sikora, E (corresponding author), Polish Acad Sci, Lab Mol Bases Aging, Nencki Inst Expt Biol, Warsaw, Poland.	e.sikora@nencki.edu.pl	Bojko, Agnieszka/AAH-7914-2020; Staniak, Karolina Anna/AAB-5958-2022	Bojko, Agnieszka/0000-0002-8680-3300; Staniak, Karolina Anna/0000-0001-8236-4665; Sikora, Ewa/0000-0002-1111-1748	National Science CentreNational Science Centre, Poland [UMO-2015/17/B/NZ3/03531]	This work was supported by the National Science Centre, grant UMO-2015/17/B/NZ3/03531 for E.S.	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J	Seiwert, N; Neitzel, C; Stroh, S; Frisan, T; Audebert, M; Toulany, M; Kaina, B; Fahrer, J				Seiwert, Nina; Neitzel, Carina; Stroh, Svenja; Frisan, Teresa; Audebert, Marc; Toulany, Mahmoud; Kaina, Bernd; Fahrer, Jorg			AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells	CELL DEATH & DISEASE			English	Article							CYTOLETHAL DISTENDING TOXIN; MAMMALIAN TARGET; IONIZING-RADIATION; DAMAGE RESPONSE; TUMOR-CELLS; APOPTOSIS; P53; RAPAMYCIN; MULTIPLE; KINASE	DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells. We show that treatment of cells with CDT or IR increased the levels of the autophagy marker LC3B-II. Consistently, an enhanced formation of autophagosomes and a decrease of the autophagy substrate p62 were observed. Both CDT and IR concomitantly suppressed mTOR signaling and stimulated the autophagic flux. DSBs were demonstrated as the primary trigger of autophagy using a DNase I-defective CDT mutant, which neither induced DSBs nor autophagy. Genetic abrogation of p53 and inhibition of ATM signaling impaired the autophagic flux as revealed by LC3B-II accumulation and reduced formation of autophagic vesicles. Blocking of DSB-induced apoptotic cell death by the pan-caspase inhibitor Z-VAD stimulated autophagy. In line with this, pharmacological inhibition of autophagy increased cell death, while ATG5 knockdown did not affect cell death after DSB induction. Interestingly, both IR and CDT caused AKT activation, which repressed DSB-triggered autophagy independent of the cellular DNA-PK status. Further knockdown and pharmacological inhibitor experiments provided evidence that the negative autophagy regulation was largely attributable to AKT2. Finally, we show that upregulation of CDT-induced autophagy upon AKT inhibition resulted in lower apoptosis and increased cell viability. Collectively, the findings demonstrate that DSBs trigger pro-survival autophagy in an ATM-and p53-dependent manner, which is curtailed by AKT2 signaling.	[Seiwert, Nina; Neitzel, Carina; Stroh, Svenja; Kaina, Bernd; Fahrer, Jorg] Univ Med Ctr Mainz, Dept Toxicol, Obere Zahlbacher Str 67, D-55131 Mainz, Germany; [Frisan, Teresa] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden; [Audebert, Marc] Univ Toulouse, Toxalim Res Ctr Food Toxicol, INRA UMR1331, ENVT,INP Purpan,UPS, Toulouse 3, France; [Toulany, Mahmoud] Univ Tubingen, Div Radiobiol & Mol Environm Res, Dept Radiat Oncol, Tubingen, Germany; [Toulany, Mahmoud] German Canc Consortium DKTK, Partnersite Tuebingen, Heidelberg, Germany; [Toulany, Mahmoud] German Canc Res Ctr, Heidelberg, Germany		Fahrer, J (corresponding author), Univ Med Ctr Mainz, Dept Toxicol, Obere Zahlbacher Str 67, D-55131 Mainz, Germany.	fahrer@uni-mainz.de	Frisan, Teresa/H-8444-2019; Seiwert, Nina/ABD-2627-2020; AUDEBERT, Marc A/C-1153-2008; Kaina, Bernd/AAE-4692-2020	Frisan, Teresa/0000-0002-1209-0942; Seiwert, Nina/0000-0003-2169-3670; AUDEBERT, Marc A/0000-0001-7898-6912; 	University Medical Center Mainz (MAIFOR) [972 8716]; Johannes-Gutenberg University Mainz (Stufe I) [973 8807]; German Research Foundation (DFG)German Research Foundation (DFG) [FA 1034/3-1, DFG TO 685/2-1]	This work was supported by the University Medical Center Mainz (MAIFOR, grant no. 972 8716), the Johannes-Gutenberg University Mainz (Stufe I, grant no. 973 8807) and the German Research Foundation (DFG-FA 1034/3-1; DFG TO 685/2-1). We are grateful to Dr. Bert Vogelstein (John Hopkins University, Baltimore, MD, USA), Dr. Eric Hendrickson (University of Minnesota, Minneapolis, MN, USA) and Dr. Thomas Brunner (University of Konstanz, Konstanz, Germany) for providing cell lines.	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AUG	2017	8								e3019	10.1038/cddis.2017.418			14	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	FG1JB	WOS:000409550500057	28837154	gold, Green Submitted, Green Published			2022-04-25	
J	Schmukler, E; Wolfson, E; Elazar, Z; Kloog, Y; Pinkas-Kramarski, R				Schmukler, Eran; Wolfson, Eya; Elazar, Zvulun; Kloog, Yoel; Pinkas-Kramarski, Ronit			Continuous treatment with FTS confers resistance to apoptosis and affects autophagy	PLOS ONE			English	Article							CELL-DEATH; AURORA KINASE; CANCER CELLS; TUMOR-GROWTH; RAS; INHIBITION; DEGRADATION; P62/SQSTM1; MECHANISMS; ARREST	High percentage of human cancers involves alteration or mutation in Ras proteins, including the most aggressive malignancies, such as lung, colon and pancreatic cancers. FTS (Salirasib) is a farnesylcysteine mimetic, which acts as a functional Ras inhibitor, and was shown to exert anti-tumorigenic effects in vitro and in vivo. Previously, we have demonstrated that short-term treatment with FTS also induces protective autophagy in several cancer cell lines. Drug resistance is frequently observed in cancer cells exposed to prolonged treatment, and is considered a major cause for therapy inefficiency. Therefore, in the present study, we examined the effect of a prolonged treatment with FTS on drug resistance of HCT-116 human colon cancer cells, and the involvement of autophagy in this process. We found that cells grown in the presence of FTS for 6 months have become resistant to FTSinduced cell growth inhibition and cell death. Furthermore, we discovered that the resistant cells exhibit altered autophagy, reduced apoptosis and changes in Ras-related signaling pathways following treatment with FTS. Moreover we found that while FTS induces an apoptosis-related cleavage of p62, the FTS-resistant cells were more resistant to apoptosis and p62 cleavage.	[Schmukler, Eran; Wolfson, Eya; Kloog, Yoel; Pinkas-Kramarski, Ronit] Tel Aviv Univ, Dept Neurobiol, Ramat Aviv, Israel; [Elazar, Zvulun] Weizmann Inst Sci, Dept Biol Chem, Rehovot, Israel		Pinkas-Kramarski, R (corresponding author), Tel Aviv Univ, Dept Neurobiol, Ramat Aviv, Israel.	lironit@post.tau.ac.il		Pinkas-Kramarski, Ronit/0000-0002-1000-369X	Israel Science FoundationIsrael Science Foundation [848/12]; Israel Cancer Association; Kauffman Prostate Cancer Research Fund	This work was supported by the Israel Science Foundation (grant No. 848/12), the Israel Cancer Association and by the Kauffman Prostate Cancer Research Fund.	Ahmed D, 2013, ONCOGENESIS, V2, DOI 10.1038/oncsis.2013.35; Baines AT, 2011, FUTURE MED CHEM, V3, P1787, DOI [10.4155/fmc.11.121, 10.4155/FMC.11.121]; Biran A, 2011, INT J CANCER, V128, P691, DOI 10.1002/ijc.25367; Bjorkoy G, 2009, METHOD ENZYMOL, V452, P181, DOI 10.1016/S0076-6879(08)03612-4; Codogno P, 2005, CELL DEATH DIFFER, V12, P1509, DOI 10.1038/sj.cdd.4401751; Ding WX, 2012, BIOL CHEM, V393, P547, DOI 10.1515/hsz-2012-0119; Downward J, 2003, NAT REV CANCER, V3, P11, DOI 10.1038/nrc969; Erlich S, 2006, BIOCHEM PHARMACOL, V72, P427, DOI 10.1016/j.bcp.2006.05.007; Garraway LA, 2012, CANCER DISCOV, V2, P214, DOI 10.1158/2159-8290.CD-12-0012; Haklai R, 1998, BIOCHEMISTRY-US, V37, P1306, DOI 10.1021/bi972032d; Haklai R, 2008, CANCER CHEMOTH PHARM, V61, P89, DOI 10.1007/s00280-007-0451-6; Halaschek-Wiener J, 2000, MOL MED, V6, P693, DOI 10.1007/BF03402049; He W, 2013, AM J TRANSL RES, V5, P359; Jemal A, 2010, CA-CANCER J CLIN, V60, P277, DOI 10.3322/caac.20073; Jiang ZH, 2014, ONCOL REP, V31, P1249, DOI 10.3892/or.2014.2986; Karnoub AE, 2008, NAT REV MOL CELL BIO, V9, P517, DOI 10.1038/nrm2438; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Kollareddy M, 2012, INVEST NEW DRUG, V30, P2411, DOI 10.1007/s10637-012-9798-6; Longley DB, 2003, NAT REV CANCER, V3, P330, DOI 10.1038/nrc1074; Matallanas D, 2003, J BIOL CHEM, V278, P4572, DOI 10.1074/jbc.M209807200; Moscat J, 2009, EMBO REP, V10, P804, DOI 10.1038/embor.2009.172; Norman JM, 2010, AUTOPHAGY, V6, P1042, DOI 10.4161/auto.6.8.13337; Rotblat B, 2008, METHOD ENZYMOL, V439, P467, DOI 10.1016/S0076-6879(07)00432-6; Sahani MH, 2014, AUTOPHAGY, V10, P431, DOI 10.4161/auto.27344; Schmukler E, 2014, ONCOTARGET, V5, P173, DOI 10.18632/oncotarget.1500; Schmukler E, 2013, ONCOTARGET, V4, P145; Shi J, 2014, CELL DEATH DIFFER, V21, P1432, DOI 10.1038/cdd.2014.58; Sridharan Savitha, 2011, Cancers (Basel), V3, P2630, DOI 10.3390/cancers3022630; Wolfson E, 2015, BIOL CELL, V107, P130, DOI 10.1111/boc.201400087; Yuan CX, 2015, DRUG DES DEV THER, V9, P487, DOI 10.2147/DDDT.S74127; Zeng RX, 2014, CELL BIOL INT, V38, P1221, DOI 10.1002/cbin.10311	31	3	3	0	1	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1932-6203			PLOS ONE	PLoS One	FEB 2	2017	12	2							e0171351	10.1371/journal.pone.0171351			19	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	EN7DB	WOS:000396161200131	28151959	Green Submitted, Green Published, gold			2022-04-25	
J	Zhu, XG; Huang, ZL; Chen, Y; Zhou, J; Hu, SQ; Zhi, QM; Song, SD; Wang, YN; Wan, DW; Gu, W; Zhou, H; Zhang, B; Cao, W; He, SB				Zhu, Xinguo; Huang, Zhilong; Chen, Yan; Zhou, Jian; Hu, Shuiqing; Zhi, Qiaoming; Song, Shiduo; Wang, Yanan; Wan, Daiwei; Gu, Wen; Zhou, Hao; Zhang, Bo; Cao, Wei; He, Songbing			Effect of CLN3 silencing by RNA interference on the proliferation and apoptosis of human colorectal cancer cells	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Colorectal cancer; CLN3; RNA interference; Proliferation; Apoptosis	BATTEN-DISEASE PROTEIN; COLON-CANCER; AUTOPHAGY; EXPRESSION; CERAMIDE; THERAPY; KINASE; DEATH; GENE	Apoptosis constitutes a system for the removal of aged, or damaged cells, which is regulated by the interplay of pro-apoptotic and antiapoptotic proteins. Previous study has shown that Juvenile Batten disease protein, CLN3, is antiapoptotic gene in NT2 neuronal precursor cells and a few types of cancers. However, in colorectal cancer, whether CLN3 also play its antiapoptotic role and the effect of targeted controlling CLN3 on the biological behavior of human colorectal cancer cell is unknown. We employed the sequence-specific siRNA silencing the CLN3 gene and investigated its effects on growth and apoptosis of colorectal cancer HCT116 cells, which has highest elevation of CLN3 expression among four colorectal cancer cell lines. After CLN3 specific siRNA transfection, mRNA and protein expression levels of CLN3 in HCT116 cells were noticeably decreased. Moreover, CLN3-siRNA inhibited the proliferation of colorectal cancer cells, promoted their apoptosis and induced G0/G1 cell cycle arrest. Our current study demonstrated that CLN3 was expressed in colorectal cancer cells at a high frequency. Moreover, CLN3 down-regulation with RNA interference can inhibit proliferation, apoptosis, and cell cycle progression of colorectal cancer cells. Our study represented a potential new approach to understanding the role of CLN3 in cancer and provides a potential novel strategy colorectal cancer therapy. (C) 2014 Elsevier Masson SAS. All rights reserved.	[Zhu, Xinguo; Huang, Zhilong; Chen, Yan; Zhou, Jian; Zhi, Qiaoming; Song, Shiduo; Gu, Wen; Zhou, Hao; Cao, Wei; He, Songbing] Soochow Univ, Dept Gen Surg, Affiliated Hosp 1, Suzhou 215006, Jiangsu, Peoples R China; [Hu, Shuiqing] Shanghai Jiao Tong Univ, Sch Med, Peoples Hosp 9, Dept Clin Labs, Shanghai 200011, Peoples R China; [Wang, Yanan] Nanjing Med Univ, Affiliated Hosp, Suzhou Municipal Hosp, Dept Clin Lab, Suzhou 215006, Peoples R China; [Wan, Daiwei] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gen Surg, Guangzhou 510000, Guangdong, Peoples R China; [He, Songbing] Shanghai Jiao Tong Univ, Sch Med, Shanghai 200025, Peoples R China; [He, Songbing] Washington Univ, Sch Med, St Louis, MO 63110 USA		He, SB (corresponding author), Soochow Univ, Dept Gen Surg, Affiliated Hosp 1, 188 Shizi St, Suzhou 215006, Jiangsu, Peoples R China.	captain_hsb@163.com			Nature Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81201905, 81100023]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2013M540374]; Nature Science Research Grants in University of Jiangsu Province of China [12KJB320009]; Medical Science and Technology Development Foundation of Jiangsu Province of China [H201209]; Innovation Program of Shanghai Municipal Education CommissionInnovation Program of Shanghai Municipal Education Commission [12YZ050]; Shanghai Postdoctoral Scientific Program of China [13R21415200]; Science and Technology Bureau of Suzhou City of China [SYS201220]; Government Overseas Scholarship from Department of Education of Jiangsu Province of China	This study was supported by Project of Nature Science Foundation of China (81201905, 81100023), China Postdoctoral Science Foundation (2013M540374), Nature Science Research Grants in University of Jiangsu Province of China (12KJB320009), Project of Medical Science and Technology Development Foundation of Jiangsu Province of China (H201209), Innovation Program of Shanghai Municipal Education Commission (12YZ050), Shanghai Postdoctoral Scientific Program of China (13R21415200) and Science and Technology Research Project of in Science and Technology Bureau of Suzhou City of China (SYS201220) and sponsored by Government Overseas Scholarship from Department of Education of Jiangsu Province of China.	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Pharmacother.	APR	2014	68	3					253	258		10.1016/j.biopha.2013.12.010			6	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	AG4NA	WOS:000335395400001	24556023				2022-04-25	
J	Pawlak, A; Strzadala, L; Kalas, W				Pawlak, Alicja; Strzadala, Leon; Kalas, Wojciech			Non-genomic effects of the NR4A1/Nur77/TR3/NGFIB orphan nuclear receptor	STEROIDS			English	Review						NR4A1; Nuclear receptor; Non-genomic; Cancer; Apoptosis; Autophagy	AUTOPHAGIC CELL-DEATH; ENDOPLASMIC-RETICULUM; ER STRESS; BCL-XL; K-RAS; NUR77; APOPTOSIS; GENE; TRANSLOCATION; TR3/NUR77	The orphan nuclear receptor NR4A1/Nur77/TR3/NGFIB acts primarily as a transcription factor to regulate the expression of multiple genes. However, increasing research attention has recently been given to non-genomic activities of NR4A1. The first description of a non-genomic action of NR4A1 referred to the conversion of anti-apoptotic Bcl-2 into a pro-apoptotic protein by direct interaction with NR4A1. In response to certain apoptotic stimuli, NR4A1 translocates from the nucleus to the mitochondrial outer membrane (MOM) where it associates with Bcl-2 and thereby causes apoptosis. Afterwards, it appeared that NR4A1 could also bind and convert other anti-apoptotic Bcl-2 family members. The latest studies indicate a significant role of NR4A1 in the process of autophagy. For example, a new NR4A1-mediated pathway specific for melanoma cells has been described where NR4A1 interacts with the adenine nucleotide translocase 1 (ANTI.) on the mitochondrial inner membrane (MIM) leading to induction of the autophagy pathway. Moreover, NR4A1 interaction with cytoplasmic p53 may also contribute to the induction of autophagy. In addition to mitochondria, NR4A1 could be translocated to the outer membrane of the endoplasmic reticulum (ER) and associate with Bcl-2 or translocon-associated protein subunit gamma (TRAP gamma) causing ER stress-induced apoptosis. NR4A1 also contributes to the proteasomal degradation of p-catenin in colon cancer cells in vitro and in vivo, as well as to the stabilization of hypoxia-inducible factor-1 alpha (HIF-1 alpha) under non-hypoxic conditions. This review summarizes research findings on non-genomic effects of NR4A1 in normal and cancer cells. (C) 2015 Elsevier Inc. All rights reserved.	[Pawlak, Alicja; Strzadala, Leon; Kalas, Wojciech] Polish Acad Sci, Ludwik Hirszfeld Inst Immunol & Expt Therapy, PL-53114 Wroclaw, Poland; [Kalas, Wojciech] Jan Dlugosz Univ Czestochowa, PL-42200 Czestochowa, Poland		Pawlak, A (corresponding author), Polish Acad Sci, Ludwik Hirszfeld Inst Immunol & Expt Therapy, Rudolfa Weigla 12, PL-53114 Wroclaw, Poland.	alicja.pawlak@iitd.pan.wroc.pl; strzadal@iitd.pan.wroc.pl; kalas@iitd.pan.wroc.pl	Kałas, Wojciech/AAB-4469-2019	Kałas, Wojciech/0000-0003-2656-5192; Strzadala, Leon/0000-0002-7323-2254	NCN Grant [2011/01/B/NZ4/00938]	This study was supported by NCN Grant No. 2011/01/B/NZ4/00938.	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J	Zhang, DS; Fei, Q; Li, J; Zhang, C; Sun, Y; Zhu, CY; Wang, FZ; Sun, YM				Zhang, Dongsheng; Fei, Qiang; Li, Juan; Zhang, Chuan; Sun, Ye; Zhu, Chunyan; Wang, Fengzhen; Sun, Yueming			2-Deoxyglucose Reverses the Promoting Effect of Insulin on Colorectal Cancer Cells In Vitro	PLOS ONE			English	Article							TARGETING SURVIVIN; DIABETES-MELLITUS; PROSTATE-CANCER; COLON-CANCER; 2-DEOXY-D-GLUCOSE; METABOLISM; AUTOPHAGY; GLUCOSE; INHIBITION; GLYCOLYSIS	An increased risk of colorectal cancer is related to the development of metabolic syndromes including hyperglycemia, and hyperinsulinemia. The high circulatory levels of glucose and/or insulin or the application of exogenous insulin may promote carcinogenesis, cancer progression and metastasis, which can be attributed to the Warburg effect or aerobic glycolysis. We attempted to resolve these existing questions by applying the glucose analog 2-deoxyglucose (2DG). According to the in vitro studies we performed, the glycolysis of colorectal cancer cells could be interrupted by 2DG as it decreased the cellular productions of ATP and lactate. In addition, 2DG induced apoptosis and cell cycle arrest, and inhibited proliferation, migration and invasion of these cells. Since insulin can stimulate the cellular uptake of hexose, including 2DG, the combination of 2DG and insulin improved the cytotoxicity of 2DG and meanwhile overcame the cancer-promoting effects of insulin. This in vitro study provided a viewpoint of 2DG as a potential therapeutic agent against colorectal cancer, especially for patients with concomitant hyperinsulinemia or treated with exogenous insulin.	[Zhang, Dongsheng; Fei, Qiang; Li, Juan; Zhang, Chuan; Sun, Ye; Zhu, Chunyan; Sun, Yueming] Nanjing Med Univ, Affiliated Hosp 1, Dept Colorectal Surg, Nanjing, Jiangsu, Peoples R China; [Fei, Qiang; Li, Juan; Zhang, Chuan; Sun, Ye; Zhu, Chunyan] Nanjing Med Univ, Sch Clin Med 1, Nanjing, Jiangsu, Peoples R China; [Wang, Fengzhen] China Pharmaceut Univ, Dept Pharmaceut, Nanjing, Jiangsu, Peoples R China		Sun, YM (corresponding author), Nanjing Med Univ, Affiliated Hosp 1, Dept Colorectal Surg, Nanjing, Jiangsu, Peoples R China.	jssunym@126.com			Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)	This study was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). No potential conflicts of interest were disclosed.	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J	Liu, J; Liu, X; Qian, JQ; Meng, C; Zhu, P; Hang, JY; Wang, YL; Xiong, B; Qiu, XD; Zhu, WZ; Yang, YM; Zhang, YN; Ling, Y				Liu, Ji; Liu, Xin; Qian, Jianqiang; Meng, Chi; Zhu, Peng; Hang, Jiaying; Wang, Yaling; Xiong, Biao; Qiu, Xiaodong; Zhu, Weizhong; Yang, Yumin; Zhang, Yanan; Ling, Yong			Development of pH/Glutathione-Responsive Theranostic Agents Activated by Glutathione S-Transferase pi for Human Colon Cancer	JOURNAL OF MEDICINAL CHEMISTRY			English	Article							TUMOR MICROENVIRONMENT; DNA-BINDING; ANTICANCER; APOPTOSIS; AUTOPHAGY; INFLAMMATION; RESISTANCE; ANALOGS; DESIGN; ALPHA	Two novel theranostic agents HJTA and HJTB have been designed and synthesized by covalently linking a beta-carboline derivative, with antitumor activities and pH-responsive fluorescence, with a 2-exomethylenecyclohexanone moiety, which can be activated by the tumor-targeting glutathione (GSH)/glutathione S-transferase pi (GST pi). These agents showed pH- and GSH-dual-responsive fluorescence in tumor cells but not in normal cells. Importantly, HJTA selectively illuminated tumor tissue for up to 7 h and generated precise visualization of orthotopic colonic tumors through the blood circulation system in intraoperative mice. Furthermore, HJTA exhibited potent and selective antiproliferative activities and colonic tumor inhibition in mice. Finally, HJTA induced great cancer cell apoptosis and autophagy by regulating the expression of apoptotic and autophagic proteins. Therefore, this pH/GSH-dual-responsive fluorescent probe with cancer-targeting therapeutic activity provides a novel tool for precise diagnosis and tumor treatment, therefore broadening the impact of multifunctional agents as theranostic precision medicines.	[Liu, Ji; Liu, Xin; Qian, Jianqiang; Meng, Chi; Zhu, Peng; Hang, Jiaying; Wang, Yaling; Xiong, Biao; Qiu, Xiaodong; Zhu, Weizhong; Yang, Yumin; Zhang, Yanan; Ling, Yong] Nantong Univ, Sch Pharm, Nantong 226001, Peoples R China; [Liu, Ji; Liu, Xin; Qian, Jianqiang; Meng, Chi; Zhu, Peng; Hang, Jiaying; Wang, Yaling; Xiong, Biao; Qiu, Xiaodong; Zhu, Weizhong; Yang, Yumin; Zhang, Yanan; Ling, Yong] Nantong Univ, Jiangsu Prov Key Lab Inflammat & Mol Drug Target, Nantong 226001, Peoples R China; [Zhu, Peng; Wang, Yaling; Ling, Yong] Nantong Univ, Coinnovat Ctr Neuroregenerat, Minist Educ & Jiangsu Prov, Key Lab Neuroregenerat, Nantong 226001, Peoples R China		Zhang, YN; Ling, Y (corresponding author), Nantong Univ, Sch Pharm, Nantong 226001, Peoples R China.; Zhang, YN; Ling, Y (corresponding author), Nantong Univ, Jiangsu Prov Key Lab Inflammat & Mol Drug Target, Nantong 226001, Peoples R China.; Ling, Y (corresponding author), Nantong Univ, Coinnovat Ctr Neuroregenerat, Minist Educ & Jiangsu Prov, Key Lab Neuroregenerat, Nantong 226001, Peoples R China.	zhangyanan@gmail.com; Lyyy111@sina.com		zhu, peng/0000-0002-4148-9135	Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31830028, 21977058]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2018 T110533, 2016 M590488, 1601136B]; Project of "Jiangsu Six Peaks of Talent" [2016-SWYY-CXTD-008, 2014-SWYY-044]; Project of "Jiangsu 333 high-level talents", Jiangsu Province Innovation Project of Postgraduate Training [KYCX19 2086]; Applied Research Projects of Nantong City [MS12018079, JC2018125]; Jiangsu Province Postdoctoral Science Foundation [2018 T110533, 2016 M590488, 1601136B]	This work was financially supported by the Natural Science Foundation of China (Nos. 31830028 and 21977058), China and Jiangsu Province Postdoctoral Science Foundation (2018 T110533, 2016 M590488, and 1601136B), the Project of "Jiangsu Six Peaks of Talent" (2016-SWYY-CXTD-008 and 2014-SWYY-044), the Project of "Jiangsu 333 high-level talents", Jiangsu Province Innovation Project of Postgraduate Training (KYCX19 2086), and Applied Research Projects of Nantong City (MS12018079 and JC2018125).	AGHIL O, 1992, ANTI-CANCER DRUG DES, V7, P67; Chatterjee A, 2018, CANCER LETT, V433, P33, DOI 10.1016/j.canlet.2018.06.028; Chen DQ, 2018, J AM CHEM SOC, V140, P7373, DOI 10.1021/jacs.7b12025; DIILIO C, 1985, CANCER LETT, V29, P37, DOI 10.1016/0304-3835(85)90120-X; Estrella V, 2013, CANCER RES, V73, P1524, DOI 10.1158/0008-5472.CAN-12-2796; Feng LL, 2018, ACS NANO, V12, P11000, DOI 10.1021/acsnano.8b05042; Gao M, 2017, CHEM SOC REV, V46, P2237, DOI 10.1039/c6cs00908e; Hamilton DS, 2003, J AM CHEM SOC, V125, P15049, DOI 10.1021/ja030396p; Hamilton DS, 2002, ORG LETT, V4, P1209, DOI 10.1021/ol025650h; Han JY, 2010, CHEM REV, V110, P2709, DOI 10.1021/cr900249z; Hengstler JG, 1998, CANCER LETT, V128, P105, DOI 10.1016/S0304-3835(98)00059-7; Huang Q, 2011, NAT MED, V17, P860, DOI 10.1038/nm.2385; Junttila MR, 2013, NATURE, V501, P346, DOI 10.1038/nature12626; Kamal A, 2015, BIOORGAN MED CHEM, V23, P5511, DOI 10.1016/j.bmc.2015.07.037; Kong C, 2019, ACS NANO, V13, P4049, DOI 10.1021/acsnano.8b08246; Kotoku N, 2011, ORG LETT, V13, P3514, DOI 10.1021/ol201327u; Kovvuri J, 2018, EUR J MED CHEM, V143, P1563, DOI 10.1016/j.ejmech.2017.10.054; Ling BP, 2019, ACS APPL MATER INTER, V11, P11157, DOI 10.1021/acsami.8b22487; Ling Y, 2019, EUR J MED CHEM, V168, P515, DOI 10.1016/j.ejmech.2019.02.054; Ling Y, 2015, J MED CHEM, V58, P9214, DOI 10.1021/acs.jmedchem.5b01052; LIU Z, 2014, ANGEW CHEM, V126, P4022, DOI DOI 10.1002/ANGE.201311161; Lu YP, 2016, EUR J PHARMACOL, V771, P130, DOI 10.1016/j.ejphar.2015.12.026; Ma WL, 2019, ACS OMEGA, V4, P15240, DOI 10.1021/acsomega.9b01863; MELHUISH WH, 1961, J PHYS CHEM-US, V65, P229, DOI 10.1021/j100820a009; Ngabire D, 2017, INT J MOL SCI, V18, DOI 10.3390/ijms18092016; Ni H, 2017, MED CHEM RES, V26, P2861, DOI 10.1007/s00044-017-1985-8; Nie XK, 2015, J APPL TOXICOL, V35, P851, DOI 10.1002/jat.3084; OBrien ML, 1996, EUR J CANCER, V32A, P967, DOI 10.1016/0959-8049(96)00051-2; Qiao CM, 2018, ADV MATER, V30, DOI 10.1002/adma.201705054; Quail DF, 2013, NAT MED, V19, P1423, DOI 10.1038/nm.3394; Song QL, 2017, NANO LETT, V17, P6366, DOI 10.1021/acs.nanolett.7b03186; Sun FH, 2019, BIOCHEM PHARMACOL, V162, P142, DOI 10.1016/j.bcp.2018.10.021; Townsend DM, 2003, ONCOGENE, V22, P7369, DOI 10.1038/sj.onc.1206940; Tredan O, 2007, J NATL CANCER I, V99, P1441, DOI 10.1093/jnci/djm135; Uthaman Saji, 2018, Biomater Res, V22, P22, DOI 10.1186/s40824-018-0132-z; Wang F, 2017, BIOMED PHARMACOTHER, V92, P672, DOI 10.1016/j.biopha.2017.05.129; Wang Q, 2018, CANCER LETT, V438, P17, DOI 10.1016/j.canlet.2018.08.028; Webb BA, 2011, NAT REV CANCER, V11, P671, DOI 10.1038/nrc3110; Wu T, 2017, CANCER LETT, V387, P61, DOI 10.1016/j.canlet.2016.01.043; Yin GX, 2019, ANGEW CHEM INT EDIT, V58, P4557, DOI 10.1002/anie.201813935; Zhang PF, 2018, J AM CHEM SOC, V140, P14980, DOI 10.1021/jacs.8b09396; Zhao ZL, 2013, ANGEW CHEM INT EDIT, V52, P7487, DOI 10.1002/anie.201302557; Zhong ZY, 2016, CELL, V166, P288, DOI 10.1016/j.cell.2016.05.051; Zou Y, 2018, J MED CHEM, V61, P1821, DOI 10.1021/acs.jmedchem.7b01096	44	7	6	7	34	AMER CHEMICAL SOC	WASHINGTON	1155 16TH ST, NW, WASHINGTON, DC 20036 USA	0022-2623	1520-4804		J MED CHEM	J. Med. Chem.	SEP 10	2020	63	17					9271	9283		10.1021/acs.jmedchem.0c00354			13	Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED); Index Chemicus (IC)	Pharmacology & Pharmacy	NR3WG	WOS:000571493400022	32787089				2022-04-25	
J	Li, JC; Frederick, ALM; Jin, Y; Guo, C; Xiao, H; Wood, RJ; Liu, ZH				Li, Jinchao; Frederick, Armina-Lyn M.; Jin, Yu; Guo, Chi; Xiao, Hang; Wood, Richard J.; Liu, Zhenhua			The Prevention of a High Dose of Vitamin D or Its Combination with Sulforaphane on Intestinal Inflammation and Tumorigenesis in Apc(1638N) Mice Fed a High-Fat Diet	MOLECULAR NUTRITION & FOOD RESEARCH			English	Article						colorectal cancer; inflammation; obesity; sulforaphane; vitamin D	HISTONE DEACETYLASE INHIBITORS; SERUM 25-HYDROXYVITAMIN D; NECROSIS-FACTOR-ALPHA; COLORECTAL-CANCER; INDUCED APOPTOSIS; MOUSE MODELS; TNF-ALPHA; IN-VITRO; COLON; AUTOPHAGY	Scope The previous study shows that obesity-promoted inflammation is responsible for the activation of the intestinal tumorigenic Wnt-signaling. The present study aims to test a dietary strategy, dietary supplementation with a high dose of vitamin D (VD) or its combination with sulforaphane (SFN) to inhibit intestinal inflammation and obesity-associated tumorigenesis. Methods and results Apc(1638N) mice are randomly divided into four groups: LF, a low-fat diet (10 kcal% fat) with 200 IU VD; HF, a high-fat diet (60 kcal% fat) with 200 IU VD; HFD, a high-fat diet with 5000 IU VD; and HFDS, a high-fat diet plus 5000 IU VD and 0.23 g SFN per approximate to 4000 kcal. VD administration decreased tumor incidence and size, and the co-administration with SFN (HFDS) magnified the effects. Inflammation and Wnt-signaling are suppressed by VD. The addition of SFN decreased the activity of histone deacetylase (HDAC) and increased autophagy. Conclusion The administration of VD, at 5000 IU level, exerts an anti-inflammatory property and leads to suppressed intestinal Wnt-signaling and tumorigenesis in obese mice. The molecular function of SFN on a high dose of VD supplementation, although displayed on the inhibition of HDAC and the activation of autophagy, needs further investigation.	[Li, Jinchao; Frederick, Armina-Lyn M.; Jin, Yu; Guo, Chi; Wood, Richard J.; Liu, Zhenhua] Univ Massachusetts, Dept Nutr, Sch Publ Hlth & Hlth Sci, Amherst, MA 01002 USA; [Jin, Yu] China Med Univ, Shengjing Hosp, Dept Gastroenterol, Shenyang 110004, Liaoning, Peoples R China; [Guo, Chi] Hunan Univ, Dept Mol Med, Changsha 410006, Hunan, Peoples R China; [Xiao, Hang] Univ Massachusetts, Dept Food Sci, Amherst, MA 01002 USA; [Liu, Zhenhua] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02153 USA		Liu, ZH (corresponding author), Univ Massachusetts, Dept Nutr, Sch Publ Hlth & Hlth Sci, Amherst, MA 01002 USA.	zliu@nutrition.umass.edu	Xiao, Hang/Y-2797-2019	Liu, Zhenhua/0000-0001-8439-055X; Xiao, Hang/0000-0001-6194-2796	USDAUnited States Department of Agriculture (USDA) [2014-67017-21762, MAS00514]; Dean's Incentive Grant, School of Public Health and Health Sciences	J.L. performed all the experiments. A.M.F., Y.J., and C.G. contributed to the collection, interpretation, and analysis of data throughout the experiment; all authors contributed to the discussion. Z.L., H.X., and R.J.W. designed the research and directed the project. J.L. and Z.L. wrote the manuscript. All authors reviewed the manuscript. This project was supported in part by USDA grants (2014-67017-21762 and MAS00514, Z.L. and R.J.W., respectively) and a Dean's Incentive Grant, School of Public Health and Health Sciences (Z.L.)	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Nutr. Food Res.	FEB	2019	63	4							1800824	10.1002/mnfr.201800824			10	Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology	HL7EY	WOS:000458902400003	30447137	Bronze			2022-04-25	
J	Xu, ZY; Chen, L; Xiao, ZG; Zhu, YH; Jiang, H; Jin, Y; Gu, C; Wu, YL; Wang, L; Zhang, W; Zuo, J; Zhou, DX; Luan, JJ; Shen, J				Xu Zhenyu; Chen Lu; Xiao Zhangang; Zhu Yanhong; Jiang Hui; Jin Yan; Gu Cheng; Wu Yilai; Wang Lin; Zhang Wen; Zuo Jian; Zhou Dexi; Luan Jiajie; Shen Jing			Potentiation of the anticancer effect of doxorubicinin drug-resistant gastric cancer cells by tanshinone IIA	PHYTOMEDICINE			English	Article						Tanshinone IIA; Multidrug resistance protein 1; Autophagy; Drug resistance; Gastric cancer	ROS-DEPENDENT APOPTOSIS; COLON-CANCER; MULTIDRUG-RESISTANCE; MOLECULAR-MECHANISMS; SALVIA-MILTIORRHIZA; P-GP; DIHYDROTANSHINONE; AUTOPHAGY; CRYPTOTANSHINONE; INHIBITION	Background: Gastric cancer is the fifth commonest cancer and the third cause of cancer-related deaths all over the world. The effectiveness of chemotherapy is still limited by drug resistance in gastric cancer. Tanshinones, abietane diterpenes isolated from the traditional Chinese medicine Danshen (Salvia miltiorrhiza), have exhibited versatile anticancer activities in particular the ability to overcome drug resistance in different cancers. Purpose: The current study aimed to explore the capacity of tanshinone IIA, the most abundant tanshinone found in the plant Danshen, to overcome drug resistance of gastric cancer cells to a commonly used anticancer drug doxorubicin. Study design: Sensitivity of cell lines to doxorubicin was determined by MTT assay. Doxorubicin resistant gastric cancer cell lines was established by step selection with increasing concentrations of doxorubicin. Cell cycle arrest, apoptosis and doxorubicin efflux were analyzed by flow cytometry. The expression of MRP1 was determined by realtime PCR and western-blot. Results: Based on the IC50 values of doxorubicin, we identified the doxorubicin-sensitive gastric cancer cell lines SNU-719 and SNU-610 as well as the cell lines relatively resistant to doxorubicin including SNU-638, SNU-668, SNU-216 and SNU-620. We also established two drug-resistant cell lines SNU-719R and SNU-610R. Despite the fact that tanshinone IIA alone showed no cytotoxicity on these gastric cells, we found the potentiation of the anticancer effect of doxorubicin in drug-resistant gastric cancer cells by tanshinone IIA. Furthermore, using doxorubicin-sensitive cell line SNU-719 and doxorubicin-resistant cell lines SNU-719R and SNU-620, we revealed the pivotal roles of MRP1. Its overexpression impaired cell cycle arrest and suppressed apoptosis in the development of both intrinsic and acquired drug resistance in gastric cancer cells to doxorubicin. Importantly, inhibition of MRP1 function enhanced cell cycle arrest, increased apoptosis and induced autophagic cell death which contributed to the capability of tanshinone IIA to potentiate the anticancer effect of doxorubicin in drugresistant gastric cancer cells. Conclusion: Tanshinone IIA is an interesting agent with potential to treat drug-resistant gastric cancer in combination therapy.	[Xu Zhenyu; Chen Lu; Zhu Yanhong; Jiang Hui; Gu Cheng; Wu Yilai; Wang Lin; Zhang Wen; Zuo Jian; Zhou Dexi; Luan Jiajie] Wannan Med Coll, Yijishan Affiliated Hosp, Dept Pharm, Wuhu, Anhui, Peoples R China; [Xiao Zhangang; Shen Jing] Southwest Med Univ, Sch Pharm, Dept Pharmacol, Lab Mol Pharmacol, Luzhou, Sichuan, Peoples R China; [Jin Yan] Wannan Med Coll, Yijishan Affiliated Hosp, Dept Gastrointestinal Surg, Wuhu, Anhui, Peoples R China		Luan, JJ (corresponding author), Wannan Med Coll, Yijishan Affiliated Hosp, Dept Pharm, Wuhu, Anhui, Peoples R China.; Shen, J (corresponding author), Southwest Med Univ, Sch Pharm, Dept Pharmacol, Lab Mol Pharmacol, Luzhou, Sichuan, Peoples R China.	luanjiajie757@163.com; crystal_stray@126.com	Jiajie, Luan/AAM-2206-2021; 周, 德喜/ABF-6374-2020	Jiajie, Luan/0000-0002-3499-1944; 	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81602240, 81503093, 81602166, 81672444]; University Natural Science Research Project of Anhui ProvinceNatural Science Foundation of Anhui Province [KJ2016A732]; Talent Research Fund of Yijiahan Hospital [YR201504]; Joint Funds of the Southwest Medical University Luzhou [2016LZXNYD-T01, 2017LZXNYD-Z05, 2017LZXNYD-J09]	This work was supported by the National Natural Science Foundation of China (Grant nos. 81602240, 81503093, 81602166, and 81672444), the University Natural Science Research Project of Anhui Province (KJ2016A732), the Talent Research Fund of Yijiahan Hospital (YR201504), the Joint Funds of the Southwest Medical University & Luzhou (2016LZXNYD-T01, 2017LZXNYD-Z05 and 2017LZXNYD-J09).	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J	Chatterji, P; Williams, PA; Whelan, KA; Samper, FC; Andres, SF; Simon, LA; Parham, LR; Mizuno, R; Lundsmith, ET; Lee, DSM; Liang, S; Wijeratne, HRS; Marti, S; Chau, L; Giroux, V; Wilkins, BJ; Wu, GD; Shah, P; Tartaglia, GG; Hamilton, KE				Chatterji, Priya; Williams, Patrick A.; Whelan, Kelly A.; Samper, Fernando C.; Andres, Sarah F.; Simon, Lauren A.; Parham, Louis R.; Mizuno, Rei; Lundsmith, Emma T.; Lee, David S. M.; Liang, Shun; Wijeratne, H. R. Sagara; Marti, Stefanie; Chau, Lillian; Giroux, Veronique; Wilkins, Benjamin J.; Wu, Gary D.; Shah, Premal; Tartaglia, Gian G.; Hamilton, Kathryn E.			Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP1/IGF2BP1	EMBO REPORTS			English	Article						colonic repair; IGF2BP1; IMP1; inflammatory bowel disease; RNA binding protein	MYC MESSENGER-RNA; PANETH CELL PHENOTYPES; CODING REGION; CRD-BP; QUANTITATIVE PREDICTIONS; IMP1 PROMOTES; IN-VITRO; AUTOPHAGY; GROWTH; TRANSLATION	RNA binding proteins, including IMP1/IGF2BP1, are essential regulators of intestinal development and cancer. Imp1 hypomorphic mice exhibit gastrointestinal growth defects, yet the specific role for IMP1 in colon epithelial repair is unclear. Our prior work revealed that intestinal epithelial cell-specific Imp1 deletion (Imp1(Delta IEC)) was associated with better regeneration in mice after irradiation. Here, we report increased IMP1 expression in patients with Crohn's disease and ulcerative colitis. We demonstrate that Imp1(Delta IEC) mice exhibit enhanced recovery following dextran sodium sulfate (DSS)-mediated colonic injury. Imp1(Delta IEC) mice exhibit Paneth cell granule changes, increased autophagy flux, and upregulation of Atg5. In silico and biochemical analyses revealed direct binding of IMP1 to MAP1LC3B, ATG3, and ATG5 transcripts. Genetic deletion of essential autophagy gene Atg7 in Imp1(Delta IEC) mice revealed increased sensitivity of double-mutant mice to colonic injury compared to control or Atg7 single mutant mice, suggesting a compensatory relationship between Imp1 and the autophagy pathway. The present study defines a novel interplay between IMP1 and autophagy, where IMP1 may be transiently induced during damage to modulate colonic epithelial cell responses to damage.	[Chatterji, Priya; Andres, Sarah F.; Mizuno, Rei; Chau, Lillian; Wu, Gary D.] Univ Penn, Dept Med, Perelman Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA; [Williams, Patrick A.; Simon, Lauren A.; Parham, Louis R.; Hamilton, Kathryn E.] Univ Penn, Dept Pediat, Childrens Hosp Philadelphia, Perelman Sch Med,Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA; [Whelan, Kelly A.] Temple Univ, Dept Pathol & Lab Med, Lewis Katz Sch Med, Philadelphia, PA 19122 USA; [Whelan, Kelly A.; Marti, Stefanie] Temple Univ, Fels Inst Canc Res & Mol Biol, Lewis Katz Sch Med, Philadelphia, PA 19122 USA; [Samper, Fernando C.; Marti, Stefanie; Tartaglia, Gian G.] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Barcelona, Spain; [Samper, Fernando C.; Tartaglia, Gian G.] Univ Pompeu Fabra, Barcelona, Spain; [Lundsmith, Emma T.] Thomas Jefferson Univ, Thomas Jefferson Med Coll, Philadelphia, PA 19107 USA; [Lee, David S. M.] Univ Penn, Genom & Computat Biol Grad Grp, Perelman Sch Med, Philadelphia, PA 19104 USA; [Liang, Shun; Wijeratne, H. R. Sagara; Shah, Premal] Rutgers State Univ, Dept Genet, New Brunswick, NJ USA; [Giroux, Veronique] Univ Sherbrooke, Dept Anat & Cell Biol, Fac Med & Hlth Sci, Sherbrooke, PQ, Canada; [Wilkins, Benjamin J.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA; [Shah, Premal] Human Genet Inst New Jersey, Piscataway, NJ USA; [Tartaglia, Gian G.] ICREA, Barcelona, Spain		Hamilton, KE (corresponding author), Univ Penn, Dept Pediat, Childrens Hosp Philadelphia, Perelman Sch Med,Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA.	hamiltonk1@email.chop.edu	Hamilton, Kathryn/AAA-9643-2022; Tartaglia, Gian Gaetano/K-1229-2014	Tartaglia, Gian Gaetano/0000-0001-7524-6310; Shah, Premal/0000-0002-8424-4218	National Center for Advancing Translational Sciences of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1TR001878. NIH K01DK100485]; Crohn's and Colitis Foundation Career Development Award; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R03DK114463, P30DK050306, T32CA115299-09, R01DK056645, K08DK099379, F32DK107052, K01DK103953, R03DK118304, R01GM103591, R35GM124976]; Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania; pilot grant program; Children's Hospital of Philadelphia Research Institute; European Union through the European Research Council [RIBOMY_LOME_309545]; Spanish Ministry of Economy and CompetitivenessSpanish Government [BFU2014-55054-P]; AGAURAgencia de Gestio D'Ajuts Universitaris de Recerca Agaur (AGAUR) [2014 SGR 00685]; Spanish Ministry of Economy and CompetitivenessSpanish Government; Centro de Excelencia Severo Ochoa 2013-2017 [SEV-2012-0208]; HHMI Medical Research Fellows Program; Fonds de Recherche en Sante du QuebecFonds de la Recherche en Sante du Quebec [P-Giroux-27692, P-Giroux-31601]; NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [T32GM008216-29]; Human Genetics Institute of New Jersey; Rutgers University; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [T32CA115299] 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) [UL1TR001878] 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) [K08DK099379, P30DK050306, K01DK100485, R01DK056645, R03DK114463, R03DK118304, K01DK103953, F32DK107052] 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) [R35GM124976, R01GM103591, T32GM008216] Funding Source: NIH RePORTER	We wish to thank Dr. Anil K. Rustgi (UPenn) and laboratory for support, discussions, and technical input. We thank UPenn Core Facilities: Molecular Pathology and Imaging, Human and Microbial Analytic Repository, Cell Culture/iPS, Flow Cytometry, and Electron Microscopy. We thank Dr. Donita Brady (UPenn) and laboratory for technical advice. We thank also Drs. T. Stappenbeck, A. Rodriguez, P. Vedula, L. Ghanem, and Y. Barash for discussions and advice. We thank Drs. Speigelman and Noubissi for Imp1-floxed mice. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001878. NIH K01DK100485 (KEH), Crohn's and Colitis Foundation Career Development Award (KEH), NIH R03DK114463 (KEH); Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania (KEH); NIH P30DK050306 and its pilot grant program (KEH); start-up funds from the Children's Hospital of Philadelphia Research Institute (KEH); NIH T32CA115299-09 (SFA); NIH R01DK056645 (PC, RM, SFA); NIH K08DK099379 (BJW); European Union Seventh Framework Programme (FP7/2007-2013), through the European Research Council and RIBOMY_LOME_309545 (GGT), the Spanish Ministry of Economy and Competitiveness (BFU2014-55054-P and fellowship to FCS), AGAUR (2014 SGR 00685), the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017' (SEV-2012-0208), NIH F32DK107052 (SFA), NIH K01DK103953 (KAW), NIH R03DK118304 (KAW), HHMI Medical Research Fellows Program (ETL), and Fonds de Recherche en Sante du Quebec (P-Giroux-27692 and P-Giroux-31601), NIH R01GM103591 (GDW). NIH R35GM124976 (SL, HRSW, PS), NIGMS T32GM008216-29 (SWF), start-up funds from Human Genetics Institute of New Jersey and Rutgers University (SL, HRSW, PS).	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JUN	2019	20	6							e47074	10.15252/embr.201847074			16	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	IF3HX	WOS:000472972600007	31061170	Green Submitted, Bronze, Green Published			2022-04-25	
J	Li, C; Xu, HL; Chen, XL; Chen, JJ; Li, X; Qiao, G; Tian, Y; Yuan, R; Su, SN; Liu, XH; Lin, XK				Li, Cong; Xu, Huanli; Chen, Xiaoliang; Chen, Jijun; Li, Xiao; Qiao, Gan; Tian, Ye; Yuan, Ru; Su, Shuonan; Liu, Xiaohui; Lin, Xiukun			Aqueous extract of clove inhibits tumor growth by inducing autophagy through AMPK/ULK pathway	PHYTOTHERAPY RESEARCH			English	Article						AMPK; anticancer; aqueous extract of clove; autophagy; traditional Chinese medicine	TRADITIONAL CHINESE MEDICINE; SYZYGIUM-AROMATICUM	Cloves (Syzygium aromaticum), a traditional Chinese medicinal herb, displays broad biological activity. In the present study, the aqueous extract of clove (AEC) was prepared, and its anticancer affects were studied. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetra-zolium (MTS) analysis revealed that AEC was able to inhibit cancer cell growth in vitro on several cancer cell lines; the IC50 is around 150 mu g/ml for human pancreatic ASPC-1 and human colon HT-29 cancer cells. Treatment of the cancer cells with AEC also diminished the colony formation significantly in both human pancreatic ASPC-1 cancer cells and human colon HT-29 cancer cells. In vivo study revealed that AEC inhibited the tumor growth significantly in HT-29 xenograft mice model. Transmission electron microscope, flow cytometry assay, and fluorescence microscope analysis confirmed that AEC is capable of inducing cell autophagy. Further study showed that AMPK/ULK pathway plays an important role in AEC-induced autophagy in cancer cells. Analysis of AEC components was performed by liquid chromatograph mass spectrometer approach, and more than nine constitutes were identified in AEC fraction. The study provides evidence that AEC has potential to be developed as a novel anticancer agent or as an adjuvant in cancer chemotherapy.	[Li, Cong; Xu, Huanli; Li, Xiao; Qiao, Gan; Tian, Ye; Yuan, Ru; Su, Shuonan; Liu, Xiaohui; Lin, Xiukun] Capital Med Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing 100069, Peoples R China; [Chen, Xiaoliang] Shanxi Datong Univ, Basic Med Sch, Datong, Peoples R China; [Chen, Jijun] Chinese Acad Sci, Kunming Inst Bot, Kunming, Yunnan, Peoples R China		Lin, XK (corresponding author), Capital Med Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing 100069, Peoples R China.	xiukunlin@126.com		Lin, Xiukun/0000-0002-0306-4953	National innovative drug development projects of China [2014ZX-09102043-001]; Sichuan Sci. and Tech Dept., China [17GJHZ0074, 2017HH0104]; Zibo Development Program of Sci. & Tech, in Shandong, China [2016kj100048]; Department of Sci and Tech in Shandong Province of China [ZR2017MH027, 2018YYSP025, ZR2017MH117, 2016GSF201183]; National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773776, 81573457]	National innovative drug development projects of China, Grant/Award Number: 2014ZX-09102043-001; Sichuan Sci. and Tech Dept., China, Grant/Award Numbers: 17GJHZ0074 and 2017HH0104; Zibo Development Program of Sci. & Tech, in Shandong, China, Grant/Award Number: 2016kj100048; Department of Sci and Tech in Shandong Province of China, Grant/Award Numbers: ZR2017MH027, 2018YYSP025, ZR2017MH117 and 2016GSF201183; National Science Foundation of China, Grant/Award Numbers: 81773776 and 81573457	Banerjee S, 2006, CARCINOGENESIS, V27, P1645, DOI 10.1093/carcin/bgi372; Chan HYL, 2014, EUR J ONCOL NURS, V18, P445, DOI 10.1016/j.ejon.2014.05.005; Cortes-Rojas Diego Francisco, 2014, Asian Pacific Journal of Tropical Biomedicine, V4, P90, DOI 10.1016/S2221-1691(14)60215-X; Draz H, 2017, CELL SIGNAL, V40, P172, DOI 10.1016/j.cellsig.2017.09.006; Ezzat SM, 2012, Z NATURFORSCH C, V67, P266, DOI 10.5560/ZNC.2012.67c0266; Feng YC, 2014, CELL RES, V24, P24, DOI 10.1038/cr.2013.168; Huo HZ, 2013, MOL CELL BIOCHEM, V378, P171, DOI 10.1007/s11010-013-1608-8; Kim J, 2011, NAT CELL BIOL, V13, P132, DOI 10.1038/ncb2152; Lee MS, 2017, MOL CARCINOGEN, V56, P2578, DOI 10.1002/mc.22702; Leng JCF, 2014, J CANCER EDUC, V29, P56, DOI 10.1007/s13187-013-0542-5; Li CA, 2017, PHYTOMEDICINE, V28, P10, DOI 10.1016/j.phymed.2017.02.008; Liu HZ, 2013, ONCOL RES, V21, P247, DOI 10.3727/096504014X13946388748910; Pourgholami MH, 1999, J ETHNOPHARMACOL, V64, P167, DOI 10.1016/S0378-8741(98)00121-4; Qi FH, 2015, BIOSCI TRENDS, V9, P16, DOI 10.5582/bst.2015.01019; Qi FH, 2011, INT IMMUNOPHARMACOL, V11, P342, DOI 10.1016/j.intimp.2010.12.007; Tian Y, 2018, PHYTOTHER RES, V32, P1320, DOI 10.1002/ptr.6064; Wang CY, 2014, AM J CHINESE MED, V42, P543, DOI 10.1142/S0192415X14500359; Wu Q, 2018, FOOD FUNCT, V9, P1736, DOI 10.1039/c7fo01964e; Yamagata K, 2018, MOL CELL BIOCHEM, V441, P9, DOI 10.1007/s11010-017-3171-1	19	11	15	3	11	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0951-418X	1099-1573		PHYTOTHER RES	Phytother. Res.	JUL	2019	33	7					1794	1804		10.1002/ptr.6367			11	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	IM3RP	WOS:000477912800005	30993793				2022-04-25	
J	Potocnjak, I; Simic, L; Gobin, I; Vukelic, I; Domitrovic, R				Potocnjak, Iva; Simic, Lidija; Gobin, Ivana; Vukelic, Iva; Domitrovic, Robert			Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway	TOXICOLOGY IN VITRO			English	Article						Colon cancer SW620 cells; Luteolin; Mitogen-activated protein kinase; Forkhead box O3a; Apoptosis; Autophagy	MESENCHYMAL TRANSITION; AUTOPHAGY; APOPTOSIS; FOXO3A; INHIBITION; PROLIFERATION; ANTIOXIDANT; CISPLATIN	The aim of this study was to investigate the mechanism of the anticancer activity of luteolin in metastatic human colon cancer SW620 cells. Luteolin dose-dependently reduced the viability and proliferation of SW620 cells and increased the expression of antioxidant enzymes. The expression of antiapoptotic protein Bcl-2 decreased whereas the expression of proapoptotic proteins Box and caspase-3 increased by luteolin treatment, resulting in increased poly (ADP-ribose) polymerase (PARP) cleavage and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity. Luteolin also increased the expression of autophagic proteins Beclin-1, autophagy-related protein 5 (Atg5) and microtubule-associated protein 1A/1B-light chain 3 beta-I/II (LC3B-I/II), while the usage of 3-methyladenine suggested a prosurvival role of autophagy. Moreover, treatment with luteolin induced reversal of the epithelial-mesenchymal transition process through the suppression of the wingless-related integration site protein (Wnt)/beta-catenin pathway. The cytotoxic activity of luteolin coincided with the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and forkhead box O3a (FOXO3a). Treatment with the mitogen-activated protein kinase kinase (MEK) inhibitor PD0325901 inhibited ERK-dependent FOXO3a phosphorylation, resulting in increased FOXO3a expression and apoptosis, with the suppression of autophagy. The results of the current study suggest the antitumor activity of luteolin in SW620 cells through the ERK/FOXO3a-dependent mechanism, as well as its antimetastatic potential.	[Potocnjak, Iva; Simic, Lidija; Vukelic, Iva; Domitrovic, Robert] Univ Rijeka, Fac Med, Dept Med Chem Biochem & Clin Chem, B Branchetta 20, Rijeka 51000, Croatia; [Gobin, Ivana] Univ Rijeka, Fac Med, Dept Microbiol & Parasitol, Rijeka, Croatia		Domitrovic, R (corresponding author), Univ Rijeka, Fac Med, Dept Med Chem Biochem & Clin Chem, B Branchetta 20, Rijeka 51000, Croatia.	robert.domitrovic@uniri.hr	Vukelić, Iva/R-8489-2018; Potočnjak, Iva/Q-9579-2018; Gobin, Ivana/O-6889-2018	Vukelić, Iva/0000-0002-4244-5206; Potočnjak, Iva/0000-0002-0815-2805; Gobin, Ivana/0000-0002-8956-4675	University of Rijeka [13.06.1.2.24, 13.06.2.2.60]	This research was supported by grants from the University of Rijeka (Projects 13.06.1.2.24 and 13.06.2.2.60).	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Vitro	AUG	2020	66								104852	10.1016/j.tiv.2020.104852			11	Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Toxicology	LS1AM	WOS:000536124600018	32268164				2022-04-25	
J	Zaanan, A; Park, JM; Tougeron, D; Huang, SB; Wu, TT; Foster, NR; Sinicrope, FA				Zaanan, Aziz; Park, Jae Myung; Tougeron, David; Huang, Shengbing; Wu, Tsung-Teh; Foster, Nathan R.; Sinicrope, Frank A.			Association of beclin 1 expression with response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal carcinoma	INTERNATIONAL JOURNAL OF CANCER			English	Article						beclin 1; rectal cancer; chemoradiation; autophagy; biomarker	PATHOLOGICAL COMPLETE RESPONSE; POSTOPERATIVE CHEMORADIOTHERAPY; PREOPERATIVE CHEMORADIATION; PROGNOSTIC IMPACT; CANCER; AUTOPHAGY; 5-FLUOROURACIL; RADIOTHERAPY; INHIBITION; RESISTANCE	Beclin 1 is an essential regulator of autophagy that is induced in response to cellular stress and serves to maintain cell survival in established tumors. We recently demonstrated that Beclin 1 suppression can sensitize colorectal cancer cells to radiation-induced DNA damage and apoptosis. Therefore, we hypothesized that the level of Beclin 1 expression may be associated with radiation sensitivity in vivo. We determined the association of Beclin 1 expression in pretreatment rectal cancer tissues with response to neoadjuvant chemoradiation in surgical resection specimens. Stages II and III (n=96) rectal adenocarcinoma patients were treated with neoadjuvant chemoradiation followed by surgical resection with curative intent. Beclin 1 was analyzed by immunohistochemistry and the expression level was dichotomized at the median value with categorization into low and high groups. We identified 56 (58.3%) and 40 (41.7%) patients whose tumors had high- versus low-level Beclin 1 expression, respectively. Rectal cancers with high versus low Beclin 1 expression were significantly less likely to be downstaged after chemoradiation treatment (45% [25/55] vs. 58% [22/38]; p=0.02). In a multivariable analysis adjusted for age, sex, histological grade and baseline tumor node metastasis (TNM) stage, the impact of Beclin 1 expression on tumor downstaging remained statistically significant (p=0.03). The association of the level of Beclin 1 expression with the rate of tumor downstaging after chemoradiation is consistent with in vitro data, and suggests that Beclin 1 may be a predictive biomarker for the efficacy of chemoradiation in patients with rectal cancer. What's new? Patients with nonmetastatic rectal cancer routinely receive chemotherapy and radiation before surgery. However, a predictive marker for the efficacy of chemoradiation is lacking. Here, the authors show that the essential autophagy protein Beclin 1 -known to protect against radiation-induced DNA damage- could be such a predictive marker. In locally advanced rectal cancer patients, high-level Beclin 1 expression in pretreatment tumor tissues was associated with a significantly reduced rate of tumor downstaging after chemoradiation and vice versa, supporting a new role of Beclin 1 as a clinical biomarker.	[Zaanan, Aziz; Park, Jae Myung; Tougeron, David; Huang, Shengbing; Sinicrope, Frank A.] Mayo Clin, Dept Med, Rochester, MN 55905 USA; [Zaanan, Aziz; Park, Jae Myung; Tougeron, David; Huang, Shengbing; Wu, Tsung-Teh; Foster, Nathan R.; Sinicrope, Frank A.] Mayo Canc Ctr, Rochester, MN 55905 USA; [Wu, Tsung-Teh] Mayo Clin, Dept Pathol & Lab Med, Rochester, MN 55905 USA; [Foster, Nathan R.] Mayo Clin, Dept Biomed Stat & Informat, Rochester, MN 55905 USA; [Sinicrope, Frank A.] Mayo Clin, Dept Oncol, Rochester, MN 55905 USA		Sinicrope, FA (corresponding author), Mayo Clin, Dept Med, 200 First St SW, Rochester, MN 55905 USA.	sinicrope.frank@mayo.edu	tougeron, david/ABF-3217-2020	tougeron, david/0000-0002-8065-9635; Zaanan, Aziz/0000-0001-8372-5653	National Cancer Institute Senior Scientist Award [K05CA-142885]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [K05CA142885, P30CA015083] 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	Grant sponsor: National Cancer Institute Senior Scientist Award; Grant number: K05CA-142885	Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Capirci C, 2008, INT J RADIAT ONCOL, V72, P99, DOI 10.1016/j.ijrobp.2007.12.019; Cerniglia GJ, 2012, MOL PHARMACOL, V82, P1230, DOI 10.1124/mol.112.080408; Chen YS, 2013, PATHOL RES PRACT, V209, P562, DOI 10.1016/j.prp.2013.06.006; Chetty R, 2012, J CLIN PATHOL, V65, P865, DOI 10.1136/jclinpath-2012-201054; Firat E, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0047357; Garcia-Aguilar J, 2011, ANN SURG, V254, P486, DOI 10.1097/SLA.0b013e31822b8cfa; Han Y, 2014, ASIAN PAC J CANCER P, V15, P4583, DOI 10.7314/APJCP.2014.15.11.4583; Janjan NA, 2001, AM J CLIN ONCOL-CANC, V24, P107, DOI 10.1097/00000421-200104000-00001; Karantza-Wadsworth V, 2007, GENE DEV, V21, P1621, DOI 10.1101/gad.1565707; Kikuchi M, 2009, BRIT J CANCER, V101, P116, DOI 10.1038/sj.bjc.6605105; Klionsky DJ, 2000, SCIENCE, V290, P1717, DOI 10.1126/science.290.5497.1717; Li J, 2010, EUR J CANCER, V46, P1900, DOI 10.1016/j.ejca.2010.02.021; MacGregor TP, 2012, J CLIN PATHOL, V65, P867, DOI 10.1136/jclinpath-2012-200958; Marusch F, 2011, ENDOSCOPY, V43, P425, DOI 10.1055/s-0030-1256111; Negri FV, 2008, BRIT J CANCER, V98, P143, DOI 10.1038/sj.bjc.6604131; Park IJ, 2012, J CLIN ONCOL, V30, P1770, DOI 10.1200/JCO.2011.39.7901; 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; Sato N, 2000, ONCOGENE, V19, P5281, DOI 10.1038/sj.onc.1203902; Sauer R, 2004, NEW ENGL J MED, V351, P1731, DOI 10.1056/NEJMoa040694; Sebag-Montefiore D, 2009, LANCET, V373, P811, DOI 10.1016/S0140-6736(09)60484-0; 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]; Sinha S, 2008, ONCOGENE, V27, pS137, DOI 10.1038/onc.2009.51; Sinicrope FA, 2008, CLIN CANCER RES, V14, P5810, DOI 10.1158/1078-0432.CCR-07-5202; Stipa F, 2006, ANN SURG ONCOL, V13, P1047, DOI 10.1245/ASO.2006.03.053; Sui XB, 2014, SCI REP-UK, V4, DOI 10.1038/srep04694; Theodoropoulos G, 2002, DIS COLON RECTUM, V45, P895, DOI 10.1007/s10350-004-6325-7; Yang ZNJ, 2011, MOL CANCER THER, V10, P1533, DOI 10.1158/1535-7163.MCT-11-0047	29	13	14	0	6	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0020-7136	1097-0215		INT J CANCER	Int. J. Cancer	SEP	2015	137	6					1498	1502		10.1002/ijc.29496			5	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CM6OT	WOS:000357808900030	25708267	Green Accepted, Bronze			2022-04-25	
J	Elamin, KM; Motoyama, K; Higashi, T; Yamashita, Y; Tokuda, A; Arima, H				Elamin, Khaled M.; Motoyama, Keiichi; Higashi, Taishi; Yamashita, Yuki; Tokuda, Azumi; Arima, Hidetoshi			Dual targeting system by supramolecular complex of folate-conjugated methyl-beta-cyclodextrin with adamantane-grafted hyaluronic acid for the treatment of colorectal cancer	INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES			English	Article						Dual targeting; Folate receptor; CD44; Methyl beta cyclodextrin; Hyaluronic acid; Supramolecular complex	DRUG-DELIVERY; CELLULAR UPTAKE; IN-VIVO; NANOPARTICLES; CELLS; AUTOPHAGY; MICE; INVOLVEMENT; ACTIVATION; THERAPY	In our previous study, we demonstrated that folate-appended methyl cyclodextrin (FA-M-beta-CyD) was a promising antitumor agent for the treatment of folate receptor-alpha (FR-alpha)-expressing tumors. In the present study, to enhance the antitumor effect of FA-M-beta-CyD against FR-alpha- and CD44-expressing colorectal cancer cells, we synthesized a dual targeting supramolecular complex composed of FA-M-beta-CyD and adamantane-grafted hyaluronic acid (Ad-HA). The supramolecular complex of Ad-HA/FA-M-beta-CyD showed higher cytotoxic activity in HCT116 cells (FR-alpha (+), CD44 (+)), a human colon cancer cell line, than FA-M-beta-CyD alone. In addition, the cytotoxic activity of Ad-HA/FA-M-beta-CyD was significantly impaired by the addition of FA and HA, as inhibitors of FR-alpha and CD44, respectively. Furthermore, tetramethylrhodamine isothiocyanate (TRITC)-labeled FA-M-beta-CyD was efficiently internalized into HCT116 cells through supramolecular complexation with Ad-HA, compared to that of TRITC-FA-M-beta-CyD alone. Additionally, Ad-HA/FA-M-beta-CyD induced mitophagy in HCT116 cells. These results suggest that Ad-HA/FA-M-beta-CyD targeted HCT116 cells, as well as induced mitophagy-mediated cell death. Notably, an intravenous injection of the Ad-HA/FA-M-beta-CyD complex in a mouse model of colorectal cancer significantly ameliorated the growth of tumor polyps. Collectively, these results suggest that Ad-HA/FA-M-beta-CyD has antiproliferation effects in tumors, based on the dual targeting activity. (C) 2018 Elsevier B.V. All rights reserved.	[Elamin, Khaled M.; Motoyama, Keiichi; Higashi, Taishi; Yamashita, Yuki; Tokuda, Azumi; Arima, Hidetoshi] Kumamoto Univ, Grad Sch Pharmaceut Sci, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan; [Arima, Hidetoshi] Kumamoto Univ, Program Leading Grad Sch HIGO Hlth Life Sci Inter, Kumamoto, Japan		Arima, H (corresponding author), Kumamoto Univ, Grad Sch Pharmaceut Sci, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, 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]; Japan Agency for Medical Research and Development (AMED)Japan Agency for Medical Research and Development (AMED) [10801104]; Center for Clinical and Translational Research of Kyushu University [A103]; Ministry of Health, Labour and WelfareMinistry of Health, Labour and Welfare, Japan [24-0003]	This work was partially supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (16K08198), the Japan Agency for Medical Research and Development (AMED, 10801104), the Center for Clinical and Translational Research of Kyushu University (A103), and the Ministry of Health, Labour and Welfare 24-0003.	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J. Biol. Macromol.	JUL 1	2018	113						386	394		10.1016/j.ijbiomac.2018.02.149			9	Biochemistry & Molecular Biology; Chemistry, Applied; Polymer Science	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry; Polymer Science	GG2EP	WOS:000432503100045	29486262				2022-04-25	
J	Iovine, B; Guardia, F; Irace, C; Bevilacqua, MA				Iovine, Barbara; Guardia, Francesca; Irace, Carlo; Bevilacqua, Maria Assunta			L-carnosine dipeptide overcomes acquired resistance to 5-fluorouracil in HT29 human colon cancer cells via downregulation of HIF1-alpha and induction of apoptosis	BIOCHIMIE			English	Article						Hypoxia-inducible factor-1; 5-Fluorouracil; L-carnosine; Chemoresistance; Apoptosis; Multi-drug resistance	SHOCK-PROTEIN 27; MULTIDRUG-RESISTANCE; HYPOXIA; THERAPY; HIF-1-ALPHA; SENSITIVITY; SUPPRESSION; MECHANISMS; EXPRESSION; AUTOPHAGY	Hypoxia-inducible factor (HIF-1 alpha) protein is over-expressed in many human cancers and is a major cause of resistance to drugs. HIF-1 alpha up-regulation decreases the effectiveness of several anticancer agents, including 5-fluorouracil (5-FU), because it induces the expression of drug efflux transporters, alters DNA repair mechanisms and modifies the balance between pro- and antiapoptotic factors. These findings suggest that inhibition of HIF-1 alpha activity may sensitize cancer cells to cytotoxic drugs. We previously reported that L-carnosine reduces HIF-1 alpha expression by inhibiting the proliferation of colon cancer cells. In the present study we investigated the effect of L-carnosine on HT29 colon cancer cells with acquired resistance to 5-FU. We found that L-carnosine reduces colon cancer cell viability, decreases HIF-1 alpha and multi-drug resistant protein MDR1-pg expression, and induces apoptosis. Moreover, the L-carnosine/5-FU combination lowers the expression of some chemoresistance markers. The combination index evaluated in vitro on the HT29-5FU cell line by median drug effect analysis reveals a significant synergistic effect. (C) 2016 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.	[Iovine, Barbara; Guardia, Francesca; Bevilacqua, Maria Assunta] Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, Via Sergio Pansini 5, I-80131 Naples, Italy; [Irace, Carlo] Univ Naples Federico II, Dipartimento Farm, Via Domenico Montesano 49, I-80131 Naples, Italy		Iovine, B (corresponding author), Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, Via Sergio Pansini 5, I-80131 Naples, Italy.	barbara.iovine@unina.it					Cecconi D, 2009, PROTEOMICS, V9, P1952, DOI 10.1002/pmic.200701089; Chen JQ, 2014, PLOS ONE, V9, DOI [10.1371/journal.pone.0085161, 10.1371/journal.pone.0101277]; Chen N, 2009, J BIOL CHEM, V284, P10004, DOI 10.1074/jbc.M805997200; Comerford KM, 2002, CANCER RES, V62, P3387; Di Gennaro E, 2009, CANCER BIOL THER, V8, P782, DOI 10.4161/cbt.8.9.8118; Donadelli M, 2007, BBA-MOL CELL RES, V1773, P1095, DOI 10.1016/j.bbamcr.2007.05.002; Erler JT, 2004, MOL CELL BIOL, V24, P2875, DOI 10.1128/MCB.24.7.2875-2889.2004; Gillet JP, 2010, METHODS MOL BIOL, V596, P47, DOI 10.1007/978-1-60761-416-6_4; Gomez-Monterrey I, 2013, J AMINO ACIDS, V2013; Hayashi R, 2012, ONCOL REP, V28, P1269, DOI 10.3892/or.2012.1935; Iovine B, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0096755; Iovine B, 2012, CANCER LETT, V315, P122, DOI 10.1016/j.canlet.2011.07.021; Iovine B, 2009, BIOCHIMIE, V91, P364, DOI 10.1016/j.biochi.2008.10.017; Kabeya Y, 2000, EMBO J, V19, P5720, DOI 10.1093/emboj/19.21.5720; Koh MY, 2010, RECENT RESULTS CANC, V180, P15, DOI 10.1007/978-3-540-78281-0_3; Koshiji M, 2005, MOL CELL, V17, P793, DOI 10.1016/j.molcel.2005.02.015; Kulshreshtha R, 2007, MOL CELL BIOL, V27, P1859, DOI 10.1128/MCB.01395-06; Li S, 2015, CURR TOP MED CHEM, V15, P720, DOI 10.2174/1568026615666150302105343; Meyerhardt JA, 2005, NEW ENGL J MED, V352, P476, DOI 10.1056/NEJMra040958; Mirjolet JF, 2000, BRIT J CANCER, V83, P1380, DOI 10.1054/bjoc.2000.1455; Mistry P, 2001, CANCER RES, V61, P749; Mizushima N, 2007, AUTOPHAGY, V3, P542, DOI 10.4161/auto.4600; Nardinocchi L, 2010, PLOS ONE, V12; Puissant A, 2012, AM J CANCER RES, V2, P397; Ravizza R, 2009, EUR J CANCER, V45, P890, DOI 10.1016/j.ejca.2008.12.021; Selvakumaran M, 2013, CLIN CANCER RES, V19, P2995, DOI 10.1158/1078-0432.CCR-12-1542; Semenza GL, 2003, NAT REV CANCER, V3, P721, DOI 10.1038/nrc1187; Silva R., 2015, PHARMACOL THERAPEUT, V123, P149; Tsuruta M, 2008, ONCOL REP, V20, P1165, DOI 10.3892/or_00000125; Vaupel P, 2007, CANCER METAST REV, V26, P225, DOI 10.1007/s10555-007-9055-1; Vitiello G, 2015, J MATER CHEM B, V3, P3011, DOI 10.1039/c4tb01807a; Wang XF, 2007, LEUKEMIA RES, V31, P989, DOI 10.1016/j.leukres.2006.09.001	32	12	12	0	17	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER	ISSY-LES-MOULINEAUX	65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE	0300-9084	1638-6183		BIOCHIMIE	Biochimie	AUG	2016	127						196	204		10.1016/j.biochi.2016.05.010			9	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	DR7LZ	WOS:000380082500022	27234614				2022-04-25	
J	Li, YH; Yu, YL; Kang, L; Lu, Y				Li, Yuhua; Yu, Yalu; Kang, Ling; Lu, Ying			Effects of chlorin e6-mediated photodynamic therapy on human colon cancer SW480 cells	INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE			English	Article						Colorectal cancer; chlorin e6; photodynamic therapy; SW480 cells	SUBCELLULAR-LOCALIZATION; COLORECTAL-CANCER; AUTOPHAGY; DEATH; APOPTOSIS; E(6); MITOCHONDRIAL; RESISTANCE; ARREST	Objective: This study is to investigate the antitumor effects and possible mechanisms of chlorin e6-mediated photodynamic therapy (Ce6-PDT) on human colon cancer SW480 cells. Methods: SW480 cells were treated with Ce6, followed by photodynamic irradiation. Subcellular localization of Ce6 in SW480 cells was observed with confocal laser scanning microscopy (LSCM). Reactive oxygen species (ROS) levels were monitored with fluorescence microscopy. Cell proliferation and apoptosis were detected by the MTT assay and flow cytometry, respectively. Scratch test and colony formation assay were employed to analyze the cell migration ability and colony formation ability. Results: LSCM showed that, in SW480 cells, Ce6 was evenly distributed within the ER and lysosomes, with nearly no distribution in the mitochondria and nuclei. When SW480 cells were subjected to Ce6-PDT, the ROS levels would be elevated, in a dose-dependent manner. Moreover, Ce6-PDT treatment could inhibit the cell proliferation and enhance the apoptotic process, in SW480 cells. However, Ce6 treatment alone without photodynamic irradiation could not induce any significant differences in the cell proliferation and apoptosis. In addition, the migration ability and colony formation ability of SW480 cells were decreased by Ce6-PDT treatment at appropriate dosages. Conclusion: Ce6-PDT treatment could enhance ROS production and apoptosis, inhibit cell proliferation, decrease migration ability and colony formation ability, in SW480 cells, in a dose-dependent manner. These findings might provide experimental evidence for the application of Ce6-PDT in clinical treatment of colorectal cancer.	[Li, Yuhua; Kang, Ling; Lu, Ying] Xinjiang Med Univ, Coll Publ Hlth, Dept Occupat & Environm Hlth, Urumqi 830011, Xinjiang, Peoples R China; [Yu, Yalu] Xinjiang Med Univ, Coll Publ Hlth, Cent Lab, Urumqi 830011, Xinjiang, Peoples R China		Kang, L (corresponding author), Xinjiang Med Univ, Coll Publ Hlth, Dept Occupat & Environm Hlth, 393 Xinyi Rd, Urumqi 830011, Xinjiang, Peoples R China.	lingkang12201@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81060186]; Xinjiang Uygur Autonomous Region Natural Science Foundation [2014211C003]	This study was supported by the National Natural Science Foundation of China (No. 81060186) and the Xinjiang Uygur Autonomous Region Natural Science Foundation (No. 2014211C003).	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J. Clin. Exp. Med.		2014	7	12					4867	4876					10	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	AZ6BP	WOS:000348303600026	25663983				2022-04-25	
J	Wang, AT; Ding, L; Wu, ZQ; Ding, R; Teng, XL; Wang, FX; Hu, ZL; Chen, L; Yu, XY; Zou, Q				Wang, Aiting; Ding, Lei; Wu, Zhongqiu; Ding, Rui; Teng, Xiao-Lu; Wang, Feixiang; Hu, Zhilin; Chen, Lei; Yu, Xiaoyan; Zou, Qiang			ZFP91 is required for the maintenance of regulatory T cell homeostasis and function	JOURNAL OF EXPERIMENTAL MEDICINE			English	Article							IFN-GAMMA; AUTOPHAGY; METABOLISM; SURVIVAL; STABILIZES; EXPRESSION; NETWORKS; CANCER; GENE	Autophagy programs the metabolic and functional fitness of regulatory T reg) cells to establish immune tolerance, yet the mechanisms governing autophagy initiation in T reg cells remain unclear. Here, we show that the E3 ubiquitin ligase ZFP91 facilitates autophagy activation to sustain T reg cell metabolic programming and functional integrity. T reg cell-specific deletion of Zfp91 caused T reg cell dysfunction and exacerbated colonic inflammation and inflammation-driven colon carcinogenesis. TCR-triggered autophagy induction largely relied on T reg cell-derived ZFP91 to restrict hyperglycolysis, which is required for the maintenance of T reg cell homeostasis. Mechanistically, ZFP91 rapidly translocated from the nucleus to the cytoplasm in response to TCR stimulation and then mediated BECN1 ubiquitination to promote BECN1-PIK3C3 complex formation. Therefore, our results highlight a ZFP91-dependent mechanism promoting TCR-initiated autophagosome maturation to maintain T reg cell homeostasis and function.	[Wang, Aiting; Wu, Zhongqiu; Ding, Rui; Teng, Xiao-Lu; Wang, Feixiang; Hu, Zhilin; Yu, Xiaoyan; Zou, Qiang] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes,Shanghai, Hongqiao Int Inst Med,Tongren Hosp,Dept Immunol &, Shanghai, Peoples R China; [Ding, Lei; Chen, Lei] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes, Shanghai Inst Immunol,Dept Immunol & Microbiol, Shanghai, Peoples R China		Yu, XY; Zou, Q (corresponding author), Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes,Shanghai, Hongqiao Int Inst Med,Tongren Hosp,Dept Immunol &, Shanghai, Peoples R China.; Chen, L (corresponding author), Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes, Shanghai Inst Immunol,Dept Immunol & Microbiol, Shanghai, Peoples R China.	lei.chen@sjtu.edu.cn; yuxy@shsmu.edu.cn; qzou1984@sjtu.edu.cn		Teng, Xiao-Lu/0000-0002-8490-4570; Wang, Aiting/0000-0003-3177-9961; Zou, Qiang/0000-0002-1362-2007	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930040, 31922025, 31870884, 31900631]; Shanghai Municipal Health and Family Planning Commission [2018YQ08]; Natural Science Foundation of ShanghaiNatural Science Foundation of Shanghai [19ZR1445700]	This study was supported by grants from the National Natural Science Foundation of China (81930040, 31922025, 31870884, 31900631), the Shanghai Municipal Health and Family Planning Commission (2018YQ08), and the Natural Science Foundation of Shanghai (19ZR1445700).	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Exp. Med.	FEB 1	2021	218	2							e20201217	10.1084/jem.20201217			14	Immunology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Research & Experimental Medicine	QI4UT	WOS:000618975300005	33355624	hybrid, Green Published			2022-04-25	
J	Sasaki, K; Tsuno, NH; Sunami, E; Tsurita, G; Kawai, K; Okaji, Y; Nishikawa, T; Shuno, Y; Hongo, K; Hiyoshi, M; Kaneko, M; Kitayama, J; Takahashi, K; Nagawa, H				Sasaki, Kazuhito; Tsuno, Nelson H.; Sunami, Eiji; Tsurita, Giichiro; Kawai, Kazushige; Okaji, Yurai; Nishikawa, Takeshi; Shuno, Yasutaka; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Kitayama, Joji; Takahashi, Koki; Nagawa, Hirokazu			Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells	BMC CANCER			English	Article							OLD DRUG; AUTOPHAGY; APOPTOSIS; GROWTH; INHIBITION; INDUCTION; DEATH; LYMPHOMA; KINASES; ARREST	Background: Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells. Methods: HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed. Results: 5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pretreatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21(Cip1) and p27(Kip1) and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti-cancer effect of 5-FU. Conclusion: Our findings suggest that the combination therapy with CQ should be a novel therapeutic modality to improve efficacy of 5-FU-based chemotherapy, possibly by inhibiting autophagy-dependent resistance to chemotherapy.	[Sasaki, Kazuhito; Tsuno, Nelson H.; Sunami, Eiji; Tsurita, Giichiro; Kawai, Kazushige; Nishikawa, Takeshi; Shuno, Yasutaka; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Kitayama, Joji; Nagawa, Hirokazu] Univ Tokyo, Fac Med Sci, Dept Surg Oncol, Tokyo 1138655, Japan; [Tsuno, Nelson H.; Okaji, Yurai; Takahashi, Koki] Univ Tokyo, Fac Med Sci, Dept Transfus Med, Tokyo 1138655, Japan		Sasaki, K (corresponding author), Univ Tokyo, Fac Med Sci, Dept Surg Oncol, Tokyo 1138655, Japan.	sasakik-sur@h.u-tokyo.ac.jp	Kawai, Kazushige/AAF-4334-2020	Kawai, Kazushige/0000-0002-5881-0036			Abeliovich H, 2000, J CELL BIOL, V151, P1025, DOI 10.1083/jcb.151.5.1025; Amaravadi RK, 2007, CLIN CANCER RES, V13, P7271, DOI 10.1158/1078-0432.CCR-07-1595; Amaravadi RK, 2007, J CLIN INVEST, V117, P326, DOI 10.1172/JCI28833; Ashktorab H, 2005, DIGEST DIS SCI, V50, P1025, DOI 10.1007/s10620-005-2698-2; Berthet C, 2007, ONCOGENE, V26, P4469, DOI 10.1038/sj.onc.1210243; BIJNSDORP IV, 2009, INT J CANC; CHOI S, CANC LETT; Dang CV, 2008, J CLIN INVEST, V118, P15, DOI 10.1172/JCI34503; Eskelinen EL, 2002, TRAFFIC, V3, P878, DOI 10.1034/j.1600-0854.2002.31204.x; Fan CD, 2006, BIOORGAN MED CHEM, V14, P3218, DOI 10.1016/j.bmc.2005.12.035; FRAILE RJ, 1980, CANCER RES, V40, P2223; Grivicich I, 2005, CHEMOTHERAPY, V51, P93, DOI 10.1159/000085617; Hu C, 2008, BIOORGAN MED CHEM, V16, P7888, DOI 10.1016/j.bmc.2008.07.076; Jiang PD, 2008, CELL PHYSIOL BIOCHEM, V22, P431, DOI 10.1159/000185488; LI J, 2005, EUR J CANCER, V46, P1900; Li J, 2009, ANN SURG ONCOL, V16, P761, DOI 10.1245/s10434-008-0260-0; Longley DB, 2003, NAT REV CANCER, V3, P330, DOI 10.1038/nrc1074; Maclean KH, 2008, J CLIN INVEST, V118, P79, DOI 10.1172/JCI33700; Munshi A, 2009, CANCER, V115, P2380, DOI 10.1002/cncr.24288; NISHIKAWA T, 2009, ANN SURG ONCOL; PAN J, CANC LETT, V293, P167; POLYAK K, 1994, CELL, V78, P59, DOI 10.1016/0092-8674(94)90572-X; Rahim R, 2009, ANTI-CANCER DRUG, V20, P736, DOI 10.1097/CAD.0b013e32832f4e50; Santamaria D, 2006, FRONT BIOSCI-LANDMRK, V11, P1164, DOI 10.2741/1871; 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; Tasdemir E, 2007, CELL CYCLE, V6, P2263, DOI 10.4161/cc.6.18.4681; WONG CH, PLOS ONE, V5, pE9996; Wu WKK, 2008, BIOCHEM BIOPH RES CO, V374, P258, DOI 10.1016/j.bbrc.2008.07.031; XIONG Y, 1993, NATURE, V366, P701, DOI 10.1038/366701a0; Xu R, 2006, HISTOL HISTOPATHOL, V21, P867, DOI 10.14670/HH-21.867; Yoshioka A, 2008, INT J ONCOL, V33, P461, DOI 10.3892/ijo_00000028; Zheng YZ, 2009, CANCER INVEST, V27, P286, DOI 10.1080/07357900802427927; Zhuang Yongxian, 2008, J Mol Signal, V3, P18, DOI 10.1186/1750-2187-3-18	34	235	252	1	42	BMC	LONDON	CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	1471-2407			BMC CANCER	BMC Cancer	JUL 15	2010	10								370	10.1186/1471-2407-10-370			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	661GG	WOS:000282713100001	20630104	Green Published, gold			2022-04-25	
J	Sun, T; Ming, L; Yan, YM; Zhang, Y; Xue, HK				Sun, Ting; Ming, Liang; Yan, Yunmeng; Zhang, Yan; Xue, Haikuo			Beclin 1 acetylation impairs the anticancer effect of aspirin in colorectal cancer cells	ONCOTARGET			English	Article						aspirin; autophagy; Beclin 1; acetylation; colorectal cancer	NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NF-KAPPA-B; SALICYLIC-ACID; MONITORING AUTOPHAGY; POTENTIAL ROLE; BREAST-CANCER; APOPTOSIS; RISK; INHIBITION; PREVENTION	Regular use of aspirin can reduce cancer incidence, recurrence, metastasis and cancer-related mortality. Aspirin suppresses proliferation and induces apoptosis and autophagy in colorectal cancer cells, but the precise mechanism is not clear. In this study, we demonstrated that aspirin induced autophagosome formation in colorectal cancer cells, but autophagic degradation was blocked through aspirin-mediated Beclin 1 acetylation. Blocked autophagic degradation weakened aspirin-induced cell death. Collectively, our findings indicate the dual roles of aspirin on autophagy, and demonstrate a new mechanism by which Beclin 1 acetylation impairs the anticancer effect of aspirin in colorectal cancer cells.	[Sun, Ting; Ming, Liang; Yan, Yunmeng; Zhang, Yan; Xue, Haikuo] Zhengzhou Univ, Affiliated Hosp 1, Dept Clin Lab, Key Clin Lab Henan Prov, Zhengzhou 450052, Henan, Peoples R China; [Sun, Ting; Ming, Liang; Yan, Yunmeng; Zhang, Yan; Xue, Haikuo] Zhengzhou Univ, Dept Lab Med, Zhengzhou 450001, Henan, Peoples R China		Ming, L (corresponding author), Zhengzhou Univ, Affiliated Hosp 1, Dept Clin Lab, Key Clin Lab Henan Prov, Zhengzhou 450052, Henan, Peoples R China.; Ming, L (corresponding author), Zhengzhou Univ, Dept Lab Med, Zhengzhou 450001, Henan, Peoples R China.	mingliangzzu@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31501123]; Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University	This research was supported by National Natural Science Foundation of China (Grant No. 31501123) and the Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University.	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J	Zhou, QM; Zhao, Y; Fu, XH; Chen, QQ; Tang, YQ; Gao, XP				Zhou, Qiming; Zhao, Yan; Fu, Xiaohong; Chen, Qianqi; Tang, Yueqiang; Gao, Xiaoping			Naturally occurring triterpene Lupane exerts anticancer effects on colorectal cancer cells via induction of apoptosis and autophagy and suppresses cell migration and invasion by targeting MMP-9	JOURNAL OF BUON			English	Article						Lupane; anticancer; apoptosis; proliferation; cell cycle arrest; flow cytometry	SECONDARY METABOLITES; SAPONINS; DRUGS	Purpose: This study was undertaken with a purpose to examine the anticancer effects of Lupane against human colorectal cancer. Methods: The SW48 colorectal cell line and CDD18Co normal colon cell line were used in this study. The CCK8 assay was used to determine cell proliferation while acridine orange (AO)/ethidium bromide (EB) and DAPI staining assays were used to detect apoptosis. Wound healing and transwell assays were used to detect the cell migration and invasion. Western blotting was used to determine protein expression. Results: Lupane inhibited the proliferation of colorectal cancer cells and the level of inhibition followed dose-dependent pattern. The antiproliferative role of Lupane was exerted via induction of apoptotic cell death. Western blot showed that the expression of Bcl-2 was decreased and that of Bax was increaced. Lupane also prompted the autophagy of the SW48 colorectal cancer cells and enhanced the expression of LC3-II. However, the expression of p62 was depleted. The treatment of Lupane also resulted to inhibition of the migratory potential of cancer cells as revealed by the wound healing assay. The invasion of SW48 cancer cells was also suppressed and was associated with suppression of metalloproteinase-9 (MMP-9) expression. Conclusion: The results indicate the anticancer potential of Lupane against the colorectal cancer growth and propagation. The study envisages the importance of natural compounds for their usage against human cancers.	[Zhou, Qiming; Zhao, Yan; Fu, Xiaohong; Chen, Qianqi; Tang, Yueqiang; Gao, Xiaoping] Huazhong Univ Sci & Technol Union, Shenzhen Hosp, Canc Ctr, Shenzhen 518052, Peoples R China		Zhou, QM (corresponding author), Huazhong Univ Sci & Technol Union, Shenzhen Hosp, 89 Taoyuan Rd, Shenzhen 518052, Peoples R China.	zqm1977122@163.com			Basic Research Projects of Shenzhen Knowledge Innovation Program [JCYj20180302144716002]	Funding from Basic Research Projects of Shenzhen Knowledge Innovation Program (NO. JCYj20180302144716002) is acknowledged.	Carpenter SR, 2009, P NATL ACAD SCI USA, V106, P1305, DOI 10.1073/pnas.0808772106; Cipollini ML, 1997, AM NAT, V150, P346, DOI 10.1086/286069; Clark AG, 2015, CURR OPIN CELL BIOL, V36, P13, DOI 10.1016/j.ceb.2015.06.004; Cmoch P, 2008, CARBOHYD RES, V343, P995, DOI 10.1016/j.carres.2008.02.011; Goodall ML, 2016, DEV CELL, V37, P337, DOI 10.1016/j.devcel.2016.04.018; Just MJ, 1998, PLANTA MED, V64, P404, DOI 10.1055/s-2006-957469; Kommera H, 2010, EUR J MED CHEM, V45, P3346, DOI 10.1016/j.ejmech.2010.04.018; Luo J, 2002, ACTA PHARM SIN, V7, P6; Oparin A. I., 2003, ORIGIN LIFE; Phillips DR, 2006, CURR OPIN PLANT BIOL, V9, P305, DOI 10.1016/j.pbi.2006.03.004; Pichersky E, 2000, TRENDS PLANT SCI, V5, P439, DOI 10.1016/S1360-1385(00)01741-6; Prakash C. V. S., 2012, Research Journal of Pharmaceutical Sciences, V1, P23; Raja A, 2010, INT J PHARMACOL, V6, P360; Rajandeep Kaur, 2011, Journal of Natural Product and Plant Resources, V1, P119; Siegel R, 2014, CA-CANCER J CLIN, V64, P104, DOI 10.3322/caac.21220; Thimmappa R, 2014, ANNU REV PLANT BIOL, V65, P225, DOI 10.1146/annurev-arplant-050312-120229; Wang YP, 2017, NATURE, V547, P99, DOI 10.1038/nature22393; WINK M, 1988, THEOR APPL GENET, V75, P225, DOI 10.1007/BF00303957; Ye YQ, 2017, J MED CHEM, V60, P6353, DOI 10.1021/acs.jmedchem.7b00679	19	2	2	1	3	IMPRIMATUR PUBLICATIONS	ATHENS	30 DEM POLIORKETES ST, ATHENS, 136 76, GREECE	1107-0625	2241-6293		J BUON	J. BUON	MAR-APR	2020	25	2					884	889					6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	NE1TJ	WOS:000562380000014	32521882				2022-04-25	
J	Gornowicz, A; Szymanowska, A; Mojzych, M; Bielawski, K; Bielawska, A				Gornowicz, Agnieszka; Szymanowska, Anna; Mojzych, Mariusz; Bielawski, Krzysztof; Bielawska, Anna			The Effect of Novel 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine Sulfonamide Derivatives on Apoptosis and Autophagy in DLD-1 and HT-29 Colon Cancer Cells	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						colorectal cancer; apoptosis; autophagy; anticancer agents; roscovitine; 5-fluorouracil	1,2,4-TRIAZINE DERIVATIVES; PLATINUM(II) COMPLEX; SILDENAFIL ANALOGS; ROSCOVITINE; TYROSINASE; ANTI-MUC1	The discovery of cytotoxic drugs is focused on designing a compound structure that directly affects cancer cells without an impact on normal cells. The mechanism of anticancer activity is mainly related with activation of apoptosis. However, recent scientific reports show that autophagy also plays a crucial role in cancer cell progression. Thus, the objective of this study was to synthesize 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine utilizing nucleophilic substitution reaction at the position N1. The biological activity of tested compounds was assessed in DLD-1 and HT-29 cell lines. The induction of apoptosis was confirmed by Annexin V binding assay and acridine orange/ethidium bromide staining. The loss of mitochondrial membrane potential and caspase-8 activity was estimated using cytometer flow analysis. The concentration of p53, LC3A, LC3B and beclin-1 was measured using the ELISA technique. Our study revealed that anticancer activity of 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine derivatives is related with initiation of apoptosis occur on the intrinsic pathway with mitochondrial membrane decrease and extrinsic with increase of activity of caspase-8. Moreover, a decrease in beclin-1, LC3A, and LC3B were observed in two cell lines after treatment with novel compounds. This study showed that novel 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine derivatives might be a potential strategy in colon cancer treatment.	[Gornowicz, Agnieszka; Szymanowska, Anna; Bielawska, Anna] Med Univ Bialystok, Dept Biotechnol, PL-15222 Bialystok, Poland; [Mojzych, Mariusz] Siedlce Univ Nat Sci & Humanities, Dept Chem, PL-08110 Siedlce, Poland; [Bielawski, Krzysztof] Med Univ Bialystok, Dept Synth & Technol Drugs, PL-15222 Bialystok, Poland		Gornowicz, A (corresponding author), Med Univ Bialystok, Dept Biotechnol, PL-15222 Bialystok, Poland.	agnieszka.gornowicz@umb.edu.pl; anna.szymanowska@umb.edu.pl; mmojzych@yahoo.com; kbiel@umb.edu.pl; anna.bielawska@umb.edu.pl	Mojzych, Mariusz/AAC-7302-2020	Mojzych, Mariusz/0000-0002-9884-6068; Gornowicz, Agnieszka/0000-0002-0945-7870; Szymanowska, Anna/0000-0003-4783-3336	Ministry of Science and Higher Education from the "Innovation Incubator 2.0" program from the European Regional Development Fund [II2.0/2019/UD/01]; Medical University of Bialystok [SUB/2/DN/20/002/2229]	This research was funded by Ministry of Science and Higher Education from the "Innovation Incubator 2.0" program from the European Regional Development Fund, grant number II2.0/2019/UD/01. This research was funded by Medical University of Bialystok, grant number SUB/2/DN/20/002/2229.	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J. Mol. Sci.	AUG	2020	21	15							5221	10.3390/ijms21155221			18	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	MZ3GG	WOS:000559010100001	32717981	Green Published, gold			2022-04-25	
J	Lu, Y; Zhang, XJ; Wang, JY; Chen, KS				Lu, Yan; Zhang, Xiujuan; Wang, Jiayue; Chen, Kaoshan			Exopolysaccharides isolated from Rhizopus nigricans induced colon cancer cell apoptosis in vitro and in vivo via activating the AMPK pathway	BIOSCIENCE REPORTS			English	Article							PROTEIN-KINASE; SIGNAL-TRANSDUCTION; SKELETAL-MUSCLE; PHOSPHORYLATION; POLYSACCHARIDES; AUTOPHAGY; ANTITUMOR; RAPTOR; GROWTH; MTOR	Colorectal cancer (CRC) is a leading cause of cancer-related human deaths. The exopolysaccharide (EPS1-1), isolated from Rhizopus nigricans, has been described as exhibiting anti-tumor and pro-apoptotic activity against CRC, although the underlying mechanism is poorly understood. Herein, we investigate how EPS1-1 induces apoptosis of CRC cells in vitro and in vivo. Our results show that, in vitro, EPS1-1 suppressed cell growth and facilitated apoptosis in a dose- and time-dependent manner by activating the AMP-activated protein kinase (AMPK) pathway in mouse colon cancer CT26 cells. However, treatment with small interfering RNAs (siRNAs) targeting AMPK alpha or with compound C, an AMPK inhibitor, interfered with the pro-apoptosis effects of EPS1-1. We also show that EPS1-1 initiated the release of reactive oxygen species (ROS) and liver kinase B1 (LKB1), both of which are necessary signals for AMPK activation. Furthermore, EPS1-1-mediated apoptosis is regulated by inactivation of mammalian target of rapamycin complex 1 (mTORC1) and activation of the jun-NH2 kinase (JNK)-p53 signaling axis dependent on AMPK activation. In vivo, azoxymethane/dextran sulfate sodium (AOM/DSS)-treated CRC mice, when administered EPS1-1, exhibited activation of the AMPK pathway, inhibition of mTORC1, and accumulation of p53 in tumor tissues. Collectively, these findings suggest that EPS1-1-induced apoptosis relies on the activation of the AMPK pathway. The present study provides evidence suggesting that EPS1-1 may be an effective target for development of novel CRC therapeutic agents.	[Lu, Yan; Zhang, Xiujuan; Wang, Jiayue; Chen, Kaoshan] Shandong Univ, Sch Life Sci, Qingdao 266000, Peoples R China; [Chen, Kaoshan] Shandong Univ, Natl Glycoengn Res Ctr, Qingdao 266000, Peoples R China; [Chen, Kaoshan] Wannan Med Coll, Anhui Prov Engn Res Ctr Polysaccharide Drugs, Anhui Prov Key Lab Act Biol Macromol, Drug Res & Dev Ctr,Sch Pharm, Wuhu 241002, Peoples R China		Chen, KS (corresponding author), Shandong Univ, Sch Life Sci, Qingdao 266000, Peoples R China.; Chen, KS (corresponding author), Shandong Univ, Natl Glycoengn Res Ctr, Qingdao 266000, Peoples R China.; Chen, KS (corresponding author), Wannan Med Coll, Anhui Prov Engn Res Ctr Polysaccharide Drugs, Anhui Prov Key Lab Act Biol Macromol, Drug Res & Dev Ctr,Sch Pharm, Wuhu 241002, Peoples R China.	ksc313@126.com			National Key Research and Development Program of China [2018YFA0902000]; Major Program of Shandong Province (Key Technology) [2015ZDJS04002]; Major State Basic Research Development Program of China (973 Program)National Basic Research Program of China [2012CB822102]; High Technology Research and Development Program of China (863 Program)National High Technology Research and Development Program of China [2012AA021501]; Natural Science Foundation of Education Department of Anhui Province [KJ2018ZD025]	This work was supported by the National Key Research and Development Program of China [grant number 2018YFA0902000]; the Major Program of Shandong Province (Key Technology) [grant number 2015ZDJS04002]; the Major State Basic Research Development Program of China (973 Program) [grant number 2012CB822102]; the High Technology Research and Development Program of China (863 Program) [grant number 2012AA021501]; and the Natural Science Foundation of Education Department of Anhui Province [grant number KJ2018ZD025].	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Rep.	JAN 14	2020	40		1						BSR20192774	10.1042/BSR20192774			17	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	KC9TM	WOS:000507514600001	31894839	Green Published, gold			2022-04-25	
J	Kocaturk, NM; Akkoc, Y; Kig, C; Bayraktar, O; Gozuacik, D; Kutlu, O				Kocaturk, Nur Mehpare; Akkoc, Yunus; Kig, Cenk; Bayraktar, Oznur; Gozuacik, Devrim; Kutlu, Ozlem			Autophagy as a molecular target for cancer treatment	EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES			English	Article; Proceedings Paper	Annual Meeting of the European-Federation-of-Pharmaceutical-Sciences (EUFEPS)	MAY 24-26, 2018	Athens, GREECE	European Federat Pharmaceut Sci		Autophagy; Cancer; Therapeutic agents	ENDOPLASMIC-RETICULUM STRESS; STARVATION-INDUCED AUTOPHAGY; TYROSINE KINASE INHIBITOR; HYPOXIA-INDUCIBLE FACTORS; CELL-DEATH; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; HISTONE DEACETYLASE; MAMMALIAN TARGET; COLON-CANCER	Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.	[Kocaturk, Nur Mehpare; Gozuacik, Devrim; Kutlu, Ozlem] Sabanci Univ, Nanotechnol Res & Applicat Ctr SUNUM, Orta Mah Univ Cad 27, TR-34956 Istanbul, Turkey; [Akkoc, Yunus; Gozuacik, Devrim] Sabanci Univ, Mol Biol Genet & Bioengn Program, Fac Engn & Nat Sci, TR-34956 Istanbul, Turkey; [Kig, Cenk] Istanbul Yeni Yuzyil Univ, Fac Med, TR-34010 Istanbul, Turkey; [Bayraktar, Oznur] Okan Univ, Dept Med Biol & Genet, Fac Med, Istanbul, Turkey		Kutlu, O (corresponding author), Sabanci Univ, Nanotechnol Res & Applicat Ctr SUNUM, Orta Mah Univ Cad 27, TR-34956 Istanbul, Turkey.	ozlemkutlu@sabanciuniv.edu	Abdulsalam, Raghad/AAR-5226-2021; kig, cenk/ABI-4009-2020; Kocaturk, Nur/V-3125-2018; Devrim, Gozuacik/C-3330-2008; AKKOC, Yunus/AAK-8853-2020	kig, cenk/0000-0002-6318-5001; Kocaturk, Nur/0000-0002-4452-9913; Devrim, Gozuacik/0000-0001-7739-2346; AKKOC, Yunus/0000-0001-5379-6151; Kutlu, Ozlem/0000-0002-3769-2536	Scientific and Technological Research Council of Turkey (TUBITAK)-1001Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114Z836]; TUBITAK-BIDEB 2211Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)	This work was supported by Scientific and Technological Research Council of Turkey (TUBITAK)-1001 Grant number: 114Z836. YA is supported by TUBITAK-BIDEB 2211 Scholarships for his PhD studies.	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J. Pharm. Sci.	JUN 15	2019	134						116	137		10.1016/j.ejps.2019.04.011			22	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED); Conference Proceedings Citation Index - Science (CPCI-S)	Pharmacology & Pharmacy	HY4ER	WOS:000468081200010	30981885		Y	N	2022-04-25	
J	Lee, YC; Su, CY; Lin, YF; Lin, CM; Fang, CY; Lin, YK; Hsiao, M; Chen, CL				Lee, Yu-Chieh; Su, Chia-Yu; Lin, Yuan-Feng; Lin, Chun-Mao; Fang, Chih-Yeu; Lin, Yen-Kuang; Hsiao, Michael; Chen, Chi-Long			Lysosomal acid phosphatase 2 is an unfavorable prognostic factor but is associated with better survival in stage II colorectal cancer patients receiving chemotherapy	ONCOTARGET			English	Article						colorectal carcinoma; lysosomal acid phosphatase 2; 5-FU; chemotherapy	GENE-EXPRESSION PROFILE; COLON-CANCER; ADJUVANT CHEMOTHERAPY; PREDICTS RECURRENCE; CELL-PROLIFERATION; TARGETING PTEN; POOR-PROGNOSIS; CARCINOMA; METASTASIS; AUTOPHAGY	Colorectal cancer (CRC) is one of the leading cancers worldwide. Surgery is the main therapeutic modality for stage II CRC. However, the implementation of adjuvant chemotherapy remains controversial and is not universally applied so far. In this study, we found that the protein expression of lysosomal acid phosphatase 2 (ACP2) was increased in CRC and that stage II CRC patients with high ACP2 expression showed a poorer outcome than those with low ACP2 expression (p = 0.004). To investigate this discrepancy, we analyzed the relation between ACP2 expression and several clinical cofactors. Among patients who received chemotherapy, those with an high expression of ACP2 showed better survival in both stage II and III CRC than those with low ACP2 expression. In stage II CRC patients, univariate analysis showed ACP2 expression and T stage to be cofactors significantly associated with overall survival (ACP2: p = 0.006; T stage: p = 0.034). Multivariate Cox proportion hazard model analysis also revealed ACP2 to be an independent prognostic factor for overall survival (ACP2: p = 0.006; T stage: p = 0.041). Furthermore, ACP2-knockdown CRC cells showed an increase in chemoresistance to 5-FU treatment and increased proliferation marker in the ACP2 knockdown clone. Taken together, our results suggested that ACP2 is an unfavorable prognostic factor for stage II CRC and may serve as a potential chemotherapy-sensitive marker to help identify a subset of stage II and III CRC patients for whom chemotherapy would improve survival.	[Lee, Yu-Chieh] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei, Taiwan; [Su, Chia-Yu; Hsiao, Michael] Acad Sinica, Genom Res Ctr, Taipei, Taiwan; [Lin, Yuan-Feng] Taipei Med Univ, Grad Inst Clin Med, Taipei, Taiwan; [Lin, Chun-Mao] Taipei Med Univ, Sch Med, Dept Biochem, Taipei, Taiwan; [Chen, Chi-Long] Taipei Med Univ, Coll Med, Dept Pathol, Taipei, Taiwan; [Chen, Chi-Long] Taipei Med Univ Hosp, Dept Pathol, Taipei, Taiwan; [Fang, Chih-Yeu] Taipei Med Univ, Wan Fang Hosp, Dept Pathol, Taipei, Taiwan; [Lin, Yen-Kuang] Taipei Med Univ, Ctr Biostat, Taipei, Taiwan; [Lee, Yu-Chieh] Taipei Med Univ, Shuang Ho Hosp, Dept Internal Med, Div Gastroenterol, Taipei, Taiwan; [Hsiao, Michael] Kaohsiung Med Univ, Coll Med, Dept Biochem, Kaohsiung, Taiwan		Hsiao, M (corresponding author), Acad Sinica, Genom Res Ctr, Taipei, Taiwan.; Chen, CL (corresponding author), Taipei Med Univ, Coll Med, Dept Pathol, Taipei, Taiwan.; Chen, CL (corresponding author), Taipei Med Univ Hosp, Dept Pathol, Taipei, Taiwan.; Hsiao, M (corresponding author), Kaohsiung Med Univ, Coll Med, Dept Biochem, Kaohsiung, Taiwan.	mhsiao@gate.sinica.edu.tw; chencl@tmu.edu.tw	Su, Chia-Yi/L-5378-2016; Fang, Chih-Yeu/AAH-5170-2021; Hsiao, Michael/U-6238-2019	Su, Chia-Yi/0000-0002-9483-4510; Fang, Chih-Yeu/0000-0002-8280-3012; Hsiao, Michael/0000-0001-8529-9213; Lin, Chun-Mao/0000-0002-8366-4026	Ministry of Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Academia SinicaAcademia Sinica - Taiwan [MOST 104-0210-01-09-02, MOST 105-0210-01-13-01]; Health and Welfare surcharge of tobacco products from the Ministry of Health and Welfare to the Comprehensive Cancer center of Taipei Medical University [MOHW105-TDU-B-212-134001]	We thank Miss Tracy Tsai for her assistance in immunohistochemistry experiments, Jennifer Liu for her assistance in cell culture experiments and Dr. YuanHung Wang (Department Medical Research, Shuang Ho Hospital, Taipei Medical University) for statistical analysis support. We would also like to thank the Ministry of Science and Technology and Academia Sinica for their financial support (MOST 104-0210-01-09-02 and MOST 105-0210-01-13-01 to M. Hsiao). This work was also funded by the Health and Welfare surcharge of tobacco products (MOHW105-TDU-B-212-134001) from the Ministry of Health and Welfare to the Comprehensive Cancer center of Taipei Medical University.	Chi JY, 2015, ONCOTARGET, V6, P23987, DOI 10.18632/oncotarget.4364; COHEN SM, 1990, SCIENCE, V249, P1007, DOI 10.1126/science.2204108; Giraldez MD, 2013, INT J CANCER, V132, P1090, DOI 10.1002/ijc.27747; Fang WL, 2012, WORLD J SURG, V36, P2131, DOI 10.1007/s00268-012-1652-7; Ferlay J, 2013, EUR J CANCER, V49, P1374, DOI 10.1016/j.ejca.2012.12.027; Gou WF, 2015, ONCOTARGET, V6, P19552, DOI 10.18632/oncotarget.3735; GRIFFIN MR, 1987, CANCER-AM CANCER SOC, V60, P2318, DOI 10.1002/1097-0142(19871101)60:9<2318::AID-CNCR2820600934>3.0.CO;2-B; Hamburg MA, 2010, NEW ENGL J MED, V363, P301, DOI 10.1056/NEJMp1006304; Holle AW, 2016, ADV DRUG DELIVER REV, V97, P270, DOI 10.1016/j.addr.2015.10.007; Isacoff WH, 1997, WORLD J SURG, V21, P748, DOI 10.1007/s002689900301; Katagiri H, 2015, INT J ONCOL, V47, P2037, DOI 10.3892/ijo.2015.3191; Kelder W, 2006, EXPERT REV ANTICANC, V6, P785, DOI 10.1586/14737140.6.5.785; Kopetz S, 2015, ONCOLOGIST, V20, P127, DOI 10.1634/theoncologist.2014-0325; Kuebler JP, 2007, J CLIN ONCOL, V25, P2198, DOI 10.1200/JCO.2006.08.2974; Kumar A, 2015, CANCER-AM CANCER SOC, V121, P527, DOI 10.1002/cncr.29072; Law BYK, 2014, SCI REP-UK, V4, DOI 10.1038/srep05510; Lee YC, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0132579; Li HH, 2015, INT J ONCOL, V47, P1379, DOI 10.3892/ijo.2015.3144; Lin CC, 2012, INT J COLORECTAL DIS, V27, P277, DOI 10.1007/s00384-011-1341-2; Lin TC, 2015, J PATHOL, V237, P50, DOI 10.1002/path.4552; Liu K, 2015, ONCOL REP, V34, P1003, DOI 10.3892/or.2015.4030; Mannan AU, 2004, NEUROGENETICS, V5, P229, DOI 10.1007/s10048-004-0197-9; Melquist S, 2007, AM J HUM GENET, V80, P769, DOI 10.1086/513320; NADLER HL, 1970, NEW ENGL J MED, V282, P302, DOI 10.1056/NEJM197002052820604; Saftig P, 1997, J BIOL CHEM, V272, P18628, DOI 10.1074/jbc.272.30.18628; Smith JJ, 2010, GASTROENTEROLOGY, V138, P958, DOI 10.1053/j.gastro.2009.11.005; Somoza-Martin JM, 2005, J ORAL MAXIL SURG, V63, P786, DOI 10.1016/j.joms.2005.02.014; Su CY, 2015, ONCOTARGET, V6, P18602, DOI 10.18632/oncotarget.4329; Thu Kelsie L, 2014, Oncoscience, V1, P326; WAHEED A, 1988, EMBO J, V7, P2351, DOI 10.1002/j.1460-2075.1988.tb03079.x; Ying HC, 2015, ONCOL LETT, V9, P1759, DOI 10.3892/ol.2015.2950; You YN, 2015, SURG ONCOL, V24, P61, DOI 10.1016/j.suronc.2015.02.001	32	0	0	1	3	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	FEB 14	2017	8	7					12120	12132		10.18632/oncotarget.14552			13	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	EK8QB	WOS:000394187400119	28076332	gold, Green Submitted, Green Published			2022-04-25	
J	Peng, QL; Lin, KS; Chang, T; Zou, L; Xing, PF; Shen, YT; Zhu, YQ				Peng, Qiliang; Lin, Kaisu; Chang, Tao; Zou, Li; Xing, Pengfei; Shen, Yuntian; Zhu, Yaqun			Identification of genomic expression differences between right-sided and left-sided colon cancer based on bioinformatics analysis	ONCOTARGETS AND THERAPY			English	Article						colon cancer; location; differentially expressed genes; bioinformatics analysis	INHIBITORS; STATISTICS; AUTOPHAGY; MUTATION; STRESS; GENES; PCNA	Introduction: More and more findings have demonstrated that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) are distinct clinical and biological entities and suggest that they should be treated as different diseases. However, the reasons why RCC and LCC harbor different clinical and biological features remain unclear. Materials and methods: To identify the genomic expression differences between RCC and LCC and uncover the mechanisms underlying these differences, we chose the gene expression profiles of GSE14333 from the Gene Expression Omnibus (GEO) database as an object of study. Then, a systematic and integrative bioinformatics analysis was performed to research the possible mechanism of the differentially expressed (DE) genes from the Gene Expression Omnibus dataset including gene ontology (GO) analysis, pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. Totally, we extracted 3,793 DE genes from samples of colon cancer including 1,961 genes upregulated in RCC and 1,832 genes upregulated in LCC from the selected dataset. Results: The results of GO and pathway enrichment analysis indicated that RCC and LCC could predispose to different pathways regulated by different genes. Based on the PPI network, PCNA, TP53, HSP90AA1, CSNK2A1, UBB, LRRK2, ABL1, PRKACA, CAV1, and JUN were identified as the key hub genes. Also, significant modules were screened from the PPI network. Conclusion: In conclusion, the present study indicated that the identified genes and pathways may promote new insights into the underlying molecular mechanisms contributing to the difference between RCC and LCC and might be used as specific therapeutic targets and prognostic markers for the personalized treatment of RCC and LCC.	[Peng, Qiliang; Zou, Li; Xing, Pengfei; Shen, Yuntian; Zhu, Yaqun] Soochow Univ, Affiliated Hosp 2, Dept Radiotherapy & Oncol, San Xiang Rd 1055, Suzhou 215004, Jiangsu, Peoples R China; [Peng, Qiliang; Zou, Li; Xing, Pengfei; Shen, Yuntian; Zhu, Yaqun] Soochow Univ, Inst Radiotherapy & Oncol, Suzhou, Peoples R China; [Peng, Qiliang; Zou, Li; Xing, Pengfei; Shen, Yuntian; Zhu, Yaqun] Suzhou Key Lab Radiat Oncol, Suzhou, Peoples R China; [Lin, Kaisu] Nantong Rich Hosp, Dept Oncol, Nantong, Peoples R China; [Chang, Tao] Sixth Peoples Hosp Kunshan, Dept Gen Surg, Kunshan, Peoples R China		Zhu, YQ (corresponding author), Soochow Univ, Affiliated Hosp 2, Dept Radiotherapy & Oncol, San Xiang Rd 1055, Suzhou 215004, Jiangsu, Peoples R China.	szzhuyaqun@sina.com			Second Affiliated Hospital of Soochow University [XKQ2015005]; Suzhou Science and Technology Development Program [SZS201509]; Suzhou Clinical Medical Center Construction Project [Szzxj201503]; Jiangsu Medical Innovation Team [CXDT-37]	This study was supported by the Second Affiliated Hospital of Soochow University Preponderant Clinic Discipline Group Project funding (XKQ2015005), Suzhou Science and Technology Development Program (SZS201509), Suzhou Clinical Medical Center Construction Project (Szzxj201503), and Jiangsu Medical Innovation Team (CXDT-37).	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J	Maraming, P; Klaynongsruang, S; Boonsiri, P; Peng, SF; Daduang, S; Leelayuwat, C; Pientong, C; Chung, JG; Daduang, J				Maraming, Pornsuda; Klaynongsruang, Sompong; Boonsiri, Patcharee; Peng, Shu-Fen; Daduang, Sakda; Leelayuwat, Chanvit; Pientong, Chamsai; Chung, Jing-Gung; Daduang, Jureerut			The cationic cell-penetrating KT2 peptide promotes cell membrane defects and apoptosis with autophagy inhibition in human HCT 116 colon cancer cells	JOURNAL OF CELLULAR PHYSIOLOGY			English	Article						antimicrobial peptide; apoptosis; autophagy; cationic cell-penetrating KT2; membrane permeability	ANTIMICROBIAL PEPTIDES; ANTIBACTERIAL ACTIVITY; ARGININE; RICH; MECHANISMS; LYSINE; SELECTIVITY; LEUKEMIA; DESIGN	The anticancer activity of cationic antimicrobial peptides (AMPs) has become more interesting because some AMPs have selective recognition against cancer cells. However, their antitumor properties and underlying mechanisms in cancer cells have not been clearly understood. In this study, we evaluated the effects of KT2 (lysine/tryptophan-rich AMP) on the cellular uptake and internalization mechanism, cell viability, surface charge of the cell membrane, membrane integrity, apoptotic cell death, and autophagy in human HCT 116 colon cancer cells. We found that KT2 interacted with the cell membrane of HCT 116 cells and was internalized into HCT 116 cells via clathrin-mediated and caveolae-mediated endocytosis mechanisms. The interaction of KT2 with cells caused cell membrane structure change, elevated membrane permeability, and KT2 also affected the lipid component. The results of atomic force microscopy showed cellular membrane defects of KT2-treated cells. The internalized KT2 induced nuclear condensation and apoptotic cell death. It elevated the apoptotic factor levels including those of cytochrome c and apoptosis-inducing factor. Furthermore, KT2 inhibited autophagy by the suppression of autophagy-related 5, autophagy-related 7, autophagy-related 16 like 1, and Beclin-1 proteins. In conclusion, these results revealed the cytotoxicity of cationic KT2 against HCT 116 cells and may help to clarify the interactions between cationic AMPs and cancer cells.	[Maraming, Pornsuda] Khon Kaen Univ, Grad Sch, Biomed Sci Program, Khon Kaen, Thailand; [Klaynongsruang, Sompong] Khon Kaen Univ, Fac Sci, Prot & Prote Res Ctr Commercial & Ind Purposes Pr, Dept Biochem, Khon Kaen, Thailand; [Boonsiri, Patcharee] Khon Kaen Univ, Fac Med, Dept Biochem, Khon Kaen, Thailand; [Peng, Shu-Fen; Chung, Jing-Gung] China Med Univ, Dept Biol Sci & Technol, 91 Hsueh Shih Rd, Taichung 40402, Taiwan; [Peng, Shu-Fen] China Med Univ Hosp, Dept Med Res, Taichung, Taiwan; [Daduang, Sakda] Khon Kaen Univ, Fac Pharmaceut Sci, Div Pharmacognosy & Toxicol, Khon Kaen, Thailand; [Leelayuwat, Chanvit; Daduang, Jureerut] Khon Kaen Univ, Fac Associated Med Sci, Ctr Res & Dev, Med Diagnost Labs, Khon Kaen 40002, Thailand; [Pientong, Chamsai] Khon Kaen Univ, HPV & EBV & Carcinogenesis Res Grp, Khon Kaen, Thailand		Chung, JG (corresponding author), China Med Univ, Dept Biol Sci & Technol, 91 Hsueh Shih Rd, Taichung 40402, Taiwan.; Daduang, J (corresponding author), Khon Kaen Univ, Fac Associated Med Sci, Ctr Res & Dev, Med Diagnost Labs, Khon Kaen 40002, Thailand.	jgchung@mail.cmu.edu.tw; jurpoo@kku.ac.th		Klaynongsruang, Sompong/0000-0003-2872-1291; Maraming, Pornsuda/0000-0002-5937-0917; Daduang, Jureerut/0000-0003-0977-4144	China Medical University, Taichung, TaiwanChina Medical University [CMU107-ASIA-17]; National Research Council of ThailandNational Research Council of Thailand (NRCT) [2558]; Khon Kaen University (Synchrotron Light Research Institute) [2559-KKU-SLRI-01-09]; Royal Golden Jubilee (RGJ) Ph.D. Scholarship [PHD/0014/2558]; Khon Kaen University [61004605]; Synchrotron Light Research Institute [2559-KKU-SLRI-01-09]	China Medical University, Taichung, Taiwan, Grant/Award Number: CMU107-ASIA-17; National Research Council of Thailand, Grant/Award Numbers: grant no. 2558, 2558; Khon Kaen University (Synchrotron Light Research Institute), Grant/Award Number: grant no. 2559-KKU-SLRI-01-09; The Royal Golden Jubilee (RGJ) Ph.D. Scholarship, Grant/Award Number: PHD/0014/2558; Khon Kaen University, Grant/Award Number: 61004605; Synchrotron Light Research Institute, Grant/Award Number: 2559-KKU-SLRI-01-09	Alves AC, 2016, BBA-BIOMEMBRANES, V1858, P2231, DOI 10.1016/j.bbamem.2016.06.025; 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Cell. Physiol.	DEC	2019	234	12					22116	22129		10.1002/jcp.28774			14	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	IV6KF	WOS:000484376600058	31073999				2022-04-25	
J	Casanova, MR; Azevedo-Silva, J; Rodrigues, LR; Preto, A				Casanova, Marta R.; Azevedo-Silva, Joao; Rodrigues, Ligia R.; Preto, Ana			Colorectal Cancer Cells Increase the Production of Short Chain Fatty Acids by Propionibacterium freudenreichii Impacting on Cancer Cells Survival	FRONTIERS IN NUTRITION			English	Article						colorectal cancer; Propionibacterium freudenreichii; probiotic; short chain fatty acids; acetate; propionate	LACTATE METABOLISM; PROTEOMIC ANALYSIS; SODIUM-BUTYRATE; SUBSP SHERMANII; COLON-CANCER; IN-VIVO; APOPTOSIS; AUTOPHAGY; MICROBIOTA; MITOCHONDRIA	Propionibacterium freudenreichii is a commercially relevant bacterium with probiotic potential.This bacterium can exert protective effects particularly against colorectal cancer (CRC), via the production of short chain fatty acids (SCFA), namely acetate and propionate. In this work, we aimed to evaluate the performance and adaptation capacity of P. freudenreichii to a simulated digestive stress using different culture media, namely YEL, Basal medium, Mimicking the Content of the Human Colon medium (MCHC) and DMEM. The effect of the fermented culture broth on CRC cells survival and of CRC cells conditioned media on the bacteria performance was also evaluated. Basal medium was found to be the best for P. freudenreichii to produce SCFA. MCHC medium, despite being the medium in which lower amounts of acetate and propionate were produced, showed higher acetate and propionate yields as compared to other media. We also observed that the presence of lactate in CRC cells conditioned growth medium resulting from cell metabolism, leads to an increased production of SCFA by the bacteria. The bacterial fermented broth successfully inhibited CRC cells proliferation and increased cell death. Our results showed for the first time that P. freudenreichii performance might be stimulated by extracellular lactate produced by CRC metabolic switch also known as "Warburg effect," where cancer cells "ferment" glucose into lactate. Additionally, our results suggest that P. freudenreichii could be potentially used as a probiotic in CRC prevention at early stages of the carcinogenesis process and might help in CRC therapeutic approaches.	[Casanova, Marta R.; Rodrigues, Ligia R.] Univ Minho, Ctr Biol Engn, Braga, Portugal; [Casanova, Marta R.; Azevedo-Silva, Joao; Preto, Ana] Univ Minho, Dept Biol, Ctr Mol & Environm Biol, Braga, Portugal		Preto, A (corresponding author), Univ Minho, Dept Biol, Ctr Mol & Environm Biol, Braga, Portugal.	apreto@bio.uminho.pt	Rodrigues, Ligia R/C-3151-2009; Preto, Ana/H-8112-2012; Casanova, Marta/AAL-5693-2020	Rodrigues, Ligia R/0000-0001-9265-0630; Preto, Ana/0000-0002-7302-0630; Casanova, Marta/0000-0002-9413-7977; Azevedo-Silva, Joao/0000-0003-1754-9254	FEDER through POFC-COMPETE; FCTPortuguese Foundation for Science and TechnologyEuropean Commission [PEst-OE/BIA/UI4050/2014]; FCT I.P [UID/BIO/04469/2013, RECI/BBB-EBI/0179/2012, FCOMP-01-0124-FEDER-027462, UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569)]; ERDF through the COMPETE2020-Programa Operacional Competitividade e Internacionalizacao (POCI); Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) [NORTE-01-0145-FEDER-00009]	The authors acknowledge the financial support from the FEDER through POFC-COMPETE and by FCT through project PEst-OE/BIA/UI4050/2014. This work was supported by FCT I.P. through the strategic funding of UID/BIO/04469/2013 unit and project ref. RECI/BBB-EBI/0179/2012 (project number FCOMP-01-0124-FEDER-027462). This work was also supported by the strategic programme UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569) funded by national funds through the FCT I.P. and by the ERDF through the COMPETE2020-Programa Operacional Competitividade e Internacionalizacao (POCI). This article is a result of the project EcoAgriFood NORTE-01-0145-FEDER-00009, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).	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Nutr.	MAY 24	2018	5								44	10.3389/fnut.2018.00044			12	Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Nutrition & Dietetics	GK7GA	WOS:000436363900001	29881727	gold, Green Published			2022-04-25	
J	Liu, L; Zhao, WM; Yang, XH; Sun, ZQ; Jin, HZ; Lei, C; Jin, B; Wang, HJ				Liu, Lin; Zhao, Wei-Min; Yang, Xin-Hui; Sun, Zhen-Qiang; Jin, Hui-Zhen; Lei, Cheng; Jin, Bo; Wang, Hai-Jiang			Effect of inhibiting Beclin-1 expression on autophagy, proliferation and apoptosis in colorectal cancer	ONCOLOGY LETTERS			English	Article						colorectal cancer; HCT116 cells; Beclin-1; small interfering RNA; autophagy; proliferation; apoptosis	BCL-X-L; CELL-DEATH; TUMOR-SUPPRESSOR; GENE; PHOSPHORYLATION; MACROAUTOPHAGY; TUMORIGENESIS; PATHOGENESIS; MECHANISMS; INDUCTION	The present study aimed to investigate the molecular mechanisms and effect of Beclin-1 on autophagy, proliferation and apoptosis in the colorectal cancer (CRC) HCT116 and SW620 cells. Beclin-1 was silenced by RNA interference (RNAi) in HTC116 and SW620 cells. Reverse transcription-polymerase chain reaction and western blot were used to measure the expression of Beclin-1. The percentage of apoptotic cells was analyzed by cell counting kit-8 (CCK-8) and flow cytometry (FCM). Cell cycle and cell proliferation were analyzed by FCM and the MTT assay. The present study created 3 groups in the two cell lines, consisting of the targeting siRNA (TS) group, in which Beclin-1 was partially silenced, non-specific siRNA (NS) group and control group (CG; without transfection). By siRNA transfection, the mRNA and protein level of Beclin-1 in the TS group were significantly inhibited compared with the NS group and CG (P<0.05). After 0, 24, 48 and 72 h, the survival rate of the cells in the TS group was significantly decreased compared with the survival rate of the cells in the NS group and CG, as detected by CCK-8 methods (P<0.05). FCM and MTT results showed the apoptotic rate of the cells in the TS group was significantly decreased compared with the rate in the NS group and CG (P<0.05), and the proliferation of the cells in the NS group was evidently increased compared with the CG. In conclusion, Beclin-1 played an important role in regulating autophagy, proliferation and apoptosis in HCT116 and SW620 cells. The inhibition of Beclin-1 by RNAi suppressed the autophagic activity and proliferation, but promoted apoptosis in CRC cells. Beclin-1 was the new target of gene therapy for CRC.	[Liu, Lin; Zhao, Wei-Min; Yang, Xin-Hui; Sun, Zhen-Qiang; Jin, Hui-Zhen; Lei, Cheng; Jin, Bo; Wang, Hai-Jiang] Xinjiang Med Univ, Canc Hosp, Dept Abdominal Surg, 789 Suzhou East St, Urumqi 830011, Xinjiang, Peoples R China		Wang, HJ (corresponding author), Xinjiang Med Univ, Canc Hosp, Dept Abdominal Surg, 789 Suzhou East St, Urumqi 830011, Xinjiang, Peoples R China.	wanghaijang_l@163.com					Behrends C, 2010, NATURE, V466, P68, DOI 10.1038/nature09204; Galadari S, 2015, APOPTOSIS, V20, P689, DOI 10.1007/s10495-015-1109-1; Gozuacik D, 2004, ONCOGENE, V23, P2891, DOI 10.1038/sj.onc.1207521; Hailey DW, 2010, CELL, V141, P656, DOI 10.1016/j.cell.2010.04.009; Jemal A, 2010, CANCER EPIDEM BIOMAR, V19, P1893, DOI 10.1158/1055-9965.EPI-10-0437; Kang R, 2011, CELL DEATH DIFFER, V18, P571, DOI 10.1038/cdd.2010.191; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Li ZM, 2014, INT J BIOL SCI, V10, P757, DOI 10.7150/ijbs.9067; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Maiuri MC, 2010, EMBO J, V29, P515, DOI 10.1038/emboj.2009.377; Ouyang L, 2012, CELL PROLIFERAT, V45, P487, DOI 10.1111/j.1365-2184.2012.00845.x; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Ren JS, 2010, ASIAN PAC J CANCER P, V11, P1587; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; THOMPSON CB, 1995, SCIENCE, V267, P1456, DOI 10.1126/science.7878464; Won KY, 2015, PATHOL RES PRACT, V211, P308, DOI 10.1016/j.prp.2014.11.005; Yang ZF, 2010, NAT CELL BIOL, V12, P814, DOI 10.1038/ncb0910-814; Ying HC, 2015, ONCOL LETT, V9, P1759, DOI 10.3892/ol.2015.2950; Yoshimori T, 2004, BIOCHEM BIOPH RES CO, V313, P453, DOI 10.1016/j.bbrc.2003.07.023; Yu L, 2004, SCIENCE, V304, P1500, DOI 10.1126/science.1096645; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100; Zalckvar E, 2009, AUTOPHAGY, V5, P720, DOI 10.4161/auto.5.5.8625; Zalckvar E, 2009, EMBO REP, V10, P285, DOI 10.1038/embor.2008.246; Zeng XH, 2006, J CELL SCI, V119, P259, DOI 10.1242/jcs.02735	25	13	16	3	5	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-1074	1792-1082		ONCOL LETT	Oncol. Lett.	OCT	2017	14	4					4319	4324		10.3892/ol.2017.6687			6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FK0DU	WOS:000413151300061	28989537	Green Published, gold			2022-04-25	
J	Gao, Q; Bi, PD; Luo, D; Guan, Y; Zeng, WL; Xiang, HY; Mi, QL; Yang, GY; Li, XM; Yang, B				Gao, Qian; Bi, Pinduan; Luo, Ding; Guan, Ying; Zeng, Wanli; Xiang, Haiying; Mi, Qili; Yang, Guangyu; Li, Xuemei; Yang, Bin			Nicotine-induced autophagy via AMPK/mTOR pathway exerts protective effect in colitis mouse model	CHEMICO-BIOLOGICAL INTERACTIONS			English	Article						Ulcerative colitis; Nicotine; Autophagy; AMPK/mTOR pathway	INFLAMMATORY-BOWEL-DISEASE; SODIUM-INDUCED COLITIS; ULCERATIVE-COLITIS; APOPTOSIS; PATHOGENESIS; CELLS; PROLIFERATION; ACTIVATION; INSIGHTS; CANCER	Epidemiological studies have shown that cigarette smoking is beneficial in ulcerative colitis and that nicotine may be responsible for this effect. However, the mechanism remains unclear. In a previous study, nicotine was found to induce autophagy in intestinal cells. Here, we evaluated the effect of nicotine-induced autophagy in a dextran sodium sulfate (DSS)-induced colitis mouse model. C57BL/6 adult male mice drank DSS water solution freely for seven consecutive days, and then tap water was administered. The effect of nicotine treatment was examined in the DSS model, including colon length, disease severity, histology of the colon tissue, and inflammation levels. Moreover, autophagy levels were detected by Western blot analysis (LC3II/LC3I, p62, and beclin-1). The levels of DSS-induced colitis were significantly decreased following nicotine treatment. The disease activity score, body weight, histologic damage scores, and the level of colonic inflammatory factors of nicotine-treated mice all decreased compared to those of the control mice. Additionally, nicotine enhanced the expression of LC3II/LC3I and beclin-1 but decreased the p62 protein level. Inhibiting autophagy by 3-MA attenuated the protective effects of nicotine on colitis. Additionally, both in vitro and in vivo experiments showed changes in AMPK-mTOR-P70S6K during this process. These results suggest that nicotine improved colitis by regulating autophagy and provided a protective effect against DSS-induced colitis.	[Gao, Qian; Guan, Ying; Zeng, Wanli; Xiang, Haiying; Mi, Qili; Yang, Guangyu; Li, Xuemei] China Tobacco Yunnan Ind Co Ltd, Yunnan Key Lab Tobacco Chem, R&D Ctr, Kunming, Yunnan, Peoples R China; [Bi, Pinduan; Luo, Ding; Yang, Bin] Kunming Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Kunming, Yunnan, Peoples R China		Yang, B (corresponding author), 295 Xichang Rd, Kunming, Yunnan, Peoples R China.; Li, XM (corresponding author), 41 Keyi Rd, Kunming 650106, Yunnan, Peoples R China.	lixuem@ynzy-tobacco.com; allan11182@163.com			Yunnan Key Laboratory of Tobacco Chemistry Project [2017539200340397]	This work was supported by the Yunnan Key Laboratory of Tobacco Chemistry Project [Grant No. 2017539200340397].	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Interact.	FEB 1	2020	317								108943	10.1016/j.cbi.2020.108943			7	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	KN4NR	WOS:000514815900008	31926917				2022-04-25	
J	Roberts, JL; Poklepovic, A; Booth, L				Roberts, Jane L.; Poklepovic, Andrew; Booth, Laurence			Curcumin interacts with sildenafil to kill GI tumor cells via endoplasmic reticulum stress and reactive oxygen/nitrogen species	ONCOTARGET			English	Article						sildenafil; autophagy; chaperone; death receptor; ER stress	PDE5 INHIBITORS ENHANCE; HUMAN COLORECTAL-CANCER; NITRIC-OXIDE; TYROSINE NITRATION; GM-CSF; PATHWAY; GROWTH; ACTIVATION; EXPRESSION; PROMOTES	The present studies focused on the ability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil to enhance the anti-cancer properties of clinically relevant concentrations of the dietary diarylheptanoid curcumin. In gastrointestinal tumor cells, sildenafil and curcumin interacted in a greater than additive fashion to kill. Inhibition of the extrinsic apoptotic pathway suppressed killing by similar to 50%, as did blockade of the intrinsic apoptotic pathway. Sildenafil and curcumin reduced mTORC1 and mTORC2 activity and increased Beclin1 levels and the numbers of autophagosomes and autolysosomes in cells in a PERK-eIF2 alpha-dependent fashion. Knock down of Beclin1 or ATG5 partially suppressed killing. In contrast, stable knock out of ATG16-L1 unexpectedly enhanced killing, an effect not altered by Beclin1/ATG5 knock down. Curcumin and sildenafil exposure reduced the expression of MCL-1, BCL-XL, thioredoxin and superoxide dismutase 2 (SOD2) in an eIF2 alpha-dependent fashion. Curcumin and sildenafil interacted in a greater than additive fashion to increase the levels of reactive oxygen species; knock down of thioredoxin or SOD2 enhanced killing and overexpression of thioredoxin or SOD2 suppressed killing. In vivo, curcumin and sildenafil interacted to suppress the growth of colon cancer tumors. Multiplex analyses of plasma taken after drug exposure at animal nadir indicated that the levels of M-CSF, CXCL-9, PDGF and G-CSF were significantly increased by [curcumin + sildenafil] and that expression of CXCL1 and CCL5 were significantly reduced. Cells isolated from in vivo treated [curcumin + sildenafil] tumors were resistant to in vitro [curcumin + sildenafil] exposure, a phenotype that was blocked by the colon cancer therapeutic regorafenib.	[Roberts, Jane L.; Poklepovic, Andrew; Booth, Laurence] Virginia Commonwealth Univ, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA; [Roberts, Jane L.; Booth, Laurence] Virginia Commonwealth Univ, Dept Mol Biol, Med Coll Virginia Campus, Richmond, VA 23298 USA; [Poklepovic, Andrew] Virginia Commonwealth Univ, Dept Med, Med Coll Virginia Campus, Richmond, VA 23298 USA		Booth, L (corresponding author), Virginia Commonwealth Univ, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA.; Booth, L (corresponding author), Virginia Commonwealth Univ, Dept Mol Biol, Med Coll Virginia Campus, Richmond, VA 23298 USA.	laurence.booth@vcuhealth.org			Universal Inc.; Dr. H.F. Young and Betts family fund;  [R01CA192613]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA192613] Funding Source: NIH RePORTER	Support for the present study was funded from the Universal Inc. Chair in Signal Transduction Research and R01CA192613. Thanks to Dr. H.F. Young and the Betts family fund for support in the purchase of the Hermes Wiscan instrument. Thanks to Dr. David. L. Boone for providing the HCT116 cell clones.	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J	Huang, ZJ; Fang, WL; Liu, WH; Wang, L; Liu, B; Liu, SM; Liu, SJ				Huang, Zhenjun; Fang, Weilun; Liu, Weihua; Wang, Li; Liu, Bin; Liu, Shiming; Liu, Shaojun			Aspirin induces Beclin-1-dependent autophagy of human hepatocellular carcinoma cell	EUROPEAN JOURNAL OF PHARMACOLOGY			English	Article						aspirin; autophagy; hepatocellular carcinoma cells; Beclin-1; AMP-activated protein kinase; mammalian target of rapamycin	CANCER STEM-CELLS; ACTIVATED PROTEIN-KINASE; LOW-DOSE ASPIRIN; COLORECTAL-CANCER; BREAST-CANCER; GROWTH; PATHWAY; COMBINATION; EXPRESSION; MECHANISM	Aspirin not only reduces the incidence of hepatocellular carcinoma (HCC) but also plays a synergistic role with chemotherapy for HCC treatment. However, the underlying mechanisms remain incompletely elucidated. Given that autophagy triggers cancer cell death, the present study examined the autophagic effect of aspirin on HCC cells. Results showed that aspirin increased LC3II/LC3I ratio, decreased p62 expression, and enhanced autophagic flux (autophagosome and autolysosome puncta) in Hep3B, HepG2, or SMMC-7721 cells, reflecting the autophagy of HCC cells. The autophagic effects of aspirin depended on Beclin-1 expression. Aspirin disrupted the interaction between Bcl-2 and Beclin-1. In addition to activating the AMP-activated protein kinase, c-Jun N-terminal kinase, and Glycogen synthase kinase-3 pathways, aspirin inhibited the mammalian-target-of rapamycin- S6K1/4E-BP1 signaling. Aspirin induced autophagy of HCC cell. This study contributes to understanding the chemoprotective and inhibitory effects of aspirin on HCC development.	[Huang, Zhenjun; Fang, Weilun; Liu, Weihua; Wang, Li; Liu, Bin; Liu, Shiming; Liu, Shaojun] Guangzhou Med Univ, Affiliated Hosp 2, Guangzhou Inst Cardiovasc Dis, Guangzhou 510260, Guangdong, Peoples R China; [Huang, Zhenjun] Guangzhou Med Univ, Affiliated Hosp 1, Expt Ctr, Guangzhou 510700, Guangdong, Peoples R China		Liu, SJ (corresponding author), Guangzhou Med Univ, Affiliated Hosp 2, Guangzhou Inst Cardiovasc Dis, Guangzhou 510260, Guangdong, Peoples R China.	shaojunliu@gzhmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81570259, 81400234]; Science and Technology Planning Project of Guangdong Province, China [2014A020212327, 2016A020215163]; Elite Programme of The Second Affiliated Hospital of Guangzhou Medical University [52010205-035]	This study was supported by research grants from National Natural Science Foundation of China (No. 81570259, 81400234), Science and Technology Planning Project of Guangdong Province, China (No. 2014A020212327, 2016A020215163) and Elite Programme of The Second Affiliated Hospital of Guangzhou Medical University (No. 52010205-035).	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J. Pharmacol.	MAR 15	2018	823						58	64		10.1016/j.ejphar.2018.01.031			7	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	FX2KG	WOS:000425888100008	29408091				2022-04-25	
J	Wu, YP; Tang, L; Wang, BK; Sun, QM; Zhao, PW; Li, WF				Wu, Yanping; Tang, Li; Wang, Baikui; Sun, Qiming; Zhao, Pengwei; Li, Weifen			The role of autophagy in maintaining intestinal mucosal barrier	JOURNAL OF CELLULAR PHYSIOLOGY			English	Review						autophagy; intestinal mucosal barrier; IECs; intestinal diseases; therapy	GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; PANETH CELL AUTOPHAGY; STEM-CELLS; EPITHELIAL-CELLS; COLORECTAL-CANCER; OXIDATIVE STRESS; CROHN-DISEASE; COLON-CANCER; NECROTIZING ENTEROCOLITIS	The intestinal mucosal barrier is the first line to defense against luminal content penetration and performs numerous biological functions. The intestinal epithelium contains a huge surface that is lined by a monolayer of intestinal epithelial cells (IECs). IECs are dominant mediators in maintaining intestinal homeostasis that drive diverse functions including nutrient absorption, physical segregation, secretion of antibacterial peptides, and modulation of immune responses. Autophagy is a cellular self-protection mechanism in response to various stresses, and accumulating studies have revealed its importance in participating physiological processes of IECs. The regulatory effects of autophagy depend on the specific IEC types. This review aims to elucidate the myriad roles of autophagy in regulating the functions of different IECs (stem cells, enterocytes, goblet cells, and Paneth cells), and present the progress of autophagy-targeting therapy in intestinal diseases. Understanding the involved mechanisms can provide new preventive and therapeutic strategies for gastrointestinal dysfunction and diseases.	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Cell. Physiol.	NOV	2019	234	11					19406	19419		10.1002/jcp.28722			14	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	IM5EX	WOS:000478018200026	31020664				2022-04-25	
J	Yao, DH; Wang, PQ; Zhang, J; Fu, LL; Ouyang, L; Wang, JH				Yao, Dahong; Wang, Peiqi; Zhang, Jin; Fu, Leilei; Ouyang, Liang; Wang, Jinhui			Deconvoluting the relationships between autophagy and metastasis for potential cancer therapy	APOPTOSIS			English	Review						Autophagy; Metastasis; Anti-metastatic agent; Cancer therapy	BREAST-CANCER; BECLIN 1; CELL-DEATH; COLORECTAL-CANCER; GASTRIC-CANCER; TUMOR PROGRESSION; HEPATOCELLULAR-CARCINOMA; MEDIATED SUPPRESSION; PULMONARY METASTASIS; SELECTIVE AUTOPHAGY	Autophagy is a highly conserved lysosome-dependent degradation process that may digest some long-lived proteins and damaged organelles. As an essential homeostasis maintaining system in normal cells, autophagy plays a key role in several pathological settings, especially cancer. Metastasis, known as a crucial hallmark of cancer progression, is the primary cause of cancer lethality. The role of autophagy in metastasis is quite complex as supportive evidence has indicated both pro-metastatic and anti-metastatic functions of autophagy. Autophagy can inhibit metastasis by restricting necrosis and mediating autophagic cell death, whereas it may also promote metastasis by enhancing cancer cell fitness in response to stress. Moreover, the function of autophagy is context- and stage-dependent. Specifically, during the early steps of metastasis, autophagy mainly serves as a suppressor, while it plays a pro-metastatic role in the later steps. Here, we focus on highlighting the dual roles of autophagy in metastasis and address the molecular mechanisms involved in this process, which may provide a new insight into cancer biology. While, we also summarize several anti-metastatic agents manipulating autophagy, in the hope of shedding light on exploration of potential novel drugs for future cancer therapy.	[Yao, Dahong; Zhang, Jin; Fu, Leilei; Ouyang, Liang] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China; [Yao, Dahong; Zhang, Jin; Fu, Leilei; Ouyang, Liang] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China; [Yao, Dahong; Wang, Jinhui] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Shenyang 110016, Peoples R China; [Wang, Peiqi] Sichuan Univ, West China Sch Stomatol, State Key Lab Oral Dis, Chengdu 610041, Peoples R China		Fu, LL; Ouyang, L (corresponding author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Fu, LL; Ouyang, L (corresponding author), Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China.	leilei_fu@163.com; ouyangliang@scu.edu.cn	Ouyang, Liang/A-2751-2010; Zhang, Jin/AAK-7593-2021	Ouyang, Liang/0000-0001-5537-8834; 	Key Projects of the National Science and Technology Pillar Program [2012BAI30B02]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81160543, 81260628, 81303270, 81172374]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2015M580794]	This work was supported in part by grants from the Key Projects of the National Science and Technology Pillar Program (No. 2012BAI30B02), National Natural Science Foundation of China (Nos. 81160543, 81260628, 81303270 and 81172374) and China Postdoctoral Science Foundation (No. 2015M580794).	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Wu XY, 2013, TUMOR BIOL, V34, P713, DOI 10.1007/s13277-012-0599-5; Yang M, 2014, MOL CANCER, V13, DOI 10.1186/1476-4598-13-43; Yu Y, 2012, AUTOPHAGY, V8, P853, DOI 10.4161/auto.20053; Yuan J, 2015, METALLOMICS, V7, P896, DOI 10.1039/c5mt00010f; Zhai HY, 2015, ONCOTARGET, V6, P19735, DOI 10.18632/oncotarget.3771; Zhan ZZ, 2014, AUTOPHAGY, V10, P257, DOI 10.4161/auto.27162; Zhang H, 2014, CELL PHYSIOL BIOCHEM, V33, P991, DOI 10.1159/000358670; Zhang MY, 2014, INT J MOL SCI, V15, P14372, DOI 10.3390/ijms150814372; Zhang RY, 2016, TUMOR BIOL, V37, P3479, DOI 10.1007/s13277-015-4086-7; Zhao XJ, 2015, AUTOPHAGY, V11, P1849, DOI 10.1080/15548627.2015.1017185; Zheng HC, 2015, ONCOTARGET, V6, P19685, DOI 10.18632/oncotarget.4081; Zitvogel L, 2012, NAT IMMUNOL, V13, P343, DOI 10.1038/ni.2224	134	17	17	0	29	SPRINGER	DORDRECHT	VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS	1360-8185	1573-675X		APOPTOSIS	Apoptosis	JUN	2016	21	6					683	698		10.1007/s10495-016-1237-2			16	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	DL3XC	WOS:000375565900002	27003389				2022-04-25	
J	Xue, Q; Wang, P; Wang, XB; Zhang, K; Liu, QH				Xue, Qin; Wang, Pan; Wang, Xiaobing; Zhang, Kun; Liu, Quanhong			Targeted inhibition of p38MAPK-enhanced autophagy in SW620 cells resistant to photodynamic therapy-induced apoptosis	LASERS IN MEDICAL SCIENCE			English	Article						PDT; p38MAPK; ROS; Autophagy; Apoptosis	COLORECTAL-CANCER CELLS; PROTEIN-KINASES; MAP KINASE; P38; ACTIVATION; DEATH; TUMORIGENESIS; SENESCENCE; HYPERICIN; EFFICACY	Photodynamic therapy (PDT) is a promising and noninvasive treatment that can induce apoptosis, autophagy, or both depending on the cell phenotype. In this work, chlorin e6 (Ce6) was used to photosensitize human colorectal cancer SW620 cells. In cells, apparent autophagy and apoptosis with dependence on intracellular reactive oxygen species (ROS) generation were detected. p38MAPK activation followed by ROS generation might be a core component in Ce6 mediate PDT (Ce6-PDT)-induced autophagy and apoptosis signaling pathway. By using p38MAPK siRNA, the results showed a marked enhancement on cell apoptosis in Ce6-PDT with increased annexin (+) apoptotic cells, nuclear condensation, caspase-3, and PARP cleavage. Besides, impairment of p38MAPK also promoted the autophagic response to photodamage as indicated by conversion of LC3 and monodansyl cadaverine (MDC) labeling patterns. It appears that Ce6-PDT induced ROS production involving activation of p38MAPK, probably to prevent SW620 cells from photodamage. Moreover, autophagy inhibitor 3-methyladenine/bafilomycin A1 greatly aggravated Ce6-PDT-induced apoptosis in SW620 cells with knockdown of p38MAPK. Taken together, this study suggests that autophagy could represent a promising field in cancer treatment and p38MAPK may be a potential therapeutic target to enhance the efficacy on clinical evaluation for the treatment of colorectal cancer.	[Xue, Qin; Wang, Pan; Wang, Xiaobing; Zhang, Kun; Liu, Quanhong] Shaanxi Normal Univ, Coll Life Sci, Minist Educ,Key Lab Med Resources & Nat Pharmaceu, Natl Engn Lab Resource Developing Endangered Chin, Xian 710062, Shaanxi, Peoples R China; [Xue, Qin] Fourth Mil Med Univ, Xijing Hosp, Dept Urol, Xian 710032, Peoples R China		Zhang, K (corresponding author), Shaanxi Normal Univ, Coll Life Sci, Minist Educ,Key Lab Med Resources & Nat Pharmaceu, Natl Engn Lab Resource Developing Endangered Chin, Xian 710062, Shaanxi, Peoples R China.	zkxian@snnu.edu.cn; lshaof@snnu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472846]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [GK201502009]	This work was supported by the National Natural Science Foundation of China (no. 81472846) and the Fundamental Research Funds for the Central Universities (GK201502009).	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Sci.	SEP	2015	30	7					1967	1975		10.1007/s10103-015-1770-1			9	Engineering, Biomedical; Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Engineering; Surgery	CQ8NA	WOS:000360863300019	26254783				2022-04-25	
J	Bajbouj, K; Schulze-Luehrmann, J; Diermeier, S; Amin, A; Schneider-Stock, R				Bajbouj, Khuloud; Schulze-Luehrmann, Jan; Diermeier, Stefanie; Amin, Amr; Schneider-Stock, Regine			The anticancer effect of saffron in two p53 isogenic colorectal cancer cell lines	BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article							ANTITUMOR-ACTIVITY; OXIDATIVE STRESS; AUTOPHAGY; BIOLOGY; CROCIN; CHEMOPREVENTION; APOPTOSIS; EXTRACT; PROTEIN; P73	Background: Saffron extract, a natural product, has been shown to induce apoptosis in several tumor cell lines. Nevertheless, the p53-dependency of saffron's mechanism of action in colon cancer remains unexplored. Material and methods: In order to examine saffron's anti-proliferative and pro-apoptotic effects in colorectal cancer cells, we treated two p53 isogenic HCT116 cell lines (HCT wildtype and HCT p53-/-) with different doses of the drug and analyzed cell proliferation and apoptosis in a time-dependent manner. MTT viability and crystal violet assays were performed in order to determine the effective dose of saffron on both cell lines. The cell cycle progress was examined by Flow cytometric analysis. Apoptosis was assessed using Annexin-PI-staining and Western Blotting for caspase 3 and PARP cleavage. Autophagy was determined by Western Blotting of the light chain 3 (LC3)-II and Beclin 1 proteins. The protein content of phospho-H2AX (gamma H2AX), a sensor of DNA double strand breaks, was also analyzed by Western Blotting. Results: Saffron extract induced a p53-dependent pattern of cell cycle distribution with a full G2/M stop in HCT116 p53 wildtype cells. However, it induced a remarkable delay in S/G2 phase transit with entry into mitosis in HCT116 p53-/- cells. The apoptotic Pre-G1 cell fraction as well as Annexin V staining and caspase 3 cleavage showed a more pronounced apoptosis induction in HCT116 p53 wildtype cells. Obviously, the significantly higher DNA-damage, reflected by gamma H2AX protein levels in cells lacking p53, was coped by up-regulation of autophagy. The saffron-induced LC3-II protein level was a remarkable indication of the accumulation of autophagosomes, a response to the cellular stress condition of drug treatment. Conclusions: This is the first study showing the effect of saffron in HCT116 colorectal cancer cells with different p53 status. Saffron induced DNA-damage and apoptosis in both cell lines. However, autophagy has delayed the induction of apoptosis in HCT116 p53-/- cells. Considering the fact that most tumors show a functional p53 inactivation, further research is needed to elucidate the long-term effects of saffron in p53-/- tumors.	[Bajbouj, Khuloud; Amin, Amr; Schneider-Stock, Regine] UAE Univ, Fac Sci, Dept Biol, Al Ain, U Arab Emirates; [Schulze-Luehrmann, Jan; Diermeier, Stefanie; Schneider-Stock, Regine] Univ Erlangen Nurnberg, Inst Pathol, D-91054 Erlangen, Germany; [Amin, Amr] Cairo Univ, Dept Zool, Cairo, Egypt		Schneider-Stock, R (corresponding author), UAE Univ, Fac Sci, Dept Biol, Al Ain, U Arab Emirates.	regine.schneider-stock@uk-erlangen.de	Amin, Amr/I-2137-2019; Schneider-Stock, Regine/H-8863-2012	Amin, Amr/0000-0001-8888-1102; Bajbouj, Khuloud/0000-0001-7344-6095	Emirates Foundation [2009-079]	This study was funded in-part by Emirates Foundation Grant # 2009-079 for AA. Authors are also grateful to Adrian Koch for his excellent technical assistance.	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Altern. Med.	MAY 28	2012	12								69	10.1186/1472-6882-12-69			9	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	031MV	WOS:000310646700001	22640402	Green Published, gold			2022-04-25	
J	Terzuoli, E; Nannelli, G; Frosini, M; Giachetti, A; Ziche, M; Donnini, S				Terzuoli, Erika; Nannelli, Ginevra; Frosini, Maria; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra			Inhibition of cell cycle progression by the hydroxytyrosol-cetuximab combination yields enhanced chemotherapeutic efficacy in colon cancer cells	ONCOTARGET			English	Article						hydroxytyrosol; cetuximab; colon cancer; cell cycle; AIF-dependent apoptosis	VIRGIN OLIVE OIL; MILL. BARK EXTRACT; HL60 CELLS; GROWTH; APOPTOSIS; KINASE; STRESS; DIHYDROXYPHENYLETHANOL; DIFFERENTIATION; PROLIFERATION	Hydroxytyrosol (HT), a polyphenol of olive oil, downregulates epidermal growth factor (EGFR) expression and inhibits cell proliferation in colon cancer (CC) cells, with mechanisms similar to that activated by the EGFR inhibitor, cetuximab. Here, we studied whether HT treatment would enhance the cetuximab inhibitory effects on cell growth in CC cells. HT-cetuximab combination showed greater efficacy in reducing cell growth in HT-29 and WiDr cells at concentrations 10 times lower than when used as single agents. This reduction was clearly linked to cell cycle blockade, occurring at G(2)/M phase. The cell cycle arrest in response to combination treatment is related to cyclins B, D1, and E, and cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 down-regulation, and to the concomitant over-expression of CDK inhibitors p21 and p27. HT and cetuximab stimulated a caspase-independent cell death cascade, promotedtranslocation of apoptosis-inducing factor (AIF) from mitochondria to nucleus and activated the autophagy process. Notably, normal colon cells and keratinocytes were less susceptible to combo induced cell death and EGFR downregulation. These results suggest a potential role of diet, containing olive oil, during cetuximab chemotherapy of colon tumor. HT may be a competent therapeutic agent in CC enhancing the effects of EGFR inhibitors.	[Terzuoli, Erika; Nannelli, Ginevra; Frosini, Maria; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra] Univ Siena, Dept Life Sci, I-53100 Siena, Italy		Ziche, M; Donnini, S (corresponding author), Univ Siena, Dept Life Sci, I-53100 Siena, Italy.	marina.ziche@unisi.it; sandra.donnini@unisi.it	Donnini, Sandra/K-9252-2019; Terzuoli, Erika/M-7346-2016	Donnini, Sandra/0000-0001-6617-1644; Ziche, Marina/0000-0002-9564-214X; FROSINI, MARIA/0000-0002-4452-8128; Terzuoli, Erika/0000-0001-9248-4505	Associazione Italiana sul Cancro (AIRC)Fondazione AIRC per la ricerca sul cancro [IG10731]; Consorzio per la tutela dell'Olio Extravergine di Oliva Toscano IGP; Regione Toscana, bando Nutraceutica, OlivaPlus Project; AIRCFondazione AIRC per la ricerca sul cancro	This work was supported by Associazione Italiana sul Cancro (AIRC) under Grant IG10731 MZ (Marina Ziche); Consorzio per la tutela dell'Olio Extravergine di Oliva Toscano IGP, and Regione Toscana, bando Nutraceutica 2014, OlivaPlus Project (Sandra Donnini). ET and GN are supported by AIRC.	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J	Noureldein, MH; Eid, AA				Noureldein, Mohamed H.; Eid, Assaad A.			Gut microbiota and mTOR signaling: Insight on a new pathophysiological interaction	MICROBIAL PATHOGENESIS			English	Article						Gut microbiota; mTOR; Butyrate; Obesity; Diabetes; Colon cancer	CONJUGATED LINOLEIC-ACID; CHAIN FATTY-ACIDS; REGULATORY T-CELLS; EXTENDS LIFE-SPAN; HEPATIC LIPOGENESIS; COMMENSAL BACTERIA; LIPID-METABOLISM; GENE-EXPRESSION; COLON-CANCER; AUTOPHAGY	The gut microbiota plays a substantial role in regulating the host metabolic and immune functions. Dysbiosis, resulting from disruption of gut microbiota, predisposes many morbid pathologies like obesity and its associated comorbidities, diabetes and inflammatory conditions including some types of cancer. There are numerous proposed signaling pathways through which alterations in gut microbiota and its metabolites can disturb the host's normal physiological functions. Interestingly, many of these processes happen to be controlled by the mammalian target of rapamycin (mTOR). The mTOR pathway responds to environmental changes and regulates accordingly many intracellular processes such as transcription, translation, cell growth, cytoskeletal organization and autophagy. In this review, we aim to highlight the cross-talk between the gut microbiota and the mTOR pathway and discuss how this emerging field of research gives a beautiful insight into how the mentioned crosstalk impacts the body's homeostasis thus leading to undesirable complications including obesity, diabetes, colon and pancreatic cancer, immune system malfunctioning and ageing. Although there are a limited number of studies investigating the crosstalk between the gut microbiota and the mTOR pathway, the results obtained so far are enough to elucidate the key role of the mTOR signaling in microbiota-associated metabolic and immune regulations.	Amer Univ Beirut, Fac Med, Dept Anat Cell Biol & Physiol Sci, Beirut, Lebanon; Amer Univ Beirut, Med Ctr, Beirut, Lebanon		Eid, AA (corresponding author), Amer Univ Beirut, Fac Med, POB 11-0236, Beirut 1107 2020, Lebanon.; Eid, AA (corresponding author), Amer Univ Beirut, Med Ctr, Dept Anat Cell Biol & Physiol Sci, POB 11-0236, Beirut 1107 2020, Lebanon.	ae94@aub.edu.lb					Alexander KL, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0181866; An JH, 2003, GENE DEV, V17, P1882, DOI 10.1101/gad.1107803; Arpaia N, 2013, NATURE, V504, P451, DOI 10.1038/nature12726; Atarashi K, 2011, SCIENCE, V331, P337, DOI 10.1126/science.1198469; Azain MJ, 2000, J NUTR, V130, P1548; Backhed F, 2004, P NATL ACAD SCI USA, V101, P15718, DOI 10.1073/pnas.0407076101; Backhed F, 2007, P NATL ACAD SCI USA, V104, P979, DOI 10.1073/pnas.0605374104; Barbara G, 2005, AM J GASTROENTEROL, V100, P2560, DOI 10.1111/j.1572-0241.2005.00230.x; Belkaid Y, 2014, CELL, V157, P121, DOI 10.1016/j.cell.2014.03.011; Bissonauth V, 2006, J NUTR BIOCHEM, V17, P597, DOI 10.1016/j.jnutbio.2005.10.010; 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Pathog.	MAY	2018	118						98	104		10.1016/j.micpath.2018.03.021			7	Immunology; Microbiology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Microbiology	GK9AE	WOS:000436528000013	29548696				2022-04-25	
J	Marmol, I; Jimenez-Moreno, N; Ancin-Azpilicueta, C; Osada, J; Cerrada, E; Rodriguez-Yoldi, MJ				Marmol, Ines; Jimenez-Moreno, Nerea; Ancin-Azpilicueta, Carmen; Osada, Jesus; Cerrada, Elena; Jesus Rodriguez-Yoldi, Maria			A Combination of Rosa Canina Extracts and Gold Complex Favors Apoptosis of Caco-2 Cells by Increasing Oxidative Stress and Mitochondrial Dysfunction	ANTIOXIDANTS			English	Article						apoptosis; autophagy; colorectal cancer; rosehip; gold complex; ROS	CISPLATIN RESISTANCE; POLYPHENOLS; CANCER; NECROPTOSIS; AUTOPHAGY; LINE	Given the alarming increase in colorectal cancer (CRC) worldwide, novel therapies are urgently needed. Plant-derived extracts have gained considerable interest in the last years due to their strong anticancer effect mediated by their unique bioactive compounds. Specifically, rosehips from Rosa canina have been successfully tested against several cancer models, including colon cancer. Moreover, gold derivatives are a promising alternative to the current platinum-based drugs commonly used in CRC chemotherapy due to their lack of affinity for DNA. Herein we have investigated the antitumor potential of a drug combination made of acidic polyphenols extracted from R. canina and the gold complex (Au(C equivalent to C-2-NC5H4) (PTA)) in Caco-2 cell line as a model of CRC. The combination triggered strong apoptosis mediated by a blockage of the autophagic flux, which might be a consequence of a reactive oxygen species (ROS) increase and mitochondrial dysfunctionality. Our results suggest that the clinical application of plant polyphenols might enhance the anticancer effect of metallodrugs and reduce drug exposure time and therefore its side effects.	[Marmol, Ines; Jesus Rodriguez-Yoldi, Maria] Univ Zaragoza, Dept Pharmacol & Physiol, Vet Fac, E-50009 Zaragoza, Spain; [Jimenez-Moreno, Nerea; Ancin-Azpilicueta, Carmen] Univ Publ Navarra, Dept Sci, INAMAT, Pamplona 31006, Spain; [Osada, Jesus] Univ Zaragoza, Dept Biochem & Mol Biol, Vet Fac, E-50009 Zaragoza, Spain; [Osada, Jesus; Jesus Rodriguez-Yoldi, Maria] Ctr Invest Biomed Red Obesidad & Nutr CIBERobn, IIS Aragon, IA2, ISCIII, Zaragoza 50009, IA, Spain; [Cerrada, Elena] Univ Zaragoza, Sci Fac, Dept Inorgan Chem, E-50009 Zaragoza, Spain		Rodriguez-Yoldi, MJ (corresponding author), Univ Zaragoza, Dept Pharmacol & Physiol, Vet Fac, E-50009 Zaragoza, Spain.; Rodriguez-Yoldi, MJ (corresponding author), Ctr Invest Biomed Red Obesidad & Nutr CIBERobn, IIS Aragon, IA2, ISCIII, Zaragoza 50009, IA, Spain.; Cerrada, E (corresponding author), Univ Zaragoza, Sci Fac, Dept Inorgan Chem, E-50009 Zaragoza, Spain.	ines.marmol9@gmail.com; nerea.jimenez@unavarra.es; ancin@unavarra.es; josada@unizar.es; ecerrada@unizar.es; mjrodyol@unizar.es	; CERRADA, ELENA/K-6790-2014	Rodriguez Yoldi, Maria Jesus/0000-0002-3595-7668; Jimenez-Moreno, Nerea/0000-0002-8065-5220; Marmol, Ines/0000-0002-3136-2480; CERRADA, ELENA/0000-0003-2457-3674	Ministerio de Economia y Competitividad, Gobierno de Espana [SAF2016-75441-R, CTQ2016-75816-C2-1-P]; CIBERobn [CB06/03/1012]; Gobierno de Aragon (Fondos FEDER "otra manera de hacer Europa") [B16-17R, E07-17R]; SUDOE (Redvalue) [SOE1/PI/E0123]; Proyecto ELENA [EFA 220/11 ELENA]	This work was supported by grants from Ministerio de Economia y Competitividad, Gobierno de Espana (SAF2016-75441-R and CTQ2016-75816-C2-1-P), CIBERobn (CB06/03/1012), Gobierno de Aragon (B16-17R and E07-17R, Fondos FEDER "otra manera de hacer Europa"), SUDOE (Redvalue, SOE1/PI/E0123) and Proyecto ELENA (EFA 220/11 ELENA).	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J	Cheng, Y; Zhang, HQ; Qu, LJ; He, Y; Routledge, MN; Gong, YY; Qiao, BL				Cheng, Ying; Zhang, Huiqin; Qu, Lejing; He, Ying; Routledge, Michael N.; Gong, Yun Yun; Qiao, Boling			Identification of rhein as the metabolite responsible for toxicity of rhubarb anthraquinones	FOOD CHEMISTRY			English	Article						Rhubarb anthraquinones; Colonic toxicities; Melanosis coli; Rhein accumulation; Apoptosis; Autophagy	MELANOSIS-COLI; LAXATIVE USE; EXTRACT	Rhubarb is a popular food in Europe with laxative properties attributed to anthraquinones. Long term usage of rhubarb anthraquinones has been linked to colonic toxicity, including the formation of melanosis coli, which is associated with increased risk of colon cancer. The major purgative anthraquinone in rhubarb is thought to be sennoside A, which is metabolised by colonic microflora. Here, we sought to identify the toxic metabolite responsible for melanosis coli in rats dosed with rhubarb anthraquinones for up to 90 days. Three metabolites were detected in rat faeces using HPLC. Of these, rhein was identified as the metabolite that accumulated most over time. Fecal flora from treated rats were capable of greater biotransformation of sennoside A to rhein compared to that from control rats. Cell culture experiments suggested that apoptosis and autophagy induced by rhein is the likely mechanism of chronic toxicity of rhubarb anthraquinones.	[Cheng, Ying; Zhang, Huiqin; Qu, Lejing; He, Ying; Qiao, Boling] Northwest Univ, Minist Educ, Key Lab Resource Biol & Modern Biotechnol Western, Xian 710069, Peoples R China; [Cheng, Ying; Zhang, Huiqin; Qu, Lejing; He, Ying; Qiao, Boling] Northwest Univ, Biomed Key Lab Shaanxi Prov, Xian 710069, Peoples R China; [Routledge, Michael N.] Univ Leeds, Sch Med, Leeds LS2 9JT, W Yorkshire, England; [Routledge, Michael N.] Jiangsu Univ, Sch Food & Biol Engn, Zhenjiang, Jiangsu, Peoples R China; [Gong, Yun Yun] Univ Leeds, Sch Food Sci & Nutr, Leeds LS2 9JT, W Yorkshire, England		Qiao, BL (corresponding author), Northwest Univ, Minist Educ, Key Lab Resource Biol & Modern Biotechnol Western, Xian 710069, Peoples R China.; Routledge, MN (corresponding author), Univ Leeds, Sch Med, Leeds LS2 9JT, W Yorkshire, England.	M.N.Routledge@leeds.ac.uk; y.gong@leeds.ac.uk; bolingq@nwu.edu.cn	Gong, Yun Yun/L-7094-2016; Routledge, Michael/N-7413-2017	Gong, Yun Yun/0000-0003-4927-5526; Routledge, Michael/0000-0001-9139-2182	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81973452]; Scientific Research Foundation of Shaanxi Provincial Key Laboratory [2018SZS-41]	This work was supported by National Natural Science Foundation of China (81973452) and Scientific Research Foundation of Shaanxi Provincial Key Laboratory (2018SZS-41).	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NOV 30	2020	331								127363	10.1016/j.foodchem.2020.127363			10	Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Food Science & Technology; Nutrition & Dietetics	NA4RW	WOS:000559806600008	32590269	Green Accepted			2022-04-25	
J	Kapral, M; Wawszczyk, J; Weglarz, L				Kapral, Malgorzata; Wawszczyk, Joanna; Weglarz, Ludmila			Regulation of MicroRNA-155 and Its Related Genes Expression by Inositol Hexaphosphate in Colon Cancer Cells	MOLECULES			English	Article						IP6; miRNAs; miR-155; FOXO3a; HIF-1 alpha; ELK3; colon cancer	APOPTOTIC DEATH; INHIBITS GROWTH; G1 ARREST; MIR-155; IP6; PROLIFERATION; INVASION; PHYTOCHEMICALS; INFLAMMATION; MODULATION	Inositol hexaphosphate (IP6), a natural dietary component, has been found as an antitumor agent by stimulating apoptosis and inhibiting cancer cell proliferation, their migration, and metastasis in diverse cancers including colon cancer. However, molecular mechanisms of its action have not been well understood. In recent years, microRNAs (miRNAs) have been reported to play important roles in a broad range of biologic processes, such as cell growth, proliferation, apoptosis, or autophagy. These small noncoding molecules regulate post-transcriptional expression of targets genes via degradation of transcript or inhibition of protein synthesis. Aberrant expression and/or dysregulation of miRNAs have been characterized during tumor development and progression, thus, they are potential molecular targets for cancer prevention. The aim of this study was to investigate the effect of IP6 on the miRNAs expression profile in Caco-2 colon cancer cells. 84 miRNAs were analyzed in Caco-2 cells treated with 2.5 mM and 5 mM IP6 by the use of PCR (Polymerase Chain Reaction) array. The effect of 5 mM IP6 on selected potential miR-155 targets was determined by real-time (RT)-qPCR and ELISA (quantitative Polymerase Chain Reaction and Enzyme-Linked Immunosorbent Assay )method. The results indicated alteration in the specific 10 miRNA expression in human colon cancer cells following their treatment with 5 mM IP6. It down-regulated 8 miRNAs (miR-155, miR-210, miR-144, miR-194, miR-26b, miR-126, miR-302c, and miR-29a) and up-regulated 2 miRNAs (miR-223 and miR-196b). In silico analysis revealed that FOXO3a, HIF-1 alpha, and ELK3 mRNAs are those of predicted targets of miR-155. IP6 at the concentration of 5 mM markedly induced FOXO3a and HIF-1a genes' expression at both mRNA and protein level and decreased the amount of ELK3 mRNA as well as protein concentration in comparison to the control. In conclusion, the present study indicates that one of the mechanisms of antitumor potential of IP6 is down-regulation of the miR-155 expression in human colon cancer cells. Moreover, the expression of genes that are targeted by miRNA are also modulated by IP6.	[Kapral, Malgorzata; Wawszczyk, Joanna; Weglarz, Ludmila] Med Univ Silesia, Fac Pharmaceut Sci Sosnowiec, Dept Biochem, Jednosci 8, PL-41200 Sosnowiec, Poland		Kapral, M (corresponding author), Med Univ Silesia, Fac Pharmaceut Sci Sosnowiec, Dept Biochem, Jednosci 8, PL-41200 Sosnowiec, Poland.	mkapral@sum.edu.pl; jwawszczyk@sum.edu.pl; lweglarz@sum.edu.pl		Kapral, Malgorzata/0000-0001-5189-1171; Wawszczyk, Joanna/0000-0001-8739-3342	Medical University of Silesia (Katowice, Poland) [KNW-1-090/K/8/I, KNW-1-018/K/7/I]	This research was funded by grants No. KNW-1-090/K/8/I, KNW-1-018/K/7/I from the Medical University of Silesia (Katowice, Poland).	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J	Dent, P; Booth, L; Roberts, JL; Poklepovic, A; Hancock, JF				Dent, Paul; Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew; Hancock, John F.			(Curcumin plus sildenafil) enhances the efficacy of 5FU and anti-PD1 therapies in vivo	JOURNAL OF CELLULAR PHYSIOLOGY			English	Article						5FU; autophagy; chaperone; colon cancer; HDAC; immunotherapy	K-RAS; INHIBITORS; PLASMA	We have extended our analyses of (curcumin+sildenafil) biology. The drug combination caused vascularization and degradation of mutant K-RAS that correlated with reduced phosphorylation of ERK1/2, AKT T308, mTORC1, mTORC2, ULK1 S757, STAT3, STAT5, and NF kappa B and increased phosphorylation of eIF2 alpha, ATM, AMPK alpha, ULK1 S317; all concomitant with elevated ATG13 S318 phosphorylation and autophagosome formation. Prior studies with drug combinations utilizing sildenafil have delineated an ATM-AMPK-ULK1 S317 pathway and an AKT-mTOR-ULK1 S757 pathway as modules which control ATG S318 phosphorylation and autophagosome formation. The knockdown of PKG reduced cell killing as well as reducing drug-enhanced phosphorylation of ATM, AMPK alpha, and ATG13. In the absence of PKG, no significant increase in ULK1 S317 phosphorylation was observed. In a Beclin1-dependent fashion, the drug combination reduced the expression of multiple histone deacetylase (HDAC) proteins, including HDAC2 and HDAC3. Molecular knockdown of HDAC2, HDAC3, and especially (HDAC2+HDAC3) significantly reduced the expression of PD-L1 and elevated expression of Class I human major histocompatibility complex. In vivo, (curcumin+sildenafil) enhanced the efficacy of 5-flurouracil against CT26 colorectal tumors. Prior exposure of established CT26 tumors to (curcumin+sildenafil) significantly enhanced the efficacy of a subsequently administered anti-PD-1 antibody. Collectively our data argue that (curcumin+sildenafil) has the potential in several settings to be an efficacious neoadjuvant therapy for colon cancer.	[Dent, Paul; Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew] Virginia Commonwealth Univ, Dept Biochem, Richmond, VA USA; [Dent, Paul; Booth, Laurence; Roberts, Jane L.] Virginia Commonwealth Univ, Dept Mol Biol, Richmond, VA USA; [Poklepovic, Andrew] Virginia Commonwealth Univ, Dept Med, Med Coll Virginia Campus, Richmond, VA 23298 USA; [Hancock, John F.] Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA		Dent, P (corresponding author), Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Richmond, VA 23298 USA.	paul.dent@vcuhealth.org			Commonwealth Health Research Board [236-04-18]; Massey Cancer Center; Universal Inc.; Chair in Signal Transduction Research	Commonwealth Health Research Board, Grant/Award Number: 236-04-18; Massey Cancer Center; Universal Inc. Chair in Signal Transduction Research	Asher GN, 2017, J CLIN PHARMACOL, V57, P185, DOI 10.1002/jcph.806; Booth L, 2019, CANCER BIOL THER, V20, P700, DOI 10.1080/15384047.2018.1551747; Booth L, 2019, CANCER BIOL THER, V20, P109, DOI 10.1080/15384047.2018.1507258; Booth L, 2019, J CELL PHYSIOL, V234, P4874, DOI 10.1002/jcp.27276; Booth L, 2018, ADV CANCER RES, V137, P1, DOI 10.1016/bs.acr.2017.11.004; Booth Laurence, 2018, Oncotarget, V9, P6062, DOI 10.18632/oncotarget.23681; Booth L, 2018, CANCER BIOL THER, V19, P797, DOI 10.1080/15384047.2018.1472190; Booth L, 2018, CANCER BIOL THER, V19, P132, DOI 10.1080/15384047.2017.1394556; Booth L, 2017, ONCOTARGET, V8, P90262, DOI 10.18632/oncotarget.21660; Cho KJ, 2016, MOL CELL BIOL, V36, P3086, DOI 10.1128/MCB.00365-16; Cuomo J, 2011, J NAT PROD, V74, P664, DOI 10.1021/np1007262; Dei Cas M, 2019, NUTRIENTS, V11, DOI 10.3390/nu11092147; Fernandez-Medarde Alberto, 2011, Genes Cancer, V2, P344, DOI 10.1177/1947601911411084; Hetz C, 2012, NAT REV MOL CELL BIO, V13, P89, DOI 10.1038/nrm3270; Hsieh C.Y., 2001, ANTICANCER RES, V21, pe2900; Kalyan A, 2018, J GASTROINTEST ONCOL, V9, P160, DOI 10.21037/jgo.2018.01.17; Kurada P, 1998, CELL, V95, P319, DOI 10.1016/S0092-8674(00)81764-X; Lao Christopher D, 2006, BMC Complement Altern Med, V6, P10, DOI 10.1186/1472-6882-6-10; Le Rolle AF, 2015, J TRANSL MED, V13, DOI 10.1186/s12967-015-0555-4; Meier P, 1998, CELL, V95, P295, DOI 10.1016/S0092-8674(00)81760-2; Oladipo O, 2011, BRIT J CANCER, V104, P480, DOI 10.1038/sj.bjc.6606055; Qi XM, 2014, ONCOTARGET, V5, P4269, DOI 10.18632/oncotarget.2001; Roberts JL, 2017, ONCOTARGET, V8, P99451, DOI 10.18632/oncotarget.19807; Spallanzani A, 2018, J CANC METASTASIS TR, V4, P28, DOI [10.20517/2394-4722.2018.31, DOI 10.20517/2394-4722.2018.31]; Thompson N, 2005, CURR OPIN PHARMACOL, V5, P350, DOI 10.1016/j.coph.2005.04.007; Vareed SK, 2008, CANCER EPIDEM BIOMAR, V17, P1411, DOI 10.1158/1055-9965.EPI-07-2693	26	13	13	0	4	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0021-9541	1097-4652		J CELL PHYSIOL	J. Cell. Physiol.	OCT	2020	235	10					6862	6874		10.1002/jcp.29580		JAN 2020	13	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	MZ8KE	WOS:000509608000001	31985048				2022-04-25	
J	Gao, TY; Liu, XX; He, BS; Pan, YQ; Wang, SK				Gao, Tianyi; Liu, Xiangxiang; He, Bangshun; Pan, Yuqin; Wang, Shukui			RETRACTED: Long non-coding RNA 91H regulates IGF2 expression by interacting with IGF2BP2 and promotes tumorigenesis in colorectal cancer (Retracted article. See vol. 49, pg. 681, 2021)	ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY			English	Article; Retracted Publication						lncRNA 91H; IGF2; IGF2BP2; CRC	CONTRIBUTES; PROGRESSION; SURVIVAL; INSULIN; FAMILY; CELLS; COLON	91H, a long non-coding antisense transcripts located on the position of the H19/IGF2 locus had been suggested to play a critical role in tumour development. However, little study had proved the mechanism in colorectal cancer (CRC). Hence, we performed this study to deeply explore the mechanism of lncRNA 91H in tumour progression. The expression of lncRNA 91H was first detected in CRC tissues and cells which was higher in vitro and in vivo than normal cells or tissues and CRC patients with high lncRNA 91H expression usually had a high risk in tumour metastasis (p < .05). Then, monodansylcadaverine (MDC) staining, scratch wound, migration and invasion assays were conducted which showed to that reduced lncRNA 91H would greatly affect tumour migration, invasion and autophagy. Finally, by RNA pull down and RNA-binding protein immunoprecipitation (RIP) assay, a significant interaction was found between lncRNA 91H and IGF2BP2 which was proved to play an important role in CRC IGF2 expression. All these results suggested lncRNA 91H promotes IGF2 expression by interacting with IGF2BP2 which would provide a new strategy in finding potential CRC diagnostic biomarkers and therapeutic targets.	[Gao, Tianyi; Wang, Shukui] Nanjing Med Univ, Nanjing Hosp 1, Dept Clin Lab, 68 Changle Rd, Nanjing 210006, Jiangsu, Peoples R China; [Liu, Xiangxiang; He, Bangshun; Pan, Yuqin] Nanjing Med Univ, Nanjing Hosp 1, Cent Lab, Nanjing, Peoples R China		Wang, SK (corresponding author), Nanjing Med Univ, Nanjing Hosp 1, Dept Clin Lab, 68 Changle Rd, Nanjing 210006, Jiangsu, Peoples R China.; Wang, SK (corresponding author), Nanjing Med Univ, Jiangsu Collaborat Innovat Ctr Canc Personalized, 68 Changle Rd, Nanjing 210006, Jiangsu, Peoples R China.	sk_wang@njmu.edu.cn		Gao, Tianyi/0000-0003-2155-7839; Reis, AlessanRSS/0000-0001-8486-7469	National Nature Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472027, 81172141, 81200401, 81903034]; Development of Nanjing Medical Science and Technology Foundation [YKK17123]	This project was supported by grants from The National Nature Science Foundation of China under Grant Nos. [81472027], [81172141], [81200401], [81903034], and The Development of Nanjing Medical Science and Technology Foundation to Tianyi Gao under Grant No. [YKK17123].	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Cell. Nanomed. Biotechnol.	JAN 1	2020	48	1					664	671		10.1080/21691401.2020.1727491			8	Biotechnology & Applied Microbiology; Engineering, Biomedical; Materials Science, Biomaterials	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Engineering; Materials Science	KO4UE	WOS:000515545800001	32070145	gold			2022-04-25	
J	Vasilevskaya, IA; Selvakumaran, M; Roberts, D; O'Dwyer, PJ				Vasilevskaya, Irina A.; Selvakumaran, Muthu; Roberts, David; O'Dwyer, Peter J.			JNK1 Inhibition Attenuates Hypoxia-Induced Autophagy and Sensitizes to Chemotherapy	MOLECULAR CANCER RESEARCH			English	Article							COLON-CANCER CELLS; JNK1-MEDIATED PHOSPHORYLATION; BCL-XL; APOPTOSIS; KINASE; STRESS; JUN; RESISTANCE; TARGET; DEATH	Inhibition of hypoxia-induced stress signaling through JNK potentiates the effects of oxaliplatin. The JNK pathway plays a role in both autophagy and apoptosis; therefore, it was determined how much of the effect of JNK inhibition on oxaliplatin sensitivity is dependent on its effect on autophagy. We studied the impact of JNK isoform downregulation in the HT29 colon adenocarcinoma cell line on hypoxia-and oxaliplatin-induced responses. Electron microscopic analyses demonstrated that both oxaliplatin-and hypoxia-induced formations of autophagosomes were reduced significantly in HT29 cells treated with the JNK inhibitor SP600125. The role of specific JNK isoforms was defined using HT29-derived cell lines stably expressing dominant-negative constructs for JNK1 and JNK2 (HTJ1.3 and HTJ2.2, respectively). These cell lines demonstrated that functional JNK1 is required for hypoxia-induced autophagy and that JNK2 does not substitute for it. Inhibition of autophagy in HTJ1.3 cells also coincided with enhancement of intrinsic apoptosis. Analysis of Bcl2-family proteins revealed hyperphosphorylation of Bcl-XL in the HTJ1.3 cell line, but this did not lead to the expected dissociation from Beclin 1. Consistent with this, knockdown of Bcl-XL in HT29 cells did not significantly affect the induction of autophagy, but abrogated hypoxic resistance to oxaliplatin due to the faster and more robust activation of apoptosis. Implications: These data suggest that balance between autophagy and apoptosis is shifted toward apoptosis by downregulation of JNK1, contributing to oxaliplatin sensitization. These findings further support the investigation of JNK inhibition in colorectal cancer treatment. (C) 2016 AACR.	[Vasilevskaya, Irina A.; Selvakumaran, Muthu; Roberts, David; O'Dwyer, Peter J.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA; [Roberts, David] Modbury Hosp, Adelaide, SA, Australia		Vasilevskaya, IA (corresponding author), Univ Penn, 1020 BRB2-3,421 Curie Blvd, Philadelphia, PA 19104 USA.	vasilevs@mail.med.upenn.edu			NCI, NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA139003, RO1CA158377]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA139003, R01CA158377] Funding Source: NIH RePORTER	This study was supported in part by R01CA139003 and RO1CA158377 from NCI, NIH.	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Cancer Res.	AUG	2016	14	8					753	763		10.1158/1541-7786.MCR-16-0035			11	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	DU5WJ	WOS:000382283900008	27216154	Green Accepted			2022-04-25	
J	Pan, HT; Wang, YJ; Na, K; Wang, Y; Wang, L; Li, ZH; Guo, CJ; Guo, DD; Wang, XY				Pan, Haitao; Wang, Yujie; Na, Kun; Wang, Ying; Wang, Lu; Li, Zhenhao; Guo, Chengjie; Guo, Dandan; Wang, Xingya			Autophagic flux disruption contributes to Ganoderma lucidum polysaccharide-induced apoptosis in human colorectal cancer cells via MAPK/ERK activation	CELL DEATH & DISEASE			English	Article							BECLIN 1; BECLIN-1-INDEPENDENT AUTOPHAGY; TARGETING AUTOPHAGY; OXIDATIVE STRESS; INHIBITION; IMPAIRS; DEATH; MITOCHONDRIA; DEGRADATION; DYSFUNCTION	Targeting autophagy may serve as a promising strategy for cancer therapy. Ganoderma lucidum polysaccharide (GLP) has been shown to exert promising anti-cancer effects. However, the underlying mechanisms remain elusive. Whether GLP regulates autophagy in cancer has never been reported. In this study, GLP induced the initiation of autophagy in colorectal cancer (CRC) HT-29 and HCT116 cells, as evidenced by enhanced level of LC3-II protein, GFP-LC3 puncta, and increased formation of double membrane vacuoles. However, GLP treatment caused marked increase of p62 expression. Addition of late stage autophagy inhibitor, chloroquine (CQ), further enhanced LC3-II and p62 level, as well as increased autophagosome accumulation, suggesting a blockage of autophagic flux by GLP in CRC cells. We then found GLP blocked autophagosome and lysosome fusion as determined by mRFP-GFP-LC3 colocalization analysis. Mechanistic study revealed that GLP-induced disruption of autophagosome-lysosome fusion is due to reduced lysosome acidification and lysosomal cathepsin activities. Cell viability and flow cytometry assays revealed that GLP-induced autophagosome accumulation is responsible for GLP-induced apoptosis in CRC cells. In line with this, inhibition of autophagy initiation by 3-methyladenine (3-MA), an early stage autophagy inhibitor, attenuated GLP-induced apoptosis. In contrast, suppression of autophagy at late stage by CQ enhanced the anti-cancer effect of GLP. Furthermore, we demonstrated that GLP-induced autophagosome accumulation and apoptosis is mediated via MAPK/ERK activation. Finally, GLP inhibited tumor growth and also inhibited autophagic flux in vivo. These results unveil new molecular mechanism underlying anti-cancer effects of GLP, suggesting that GLP is a potent autophagy inhibitor and might be useful in anticancer therapy.	[Pan, Haitao; Wang, Yujie; Na, Kun; Wang, Ying; Wang, Lu; Guo, Chengjie; Guo, Dandan; Wang, Xingya] Zhejiang Chinese Med Univ, Dept Pharmaceut Sci, 548 Binwen Rd, Hangzhou 310053, Zhejiang, Peoples R China; [Li, Zhenhao] Zhejiang Shouxiangu Inst Rare Med Plant, 12,Huanglong 3rd Rd, Wuyi 321200, Zhejiang, Peoples R China		Wang, XY (corresponding author), Zhejiang Chinese Med Univ, Dept Pharmaceut Sci, 548 Binwen Rd, Hangzhou 310053, Zhejiang, Peoples R China.	xywang@zcmu.edu.cn		Wang, Xingya/0000-0001-6986-3240	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81473397]; Science and Technology Department of Zhejiang Province Foundation [2019C02100]	We thank Dr. Thomas E. Eling at the National Institute of Environmental Health Sciences (NIEHS) for proofreading this manuscript. We also thank Junying Li and Li Xie at the Bio-ultrastructure Analysis Laboratory of Agrobiology and Environmental Sciences of Zhejiang University for providing technique support for TEM analysis. This study was supported by the National Natural Science Foundation of China (grant no. 81473397), and the Science and Technology Department of Zhejiang Province Foundation (2019C02100).	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Zhao Y, 2010, NAT CELL BIOL, V12, P665, DOI 10.1038/ncb2069; Zhou J, 2012, AUTOPHAGY, V8, P338, DOI 10.4161/auto.18721	76	51	56	15	34	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	2041-4889			CELL DEATH DIS	Cell Death Dis.	JUN 11	2019	10								456	10.1038/s41419-019-1653-7			18	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	IC6ZO	WOS:000471121800004	31186406	gold, Green Published			2022-04-25	
J	Kang, XJ; Wang, HY; Peng, HG; Chen, BF; Zhang, WY; Wu, AH; Xu, Q; Huang, YZ				Kang, Xue-jia; Wang, Hui-yuan; Peng, Hui-ge; Chen, Bin-fan; Zhang, Wen-yuan; Wu, Ai-hua; Xu, Qin; Huang, Yong-zhuo			Codelivery of dihydroartemisinin and doxorubicin in mannosylated liposomes for drug-resistant colon cancer therapy	ACTA PHARMACOLOGICA SINICA			English	Article						human colon cancer; multidrug resistance; doxorubicin; dihydroartemisinin; combination therapy; tumor-targeted delivery; mannosylated liposome; mannose receptor	BREAST-CANCER; CELLS; AUTOPHAGY; APOPTOSIS; MECHANISMS; STRATEGIES; MORTALITY	Multidrug resistance (MDR) is a major hurdle in cancer chemotherapy and makes the treatment benefits unsustainable. Combination therapy is a commonly used method for overcoming MDR. In this study we investigated the anti-MDR effect of dihydroartemisinin (DHA), a derivative of artemisinin, in combination with doxorubicin (Dox) in drug-resistant human colon tumor HCT8/ADR cells. We developed a tumor-targeting codelivery system, in which the two drugs were co-encapsulated into the mannosylated liposomes (Manliposomes). The Man-liposomes had a mean diameter of 158.8 nm and zeta potential of -15.8 mV. In the HCT8/ADR cells that overexpress the mannose receptors, the Man-liposomes altered the intracellular distribution of Dox, resulting in a high accumulation of Dox in the nuclei and thus displaying the highest cytotoxicity (IC50=0.073 mu g/mL) among all the groups. In a subcutaneous HCT8/ADR tumor xenograft model, administration of the Man-liposomes resulted in a tumor inhibition rate of 88.59%, compared to that of 47.46% or 70.54%, respectively, for the treatment with free Dox or free Dox+ DHA. The mechanisms underlying the anti-MDR effect of the Manliposomes involved preferential nuclear accumulation of the therapeutic agents, enhanced cancer cell apoptosis, downregulation of Bcl-xl, and the induction of autophagy.	[Kang, Xue-jia; Wu, Ai-hua; Xu, Qin] Guangzhou Univ Chinese Med, Inst Trop Med, Guangzhou 510405, Guangdong, Peoples R China; [Kang, Xue-jia; Wang, Hui-yuan; Peng, Hui-ge; Chen, Bin-fan; Zhang, Wen-yuan; Wu, Ai-hua; Huang, Yong-zhuo] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China		Xu, Q (corresponding author), Guangzhou Univ Chinese Med, Inst Trop Med, Guangzhou 510405, Guangdong, Peoples R China.; Huang, YZ (corresponding author), Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China.	xuqin@gzucm.edu.cn; yzhuang@simm.ac.cn	Huang, Yongzhuo/A-4688-2013	Huang, Yongzhuo/0000-0001-7067-8915	973 Program, ChinaNational Basic Research Program of China [2014CB931900, 2013CB932503]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81373357, 81422048, 81402883, 81521005, 81673382]; Scientific Research and Equipment Development Project, Chinese Academy of Sciences [YZ201437]	This work was supported by the 973 Program, China (2014CB931900 and 2013CB932503) and the National Natural Science Foundation of China (81373357, 81422048, 81402883, 81521005, and 81673382). It was also partially supported by the Scientific Research and Equipment Development Project, Chinese Academy of Sciences (YZ201437).	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Sin.	JUN	2017	38	6			SI		885	896		10.1038/aps.2017.10			12	Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	EW5EB	WOS:000402526900013	28479604	Green Published, Bronze			2022-04-25	
J	Raju, GSR; Pavitra, E; Merchant, N; Lee, H; Prasad, GLV; Nagaraju, GP; Huh, YS; Han, YK				Raju, G. Seeta Rama; Pavitra, E.; Merchant, Neha; Lee, Hoomin; Prasad, Ganji Lakshmi Vara; Nagaraju, Ganji Purnachandra; Huh, Yun Suk; Han, Young-Kyu			Targeting autophagy in gastrointestinal malignancy by using nanomaterials as drug delivery systems	CANCER LETTERS			English	Review						Autophagy; Nanomaterial; Gastric cancer; Pancreatic cancer; Liver cancer	HEPATOCELLULAR-CARCINOMA CELLS; HYPOXIA-INDUCED AUTOPHAGY; ESOPHAGEAL CANCER-CELLS; COLON-CANCER; SIGNALING PATHWAYS; VACUOLATING CYTOTOXIN; ESOPHAGOGASTRIC CANCER; OXIDE NANOPARTICLES; GROWTH-INHIBITION; INDUCE AUTOPHAGY	Autophagy is a conserved catabolic process involving large protein degradation by a ubiquitous auto-phagosomic signaling pathway, which is essential for cellular homeostasis. It is triggered by environmental factors such as stress, lack of nutrients, inflammation, and eliminating intracellular pathogens. Although the mechanisms underlying autophagy are still unclear, increasing evidence illuminates the magnitude of autophagy in a wide range of physiological processes and human diseases. Simultaneously, research community has focused on the triggering of autophagy by the internalization of engineered nanomaterials, which indicates a new line of revolution in cancer cure. However, most studies on nanoparticle-induced autophagy focus on brain, breast, and cervical cancers; limited reports are available on gastrointestinal (GI) cancers. Therefore, the aim of this mini review is to discuss in detail the role of autophagy in GI malignancy and the status of research on nanoparticle-induced autophagy. (C) 2018 Elsevier B.V. All rights reserved.	[Raju, G. Seeta Rama; Han, Young-Kyu] Dongguk Univ Seoul, Dept Energy & Mat Engn, Seoul 04620, South Korea; [Pavitra, E.; Lee, Hoomin; Huh, Yun Suk] Inha Univ, Dept Biol Engn, BSRC, 100 Inha Ro, Incheon 22212, South Korea; [Merchant, Neha; Nagaraju, Ganji Purnachandra] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA; [Prasad, Ganji Lakshmi Vara] Dr LV Prasad Diagnost & Res Lab, Hyderabad 500004, Telangana, India		Han, YK (corresponding author), Dongguk Univ Seoul, Dept Energy & Mat Engn, Seoul 04620, South Korea.; Huh, YS (corresponding author), Inha Univ, Dept Biol Engn, BSRC, 100 Inha Ro, Incheon 22212, South Korea.; Nagaraju, GP (corresponding author), Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA.	pganji@emory.edu; yunsukhuh@inha.ac.kr; ykenergy@dongguk.edu	Merchant, Neha/AAW-3369-2021; Nagaraju, Purnachandra/D-4193-2011; Pavitra, E./A-1005-2014; Raju, Ganji Seeta Rama/D-3428-2011	Nagaraju, Purnachandra/0000-0002-4989-5234; Pavitra, E./0000-0002-8066-6309; Raju, Ganji Seeta Rama/0000-0002-3170-7506	Ministry of Science, ICT & Future Planning [2016R1A2B4013374, 2014R1A5A1009799]	The authors are grateful for the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (2016R1A2B4013374 and 2014R1A5A1009799).	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J	Margalef, P; Colomer, C; Villanueva, A; Montagut, C; Iglesias, M; Bellosillo, B; Salazar, R; Martinez-Iniesta, M; Bigas, A; Espinosa, L				Margalef, Pol; Colomer, Carlota; Villanueva, Alberto; Montagut, Clara; Iglesias, Mar; Bellosillo, Beatriz; Salazar, Ramon; Martinez-Iniesta, Maria; Bigas, Anna; Espinosa, Lluis			BRAF-induced tumorigenesis is IKK alpha-dependent but NF-kappa B-independent	Science Signaling			English	Article							COLORECTAL-CANCER; RAF INHIBITORS; GENE-EXPRESSION; PROSTATE-CANCER; MEK INHIBITION; MAPK PATHWAY; KINASE-ALPHA; COLON-CANCER; ACTIVATION; MELANOMA	KRAS mutations contribute to cell proliferation and survival in numerous cancers, including colorectal cancers (CRC). One pathway through which mutant KRAS acts is an inflammatory pathway that involves the kinase IKK and activates the transcription factor NF-kappa B. BRAF, a kinase that is downstream of KRAS, is mutated in a subset of CRC and is predictive of poor prognosis and therapeutic resistance. We found that, in contrast to mutant KRAS, mutant BRAF (BRAF(V600E)) did not trigger NF-kappa B activation but instead triggered the phosphorylation of a proteolytic fragment of IKK alpha (p45-IKK alpha) in CRC cells. BRAF(V600E) CRC cells had a high abundance of phosphorylated p45-IKK alpha, which was decreased by a RAF inhibitor. However, the abundance and DNA binding of NF-kappa B in these cells were unaffected by the RAF inhibitor, and expression of BRAF(V600E) in human embryonic kidney-293T cells did not activate an NF-kappa B reporter. Moreover, BRAF-induced transformation of NIH-3T3 cells and BRAF-dependent transcription required phosphorylation of p45-IKK alpha. The kinase TAK1, which was associated with the endosomal compartment, phosphorylated p45-IKK alpha. Inhibition of endosomal vacuolar adenosine triphosphatase (V-ATPase) with chloroquine or bafilomycin A1 blocked p45-IKK alpha phosphorylation and induced apoptosis in BRAF-mutant CRC cells independent of autophagy. Treating mice with V-ATPase inhibitors reduced the growth and metastasis of BRAF(V600E) xenograft tumors in the cecum of mice.	[Margalef, Pol; Colomer, Carlota; Bigas, Anna; Espinosa, Lluis] Inst Hosp del Mar Invest Med IMIM, Barcelona 08003, Spain; [Villanueva, Alberto; Martinez-Iniesta, Maria] Inst Catala Oncol, Inst Invest Biomed Bellvitge IDIBELL, Lab Recerca Translac, Barcelona 08907, Spain; [Montagut, Clara] Univ Pompeu Fabra, IMIM, Dept Oncol, Barcelona 08003, Spain; [Iglesias, Mar; Bellosillo, Beatriz] IMIM, Dept Pathol, Barcelona 08003, Spain; [Salazar, Ramon] Bellvitge Hosp, Dept Oncol, Barcelona 08907, Spain		Espinosa, L (corresponding author), Inst Hosp del Mar Invest Med IMIM, Parc Recerca Biomed Barcelona, Barcelona 08003, Spain.	lespinosa@imim.es	Espinosa, Lluis/ABA-4564-2020; Bigas, Anna/A-7457-2014	Espinosa, Lluis/0000-0002-2897-4099; Martinez-Iniesta, Maria/0000-0001-6252-6671; Bigas, Anna/0000-0003-4801-6899	Formacion de Profesorado Universitario (FPU)Spanish Government [AP2009-2892]; Instituto de Salud Carlos III-FEDER grant [PI13/00448]; RTICCS/FEDEREuropean Commission [RD12/0036/0054, RD09/0076/00036]; Pla Director d'Oncologia de Catalunya (XBTC); AGAURAgencia de Gestio D'Ajuts Universitaris de Recerca Agaur (AGAUR) [SGR23]	P.M. is a recipient of a Formacion de Profesorado Universitario (FPU) fellowship (AP2009-2892), and L.E. is an investigator at the Carlos III program. This work was further supported by Instituto de Salud Carlos III-FEDER grants PI13/00448, AGAUR (SGR23), and RTICCS/FEDER (RD12/0036/0054 and RD09/0076/00036) and "Xarxa de Bancs de tumors" sponsored by the Pla Director d'Oncologia de Catalunya (XBTC).	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Signal.	APR 21	2015	8	373							ra38	10.1126/scisignal.2005886			12	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	CG6AI	WOS:000353376900003	25900832	Green Accepted			2022-04-25	
J	Senawong, T; Wongphakham, P; Saiwichai, T; Phaosiri, C; Kumboonma, P				Senawong, Thanaset; Wongphakham, Paweena; Saiwichai, Thussanee; Phaosiri, Chanokbhorn; Kumboonma, Pakit			Histone deacetylase inhibitory activity of hydroxycapsaicin, a synthetic derivative of capsaicin, and its cytotoxic effects against human colon cancer cell lines	TURKISH JOURNAL OF BIOLOGY			English	Article						Capsaicin; apoptosis; cell-cycle arrest; cytotoxicity; HDAC inhibitor; colon cancer	HOT CHILI-PEPPERS; CYCLE ARREST; APOPTOSIS; ACTIVATION; AUTOPHAGY; DEATH; INDUCTION; THERAPY; DIHYDROCAPSAICIN; INFLAMMATION	Capsaicin possesses cytotoxic/anticancer activity and shares some common structural features, including a benzene ring and a long hydrophobic carbon tail, with the histone deacetylase (HDAC) inhibitors trichostatin A and suberoylanilide hydroxamic acid. The aims of this study were to investigate HDAC inhibitory and cytotoxic activities of a synthetic derivative of capsaicin, hydroxycapsaicin (6-hydroxy-N-(4-hydroxy-3-methoxybenzyl)-8-methylnonenamide), in colon cancer cell lines. Hydroxycapsaicin inhibited HDAC activity in vitro (IC50 = 72 mu M) much more effectively than the prototype capsaicin (IC50 > 13.1 mM) and also exhibited HDAC inhibitory activity in human cells (HeLa cells). MTT assay demonstrated that hydroxycapsaicin was less toxic than capsaicin against both cancer and noncancer cells; however, hydroxycapsaicin, with greater HDAC inhibitory activity, was more effective than capsaicin at inducing apoptosis in colon cancer cell lines, especially in HCT116 cells. Hydroxycapsaicin appeared to induce less apoptotic cell death than capsaicin in Vero cells. Moreover, only hydroxycapsaicin induced S-phase cell-cycle arrest in both HT29 and HCT116 cells. The current study demonstrates that hydroxycapsaicin can act as a novel HDAC inhibitor, which would lead to a promising strategy for the development of safe and effective chemotherapeutic drugs from the abundant natural capsaicin of chili pepper.	[Senawong, Thanaset; Wongphakham, Paweena; Saiwichai, Thussanee] Khon Kaen Univ, Dept Biochem, Fac Sci, Khon Kaen, Thailand; [Phaosiri, Chanokbhorn; Kumboonma, Pakit] Khon Kaen Univ, Dept Chem, Fac Sci, Khon Kaen, Thailand; [Senawong, Thanaset; Phaosiri, Chanokbhorn] Khon Kaen Univ, Nat Prod Res Unit, Fac Sci, Khon Kaen 40002, Thailand; [Senawong, Thanaset] Khon Kaen Univ, Food & Prod Chem Anal Res Grp, Fac Sci, Khon Kaen 40002, Thailand		Senawong, T (corresponding author), Khon Kaen Univ, Dept Biochem, Fac Sci, Khon Kaen, Thailand.	sthanaset@kku.ac.th	Phaosiri, Chanokbhorn/AAF-7797-2020	Phaosiri, Chanokbhorn/0000-0002-0108-0204	Khon Kaen University	This work was supported by Khon Kaen University through a Researcher Training Grant (to TS). We are thankful to Professor Nison Sattayasai and Associate Professor Veerapol Kukongviriyapan, Khon Kaen University, Thailand, for technical advice and coordination for the use of microplate spectrofluorometer, respectively.	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J. Biol.		2015	39	3					370	379		10.3906/biy-1409-60			10	Biology	Science Citation Index Expanded (SCI-EXPANDED)	Life Sciences & Biomedicine - Other Topics	CK6SM	WOS:000356358200003		Bronze, Green Submitted			2022-04-25	
J	Milczarek, M; Pogorzelska, A; Wiktorska, K				Milczarek, Malgorzata; Pogorzelska, Anna; Wiktorska, Katarzyna			Synergistic Interaction between 5-FU and an Analog of Sulforaphane-2-Oxohexyl Isothiocyanate-In an In Vitro Colon Cancer Model	MOLECULES			English	Article						5-fluorouracil; isothiocyanates; sulforaphane; synergistic effect	CELL-CYCLE; GROWTH-INHIBITION; APOPTOSIS; 5-FLUOROURACIL; AUTOPHAGY; COMBINATION; ACID; OXALIPLATIN; SENSITIZES; METABOLITE	Combination therapy is based on the beneficial effects of pharmacodynamic interaction (synergistic or additive) between combined drugs or substances. A considerable group of candidates for combined treatments are natural compounds (e.g., isothiocyanates) and their analogs, which are tested in combination with anticancer drugs. We tested the anticancer effect of the combined treatment of isothiocyanate 2-oxohexyl isothiocyanate and 5-fluorouracil in colon and prostate cancer cell lines. The type of interaction was described using the Chou-Talalay method. The cytostatic and cytotoxic activities of the most promising combined treatments were investigated. In conclusion, we showed that combined treatment with 5-fluorouracil and 2-oxohexyl isothiocyanate acted synergistically in colon cancer. This activity is dependent on the cytostatic properties of the tested compounds and leads to the intensification of their individual cytotoxic activity. The apoptotic process is considered to be the main mechanism of cytotoxicity in this combined treatment.	[Milczarek, Malgorzata; Pogorzelska, Anna; Wiktorska, Katarzyna] Natl Med Inst, Dept Drug Biotechnol & Bioinformat, 30-34 Chelmska St, PL-00725 Warsaw, Poland		Milczarek, M; Wiktorska, K (corresponding author), Natl Med Inst, Dept Drug Biotechnol & Bioinformat, 30-34 Chelmska St, PL-00725 Warsaw, Poland.	m.milczarek@nil.gov.pl; a.pogorzelska@nil.gov.pl; k.wiktorska@nil.gov.pl		Pogorzelska, Anna/0000-0002-4006-2682; Wiktorska, Katarzyna/0000-0002-2731-9535; Milczarek, Malgorzata/0000-0003-1209-9477	National Science Center, PolandNational Science Centre, Poland [N/NZ5/02634]; National Medicines Institute, Warsaw, Poland	This research was funded by the National Science Center, Poland, grant number N/NZ5/02634, and by the National Medicines Institute, Warsaw, Poland, from statutory funding.	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J	Pool, H; Campos-Vega, R; Herrera-Hernandez, MG; Garcia-Solis, P; Garcia-Gasca, T; Sanchez, IC; Luna-Barcenas, G; Vergara-Castaneda, H				Pool, Hector; Campos-Vega, Rocio; Guadalupe Herrera-Hernandez, Maria; Garcia-Solis, Pablo; Garcia-Gasca, Teresa; Sanchez, Isaac Cornelius; Luna-Barcenas, Gabriel; Vergara-Castaneda, Heyde			Development of genistein-PEGylated silica hybrid nanomaterials with enhanced antioxidant and antiproliferative properties on HT29 human colon cancer cells	AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH			English	Article						Colorectal cancer; genistein; PEGylated silica nanoparticles; hybrid nanomaterials; antiproliferative effects; mechanisms of programmed cell death	DRUG-DELIVERY; HYDROGEN-PEROXIDE; IN-VITRO; NANOPARTICLES; APOPTOSIS; ENCAPSULATION; AUTOPHAGY; TOXICITY; CAPACITY; RELEASE	The anticancer use of genistein (Gen) has been severely limited due to its low water solubility, low bioavailability, and instability under experimental conditions. To overcome these limitations, we propose a formulation of a hybrid nanomaterial (HNM) based upon the incorporation of Gen into PEGylated silica nanoparticles (PEG-SiNPs) (Gen-PEG-SiHNM), where their physicochemical and biological effects on HT29 cells were evaluated. Genistein-loaded PEGylated silica hybrid nanomaterials were obtained by a simple end effective aqueous dispersion method. Physicochemical properties were determined by its mean particle size, surface charge, amount of cargo, spectroscopic properties, release profiles and aqueous solubility. In vitro biological performance was carried out by evaluating its antioxidant capacity and elucidating its antiproliferative mechanistic. Results showed that small (ca. 33 nm) and spherical particles were obtained with positive surface charge (+9.54 mV). Infrared analyses determined that encapsulation of genistein was successfully achieved with an efficiency of 51%; it was observed that encapsulation process enhanced the aqueous dispersibility of genistein and cumulative release of genistein was pH-dependent. More important, after encapsulation data showed that Gen potentiated its antioxidant and antiproliferative effects on HT29 human colon cancer cells by the modulation of endogenous antioxidant enzymes and H2O2 production, which simultaneously activated two different processes of cell death (apoptosis and autophagy), unlike free genistein that only activated one (apoptosis) in a lower proportion. Overall, our data support that Gen-PEG-SiHNM could be potentially used as alternative treatment for colorectal cancer in a near future.	[Pool, Hector; Luna-Barcenas, Gabriel] Inst Politecn Nacl, Unidad Queretaro, Ctr Invest & Estudios Avanzados CINVESTAV, Juriquilla 76230, Queretaro, Mexico; [Campos-Vega, Rocio] Univ Autonoma Queretaro, Fac Quim, Dept Invest & Posgrad Alimentos, Queretaro 76010, Mexico; [Guadalupe Herrera-Hernandez, Maria] INIFAP, Unidad Biotecnol, Campo Expt Bajio, Celaya 38110, Guanajuato, Mexico; [Garcia-Solis, Pablo; Vergara-Castaneda, Heyde] Univ Autonoma Queretaro, Fac Med, Dept Invest Biomed, Queretaro 76176, Queretaro, Mexico; [Garcia-Gasca, Teresa] Univ Autonoma Queretaro, Fac Ciencias Nat, Juriquilla 76230, Queretaro, Mexico; [Sanchez, Isaac Cornelius] Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA		Pool, H (corresponding author), Inst Politecn Nacl, Unidad Queretaro, Ctr Invest & Estudios Avanzados CINVESTAV, Juriquilla 76230, Queretaro, Mexico.	gabriel.luna@cinvestav.mx; hayvergarac@gmail.com	Luna-Barcenas, Gabriel/B-7243-2016; Garcia-Solis, Pablo/B-8572-2013; Luna-Barcenas, Gabriel/B-4433-2011	Luna-Barcenas, Gabriel/0000-0002-1162-6928; Garcia-Solis, Pablo/0000-0002-7483-0555; Reyes Pool, Hector/0000-0002-6742-3839	National Council of Science and Technology (CONACYT) of MexicoConsejo Nacional de Ciencia y Tecnologia (CONACyT)	Authors would like to thank The National Council of Science and Technology (CONACYT) of Mexico for postdoctoral fellowships and partial support for this work. We also thank MSc Araceli Mauricio and MSc Lourdes Palma-Tirado for the technical support in DRIFT and TEM analyses, respectively.	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J. Transl. Res.		2018	10	8					2306	+					19	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	GS5QU	WOS:000443724100007	30210672				2022-04-25	
J	Yi, JY; Jung, YJ; Choi, SS; Hwang, J; Chung, E				Yi, Jae Youn; Jung, Yu-Jin; Choi, Sun Shim; Hwang, Jungjin; Chung, Eunkyung			Autophagy-mediated anti-tumoral activity of imiquimod in Caco-2 cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Imiquimod; TLR7; Autophagy; Anti-tumoral activity; TNF-alpha; Apoptosis; Caco-2 cells	RESPONSE MODIFIER IMIQUIMOD; VIRAL RECOGNITION; DENDRITIC CELLS; CANCER-THERAPY; APOPTOSIS; DEATH; IMIDAZOQUINOLINES; CARCINOMA; INDUCTION; MELANOMA	Imiquimod (IMQ) is recognized as a topical immune response modifier compound that enhances immune responses with anti-viral and anti-tumoral activities. Its anti-tumoral effects have been previously demonstrated in a variety of cancer cells, and were identified as indirect responses mediated by the immune modulation Of cutaneous dendritic cells. Recently, the pro-apoptotic activities Of IMQ occuring Via the modulation of bcl-2 family have been reported in several tumor cells. In this Study, we first observed IMQ-initiated autophagy determined by vesicular organelle formation and the generation of LC3-II in Caco-2 human colonic adenocarcinoma cells, which expressing functional TLR7. Additionally, IMQ-induced autophagy resulted in cell death Occurring independently of molecular changes of apoptotic markers. Loxoribine also induced autophagy and autophagy-induced cell death at less potent than IMQ. Moreover. the activation of autophagy by rapamycin induced enhanced cell death in TNF-alphatreated Caco-2 cells, which were autophagy and cell death-resistant. Our results led LIS to Conclude that IMQ exerts a direct effect oil the anti-tumoral activity of Caco-2 cells via autophagy-induced cell death. In conclusion, the modulation of autophagy might be applied in a potential cancer therapy for (be treatment of colon cancer cells. (C) 2009 Elsevier Inc. All rights reserved.	[Chung, Eunkyung] Hallym Univ, Dept Biomed Sci, Chunchon 200702, South Korea; [Yi, Jae Youn] Korea Inst Radiol & Med Sci, Lab Modulat Radiobiol Response, Seoul 139706, South Korea; [Jung, Yu-Jin] Kangwon Natl Univ, Med & Biomat Res Ctr, Chunchon 200701, South Korea; [Jung, Yu-Jin] Kangwon Natl Univ, Dept Biol, Chunchon 200701, South Korea; [Choi, Sun Shim] Kangwon Natl Univ, Dept Mol & Med Biotechnol, Chunchon 200701, South Korea; [Hwang, Jungjin] Univ Ulsan, Coll Med, Asan Med Ctr, Inst Innovat Canc Res, Seoul 138736, South Korea		Chung, E (corresponding author), Hallym Univ, Dept Biomed Sci, 39 Hallymdaehak Gil, Chunchon 200702, South Korea.	chungek@hallym.ac.kr	Hwang, Jung Jin/F-3424-2014		Korean Government MOEHRDMinistry of Education & Human Resources Development (MOEHRD), Republic of KoreaKorean Government [KRF-2006-003-C00220]; Nuclear Research Development Program of the Korea Science and Engineering Foundation KOSEFKorea Science and Engineering Foundation [M2070600005-08BO600-00510]; Korean Ministry of Science and TechnologyMinistry of Science and Technology (MOST) Korea [2007-00324]	This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund, KRF-2006-003-C00220), Nuclear Research Development Program of the Korea Science and Engineering Foundation KOSEF (M2070600005-08BO600-00510), and National Nuclear Research & Development Program of the Korean Ministry of Science and Technology (2007-00324).	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Biophys. Res. Commun.	AUG 28	2009	386	3					455	458		10.1016/j.bbrc.2009.06.046			4	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	474DH	WOS:000268262100008	19527683				2022-04-25	
J	Chen, YQ; Gibson, SB				Chen, Yongqiang; Gibson, Spencer B.			Three dimensions of autophagy in regulating tumor growth: cell survival/death, cell proliferation, and tumor dormancy	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE			English	Article						Autophagy; Cell survival; Cell death; Proliferation; Tumor dormacy; Tumor growth	STARVATION-INDUCED AUTOPHAGY; CANCER-CELLS; UROKINASE RECEPTOR; SUPPRESSES PROLIFERATION; PROSTATE-CANCER; HUMAN CARCINOMA; COLON-CANCER; DEATH; AMPK; MECHANISMS	Autophagy is an intracellular lysosomal degradation process involved in multiple facets of cancer biology. Various dimensions of autophagy are associated with tumor growth and cancer progression, and here we focus on the dimensions involved in regulation of cell survival/cell death, cell proliferation and tumor dormancy. The first dimension of autophagy supports cell survival under stress within tumors and under certain contexts drives cell death, impacting tumor growth. The second dimension of autophagy promotes proliferation through directly regulating cell cycle or indirectly maintaining metabolism, increasing tumor growth. The third dimension of autophagy facilitates tumor cell dormancy, contributing to cancer treatment resistance and cancer recurrence. The intricate relationship between these three dimensions of autophagy influences the extent of tumor growth and cancer progression. In this review, we summarize the roles of the three dimensions of autophagy in tumor growth and cancer progression, and discuss unanswered questions in these fields.	[Chen, Yongqiang; Gibson, Spencer B.] Univ Manitoba, CancerCare Manitoba Res Inst, CancerCare Manitoba, Winnipeg, MB, Canada; [Gibson, Spencer B.] Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada		Chen, YQ (corresponding author), Univ Manitoba, CancerCare Manitoba Res Inst, CancerCare Manitoba, Winnipeg, MB, Canada.	ychen2@cancercare.mb.ca	Chen, Yongqiang/ABF-6081-2021	Chen, Yongqiang/0000-0003-2309-5674	CancerCare Manitoba Foundation	This work was supported by a grant from the CancerCare Manitoba Foundation awarded to S.B.G.	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Biophys. Acta-Mol. Basis Dis.	DEC 1	2021	1867	12							166265	10.1016/j.bbadis.2021.166265		SEP 2021	10	Biochemistry & Molecular Biology; Biophysics; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics; Cell Biology	US0VF	WOS:000697154300019	34487813				2022-04-25	
J	Lan, L; Appelman, C; Smith, AR; Yu, J; Larsen, S; Marquez, RT; Liu, H; Wu, XQ; Gao, P; Roy, A; Anbanandam, A; Gowthaman, R; Karanicolas, J; De Guzman, RN; Rogers, S; Aube, J; Ji, M; Cohen, RS; Neufeld, KL; Xu, L				Lan, Lan; Appelman, Carl; Smith, Amber R.; Yu, Jia; Larsen, Sarah; Marquez, Rebecca T.; Liu, Hao; Wu, Xiaoqing; Gao, Philip; Roy, Anuradha; Anbanandam, Asokan; Gowthaman, Ragul; Karanicolas, John; De Guzman, Roberto N.; Rogers, Steven; Aube, Jeffrey; Ji, Min; Cohen, Robert S.; Neufeld, Kristi L.; Xu, Liang			Natural product (-)-gossypol inhibits colon cancer cell growth by targeting RNA-binding protein Musashi-1	MOLECULAR ONCOLOGY			English	Article						RNA binding protein; Wnt; Notch; Musashi-1; Colon cancer	STEM-CELL; IN-VITRO; PROSTATE-CANCER; EXPRESSION; GOSSYPOL; MARKER; FAMILY; IDENTIFICATION; PROLIFERATION; APOPTOSIS	Musashi-1 (MSI1) is an RNA-binding protein that acts as a translation activator or repressor of target mRNAs. The best-characterized MSI1 target is Numb mRNA, whose encoded protein negatively regulates Notch signaling. Additional MSI1 targets include the mRNAs for the tumor suppressor protein APC that regulates Wnt signaling and the cyclin-dependent kinase inhibitor P21(WAF-1). We hypothesized that increased expression of NUMB, P21 and APC, through inhibition of MSI1 RNA-binding activity might be an effective way to simultaneously downregulate Wnt and Notch signaling, thus blocking the growth of a broad range of cancer cells. We used a fluorescence polarization assay to screen for small molecules that disrupt the binding of MSI1 to its consensus RNA binding site. One of the top hits was (-)-gossypol (Ki = 476 +/- 273 nM), a natural product from cottonseed, known to have potent anti-tumor activity and which has recently completed Phase IIb clinical trials for prostate cancer. Surface plasmon resonance and nuclear magnetic resonance studies demonstrate a direct interaction of (-)-gossypol with the RNA binding pocket of MSI1. We further showed that (-)-gossypol reduces Notch/Wnt signaling in several colon cancer cell lines having high levels of MSI1, with reduced SURVIVIN expression and increased apoptosis/autophagy. Finally, we showed that orally administered (-)-gossypol inhibits colon cancer growth in a mouse xenograft model. Our study identifies (-)-gossypol as a potential small molecule inhibitor of MSI1-RNA interaction, and suggests that inhibition of MSI1's RNA binding activity may be an effective anti-cancer strategy. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.	[Lan, Lan; Appelman, Carl; Smith, Amber R.; Yu, Jia; Larsen, Sarah; Marquez, Rebecca T.; Liu, Hao; Wu, Xiaoqing; Gowthaman, Ragul; Karanicolas, John; De Guzman, Roberto N.; Neufeld, Kristi L.; Xu, Liang] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA; [Gao, Philip] Univ Kansas, COBRE Prot Prod Grp, Lawrence, KS 66045 USA; [Roy, Anuradha] Univ Kansas, High Throughput Screening Lab, Lawrence, KS 66045 USA; [Anbanandam, Asokan] Univ Kansas, BioNMR Core Facil, Lawrence, KS 66045 USA; [Gowthaman, Ragul; Karanicolas, John] Univ Kansas, Ctr Bioinformat, Lawrence, KS 66045 USA; [Rogers, Steven; Aube, Jeffrey] Univ Kansas, Ctr Canc Expt Therapeut, Ctr Biomed Res Excellence, Lawrence, KS 66045 USA; [Aube, Jeffrey] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66045 USA; [Aube, Jeffrey] Univ Kansas, Ctr Chem Methodol & Lib Dev, Lawrence, KS 66045 USA; [Aube, Jeffrey] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA; [Ji, Min] Southeast Univ, Sch Chem & Chem Engn, Nanjing, Jiangsu, Peoples R China; [Cohen, Robert S.] Clemson Univ, Dept Biol Sci, Clemson, SC 29634 USA; [Xu, Liang] Univ Kansas, Ctr Canc, Dept Radiat Oncol, Kansas City, KS USA		Xu, L (corresponding author), Univ Kansas, Dept Mol Biosci, 4002 Haworth Hall,1200 Sunnyside Ave, Lawrence, KS 66045 USA.	xul@ku.edu	Wu, Xiaoqing/D-3569-2016; LAN, LAN/N-8872-2018; Liu, Hao/J-1911-2014	Wu, Xiaoqing/0000-0003-2076-4107; Liu, Hao/0000-0003-2343-4998; Roy, Anuradha/0000-0002-1057-1443; Neufeld, Kristi/0000-0003-3653-9385; Gowthaman, Ragul/0000-0002-0008-6401; Aube, Jeffrey/0000-0003-1049-5767	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 CA178831]; K-INBRE Bridging Grant [P20 GM103418]; Kansas Bioscience Authority Rising Star Award; University of Kansas Cancer Center Pilot Grant; NIH COBRE at KU CCET Pilot Project [P30 RR030926]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 AI074856]; University of Kansas Bold Aspiration Strategic Initiative Award; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA178831] 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) [P30RR030926] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R01AI074856] 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) [P20GM103418, P30GM110761] Funding Source: NIH RePORTER	This study was supported in part by National Institutes of Health grant R01 CA178831 (to L. X., K. N., J. A.), K-INBRE (P20 GM103418) Bridging Grant; Kansas Bioscience Authority Rising Star Award, and University of Kansas Cancer Center Pilot Grant (to L. X.); NIH COBRE at KU CCET Pilot Project (P30 RR030926 to K. N.), NIH R01 AI074856 (to R. N. D.), and the University of Kansas Bold Aspiration Strategic Initiative Award (to L. X. and K. N.). The sponsors had no role in the study design, in the collection, analysis, and interpretation of data.	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Oncol.	AUG	2015	9	7					1406	1420		10.1016/j.molonc.2015.03.014			15	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CP4XB	WOS:000359884800015	25933687	Green Accepted, hybrid, Green Published			2022-04-25	
J	Zheng, F; Yang, WJ; Sun, KJ; Wan, XM; Man, N; Wen, LP				Zheng, Fang; Yang, Wen-Jun; Sun, Ke-Jing; Wan, Xiao-Mei; Man, Na; Wen, Long-Ping			Hoechst 33342-induced autophagy protected HeLa cells from caspase-independent cell death with the participation of ROS	FREE RADICAL RESEARCH			English	Article						Hoechst 33342; autophagy; caspase-independent cell death; ROS	MALIGNANT GLIOMA-CELLS; 33342 INDUCES APOPTOSIS; COLON-CANCER CELLS; I IN-VIVO; ARSENIC TRIOXIDE; MACROAUTOPHAGY; INDUCTION; GENES; DEGRADATION	Autophagy, an evolutionarily-conserved intracellular organelle and protein degradation process, may exhibit drastically different effects on cell survival depending on the particular environmental and culturing conditions. Hoechst 33342 (HO), a fluorescent dye widely used for staining DNA, has been reported to induce apoptosis in mammalian cells. Here we showed that, in addition to caspase-independent cell death, HO also induced autophagy in HeLa cells, as evidenced by the accumulation of autophagosomes, LC3 form conversion and LC3 puncta formation in a cell line stably expressing GFP-LC3. HO treatment led to generation of reactive oxygen species (ROS), and inhibition of ROS with N-acetyl-L-cysteine (NAC) abrogated both autophagy and caspase-independent cell death. Finally, autophagy played a protective role against caspase-independent cell death, as cell death induced by HO was enhanced under pharmacological and siRNA-mediated genetic inhibition of autophagy.	[Wen, Long-Ping] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China; [Wen, Long-Ping] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China		Wen, LP (corresponding author), Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China.	manna@mail.ustc.edu.cn; lpwen@ustc.edu.cn		Wen, Longping/0000-0003-0384-4578	Chinese Ministry of Sciences [2007CB935800, 2010CB912804]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30721002, 31071211, 30830036, 31170966, 31101020]; Chinese Academy of SciencesChinese Academy of Sciences [KSCX2-YW-R-139]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [WK2070000008]; Scientific and Technological Major Special Project [2009ZX09103-650]	We thank Noboru Mizushima for providing LC3 plasmid. This work was supported by grants from the Chinese Ministry of Sciences 973 Program (2007CB935800, 2010CB912804), Natural Science Foundation of China (#30721002, #31071211, #30830036, #31170966, #31101020), Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-YW-R-139), the Fundamental Research Funds for the Central Universities (WK2070000008) and Scientific and Technological Major Special Project (2009ZX09103-650).	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Res.	JUN	2012	46	6					740	749		10.3109/10715762.2012.670701			10	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	939RW	WOS:000303832700004	22375792				2022-04-25	
J	Was, H; Barszcz, K; Czarnecka, J; Kowalczyk, A; Bernas, T; Uzarowska, E; Koza, P; Klejman, A; Piwocka, K; Kaminska, B; Sikora, E				Was, Halina; Barszcz, Kamila; Czarnecka, Joanna; Kowalczyk, Agata; Bernas, Tytus; Uzarowska, Ewelina; Koza, Paulina; Klejman, Agata; Piwocka, Katarzyna; Kaminska, Bozena; Sikora, Eva			Bafilomycin A1 triggers proliferative potential of senescent cancer cells in vitro and in NOD/SCID mice	ONCOTARGET			English	Article						colon cancer; chemotherapy; senescence; autophagy; angiogenesis	ACCELERATED CELLULAR SENESCENCE; ENDOTHELIAL GROWTH-FACTOR; STEM-CELLS; SELF-RENEWAL; MITOTIC CATASTROPHE; BETA-GALACTOSIDASE; CYCLE ARREST; TUMOR-CELLS; AUTOPHAGY; POLYPLOIDY	Anticancer therapies that induce DNA damage tend to trigger senescence in cancer cells, a process known as therapy-induced senescence (TIS). Such cells may undergo atypical divisions, thus contributing to tumor re-growth. Accumulation of senescent cancer cells reduces survival of patients after chemotherapy. As senescence interplays with autophagy, a dynamic recycling process, we sought to study whether inhibition of autophagy interferes with divisions of TIS cells. We exposed human colon cancer HCT116 cells to repeated cycles of a chemotherapeutic agent doxorubicin (doxo) and demonstrated induction of hallmarks of TIS (e.g. growth arrest, hypertrophy, poliploidization and secretory phenotype) and certain properties of cancer stem cells (increased NANOG expression, percentages of CD24+ cells and side population). Colonies of small and highly proliferative progeny appeared shortly after drug removal. Treatment with bafilomycin A1 (BAF A1), an autophagy inhibitor, postponed short term in vitro cell re-population. It was associated with reduction in the number of diploid and increase in the number of poliploid cells. In a long term, a pulse of BAF A1 resulted in reactivation of autophagy in a subpopulation of HCT116 cells and increased proliferation. Accordingly, the senescent HCT116 cells treated with BAF A1 when injected into NOD/SCID mice formed tumors, in contrast to the controls. Our results suggest that senescent cancer cells that appear during therapy, can be considered as dormant cells that contribute to cancer re-growth, when chemotherapeutic treatment is stopped. These data unveil new mechanisms of TIS-related cancer maintenance and re-population, triggered by a single pulse of BAF A1 treatment.	[Was, Halina; Barszcz, Kamila; Czarnecka, Joanna; Sikora, Eva] Polish Acad Sci, Nencki Inst Expt Biol, Lab Mol Basis Ageing, PL-02093 Warsaw, Poland; [Was, Halina; Barszcz, Kamila; Czarnecka, Joanna; Kaminska, Bozena] Polish Acad Sci, Nencki Inst Expt Biol, Mol Neurobiol Lab, PL-02093 Warsaw, Poland; [Kowalczyk, Agata; Piwocka, Katarzyna] Polish Acad Sci, Nencki Inst Expt Biol, Lab Cytometry, PL-02093 Warsaw, Poland; [Bernas, Tytus] Polish Acad Sci, Nencki Inst Expt Biol, Lab Imaging Tissue Struct & Funct, PL-02093 Warsaw, Poland; [Uzarowska, Ewelina; Koza, Paulina; Klejman, Agata] Polish Acad Sci, Nencki Inst Expt Biol, Lab Anim Models, PL-02093 Warsaw, Poland; [Koza, Paulina] Polish Acad Sci, Nencki Inst Expt Biol, Neurobiol Lab, PL-02093 Warsaw, Poland		Was, H (corresponding author), Polish Acad Sci, Nencki Inst Expt Biol, Lab Mol Basis Ageing, PL-02093 Warsaw, Poland.; Was, H (corresponding author), Polish Acad Sci, Nencki Inst Expt Biol, Mol Neurobiol Lab, PL-02093 Warsaw, Poland.	h.was@nencki.gov.pl	Klejman, Agata/AAC-1844-2021; Kaminska, Bozena/B-2915-2014; Kaminska, Bozena/H-4592-2011; Czarnecka-Herok, Joanna/ABD-8148-2020	Klejman, Agata/0000-0001-6083-9957; Kaminska, Bozena/0000-0002-2642-4616; Sikora, Ewa/0000-0002-1111-1748; Piwocka, Katarzyna/0000-0001-6676-5282; Koza, Paulina/0000-0001-8311-4027; Was, Halina/0000-0003-2743-0337; Kominek, Agata/0000-0003-1567-9442; Czarnecka-Herok, Joanna/0000-0002-7287-3615	Foundation for Polish ScienceFoundation for Polish ScienceEuropean Commission; European Union under the European Social Fund [125/UD/SKILLS/2013]; Ministry of Science and Higher EducationMinistry of Science and Higher Education, PolandEuropean Commission [IP2012 062172]; National Science CenterNational Science Centre, Poland [2013/09/B/NZ3/01389, 2012/05/E/ST2/02180]; EU FP7 Project BIO-IMAGINE: BIO-IMAGing in research INnovation and Education [264173]; Ministry of Science and Higher EducationMinistry of Science and Higher Education, PolandEuropean Commission	This work was supported by the Foundation for Polish Science co-financed by the European Union under the European Social Fund (grant 125/UD/SKILLS/2013), the Ministry of Science and Higher Education (grant IP2012 062172), and the National Science Center (grants 2013/09/B/NZ3/01389 and 2012/05/E/ST2/02180). H.W. is the recipient of a fellowship from EU FP7 Project BIO-IMAGINE: BIO-IMAGing in research INnovation and Education, GA No. 264173 that was obtained by Nencki Institute of Experimental Biology. H.W. is the recipient of a scholarship for young and outstanding investigators from the Ministry of Science and Higher Education.	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C., 2012, Experimental Oncology, V34, P298; Wu PC, 2010, CELL DEATH DIS, V1, DOI 10.1038/cddis.2010.47; Yeung TM, 2010, P NATL ACAD SCI USA, V107, P3722, DOI 10.1073/pnas.0915135107; Young ARJ, 2010, CURR OPIN CELL BIOL, V22, P234, DOI 10.1016/j.ceb.2009.12.005; Zhang D, 2014, BIOMED RES INT, V2014, DOI 10.1155/2014/432652; Zhang S, 2014, ONCOGENE, V33, P116, DOI 10.1038/onc.2013.96; Zhang SW, 2014, INT J CANCER, V134, P508, DOI 10.1002/ijc.28319	70	26	26	0	3	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	FEB 7	2017	8	6					9303	9322		10.18632/oncotarget.14066			20	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	EK8NX	WOS:000394181800035	28030837	Green Published, gold, Green Submitted			2022-04-25	
J	Manogaran, P; Somasundaram, B; Viswanadha, VP				Manogaran, Prasath; Somasundaram, Bharath; Viswanadha, Vijaya Padma			Reversal of cisplatin resistance by neferine/isoliensinine and their combinatorial regimens with cisplatin-induced apoptosis in cisplatin-resistant colon cancer stem cells (CSCs)	JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY			English	Article						cisplatin resistant colon cancer stem cells (CSCs); colorectal cancer (CRC); isoliensinine; neferine; PI3K; pAKT; mTOR & apoptosis	PI3K/AKT/MTOR PATHWAY; MULTIDRUG-RESISTANCE; IN-VITRO; NEFERINE; CURCUMIN; AUTOPHAGY; GEFITINIB; BLOCKADE	Cisplatin chemotherapy to the colorectal cancer cells (CRCs) is accompanied by dose-limiting adverse effects along with the acquisition of drug resistance implicating low therapeutic outcomes. The present study is aimed to evaluate the chemosensitizing efficacy of neferine/isoliensinine or combinatorial regimen of neferine/isoliensinine with cisplatin against CSCs (cisplatin resistant colon stem cells). CSCs were developed using pulse exposure of cisplatin to parental HCT-15 cells. Neferine/isoliensinine or combinatorial regimens of Neferine/isoliensinine and cisplatin exhibited a stronger cytotoxic activity against CSCs compared to control. IC50 doses were found to be 6.5 mu M for neferine, 12.5 mu M for isoliensinine, and 120 mu M for cisplatin respectively. Furthermore, the combinatorial regimen of a low dose of cisplatin (40 mu M) with 4 mu M neferine/8 mu M isoliensinine induced cell death in a synergistic manner as described by isobologram. Neferine/isoliensinine could confer extensive intracellular reactive oxygen species generation in CSCs. Neferine/isoliensinine or combinatorial regimens dissipated mitochondrial membrane potential and enhanced intracellular [Ca2+]i, which were measured by spectroflurimetry. Furthermore, these combinatorial regimens induced a significant increase in the sub G0 phase of cell cycle arrest and PI uptake and alleviated the expression of ERCC1 in CSCs. Combinatorial regimens or neferine/isoliensinine treatments downregulated the cell survival protein expression (PI3K/pAkt/mTOR) and activated mitochondria-mediated apoptosis by upregulating Bax, cytochrome c, caspase-3, and PARP cleavage expression while downregulating the BCl-2 expression in CSCs. Our study confirms the chemosensitizing efficacy of neferine/isoliensinine or combinatorial regimens of neferine/isoliensinine with a low dose of cisplatin against CSCs.	[Manogaran, Prasath; Somasundaram, Bharath; Viswanadha, Vijaya Padma] Bharathiar Univ, Dept Biotechnol, Translat Res Lab, Coimbatore 641046, Tamil Nadu, India		Viswanadha, VP (corresponding author), Bharathiar Univ, Dept Biotechnol, Translat Res Lab, Coimbatore 641046, Tamil Nadu, India.	vvijayapadma@rediffmail.com			Indian Council of Medical ResearchIndian Council of Medical Research (ICMR) [2017-3490/SCR-BMS]	Indian Council of Medical Research, Grant/Award Number: File no. 2017-3490/SCR-BMS	Baskaran R, 2016, BIOFACTORS, V42, P407, DOI 10.1002/biof.1286; Berghmans T, 2017, Rev Med Brux, V38, P175; Cavazzoni A, 2012, CANCER LETT, V323, P77, DOI 10.1016/j.canlet.2012.03.034; Chan MM, 2018, CANCER LETT, V433, P53, DOI 10.1016/j.canlet.2018.06.034; Charafe-Jauffret E, 2009, CANCER RES, V69, P1302, DOI 10.1158/0008-5472.CAN-08-2741; Chen Y, 2017, NUTRIENTS, V9, DOI 10.3390/nu9060572; Cho Y, 2020, FRONT ONCOL, V10, DOI 10.3389/fonc.2020.00764; Coombs MRP, 2016, CANCER LETT, V380, P424, DOI 10.1016/j.canlet.2016.06.023; Janmaat ML, 2003, CLIN CANCER RES, V9, P2316; Jaudan A, 2018, PLOS ONE, V13, DOI 10.1371/journal.pone.0191523; Jiao LJ, 2017, SCI REP-UK, V7, DOI 10.1038/srep46524; Liou GY, 2010, FREE RADICAL RES, V44, P479, DOI 10.3109/10715761003667554; Lu WD, 2013, CLINICS, V68, P694, DOI 10.6061/clinics/2013(05)18; Manogaran P, 2021, CANCER INVEST, V39, P349, DOI 10.1080/07357907.2021.1894569; Matsui, 2016, MEDICINE, V95, P8; Morgan RG, 2018, BRIT J CANCER, V118, P1410, DOI 10.1038/s41416-018-0118-6; O'Brien CA, 2010, CLIN CANCER RES, V16, P3113, DOI 10.1158/1078-0432.CCR-09-2824; Pardoll DM, 2012, NAT REV CANCER, V12, P252, DOI 10.1038/nrc3239; Poornima P, 2014, FOOD CHEM TOXICOL, V68, P87, DOI 10.1016/j.fct.2014.03.008; Poornima P, 2013, FOOD CHEM, V141, P3598, DOI 10.1016/j.foodchem.2013.05.138; Poornima P, 2013, FOOD CHEM, V136, P659, DOI 10.1016/j.foodchem.2012.07.112; Raghavan S, 2015, BIOORG MED CHEM LETT, V25, P3601, DOI 10.1016/j.bmcl.2015.06.068; Ramasamy TS, 2015, CANCER CELL INT, V15, DOI 10.1186/s12935-015-0241-x; Ranjan A, 2019, INT J MOL SCI, V20, DOI 10.3390/ijms20204981; Rayburn Elizabeth R, 2009, Mol Cell Pharmacol, V1, P29; Reya T, 2001, NATURE, V414, P105, DOI 10.1038/35102167; Sivalingam KS, 2017, J CELL BIOCHEM, V118, P2865, DOI 10.1002/jcb.25937; Skarkova V, 2019, CELLS-BASEL, V8, DOI 10.3390/cells8030234; Song BC, 2013, J SURG RES, V185, P399, DOI 10.1016/j.jss.2013.05.093; Takebe N, 2010, CLIN CANCER RES, V16, P3106, DOI 10.1158/1078-0432.CCR-09-2934; Tang XQ, 2005, ACTA PHARMACOL SIN, V26, P1009, DOI 10.1111/j.1745-7254.2005.00149.x; Tong YX, 2019, EXP THER MED, V18, P3793, DOI 10.3892/etm.2019.8027; Tsai MS, 2011, MOL PHARMACOL, V80, P136, DOI 10.1124/mol.111.071316; Wang M, 2019, INT J BIOL SCI, V15, P1200, DOI 10.7150/ijbs.33710; Wang SH, 2018, BMC COMPLEM ALTERN M, V18, DOI 10.1186/s12906-018-2300-z; Xiong YQ, 2003, ACTA PHARMACOL SIN, V24, P332; Xu LM, 2016, TUMOR BIOL, V37, P8721, DOI 10.1007/s13277-015-4737-8; Yano S, 2006, J AGR FOOD CHEM, V54, P5203, DOI 10.1021/jf0607361; Yilmazer Acelya, 2018, Biotechnology Reports, V17, P24, DOI 10.1016/j.btre.2017.11.004; Zhao ZQ, 2016, ONCOL LETT, V12, P63, DOI 10.3892/ol.2016.4606; Zhou J, 2013, TOXICOL LETT, V222, P139, DOI 10.1016/j.toxlet.2013.07.022	41	0	0	3	3	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	1095-6670	1099-0461		J BIOCHEM MOL TOXIC	J. Biochem. Mol. Toxicol.	MAR	2022	36	3							e22967	10.1002/jbt.22967		DEC 2021	18	Biochemistry & Molecular Biology; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Toxicology	ZS3SP	WOS:000731265600001	34921482				2022-04-25	
J	Guo, BQ; Xiong, XP; Hasani, S; Wen, YA; Li, AT; Martinez, R; Skaggs, AT; Gao, TY				Guo, Bianqin; Xiong, Xiaopeng; Hasani, Sumati; Wen, Yang-An; Li, Austin T.; Martinez, Rebecca; Skaggs, Ashley T.; Gao, Tianyan			Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2 alpha phosphorylation and chemoresistance in colon cancer	CELL DEATH & DISEASE			English	Article							CELL MOTILITY; PHOSPHATASE; EXPRESSION; AKT; TRANSLATION; INHIBITION; RESISTANCE; SURVIVAL; CREP	Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2 alpha as well as the expression of autophagy-associated genes downstream of the eIF2 alpha/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2 alpha and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2 alpha/ATF4 signaling axis in colon cancer cells.	[Guo, Bianqin] Chongqing Univ, Chongqing Key Lab Translat Res Canc Metastasis &, Canc Hosp, Chongqing 400030, Peoples R China; [Xiong, Xiaopeng; Hasani, Sumati; Wen, Yang-An; Skaggs, Ashley T.; Gao, Tianyan] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40506 USA; [Hasani, Sumati; Skaggs, Ashley T.; Gao, Tianyan] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA; [Li, Austin T.] Paul Laurence Dunbar High Sch, Lexington, KY USA; [Martinez, Rebecca] Univ Kentucky, Coll Agr Food & Environm, Agr & Med Biotechnol Program, Lexington, KY USA; [Li, Austin T.] Princeton Univ, Princeton, NJ 08544 USA		Gao, TY (corresponding author), Univ Kentucky, Markey Canc Ctr, Lexington, KY 40506 USA.; Gao, TY (corresponding author), Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA.	tianyan.gao@uky.edu		, Ashley Skaggs/0000-0001-6732-1640	Chongqing Science and Technology CommissionNatural Science Foundation Project of CQ CSTC [cstc2020jcyj-msxmX0907]; National Science Foundation Graduate Research Fellowship AwardNational Science Foundation (NSF) [1839289]; NRSAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [F31CA260840]; Biostatistics and Bioinformatics, Biospecimen Procurement and Translational Pathology, Flow Cytometry and Immune Monitoring, and Redox Metabolism Shared Resource Facilities of the University of Kentucky Markey Cancer Center [P30CA177558];  [R01CA133429]	This work was supported by R01CA133429 (TG). BG was supported by funding from Chongqing Science and Technology Commission (cstc2020jcyj-msxmX0907). ATS was supported by the National Science Foundation Graduate Research Fellowship Award (#1839289). SH was supported by NRSA F31CA260840 predoctoral fellowship. The studies were conducted with support provided by the Biostatistics and Bioinformatics, Biospecimen Procurement and Translational Pathology, Flow Cytometry and Immune Monitoring, and Redox Metabolism Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558). The summary diagram was created with BioRender.com.	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OCT 18	2021	12	11							960	10.1038/s41419-021-04251-0			9	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	WI6VR	WOS:000708496600006	34663797	Green Published, gold			2022-04-25	
J	Yang, MP; Zhao, H; Guo, L; Zhang, QY; Zhao, L; Bai, SP; Zhang, MH; Xu, SQ; Wang, FJ; Wang, XH; Zhao, B				Yang, Maopeng; Zhao, Hong; Guo, Li; Zhang, Qingyuan; Zhao, Ling; Bai, Shuping; Zhang, Minghui; Xu, Sanqi; Wang, Fujing; Wang, Xiaohong; Zhao, Bin			Autophagy-based survival prognosis in human colorectal carcinoma	ONCOTARGET			English	Article						Colorectal carcinoma; autophagy; Beclin 1; LC 3B; Bcl-xL	MALIGNANT PHENOTYPE; THERAPEUTIC TARGET; POOR-PROGNOSIS; CHROMOSOME 17Q; BECLIN 1; TUMOR; EXPRESSION; PROGRESSION; ENERGY; MITOCHONDRIA	The role of autophagy in cancers is controversial. Here we aim to determine the prognostic significance of autophagy in colorectal carcinoma patients, thereby allowing more rational development of therapeutic strategies. Through transmission electron microscopy, our data first demonstrated high frequency of defective mitochondria was strongly associated with poor overall survival in colorectal carcinoma. Next immunohistochemical study showed the expressions of Beclin 1, LC3B and Bcl-xL in both the center of tumor and adjacent noncancerous mucosal region were also correlated with overall survivals. We developed an autophagy signature for prognosis based on these three major autophagic proteins, further analysis suggested it was an independent prognostic biomarker and had its value even within single clinical stage. Combined TNM stage and this signature could significantly improve the accuracy of survival prognosis. To validate these immunohistochemical results, an internal testing cohort and an independent population were also included. Our findings suggest that autophagy plays an important role in the clinical cancer progression. Therefore autophagic proteins may be valuable prognostic biomarkers in the therapy of colorectal carcinoma and possibly other types of cancers.	[Yang, Maopeng; Zhao, Hong; Guo, Li; Zhang, Qingyuan; Zhao, Ling; Bai, Shuping; Zhang, Minghui; Xu, Sanqi; Wang, Xiaohong] Harbin Med Univ, Dept Med Oncol, Affiliated Hosp 3, Harbin, Heilongjiang, Peoples R China; [Wang, Fujing] Harbin Med Univ, Dept Gen Surg, Affiliated Hosp 2, Harbin, Heilongjiang, Peoples R China; [Zhao, Bin] Harbin Med Univ Daqing, Coll Basic Med, Harbin, Heilongjiang, Peoples R China		Wang, FJ (corresponding author), Harbin Med Univ, Dept Gen Surg, Affiliated Hosp 2, Harbin, Heilongjiang, Peoples R China.	fujingwang@yeah.net; drxiaohongwang@163.com; bin.science@gmail.com					Chen N, 2011, CANCER BIOL THER, V11, P157, DOI 10.4161/cbt.11.2.14622; Choi AMK, 2013, NEW ENGL J MED, V368, P651, DOI [10.1056/NEJMra1205406, 10.1056/NEJMc1303158]; Cully M, 2006, NAT REV CANCER, V6, P184, DOI 10.1038/nrc1819; Cunningham D, 2010, LANCET, V375, P1030, DOI 10.1016/S0140-6736(10)60353-4; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; Degtyarev M, 2008, J CELL BIOL, V183, P101, DOI 10.1083/jcb.200801099; Ding ZB, 2008, CANCER RES, V68, P9167, DOI 10.1158/0008-5472.CAN-08-1573; Dong LW, 2011, AUTOPHAGY, V7, P1222, DOI 10.4161/auto.7.10.16610; Eskelinen EL, 2011, AUTOPHAGY, V7, P935, DOI 10.4161/auto.7.9.15760; GAO X, 1995, ONCOGENE, V11, P1241; Giatromanolaki A, 2010, J CLIN PATHOL, V63, P867, DOI 10.1136/jcp.2010.079525; Guo GF, 2011, WORLD J GASTROENTERO, V17, P4779, DOI 10.3748/wjg.v17.i43.4779; HANLEY JA, 1983, RADIOLOGY, V148, P839, DOI 10.1148/radiology.148.3.6878708; Hezel AF, 2008, ONCOGENE, V27, P6908, DOI 10.1038/onc.2008.342; Hollville E, 2014, MOL CELL, V55, P451, DOI 10.1016/j.molcel.2014.06.001; Jemal A, 2011, CA-CANCER J CLIN, V61, P69, DOI [10.3322/caac.20107, 10.3322/caac.20115]; Karantza-Wadsworth V, 2007, GENE DEV, V21, P1621, DOI 10.1101/gad.1565707; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Koppenol WH, 2011, NAT REV CANCER, V11, P325, DOI 10.1038/nrc3038; Krizhanovsky V, 2008, COLD SH Q B, V73, P513, DOI 10.1101/sqb.2008.73.048; Lai K, 2014, J CLIN PATHOL, V67, P854, DOI 10.1136/jclinpath-2014-202529; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Li BX, 2009, AUTOPHAGY, V5, P303, DOI 10.4161/auto.5.3.7491; Liang JY, 2007, NAT CELL BIOL, V9, P218, DOI 10.1038/ncb1537; Lin HX, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0060516; Liu N, 2012, LANCET ONCOL, V13, DOI 10.1016/S1470-2045(12)70102-X; Maiuri MC, 2009, CELL DEATH DIFFER, V16, P87, DOI 10.1038/cdd.2008.131; Maiuri MC, 2007, EMBO J, V26, P2527, DOI 10.1038/sj.emboj.7601689; Marino G, 2014, NAT REV MOL CELL BIO, V15, P81, DOI 10.1038/nrm3735; Martinez-Outschoorn UE, 2011, CELL CYCLE, V10, P4208, DOI 10.4161/cc.10.24.18487; Mathew R, 2007, GENE DEV, V21, P1367, DOI 10.1101/gad.1545107; Nieman KM, 2011, NAT MED, V17, P1498, DOI 10.1038/nm.2492; Nunnari J, 2012, CELL, V148, P1145, DOI 10.1016/j.cell.2012.02.035; Qu XP, 2003, J CLIN INVEST, V112, P1809, DOI 10.1172/JCI200320039; Rabinowitz JD, 2010, SCIENCE, V330, P1344, DOI 10.1126/science.1193497; Rubinsztein DC, 2012, NAT REV DRUG DISCOV, V11, P709, DOI 10.1038/nrd3802; SAITO H, 1993, CANCER RES, V53, P3382; Tanida Isei, 2008, V445, P77, DOI 10.1007/978-1-59745-157-4_4; Yang HI, 2011, LANCET ONCOL, V12, P568, DOI 10.1016/S1470-2045(11)70077-8; Young ARJ, 2009, GENE DEV, V23, P798, DOI 10.1101/gad.519709; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100; Zhao H, 2013, MED ONCOL, V30, DOI 10.1007/s12032-013-0475-1; Zhou WH, 2012, AUTOPHAGY, V8, P389, DOI 10.4161/auto.18641; Zlobec I, 2007, J CLIN PATHOL, V60, P1112, DOI 10.1136/jcp.2006.044537	44	34	34	0	2	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	MAR 30	2015	6	9					7084	7103		10.18632/oncotarget.3054			20	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	CF8GI	WOS:000352793800045	25762626	Green Submitted, gold, Green Published			2022-04-25	
J	Packiriswamy, N; Coulson, KF; Holcombe, SJ; Sordillo, LM				Packiriswamy, Nandakumar; Coulson, Kari F.; Holcombe, Susan J.; Sordillo, Lorraine M.			Oxidative stress-induced mitochondrial dysfunction in a normal colon epithelial cell line	WORLD JOURNAL OF GASTROENTEROLOGY			English	Article						Colon cancer cell line; CRL. 1790 cells; Inflammation; Mitochondria; Microbial stimulation; Interleukin-8; Autophagy	INFLAMMATORY-BOWEL-DISEASE; ESCHERICHIA-COLI; METABOLIC STRESS; CANCER-CELLS; DNA-DAMAGE; TNF-ALPHA; IN-VITRO; EXPRESSION; BARRIER; ACID	AIM To determine how a normal human colon cell line reacts to microbial challenge as a way to study oxidative stress-induced responses associated with inflammatory bowel disease. METHODS Normal human colon epithelial cells (ATCC (R) CRL. 1790 T) were stimulated with either heat killed E. coli or heat killed murine cecal contents (HKC) and examined for several relevant biomarkers associated with inflammation and oxidative stress including cytokine production, mitochondrial autophagy and oxidant status. TNF alpha, IL-1 beta and IL-8 protein concentrations were measured within the supernatants. Fluorescent microscopy was performed to quantify the production of reactive oxygen species (ROS) using an oxidation responsive fluorogenic probe. Mitochondrial morphology and mitochondrial membrane potential was assessed by dual staining using COXIV antibody and a dye concentrating in active mitochondria. Mitochondrial ROS scavenger was used to determine the source of ROS in stimulated cells. Autophagy was detected by staining for the presence of autophagic vesicles. Positive controls for autophagy and ROS/RNS experiments were treated with rapamycin and chloroquine. Mitochondrial morphology, ROS production and autophagy microscopy experiments were analyzed using a custom acquisition and analysis microscopy software (ImageJ). RESULTS Exposing CRL. 1790 cells to microbial challenge stimulated cells to produce several relevant biomarkers associated with inflammation and oxidative stress. Heat killed cecal contents treatment induced a 10-12 fold increase in IL-8 production by CRL. 1790 cells compared to unstimulated controls at 6 and 12 h (P < 0.001). Heat killed E. coli stimulation resulted in a 4-5 fold increase in IL-8 compared to the unstimulated control cells at each time point (P < 0.001). Both heat killed E. coli and HKC stimulated robust ROS production at 6 (P < 0.001), and 12 h (P < 0.01). Mitochondrial morphologic abnormalities were detected at 6 and 12 h based on reduced mitochondrial circularity and decreased mitochondrial membrane potential, P < 0.01. Microbial stimulation also induced significant autophagy at 6 and 12 h, P < 0.01. Lastly, blocking mitochondrial ROS generation using mitochondrial specific ROS scavenger reversed microbial challenge induced mitochondrial morphologic abnormalities and autophagy. CONCLUSION The findings from this study suggest that CRL. 1790 cells may be a useful alternative to other colon cancer cell lines in studying the mechanisms of oxidative stress events associated with intestinal inflammatory disorders.	[Packiriswamy, Nandakumar; Coulson, Kari F.; Holcombe, Susan J.; Sordillo, Lorraine M.] Michigan State Univ, Dept Large Anim Clin Sci, Coll Vet Med, 784 Wilson Rd, E Lansing, MI 48824 USA		Sordillo, LM (corresponding author), Michigan State Univ, Dept Large Anim Clin Sci, Coll Vet Med, 784 Wilson Rd, E Lansing, MI 48824 USA.	sordillo@msu.edu	Packiriswamy, Nandakumar/S-9400-2019	Sordillo, Lorraine/0000-0001-8873-3134; Packiriswamy, Nandakumar/0000-0002-8415-9187	Detroit, Michigan	Supported by an endowment from the Matilda R. Wilson Fund in Detroit, Michigan.	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Gastroenterol.	MAY 21	2017	23	19					3427	3439		10.3748/wjg.v23.i19.3427			13	Gastroenterology & Hepatology	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology	EV6QY	WOS:000401897100006	28596679	Green Submitted, Green Published, hybrid			2022-04-25	
J	Shi, WN; Cui, SX; Song, ZY; Wang, SQ; Sun, SY; Yu, XF; Li, Y; Zhang, YH; Gao, ZH; Qu, XJ				Shi, Wen-Na; Cui, Shu-Xiang; Song, Zhi-Yu; Wang, Shu-Qing; Sun, Shi-Yue; Yu, Xin-Feng; Li, Ye; Zhang, Yu-Hang; Gao, Zu-Hua; Qu, Xian-Jun			Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXR alpha by K48/K63-linked polyubiquitination	ONCOTARGET			English	Article						sphingosine kinase 2 (SphK2); retinoid therapy resistance; cytoplasmic RXR alpha; polyubiquitination	RETINOID-X-RECEPTORS; CELL LUNG-CANCER; SELECTIVE AUTOPHAGY; NUCLEAR EXPORT; UBIQUITIN; ACID; EXPRESSION; GROWTH; APOPTOSIS; KINASE	The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well- studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor alpha (RXR alpha) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination. Human colonic adenocarcinoma HCT-116 cells transfected with SphK2 (HCT-116(Sphk2) cells) demonstrate resistance to ATRA therapy as determined by in vitro and in vivo assays. Sphk2 overexpression increases the ATRA-induced nuclear RXRa export to cytoplasm and then rapidly degrades RXRa through the polyubiquitination pathway. We further show that Sphk2 activates the ubiquitin-proteasome system through the signal mechanisms of (1) K48-linked proteosomal degradation and (2) K63-linked ubiquitin-dependent autophagic degradation. These results provide new insights into the biological functions of Sphk2 and the molecular mechanisms that underlie the Sphk2-mediated resistance to retinoid therapy.	[Shi, Wen-Na; Song, Zhi-Yu; Wang, Shu-Qing; Sun, Shi-Yue; Yu, Xin-Feng; Li, Ye; Zhang, Yu-Hang; Qu, Xian-Jun] Capital Med Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing, Peoples R China; [Cui, Shu-Xiang] Capital Med Univ, Sch Publ Hlth, Dept Toxicol & Sanit Chem, Beijing Key Lab Environm Toxicol, Beijing, Peoples R China; [Gao, Zu-Hua] McGill Univ, Dept Pathol, Montreal, PQ, Canada		Qu, XJ (corresponding author), Capital Med Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing, Peoples R China.; Gao, ZH (corresponding author), McGill Univ, Dept Pathol, Montreal, PQ, Canada.	zu-hua.gao@mcgill.ca; quxj@ccmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81373436, 81373435, 91229113]; Beijing Science Foundation [7142017]; Research Institute of the McGill University Health Centre	This work was supported by the National Natural Science Foundation of China (81373436, 81373435 and 91229113) and the Beijing Science Foundation (7142017). We thank the Research Institute of the McGill University Health Centre for their financial support.	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J	Cheng, CY; Lin, YH; Su, CC				Cheng, Chun-Yuan; Lin, Yi-Hsiang; Su, Chin-Cheng			Anti-tumor activity of Sann-Joong-Kuey-Jian-Tang alone and in combination with 5-fluorouracil in a human colon cancer colo 205 cell xenograft model	MOLECULAR MEDICINE REPORTS			English	Article						Sann-Joong-Kyuy-Jian-Tang; 5-fluorouracil; colo 205 cell xenograft model; microtubule-associated protein light chain 3	TRADITIONAL CHINESE MEDICINE; PROTEIN EXPRESSION; IN-VITRO; AUTOPHAGY; CYCLE	Malignant tumors are the leading cause of death in Taiwan; among these, colon cancer ranks third as I cause of cancer-related death. Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicinal prescription, has been used to treat lymph node diseases and infectious lesions, and exhibits cytotoxic activity in many cancer cell lines. Our previous Studies demonstrated that SJKJT inhibits the proliferation of human colon cancer colo 205 cells in vitro. The aim of this study was to evaluate the anti-tumor activity of SJKJT alone and in combination with 5-fluorouracil (5-FU) in vivo. SCID mice bearing human colon cancer colo 205 cell xenografts were administered SJKJT alone (30 mg/kg daily, p.o.), SJKJT (30 mg/kg daily, p.o.) in combination with 5-FU (30 mg/kg weekly, i.p.), or vehicle alone. At the end of the 4-week dosing schedule, the tumor and animal body weights were individually measured. The SCID mice were sacrificed with CO, inhalation, the xenograft tumors were dissected, and the protein expression of microtubule-associated protein light chain 3 (MAP-LC3-II) in colo 205 xenograft tumors was measured by Western blotting. In the control, SJKJT-, and SJKJT Plus 5-FU-treated mice, the tumor weights were 6.37 +/- 2.57, 0.43 +/- 0.35 and 1.63 +/- 0.46 g, and the mice body weights were 29 +/- 0.55, 29 +/- 2.71 and 27 +/- 0.77 g, respectively. Treatment with SJKJT resulted in a reduction in tumor weight compared with the control group, indicating that SJKJT inhibits tumor growth in a colo 205 xenograft model. SJKJT also increased LC3-II protein expression as compared to the controls. The present study shows that SJKJT alone or in combination with 5-FU has a positive effect on the treatment of SCID mice hearing human colon cancer colo 205 cell xenografts. This suggests that SJKJT has therapeutic potential in the treatment of human colon cancer.	[Cheng, Chun-Yuan] Chun Shan Med Univ, Inst Med, Taichung 40201, Taiwan; [Cheng, Chun-Yuan] Changhua Christian Hosp, Changhua 500, Taiwan; [Lin, Yi-Hsiang; Su, Chin-Cheng] Tzu Chi Univ, Inst Pharmacol & Toxicol, Hualien 97004, Taiwan; [Su, Chin-Cheng] Buddhist Tzu Chi Gen Hosp, Div Gen Surg, Hualien 97004, Taiwan		Su, CC (corresponding author), Buddhist Tzu Chi Gen Hosp, Div Gen Surg, 707,Sec 3,Chung Yang Rd, Hualien 970, Taiwan.	succ.maeva@msa.hinet.net			Research Section of the Buddhist Tzu Chi General Hospital, Hualien, Taiwan [TCRD97-05]	This Study was Supported by grant no. TCRD97-05 from the Research Section of the Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C.	BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3; Chen HC, 2004, FOOD CHEM TOXICOL, V42, P1251, DOI 10.1016/j.fct.2004.03.002; Cheng CY, 2010, MOL MED REP, V3, P63, DOI 10.3892/mmr_00000219; Cheng CY, 2009, MOL MED REP, V2, P707, DOI 10.3892/mmr_00000160; CLARKE PGH, 1990, ANAT EMBRYOL, V181, P195, DOI 10.1007/bf00174615; Department of Health Executive Yuan Taipei Taiwan R.O.C, 2008, STAT CAUS DEATH, P33; Efferth T, 2008, MOL CANCER THER, V7, P152, DOI 10.1158/1535-7163.MCT-07-0073; Eskelinen EL, 2002, TRAFFIC, V3, P878, DOI 10.1034/j.1600-0854.2002.31204.x; Hsu YL, 2006, BIOL PHARM BULL, V29, P2388, DOI 10.1248/bpb.29.2388; James K, 1999, J NATL CANCER I, V91, P523, DOI 10.1093/jnci/91.6.523; Jemal A, 2004, CA-CANCER J CLIN, V54, P8, DOI 10.3322/canjclin.54.1.8; Kirkegaard K, 2004, NAT REV MICROBIOL, V2, P301, DOI 10.1038/nrmicro865; Moretti L, 2007, DRUG RESIST UPDATE, V10, P135, DOI 10.1016/j.drup.2007.05.001; Parekh HS, 2009, MOL CANCER, V8, DOI 10.1186/1476-4598-8-21; Rauh Rolf, 2007, Chin Med, V2, P8; Su CC, 2008, INT J MOL MED, V22, P357, DOI 10.3892/ijmm_00000030	16	6	6	0	4	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1791-2997	1791-3004		MOL MED REP	Mol. Med. Rep.	MAR-APR	2010	3	2					227	231		10.3892/mmr_00000244			5	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	559KD	WOS:000274822200005	21472226				2022-04-25	
J	Pelissier-Rota, MA; Pelosi, L; Meresse, P; Jacquier-Sarlin, MR				Pelissier-Rota, Marjolaine A.; Pelosi, Ludovic; Meresse, Patrick; Jacquier-Sarlin, Muriel R.			Nicotine-induced cellular stresses and autophagy in human cancer colon cells: A supportive effect on cell homeostasis via up-regulation of Cox-2 and PGE(2) production	INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY			English	Article						Nicotine; Colorectal cancer; Autophagy; Cox-2; PGE(2); Cell homeostasis	ENDOPLASMIC-RETICULUM STRESS; INFLAMMATORY-BOWEL-DISEASE; UNFOLDED PROTEIN RESPONSE; NF-KAPPA-B; CYCLOOXYGENASE-2 EXPRESSION; GROWTH-FACTOR; VAGUS NERVE; ACETYLCHOLINE-RECEPTORS; ULCERATIVE-COLITIS; OXIDATIVE STRESS	Nicotine, one of the active components in cigarette smoke, has been described to contribute to the protective effect of smoking in ulcerative colitis (UC) patients. Furthermore, the nicotinic acetylcholine receptor alpha 7 subunit (alpha 7nAChR) expressed on immune cells, is an essential regulator of inflammation. As intestinal epithelial cells also express alpha 7nAChR, we investigated how nicotine could participate in the homeostasis of intestinal epithelial cells. First, using the human adenocarcinoma cell line HT-29, we revealed that nicotine, which triggers an influx of extracellular Ca2+ following alpha 7nAChR stimulation, induces mitochondrial reactive oxygen species (ROS) production associated with a disruption of the mitochondrial membrane potential and endoplasmic reticulum stress. This results in caspase-3 activation, which in turn induces apoptosis. Additionally, we have shown that nicotine induces a P13-K dependent up-regulation of cyclooxygenase-2 (Cox-2) expression and prostaglandin E2 (PGE(2)) production. In this context, we suggest that this key mediator participates in the cytoprotective effects of nicotine against apoptosis by stimulating autophagy in colon cancer cells. Our results provide new insight into one potential mechanism by which nicotine could protect from UC and suggest an anti-inflammatory role for the cholinergic pathway at the epithelial cell level. (C) 2015 Elsevier Ltd. All rights reserved.	[Pelissier-Rota, Marjolaine A.; Jacquier-Sarlin, Muriel R.] INSERM, Equipe Stress & Interact Neurodigest, U836, F-38042 Grenoble 09, France; [Pelissier-Rota, Marjolaine A.; Jacquier-Sarlin, Muriel R.] Univ Grenoble 1, Grenoble Inst Neurosci, F-38041 Grenoble 09, France; [Pelosi, Ludovic] CNRS, Equipe Genom & Evolut Microorganismes, UMR 5163, F-38042 Grenoble 9, France; [Pelosi, Ludovic] Univ Grenoble 1, Lab Adaptat & Pathogen Microorganismes, F-38041 Grenoble 09, France; [Meresse, Patrick] Univ Grenoble 1, Ctr Univ Biol Expt, F-38041 Grenoble 09, France		Jacquier-Sarlin, MR (corresponding author), Grenoble Inst Neurosci, Ctr Rech, INSERM, Equipe Stress & Interact Neurodigest,U836, Site Sante BP 170 La Tronche, F-38042 Grenoble 9, France.	muriel.jacquier-sarlin@ujf-grenoble.fr	Pelosi, Ludovic/AAB-9832-2020; Jacquier-Sarlin, Muriel/ABF-4923-2021	Pelosi, Ludovic/0000-0002-4198-5681; Jacquier-Sarlin, Muriel/0000-0001-8501-7511	Association pour la Recherche sur le CancerFondation ARC pour la Recherche sur le CancerAustralian Research CouncilEuropean Commission; Ligue Nationale contre le CancerLigue nationale contre le cancer; Universite Joseph Fourier; Ministre de la Recherche et de l'Enseignement Superieur	The authors gratefully acknowledge grant support from Association pour la Recherche sur le Cancer, Ligue Nationale contre le Cancer and the Universite Joseph Fourier. Pelissier-Rota is the recipient of a fellowship from the Ministre de la Recherche et de l'Enseignement Superieur.	Albuquerque EX, 2009, PHYSIOL REV, V89, P73, DOI 10.1152/physrev.00015.2008; Barbieri SS, 2004, FREE RADICAL BIO MED, V37, P156, DOI 10.1016/j.freeradbiomed.2004.04.020; Benbrook D. 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J	Ji, LY; Fu, JH; Hao, J; Ji, Y; Wang, HY; Wang, ZY; Wang, P; Xiao, H				Ji, Liyun; Fu, Jihong; Hao, Jie; Ji, Yin; Wang, Huiyu; Wang, Zeyuan; Wang, Peng; Xiao, Hua			Proteomics analysis of tissue small extracellular vesicles reveals protein panels for the reoccurrence prediction of colorectal cancer	JOURNAL OF PROTEOMICS			English	Article						Small extracellular vesicles; Reoccurence; Colorectal cancer; parallel&nbsp; reaction monitoring; Protein&nbsp; panel	ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER; COLON-CANCER; STAGE-II; CELL; RECURRENCE; EXPRESSION; MARKER; METASTASIS; AUTOPHAGY	Many stage II/III colorectal cancer (CRC) patients might relapse after routine treatment and there is a great need of reliable biomarkers for predicting its reoccurrence risk. Small extracellular vesicles (sEVs) could regulate many pathophysiological processes of diseases, which are promising source for biomarker discovery. In this study, we implemented a MS-based workflow that utilizes data-dependent acquisition (DDA) for discovery and parallel reaction monitoring (PRM) for validation of high relapse risk related biomarkers. We compared the protein profiling of sEVs from CRC tissues and paired adjacent tissues in relapsed group (n = 5) and non-relapsed group (n = 5). 417 and 1140 proteins were differentially expressed between the tumor tissues and adjacent tissues in relapsed group and non-relapsed group, respectively. Bioinformatics analysis showed that immunity of the relapsed patients (Z-score - 0.69) was relatively poorer than the non-relapsed patients (Z-score 2.59), while chronic inflammatory response was activated (Z-score 3.0), which might enhance the reoccurrence risk. Four proteins (HLA-DPA1, S100P, NUP205, PCNA) showed significant expressions in the adjacent tissues of the relapsed group by PRM validation. ROC analysis of HLA-DPA1 (AUC = 0.96) achieved the best classification accuracy in separating the relapsed group and the non-relapsed group. Our data demonstrate that tissue-derived sEVs harbor prognostic proteomic signatures of CRC. Significance: In this research, our proteomics analysis of tissue sEVs revealed that poor immunity as well as chronic inflammatory of the CRC relapsed patient likely lead to poor prognosis and high risk of reoccurrence. The significant expression levels of four proteins (HLA-DPA1, S100P, NUP205, PCNA) in the adjacent tissues of the relapsed group might be used to predict the risk of relapse in postoperative follow-ups.	[Ji, Liyun; Wang, Huiyu; Wang, Zeyuan; Xiao, Hua] Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, State Key Lab Microbial Metab, Joint Int Res Lab Metab & Dev Sci, Shanghai 200240, Peoples R China; [Fu, Jihong] Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Colorectal Surg, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China; [Hao, Jie] Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, Shanghai 200240, Peoples R China; [Ji, Yin; Wang, Peng] Jiangsu Simcere Pharmaceut Co Ltd, State Key Lab Translat Med & Innovat Drug Dev, Nanjing 210042, Peoples R China		Xiao, H (corresponding author), Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, State Key Lab Microbial Metab, Joint Int Res Lab Metab & Dev Sci, Shanghai 200240, Peoples R China.; Wang, P (corresponding author), Jiangsu Simcere Pharmaceut Co Ltd, State Key Lab Translat Med & Innovat Drug Dev, Nanjing 210042, Peoples R China.	peng.wang@simceregroup.com; huaxiao@sjtu.edu.cn	Xiao, Hua/I-7429-2013	Xiao, Hua/0000-0002-2831-0436	Natural Science Foundation of ShanghaiNatural Science Foundation of Shanghai [21ZR1433200]; National Key Research and Development Program of China [2017YFC1200204]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21675110, 21305087]; Key Scientific Project of Shanghai Jiao Tong University [TMSK-2020-130, YG2017MS80, YG2015QN45, ZH2018QNA65]; Recruitment Program of Global Youth Experts of China; National High-tech R&D Program of China (863 Program)National High Technology Research and Development Program of China [2014AA020545]	This work was supported by grants from the Natural Science Foun-dation of Shanghai (No. 21ZR1433200) , the National Key Research and Development Program of China (No. 2017YFC1200204) , the National Natural Science Foundation of China (No. 21675110, No. 21305087) ; and the Key Scientific Project of Shanghai Jiao Tong University (No. TMSK-2020-130, No. YG2017MS80, No. YG2015QN45, No. ZH2018QNA65) ; H.X. is supported by the Recruitment Program of Global Youth Experts of China and National High-tech R&D Program of China (863 Program, No.2014AA020545) .	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J	Nishikawa, T; Tsuno, NH; Okaji, Y; Sunami, E; Shuno, Y; Sasaki, K; Hongo, K; Kaneko, M; Hiyoshi, M; Kawai, K; Kitayama, J; Takahashi, K; Nagawa, H				Nishikawa, Takeshi; Tsuno, Nelson H.; Okaji, Yurai; Sunami, Eiji; Shuno, Yasutaka; Sasaki, Kazuhito; Hongo, Kumiko; Kaneko, Manabu; Hiyoshi, Masaya; Kawai, Kazushige; Kitayama, Joji; Takahashi, Koki; Nagawa, Hirokazu			The inhibition of autophagy potentiates anti-angiogenic effects of sulforaphane by inducing apoptosis	ANGIOGENESIS			English	Article						Autophagy; Endothelial cells; Sulforaphane; Apoptosis; 3-Methyladenine; Angiogenesis	CELL-CYCLE ARREST; COLON-CANCER; CRUCIFEROUS VEGETABLES; GROWTH; ISOTHIOCYANATES; PROLIFERATION; ENDOTHELIUM; PROGRESSION; BROCCOLI; ENZYMES	Sulforaphane (SUL), a kind of isothiocyanate, has recently been focused due to its strong pro-apoptotic effect on cancer cells as well as tumor vascular endothelial cells (ECs). And recently, we demonstrated the induction of autophagy by colon cancer cells as a protective mechanism against SUL. In the present study, we aimed to investigate the possible role of autophagy induction by ECs as a defense mechanism against SUL. Human umbilical vein endothelial cells (HUVECs) were used as the in vitro model of angiogenic ECs. The induction of autophagy was evaluated by the detection of acidic vesicular organelles (AVOs) by flow-cytometry, after the staining with acridine orange, as well as the detection of light chain 3(LC3) by Western blot. Finally, the functional implication of autophagy inhibition and SUL treatment in ECs was investigated by their ability to form vascular-like structures on Matrigel. Treatment of HUVECs with relatively low concentrations of SUL for 16 h resulted in the evident formation of AVOs and the recruitment of LC3 to autophagosomes, the pathognomonic features of autophagy. Co-treatment of cells with the specific autophagy inhibitor (3-methyladenine) potentiated the proapoptotic effect of SUL. And inhibition of autophagy potentiated the inhibitory effect of SUL on the ability of ECs to form capillary-like structures. Similar to cancer cells, ECs induced autophagy in response to the pro-apoptotic agent, SUL, and the inhibition of autophagy potentiated the pro-apoptotic effect. These findings open premises for the use of autophagy inhibitors in combination with anti-angiogenic agents.	[Nishikawa, Takeshi; Tsuno, Nelson H.; Sunami, Eiji; Shuno, Yasutaka; Sasaki, Kazuhito; Hongo, Kumiko; Kaneko, Manabu; Hiyoshi, Masaya; Kawai, Kazushige; Kitayama, Joji; Nagawa, Hirokazu] Univ Tokyo, Dept Surg Oncol, Fac Med, Bunkyo Ku, Tokyo 1138655, Japan; [Tsuno, Nelson H.; Okaji, Yurai; Takahashi, Koki] Univ Tokyo, Dept Transfus Med, Fac Med, Tokyo 1138655, Japan		Nishikawa, T (corresponding author), Univ Tokyo, Dept Surg Oncol, Fac Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan.	takn-tky@umin.ac.jp	Kawai, Kazushige/AAF-4334-2020	Kawai, Kazushige/0000-0002-5881-0036			Asakage Masahiro, 2006, Angiogenesis, V9, P83, DOI 10.1007/s10456-006-9034-0; Bertl E, 2006, MOL CANCER THER, V5, P575, DOI 10.1158/1535-7163.MCT-05-0324; Bonnesen C, 2001, CANCER RES, V61, P6120; CAREW JS, 2009, J CELL MOL MED; Chiao JW, 2002, INT J ONCOL, V20, P631; Dong ZW, 2009, TOXICOL IN VITRO, V23, P105, DOI 10.1016/j.tiv.2008.11.003; Fahey JW, 1997, P NATL ACAD SCI USA, V94, P10367, DOI 10.1073/pnas.94.19.10367; Fahey JW, 2001, PHYTOCHEMISTRY, V56, P5, DOI 10.1016/S0031-9422(00)00316-2; Gamet-Payrastre L, 2000, CANCER RES, V60, P1426; Gewirtz DA, 2009, RADIOTHER ONCOL, V92, P323, DOI 10.1016/j.radonc.2009.05.022; Hecht SS, 2000, DRUG METAB REV, V32, P395, DOI 10.1081/DMR-100102342; Herman-Antosiewicz A, 2006, CANCER RES, V66, P5828, DOI 10.1158/0008-5472.CAN-06-0139; Higdon JV, 2007, PHARMACOL RES, V55, P224, DOI 10.1016/j.phrs.2007.01.009; Jackson SJT, 2007, VASC PHARMACOL, V46, P77, DOI 10.1016/j.vph.2006.06.015; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; Lomonaco SL, 2009, INT J CANCER, V125, P717, DOI 10.1002/ijc.24402; NGUYEN TMB, 2009, J CELL MOL MED; Nishikawa T, 2009, ANN SURG ONCOL, V16, P534, DOI 10.1245/s10434-008-0215-5; Okaji Y, 2004, CANCER SCI, V95, P85, DOI 10.1111/j.1349-7006.2004.tb03175.x; Okaji Y, 2008, EUR J CANCER, V44, P383, DOI 10.1016/j.ejca.2007.10.018; Pappa G, 2007, MOL NUTR FOOD RES, V51, P977, DOI 10.1002/mnfr.200700115; Shan Y, 2006, INT J ONCOL, V29, P883; Singh AV, 2004, CARCINOGENESIS, V25, P83, DOI 10.1093/carcin/bgg178; Singh SV, 2004, J BIOL CHEM, V279, P25813, DOI 10.1074/jbc.M313538200; Tsuboi Y, 2009, J NEUROSURG, V110, P594, DOI 10.3171/2008.8.JNS17648; Vazquez-Martin A, 2009, PLOS ONE, V4, DOI 10.1371/journal.pone.0006251; ZHANG YS, 1992, P NATL ACAD SCI USA, V89, P2399, DOI 10.1073/pnas.89.6.2399	27	43	44	0	4	SPRINGER	DORDRECHT	VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS	0969-6970	1573-7209		ANGIOGENESIS	Angiogenesis	SEP	2010	13	3					227	238		10.1007/s10456-010-9180-2			12	Peripheral Vascular Disease	Science Citation Index Expanded (SCI-EXPANDED)	Cardiovascular System & Cardiology	652BX	WOS:000281976900004	20694744				2022-04-25	
J	Liang, CY; Jung, JU				Liang, Chengyu; Jung, Jae U.			Autophagy genes as tumor suppressors	CURRENT OPINION IN CELL BIOLOGY			English	Article							CELL-DEATH; PHOSPHATIDYLINOSITOL 3-KINASE; MICROSATELLITE INSTABILITY; METABOLIC STRESS; CROHNS-DISEASE; SACCHAROMYCES-CEREVISIAE; REGULATES AUTOPHAGY; PROTEIN COMPLEX; CANCER CELLS; COLON-CANCER	Autophagy, originally described as a universal lysosome-dependent bulk degradation of cytoplasmic components upon nutrient deprivation, has since been shown to influence diverse aspects of homeostasis and is implicated in a wide variety of pathological conditions, including cancer. The list of autophagy-related (Atg) genes associated with the initiation and progression of human cancer as well as with responses to cancer therapy continues to grow as these genes are being discovered. However, whether Atg genes work through their expected mechanisms of autophagy regulation and/or through as-yet-undefined functions in the development of cancer remains to be further clarified. Here we review recent advances in the knowledge of the molecular basis of autophagy genes and their biological outputs during tumor development. A better understanding of the mechanistic link between cellular autophagy and tumor growth control may ultimately better human cancer treatments.	[Liang, Chengyu; Jung, Jae U.] Univ So Calif, Dept Mol Microbiol & Immunol, Keck Sch Med, Los Angeles, CA 90033 USA		Liang, CY (corresponding author), Univ So Calif, Dept Mol Microbiol & Immunol, Keck Sch Med, Los Angeles, CA 90033 USA.	chengyu.liang@usc.edu		LIANG, CHENGYU/0000-0001-6082-2143	U.S. Public Health ServiceUnited States Department of Health & Human ServicesUnited States Public Health Service [CA140964, AI083841]; Leukemia & Lymphoma Society of USA; Wright Foundation; Baxter Foundation; Fletcher Jones Foundation; Hastings Foundation; Korean GRL Program [K20815000001];  [CA82057];  [CA91819];  [CA31363];  [CA115284];  [A1073099]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA140964, R01CA115284, R01CA082057, R01CA031363, R01CA091819] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R01AI073099, R21AI083841] Funding Source: NIH RePORTER	We apologize to all scientists whose work could not be cited here due to limited space. We thank Stacy Lee for her critical reading of the manuscript. This work was partly supported by U.S. Public Health Service grants CA140964, AI083841, the Leukemia & Lymphoma Society of USA, the Wright Foundation, and the Baxter Foundation (C. Liang) and CA82057, CA91819, CA31363, CA115284, A1073099, Fletcher Jones Foundation, Hastings Foundation, and Korean GRL Program K20815000001 (JUJ).	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Zhang M, 2009, BIOSCIENCE REP, V29, P193, DOI 10.1042/BSR20090032; Zhong Y, 2009, NAT CELL BIOL, V11, P468, DOI 10.1038/ncb1854	80	58	61	0	7	CURRENT BIOLOGY LTD	LONDON	84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND	0955-0674			CURR OPIN CELL BIOL	Curr. Opin. Cell Biol.	APR	2010	22	2					226	233		10.1016/j.ceb.2009.11.003			8	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	598NS	WOS:000277845300016	19945837	Green Accepted			2022-04-25	
J	Yan, L; Gong, YZ; Shao, MN; Ruan, GT; Xie, HL; Liao, XW; Wang, XK; Han, QF; Zhou, X; Zhu, LC; Gao, F; Gan, JL				Yan, Ling; Gong, Yi-Zhen; Shao, Meng-Nan; Ruan, Guo-Tian; Xie, Hai-Lun; Liao, Xi-Wen; Wang, Xiang-Kun; Han, Quan-Fa; Zhou, Xin; Zhu, Li-Cheng; Gao, Feng; Gan, Jia-Liang			Distinct diagnostic and prognostic values of gamma-aminobutyric acid type A receptor family genes in patients with colon adenocarcinoma	ONCOLOGY LETTERS			English	Article						gamma-aminobutyric acid type A receptor; mRNA; colon adenocarcinoma; diagnosis; prognosis	MEMBRANE-POTENTIAL DIFFERENCES; COLORECTAL-CANCER RISK; CYTOSCAPE PLUGIN; CELL-MIGRATION; EXPRESSION; GROWTH; METABOLISM; AUTOPHAGY; ADHESION; TISSUES	In the present study, the significance ofGABA(A)genes in colon adenocarcinoma (COAD) were investigated from the view of diagnosis and prognosis. All data were achieved from The Cancer Genome Atlas. Overall survival was analyzed by the Kaplan-Meier analyses and Cox regression model and the hazard ratios and 95% confidence interval were calculated for computation. The Database for Annotation, Visualization and Integrated Discovery, and the Biological Networks Gene Ontology (BiNGO) softwares were applied to assess the biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway analysis to predict the biological function ofGABA(A)genes. The associated Gene Ontology and KEGG pathways were conducted by Gene Set Enrichment Analysis (GSEA). From receiver operating characteristics curves analysis, it was found that the expression ofGABR, gamma-aminobutyric acid type A receptorGABRA2, GABRA3, GABRB2, GABRB3, GABRG2, GABRG3, GABRD, GABREwere correlated with COAD occurrence [P<0.0001, area under the curve (AUC)>0.7]. The low expression of theGABRB1, GABRD, GABRPandGABRQin genes after tumor staging adjustment were positively correlated with the overall survival rate [P=0.049, hazard ratio (HR)=1.517, 95% confidence interval (CI)=1.001-2.297; P=0.006, HR=1.807, 95% CI=1.180-2.765; P=0.005, HR=1.833, 95% CI=1.196-2.810; P=0.034, HR=1.578, 95% CI=1.036-2.405). GSEA showed enrichment of cell matrix adhesion, integrin binding, angiogenesis, endothelial growth factor and endothelial migration regulation in patients with COAD withGABRDoverexpression.GABRB1, GABRD, GABRP and GABRQwere associated with the prognostic factors of COAD. The expression levels ofGABRA2, GABRA3, GABRB2, GABRB3, GABRG2, GABRDandGABREmay allow differentiation between tumor tissues and adjacent normal tissues.	[Yan, Ling; Gong, Yi-Zhen; Ruan, Guo-Tian; Xie, Hai-Lun; Gao, Feng; Gan, Jia-Liang] Guangxi Med Univ, Dept Colorectal & Anal Surg, Affiliated Hosp 1, 6 Shuang Yong Rd, Nanning 530021, Guangxi Zhuang, Peoples R China; [Shao, Meng-Nan] Guangxi Med Univ, Life Sci Inst, Nanning 530021, Guangxi Zhuang, Peoples R China; [Liao, Xi-Wen; Wang, Xiang-Kun; Han, Quan-Fa; Zhou, Xin] Guangxi Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Nanning 530021, Guangxi Zhuang, Peoples R China; [Zhu, Li-Cheng] Guangxi Med Univ, Sch Preclin Med, Dept Immunol, Nanning 530021, Guangxi Zhuang, Peoples R China		Gan, JL (corresponding author), Guangxi Med Univ, Dept Colorectal & Anal Surg, Affiliated Hosp 1, 6 Shuang Yong Rd, Nanning 530021, Guangxi Zhuang, Peoples R China.	gjl5172@163.com			Innovation Project of Guangxi Graduate Education [JGY2019052]; Self-financing Scientific Research Project of Guangxi Zhuang Autonomous Region Health Commission, China [Z20180959]	The present study was supported by the Innovation Project of Guangxi Graduate Education (grant no. JGY2019052) and Self-financing Scientific Research Project of Guangxi Zhuang Autonomous Region Health Commission, China (grant no. Z20180959).	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Lett.	JUL	2020	20	1					275	291		10.3892/ol.2020.11573			17	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	MG4OT	WOS:000546013100028	32565954	gold, Green Published			2022-04-25	
J	Jang, YM; Park, NY; Rostgaard-Hansen, AL; Huang, JJ; Jiang, Q				Jang, Yumi; Park, Na-Young; Rostgaard-Hansen, Agnetha Linn; Huang, Jianjie; Jiang, Qing			Vitamin E metabolite 13 '-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice	FREE RADICAL BIOLOGY AND MEDICINE			English	Article						Cancer; Sphingolipid; Vitamin E metabolites; Autophagy; Apoptosis	LONG-CHAIN CARBOXYCHROMANOLS; GAMMA-TOCOPHEROL; DIHYDROCERAMIDE DESATURASE; NATURAL FORMS; CERAMIDE; ACID; AZOXYMETHANE; TOCOTRIENOL; PATHWAY; CARCINOGENESIS	Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied delta T-13'-COOH and delta TE-13'-COOH, which are metabolites of delta-tocopherol and delta-tocotrienol, respectively. delta TE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and delta-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOH-induced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, delta TE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents. (C) 2016 Elsevier Inc. All rights reserved.	[Jang, Yumi; Park, Na-Young; Rostgaard-Hansen, Agnetha Linn; Huang, Jianjie; Jiang, Qing] Purdue Univ, Dept Nutr Sci, 700 W State St,Stone Hall G1A, W Lafayette, IN 47907 USA		Jiang, Q (corresponding author), Purdue Univ, Dept Nutr Sci, 700 W State St,Stone Hall G1A, W Lafayette, IN 47907 USA.	qjiang@purdue.edu			National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21CA152588, R01AT006882]; NIH via Purdue Center for Cancer Research [P30CA023168]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R21CA152588, P30CA023168] Funding Source: NIH RePORTER; NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Complementary & Alternative Medicine [R01AT006882] Funding Source: NIH RePORTER	The authors would like to thank Amber S Jannasch for helps with LC-MS/MS analyses of sphingolipids. This study was in part supported by grants R21CA152588 and R01AT006882 (to QJ) from National Institutes of Health. This project was also partially supported by NIH grant P30CA023168 via Purdue Center for Cancer Research.	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Biol. Med.	JUN	2016	95						190	199		10.1016/j.freeradbiomed.2016.03.018			10	Biochemistry & Molecular Biology; Endocrinology & Metabolism	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Endocrinology & Metabolism	DM2IH	WOS:000376169800016	27016075	Green Accepted			2022-04-25	
J	Li, YL; Yang, J; Wang, HY; Qiao, W; Guo, YF; Zhang, ST; Guo, YJ				Li, Yilong; Yang, Jie; Wang, Hengyang; Qiao, Wei; Guo, Yongfeng; Zhang, Shengtao; Guo, Yajuan			FNDC3B, Targeted by miR-125a-5p and miR-217, Promotes the Proliferation and Invasion of Colorectal Cancer Cells via PI3K/mTOR Signaling	ONCOTARGETS AND THERAPY			English	Article						FNDC3B; colorectal cancer; proliferation; invasion; microRNA; PI3K/mTOR	EPITHELIAL-MESENCHYMAL TRANSITION; COLON-CANCER; APOPTOSIS; METASTASIS; STATISTICS; AUTOPHAGY; MIGRATION; PATHWAY; FAD104	Background: Fibronectin type III domain containing 3B (FNDC3B) acts as an oncogene in various cancers, and abnormal expression of FNDC3B has been found in colorectal cancer (CRC). Our study aimed to illustrate the role of FNDC3B in CRC development. Methods: Through RT-qPCR and western blotting assays, the mRNA and protein expressions of target genes were measured. CCK-8 and MTT methods were used to detect cell proliferation. Invasion ability was determined using Transwell assay. TargetScan platform and luciferase reporter gene assay were performed to predict and validate the bindings between FNDC3B and miR-125a-5p or miR-217. Besides, the expression correlationwas measured by Pearson'sCorrelation analysis. Results: We found that FNDC3B was significantly upregulated in CRC tissues and tumor cell lines, and high expression of FNDC3B predicted a poor survival outcome. The bindings between FNDC3B and miR-125a-5p and miR-217 were respectively at the motifs of CUCAGGG and AUGCAGU. MiR-125a-5p and miR-217 were downregulated in CRC tissues, and both were negatively correlated with FNDC3B expression. Subsequently, the downregulated miR-125a-5p and miR-217 were confirmed as contributors FNDC3B upregulation in CRC. A loss-of-function assay demonstrated that FNDC3B knockdown inhibited the proliferation of CRC cells, while FNDC3B overexpression promoted the proliferation and invasion of tumor cells. Besides, we validated that PI3K/mTOR signaling was involved in the regulation of FNDC3B on the proliferation and invasion of CRC cells. Conclusion: Generally, our findings demonstrated that FNDC3B facilitated cell proliferation and invasion via PI3K/mTOR signaling, and further promoted CRC progression. The novel miR-125a-5p/FNDC3B and miR-217/FNDC3B axes might be new targets for CRC prognosis and therapy.	[Li, Yilong; Yang, Jie; Wang, Hengyang; Qiao, Wei; Guo, Yongfeng; Zhang, Shengtao; Guo, Yajuan] Ninth Hosp Xian, Dept Gen Surg 1, Xian 710054, Shaanxi, Peoples R China		Guo, YJ (corresponding author), Ninth Hosp Xian, 151 Eastern Sect South Second Ring Rd, Xian 710054, Shaanxi, Peoples R China.	yajuanguo123@163.com					Bartel DP, 2009, CELL, V136, P215, DOI 10.1016/j.cell.2009.01.002; Bian YZ, 2019, CANCER BIOL THER, V20, P886, DOI 10.1080/15384047.2019.1579959; Cao ZX, 2017, J ETHNOPHARMACOL, V202, P20, DOI 10.1016/j.jep.2016.07.028; Chen S, 2017, ONCOL LETT, V14, P6671, DOI 10.3892/ol.2017.7044; Chen WQ, 2016, CA-CANCER J CLIN, V66, P115, DOI 10.3322/caac.21338; Conza GD, 2017, CELL REP, V18, P1699, DOI [10.1016/j.celrep.2017.01.051, DOI 10.1016/J.CELREP.2017.01.051]; Dienstmann R, 2017, NAT REV CANCER, V17, P79, DOI 10.1038/nrc.2016.126; Duan SY, 2018, J EXP CLIN CANC RES, V37, DOI 10.1186/s13046-018-0980-3; Gao Y, 2015, MED ONCOL, V32, DOI 10.1007/s12032-014-0362-4; Jiang QG, 2014, MOL BIOL REP, V41, P3359, DOI 10.1007/s11033-014-3198-2; Kishimoto K, 2011, EXP CELL RES, V317, P2110, DOI 10.1016/j.yexcr.2011.06.003; Kishimoto K, 2010, BIOCHEM BIOPH RES CO, V397, P187, DOI 10.1016/j.bbrc.2010.05.077; Li JZ, 2018, MOL THER-NUCL ACIDS, V10, P426, DOI 10.1016/j.omtn.2017.12.022; Lin CH, 2016, ONCOTARGET, V7, P49498, DOI 10.18632/oncotarget.10374; Liu HY, 2017, CANCER GENE THER, V24, P244, DOI 10.1038/cgt.2017.8; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Nishizuka M, 2009, EXP CELL RES, V315, P809, DOI 10.1016/j.yexcr.2008.12.013; Siegel RL, 2017, CA-CANCER J CLIN, V67, P177, DOI 10.3322/caac.21395; Singh SS, 2018, ONCOGENE, V37, P1142, DOI 10.1038/s41388-017-0046-6; Sun XL, 2018, J BIOCHEM MOL TOXIC, V32, DOI 10.1002/jbt.22028; Tang JJ, 2014, ONCOTARGET, V5, P10778, DOI 10.18632/oncotarget.2502; Tong ZG, 2015, BIOMED PHARMACOTHER, V75, P129, DOI 10.1016/j.biopha.2015.07.036; Verhoeff SR, 2016, INT J CANCER, V139, P187, DOI 10.1002/ijc.30053; Wang HY, 2016, BRIT J HAEMATOL, V172, P987, DOI 10.1111/bjh.13552; Xu HS, 2017, BIOMED PHARMACOTHER, V87, P405, DOI 10.1016/j.biopha.2016.12.100; Ye H, 2018, CHIN MED, V9, P720; Yin Y, 2016, ONCOTARGET, V7, P86755, DOI 10.18632/oncotarget.13550; Ying-Zi L, 2014, INT J ONCOL, V45, P104, DOI [10.3892/ijo.2014.2392, DOI 10.3892/IJO.2014.2392]; Zhang N, 2016, ONCOL LETT, V12, P4589, DOI 10.3892/ol.2016.5249; Zhang T, 2018, WORLD J GASTROENTERO, V24, P3538, DOI 10.3748/wjg.v24.i31.3538; Zhang XL, 2015, INT J MOL MED, V35, P1301, DOI 10.3892/ijmm.2015.2126; Zhang Y, 2018, MOL CANCER, V17, DOI 10.1186/s12943-017-0753-1; Zhong ZM, 2018, ONCOL REP, V39, P1853, DOI 10.3892/or.2018.6231	33	6	6	0	2	DOVE MEDICAL PRESS LTD	ALBANY	PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND	1178-6930			ONCOTARGETS THER	OncoTargets Ther.		2020	13						3501	3510		10.2147/OTT.S226520			10	Biotechnology & Applied Microbiology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Oncology	OH7SZ	WOS:000582795100001	32431508	gold, Green Published			2022-04-25	
J	Huang, CY; Chiang, SF; Chen, WTL; Ke, TW; Chen, TW; You, YS; Lin, CY; Chao, KSC				Huang, Chih-Yang; Chiang, Shu-Fen; Chen, William Tzu-Liang; Ke, Tao-Wei; Chen, Tsung-Wei; You, Ying-Shu; Lin, Chen-Yu; Chao, K. S. Clifford			HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer	CELL DEATH & DISEASE			English	Article							GLYCATION END-PRODUCTS; ADVANCED RECTAL-CANCER; DRUG-RESISTANCE; AUTOPHAGY; FISSION; EXPRESSION; AMPHOTERIN; PROGRESSION; RECEPTOR; OXALIPLATIN	Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1(Ser616) are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1(Ser616) within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.	[Huang, Chih-Yang] China Med Univ, China Med Univ Hosp, Translat Res Core, Taichung 40402, Taiwan; [Huang, Chih-Yang] HungKuang Univ, Dept Nutr, Taichung 43302, Taiwan; [Chiang, Shu-Fen; You, Ying-Shu; Lin, Chen-Yu; Chao, K. S. Clifford] China Med Univ, China Med Univ Hosp, Canc Ctr, Taichung 40402, Taiwan; [Chen, William Tzu-Liang; Ke, Tao-Wei] China Med Univ, China Med Univ Hosp, Dept Colorectal Surg, Taichung 40402, Taiwan; [Chen, Tsung-Wei] China Med Univ, China Med Univ Hosp, Dept Pathol, Taichung 40402, Taiwan; [Huang, Chih-Yang] China Med Univ, Grad Inst Basic Med Sci, Taichung 40402, Taiwan; [Huang, Chih-Yang] China Med Univ, Sch Chinese Med, Taichung 40402, Taiwan; [Huang, Chih-Yang] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 41354, Taiwan; [Huang, Chih-Yang] China Med Univ, China Med Univ Hosp, Med Res Ctr Exosomes & Mitochondria Related Dis, Taichung 40402, Taiwan		Huang, CY (corresponding author), China Med Univ, China Med Univ Hosp, Translat Res Core, Taichung 40402, Taiwan.; Huang, CY (corresponding author), HungKuang Univ, Dept Nutr, Taichung 43302, Taiwan.; Huang, CY (corresponding author), China Med Univ, Grad Inst Basic Med Sci, Taichung 40402, Taiwan.; Huang, CY (corresponding author), China Med Univ, Sch Chinese Med, Taichung 40402, Taiwan.; Huang, CY (corresponding author), China Med Univ, China Med Univ Hosp, Med Res Ctr Exosomes & Mitochondria Related Dis, Taichung 40402, Taiwan.	cyhuag@mail.cmu.edu.tw	Chen, William Tzu-Liang/ABA-5673-2021; Huang, Kevin Chih-Yang/Q-4862-2016	Huang, Kevin Chih-Yang/0000-0002-0266-3233; Huang, Chih-Yang/0000-0003-2347-0411	National Core Facility Program for Biotechnology Grants of MOST [MOST 1042319- B-001-001-]; Ministry of Health and Welfare, Taiwan [MOHW107-TDU-B-212-123004]; Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (Taiwan) [MOHW107-TDU-B-212-114024]; China Medical University Hospital, Taiwan [DMR-107-126]; Translation Research Core, China Medical University Hospital	The experiments and data analysis were performed using the Medical Research Core Facilities Center, Office of Research & Development at China Medical University, Taichung, Taiwan. We are grateful for the tissue microarray (TMA) support from the Translation Research Core, China Medical University Hospital. The lentivirus carrying shRNAs were obtained from the National Core Facility for Manipulation of Gene Function by RNAi, miRNA, miRNA sponges, and CRISPR/Genomic Research Center, Academia Sinica and supported by the National Core Facility Program for Biotechnology Grants of MOST (MOST 1042319- B-001-001-). This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW107-TDU-B-212-114024, Taiwan) and China Medical University Hospital, Taiwan (DMR-107-126).	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SEP 26	2018	9								1004	10.1038/s41419-018-1019-6			15	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	GV6YY	WOS:000446268400002	30258050	gold, Green Published			2022-04-25	
J	Zhang, HH; Tang, JL; Li, C; Kong, JL; Wang, JY; Wu, YH; Xu, EP; Lai, MD				Zhang, Honghe; Tang, Jinlong; Li, Chen; Kong, Jianlu; Wang, Jingyu; Wu, Yihua; Xu, Enping; Lai, Maode			MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells	CANCER LETTERS			English	Article						MiR-22; 5-FU; Autophagy; Apoptosis; Colorectal cancer	BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; IN-VITRO; 5-FLUOROURACIL; RESISTANCE; MICRORNAS; SUPPRESSOR; SURVIVAL; CHEMOTHERAPY; GENES	Autophagy has become one of the most important mechanisms of chemotherapy resistance by supporting the survival of tumor cells under metabolic and therapeutic stress. Here, we showed that miR-22 inhibited autophagy and promoted apoptosis to increase the sensitivity of colorectal cancer (CRC) cells to 5-fluorouracil (5-FU) treatment both in vitro and in vivo. B-cell translocation gene 1 (BTG1) was identified as a new target of miR-22, which could reverse the inhibition of autophagy induced by miR-22. Thus, miR-22 may function as an important switch between autophagy and apoptosis to regulate 5-FU sensitivity through post-transcriptional silencing of BTG1. Promisingly, miR-22 could be considered as both a predictor of 5-FU sensitivity for personalized treatment and a therapeutic target for colorectal cancer. (C) 2014 Elsevier Ireland Ltd. All rights reserved.	[Zhang, Honghe; Tang, Jinlong; Li, Chen; Kong, Jianlu; Wang, Jingyu; Wu, Yihua; Xu, Enping; Lai, Maode] Zhejiang Univ, Sch Med, Dept Pathol, Hangzhou 310003, Zhejiang, Peoples R China; [Tang, Jinlong] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Pathol, Hangzhou 310003, Zhejiang, Peoples R China; [Wang, Jingyu] First Hosp Jiaxing, Dept Pathol, Jiaxing, Peoples R China; [Zhang, Honghe; Li, Chen; Kong, Jianlu; Xu, Enping; Lai, Maode] Key Lab Dis Prote Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China		Xu, EP (corresponding author), Zhejiang Univ, Sch Med, Dept Pathol, Hangzhou 310003, Zhejiang, Peoples R China.	lmp@zju.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81090421, 81171938, 81201557, 81302455]; Natural Science Foundation of ZhejiangNatural Science Foundation of Zhejiang Province [LY12H16017]	This research is supported by National Natural Science Foundation of China (81090421, 81171938, 81201557 and 81302455) and Natural Science Foundation of Zhejiang (LY12H16017). We thank Prof Wei Liu (College of Medicine, Zhejiang University) for providing the GFP-LC3 plasmid. We also thank Prof. Lain Charles Bruce (College of Medicine, Zhejiang University) for English language assistance.	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JAN 28	2015	356	2	B				781	790		10.1016/j.canlet.2014.10.029			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AZ1NL	WOS:000348005500051	25449431				2022-04-25	
J	Kamarudin, MNA; Sarker, MMR; Zhou, JR; Parhar, I				Kamarudin, Muhamad Noor Alfarizal; Sarker, Md. Moklesur Rahman; Zhou, Jin-Rong; Parhar, Ishwar			Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects	JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH			English	Review						Metformin; Colorectal cancer; Cancer; Type 2 diabetes mellitus; Chemopreventive; Anticancer	TRAIL-INDUCED APOPTOSIS; ABERRANT CRYPT FOCI; COLON-CANCER; DIABETES-MELLITUS; PANCREATIC-CANCER; MCL-1 DEGRADATION; PROSTATE-CANCER; REDUCED RISK; DOUBLE-BLIND; IN-VITRO	Growing evidence showed the increased prevalence of cancer incidents, particularly colorectal cancer, among type 2 diabetic mellitus patients. Antidiabetic medications such as, insulin, sulfonylureas, dipeptyl peptidase (DPP) 4 inhibitors and glucose-dependent insulinotropic peptide (GLP-1) analogues increased the additional risk of different cancers to diabetic patients. Conversely, metformin has drawn attention among physicians and researchers since its use as antidiabetic drug exhibited beneficial effect in the prevention and treatment of cancer in diabetic patients as well as an independent anticancer drug. This review aims to provide the comprehensive information on the use of metformin at preclinical and clinical stages among colorectal cancer patients. We highlight the efficacy of metformin as an anti-proliferative, chemopreventive, apoptosis inducing agent, adjuvant, and radio-chemosensitizer in various colorectal cancer models. This multifarious effects of metformin is largely attributed to its capability in modulating upstream and downstream molecular targets involved in apoptosis, autophagy, cell cycle, oxidative stress, inflammation, metabolic homeostasis, and epigenetic regulation. Moreover, the review highlights metformin intake and colorectal cancer risk based on different clinical and epidemiologic results from different gender and specific population background among diabetic and non-diabetic patients. The improved understanding of metformin as a potential chemotherapeutic drug or as neo-adjuvant will provide better information for it to be used globally as an affordable, well-tolerated, and effective anticancer agent for colorectal cancer.	[Kamarudin, Muhamad Noor Alfarizal; Parhar, Ishwar] Monash Univ Malaysia, Jeffrey Cheah Sch Med & Hlth Sci, BRIMS, Bandar Sunway 47500, Selangor, Malaysia; [Sarker, Md. Moklesur Rahman] State Univ Bangladesh, Dept Pharm, 77 Satmasjid Rd, Dhaka 1205, Bangladesh; [Sarker, Md. Moklesur Rahman] Hlth Med Sci Res Ltd, 3-1 Block F, Dhaka 1207, Bangladesh; [Zhou, Jin-Rong] Harvard Med Sch, Dept Surg, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA		Kamarudin, MNA (corresponding author), Monash Univ Malaysia, Jeffrey Cheah Sch Med & Hlth Sci, BRIMS, Bandar Sunway 47500, Selangor, Malaysia.; Sarker, MMR (corresponding author), State Univ Bangladesh, Dept Pharm, 77 Satmasjid Rd, Dhaka 1205, Bangladesh.	MuhamadNoor.Alfarizal@monash.edu; moklesur2002@yahoo.com	Sarker, Moklesur Rahman/AAH-9492-2019; KAMARUDIN, MUHAMAD NOOR ALFARIZAL/S-3187-2018; Sarker, Moklesur Rahman/G-2396-2014	Sarker, Moklesur Rahman/0000-0001-9795-0608; Sarker, Moklesur Rahman/0000-0002-0787-0944; Kamarudin, Alfarizal/0000-0003-2505-1018	Brain Research Institute Monash Sunway (BRIMS); Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia	The authors would like to thank the funding from Brain Research Institute Monash Sunway (BRIMS) and Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia.	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Exp. Clin. Cancer Res.	DEC 12	2019	38	1							491	10.1186/s13046-019-1495-2			23	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JV9ZH	WOS:000502718400003	31831021	Green Published, gold			2022-04-25	
J	Kim, BK; Nam, SW; Min, BS; Ban, HS; Paik, S; Lee, K; Im, JY; Lee, Y; Park, JT; Kim, SY; Kim, M; Lee, H; Won, M				Kim, Bo-Kyung; Nam, Soon Woo; Min, Byung Soh; Ban, Hyun Seung; Paik, Soonmyung; Lee, Kyeong; Im, Joo-Young; Lee, Youngjoo; Park, Joon-Tae; Kim, Seon-Young; Kim, Mirang; Lee, Hongsub; Won, Misun			Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer	BRITISH JOURNAL OF CANCER			English	Article							INDUCED APOPTOSIS; ROCK INHIBITOR; COLON-CANCER; AUTOPHAGY; PROTEIN; SCREEN; ACTIVATION; THERAPY; MEMBERS; GROWTH	BACKGROUND: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1 alpha accumulation. METHODS: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library. RESULTS: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression. CONCLUSIONS: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.	[Kim, Bo-Kyung; Im, Joo-Young; Lee, Youngjoo; Kim, Seon-Young; Kim, Mirang; Won, Misun] KRIBB, Personalized Genom Med Res Ctr, Daejeon 34141, South Korea; [Nam, Soon Woo] Catholic Univ Korea, Incheon St Marys Hosp, 56 Dongsuro Bupyunggu, Incheon 06591, South Korea; [Min, Byung Soh; Paik, Soonmyung] Yonsei Univ, Serverance Biomed Sci Inst, Coll Med, Seoul 03722, South Korea; [Ban, Hyun Seung] KRIBB, Metab Regulat Res Ctr, Daejeon 34141, South Korea; [Lee, Kyeong] Dongguk Univ Seoul, Coll Pharm, Goyang 410820, South Korea; [Park, Joon-Tae; Lee, Hongsub] ILDONG Pharmaceut Co Ltd, Drug Discovery Team, Hwaseong 445811, Hwaseong, South Korea; [Won, Misun] Korea Univ Sci & Technol UST, KRIBB Sch Biosci, Dept Funct Genom, 217 Gajeong Ro, Daejeon 34113, South Korea		Won, M (corresponding author), KRIBB, Personalized Genom Med Res Ctr, Daejeon 34141, South Korea.; Won, M (corresponding author), Korea Univ Sci & Technol UST, KRIBB Sch Biosci, Dept Funct Genom, 217 Gajeong Ro, Daejeon 34113, South Korea.	misun@kribb.re.kr	; Ban, Hyun Seung/F-9526-2014	Paik, Soonmyung/0000-0001-9688-6480; Ban, Hyun Seung/0000-0002-2698-6037	KRIBB Initiative program [KGM4751713]; National Research Foundation (NRF) [NRF-2017R1A2B2011936, NRF-2018R1A5A2023127]; Health Technology RD [HI13C2162]	This work was supported by the KRIBB Initiative program (KGM4751713), National Research Foundation (NRF) (NRF-2017R1A2B2011936 and NRF-2018R1A5A2023127) and Health Technology R&D (HI13C2162).	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J. Cancer	NOV 27	2018	119	11					1347	1357		10.1038/s41416-018-0289-1			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	HC2LS	WOS:000451634100006	30420612	Green Published, hybrid			2022-04-25	
J	Tan, ML; Tan, HK; Oon, CE; Kuroyanagi, M; Muhammad, TST				Tan, Mei Lan; Tan, Heng Kean; Oon, Chern Ein; Kuroyanagi, Masanori; Muhammad, Tengku Sifzizul Tengku			Identification of genes involved in the regulation of 14-deoxy-11,12-didehydroandrographolide-induced toxicity in T-47D mammary cells	FOOD AND CHEMICAL TOXICOLOGY			English	Article						14-Deoxy-11,12-didehydroandrographolide; Cytotoxic; Gene expression; Autophagic; Apoptotic	ANDROGRAPHIS-PANICULATA EXTRACT; MAJOR DITERPENOID CONSTITUENTS; BREAST-CANCER CELLS; DOWN-REGULATION; BINDING-PROTEIN; COLON-CANCER; CYCLE ARREST; TRANSCRIPTIONAL ACTIVITY; MICROARRAY ANALYSIS; INDUCED APOPTOSIS	14-Deoxy-11,12-didehydroandrographolide is one of the principle compounds of the medicinal plant, Andrographis paniculata Nees. This study explored the mechanisms of 14-deoxy-11,12-didehydroandrographolide-induced toxicity and non-apoptotic cell death in T-47D breast carcinoma cells. Gene expression analysis revealed that 14-deoxy-11,12-didehydroandrographolide exerted its cytotoxic effects by regulating genes that inhibit the cell cycle or promote cell cycle arrest. This compound regulated genes that are known to reduce/inhibit cell proliferation, induce growth arrest and suppress cell growth. The growth suppression activities of this compound were demonstrated by a downregulation of several genes normally found to be over-expressed in cancers. Microscopic analysis revealed positive monodansylcadaverine (MDC) staining at 8 h, indicating possible autophagosomes. TEM analysis revealed that the treated cells were highly vacuolated, thereby suggesting that 14-deoxy-11,12-didehydroandrographolide may cause autophagic morphology in these cells. This morphology may be correlated with the concurrent expression of genes known to affect lysosomal activity, ion transport, protein degradation and vesicle transport. Interestingly, some apoptotic-like bodies were found, and these bodies contained multiple large vacuoles, suggesting that this compound is capable of eliciting a combination of apoptotic and autophagic-like morphological characteristics. (C) 2011 Elsevier Ltd. All rights reserved.	[Tan, Mei Lan; Tan, Heng Kean; Muhammad, Tengku Sifzizul Tengku] Minist Sci Technol & Innovat Malaysia, Malaysian Inst Pharmaceut & Nutraceut, Halaman Bukit Gambir 11700, Pulau Pinang, Malaysia; [Tan, Mei Lan] Univ Sains Malaysia, Adv Med & Dent Inst, George Town, Malaysia; [Oon, Chern Ein] Univ Oxford, Mol Oncol Labs, Canc Res UK, Weatherall Inst Mol Med,John Radcliffe Hosp, Oxford OX1 2JD, England; [Kuroyanagi, Masanori] Tokushima Bunri Univ, Fac Pharmaceut Sci, Kagawa 7692193, Japan; [Muhammad, Tengku Sifzizul Tengku] Univ Malaysia Terengganu, Fac Sci & Technol, Kuala Terengganu 21030, Terengganu, Malaysia		Tan, ML (corresponding author), Minist Sci Technol & Innovat Malaysia, Malaysian Inst Pharmaceut & Nutraceut, Halaman Bukit Gambir 11700, Pulau Pinang, Malaysia.	tanml@usm.my	Oon, Chern E/B-3684-2013; Lan, Tan Mei/E-3500-2012; Muhammad, Tengku Sifzizul Tengku/AAW-7767-2021	Oon, Chern E/0000-0002-4685-6408; Lan, Tan Mei/0000-0001-6565-699X; Tengku Muhammad, Tengku Sifzizul/0000-0002-9275-7988	Fundamental Research Grant Scheme (FRGS); Higher Education Ministry Malaysia; R&D Initiatives Grant; Ministry of Science, Technology and Innovation MalaysiaMinistry of Energy, Science, Technology, Environment and Climate Change (MESTECC), Malaysia	This work was fully supported by the Fundamental Research Grant Scheme (FRGS), Higher Education Ministry Malaysia and partly supported by the R&D Initiatives Grant, Ministry of Science, Technology and Innovation Malaysia.	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Toxicol.	FEB	2012	50	2					431	444		10.1016/j.fct.2011.11.001			14	Food Science & Technology; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology; Toxicology	904SS	WOS:000301218800047	22101062				2022-04-25	
J	Lee, SH; Jeong, EG; Yoo, NJ; Lee, SH				Lee, Sung Hak; Jeong, Eun Goo; Yoo, Nam Jin; Lee, Sug Hyung			Mutational and expressional analysis of BNIP3, a pro-apoptotic Bcl-2 member, in gastric carcinomas	APMIS			English	Article						BNIP3; expression; mutation; gastric carcinoma; apoptosis	CELL-DEATH; INTERACTING PROTEIN; SOMATIC MUTATIONS; COLON CANCERS; BH3 DOMAIN; GENE; MITOCHONDRIAL; HYPOXIA; METHYLATION; MARKER	Cell death deregulation is a hallmark of human cancers. BNIP3 was initially identified as a proapoptotic member of the Bcl-2 family and plays an important role in apoptosis, necrosis and autophagy. The aim of this study was to see whether alterations of BNIP3 protein expression and somatic mutation of the BNIP3 gene are characteristics of human cancers. We analyzed the expression of BNIP3 protein in 60 gastric adenocarcinomas by immunohistochemistry. In addition, we analyzed BNIP3 mutation in the DNA sequences encoding BH3 (Bcl-2 homology3) and TM (transmembrane) domains that are important in the cell death function of BNIP3 by single-strand conformation polymorphism (SSCP) in 48 colorectal, 48 gastric, and 48 breast carcinomas, and 48 acute leukemias. By immunohistochemistry, BNIP3 protein was detected in 40 of the 60 carcinomas (67%). Both early and advanced gastric carcinomas expressed BNIP3. There was no significant association between BNIP3 expression and clinicopathologic characteristics, including invasion, metastasis and stage. In contrast to the cancer cells, epithelial cells in normal gastric mucosa showed no or weak expression of BNIP3. Mutational analysis revealed BNIP3 mutation in neither the BH3 nor the TM domain, suggesting that BNIP3 mutation in these domains is not a direct target of inactivation in gastric, colorectal and breast carcinomas, and acute leukemias. Increased expression of BNIP3 in the malignant gastric epithelial cells compared to the normal mucosal epithelial cells suggests that BNIP3 expression might play a role in gastric carcinoma development.	Catholic Univ Korea, Coll Med, Dept Pathol, Seoul 137701, South Korea		Lee, SH (corresponding author), Catholic Univ Korea, Coll Med, Dept Pathol, 505 Banpo Dong, Seoul 137701, South Korea.	suhulee@catholic.ac.kr					Arena V, 2003, GENE CHROMOSOME CANC, V38, P91, DOI 10.1002/gcc.10245; Bacon AL, 2007, ONCOGENE, V26, P132, DOI 10.1038/sj.onc.1209761; Burton TR, 2006, INT J CANCER, V118, P1660, DOI 10.1002/ijc.21547; Chen G, 1999, J BIOL CHEM, V274, P7, DOI 10.1074/jbc.274.1.7; Daido S, 2004, CANCER RES, V64, P4286, DOI 10.1158/0008-5472.CAN-03-3084; Hanahan D, 2000, CELL, V100, P57, DOI 10.1016/S0092-8674(00)81683-9; Kondo S, 2000, CANCER RES, V60, P4328; Kononen J, 1998, NAT MED, V4, P844, DOI 10.1038/nm0798-844; Kothari S, 2003, ONCOGENE, V22, P4734, DOI 10.1038/sj.onc.1206666; Lee JW, 2004, CARCINOGENESIS, V25, P1371, DOI 10.1093/carcin/bgh145; Lee SH, 1999, ONCOGENE, V18, P3754, DOI 10.1038/sj.onc.1202769; Luo X, 1998, CELL, V94, P481, DOI 10.1016/S0092-8674(00)81589-5; Marx J, 2006, SCIENCE, V312, P1160, DOI 10.1126/science.312.5777.1160; Murai M, 2005, CLIN CANCER RES, V11, P1021; Nam NJ, 2002, APMIS, V110, P825, DOI 10.1034/j.1600-0463.2002.1101109.x; Oda E, 2000, SCIENCE, V288, P1053, DOI 10.1126/science.288.5468.1053; Palmerini F, 2001, HUM PATHOL, V32, P461, DOI 10.1053/hupa.2001.24328; Rampino N, 1997, SCIENCE, V275, P967, DOI 10.1126/science.275.5302.967; Ray R, 2000, J BIOL CHEM, V275, P1439, DOI 10.1074/jbc.275.2.1439; Reed JC, 2000, AM J PATHOL, V157, P1415, DOI 10.1016/S0002-9440(10)64779-7; Schmidt-Kastner R, 2004, BRAIN RES, V1001, P133, DOI 10.1016/j.brainres.2003.11.065; Soung YH, 2004, HUM GENET, V115, P112, DOI 10.1007/s00439-004-1129-3; Soung YH, 2005, CANCER RES, V65, P815; Sowter HM, 2001, CANCER RES, V61, P6669; Sturm I, 2006, CELL DEATH DIFFER, V13, P619, DOI 10.1038/sj.cdd.4401782; Tan EY, 2007, CLIN CANCER RES, V13, P467, DOI 10.1158/1078-0432.CCR-06-1466; Vande Velde C, 2000, MOL CELL BIOL, V20, P5454, DOI 10.1128/MCB.20.15.5454-5468.2000; YANG E, 1995, CELL, V80, P285, DOI 10.1016/0092-8674(95)90411-5; Yasuda M, 1998, J BIOL CHEM, V273, P12415, DOI 10.1074/jbc.273.20.12415	29	11	12	0	5	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0903-4641	1600-0463		APMIS	APMIS	NOV	2007	115	11					1274	1280		10.1111/j.1600-0643.2007.00795.x			7	Immunology; Microbiology; Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Microbiology; Pathology	239JJ	WOS:000251514300011	18092960				2022-04-25	
J	Sun, XF; Zhu, MJ				Sun, Xiaofei; Zhu, Mei-Jun			AMP-activated protein kinase: a therapeutic target in intestinal diseases	OPEN BIOLOGY			English	Review						AMPK; absorption; barrier function; colorectal cancer; intestinal health; intestinal inflammation	FATTY-ACID OXIDATION; TIGHT JUNCTION PROTEINS; HUMAN SKELETAL-MUSCLE; COLON-CANCER CELLS; INDUCED APOPTOSIS; GUT MICROBIOTA; EPITHELIAL DIFFERENTIATION; GLUCOSE-ABSORPTION; GROWTH-INHIBITION; PEPTIDE-TRANSPORT	Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a highly conserved energy sensor, has a crucial role in cardiovascular, neurodegenerative and inflammatory diseases, as well as in cancer and metabolic disorders. Accumulating studies have demonstrated that AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine, indicating an essential role of AMPK in intestinal health. AMPK inactivation is an aetiological factor in intestinal dysfunctions. This review summarizes the favourable outcomes of AMPK activation on intestinal health, and discusses AMPK as a potential therapeutic target for intestinal diseases.	[Sun, Xiaofei; Zhu, Mei-Jun] Washington State Univ, Sch Food Sci, Pullman, WA 99164 USA; [Sun, Xiaofei; Zhu, Mei-Jun] Univ Idaho, Sch Food Sci, Moscow, ID 83844 USA		Zhu, MJ (corresponding author), Washington State Univ, Sch Food Sci, Pullman, WA 99164 USA.; Zhu, MJ (corresponding author), Univ Idaho, Sch Food Sci, Moscow, ID 83844 USA.	meijun.zhu@wsu.edu	Sun, Xiaofei/S-9786-2018	Sun, Xiaofei/0000-0002-4835-9309	Washington State University Agricultural Research Center Emerging Research Issues Internal Competitive [10A-3057-8640];  [NIHR15HD073864]	This work was partially supported by NIHR15HD073864 and Washington State University Agricultural Research Center Emerging Research Issues Internal Competitive grant no. (10A-3057-8640).	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J	Ba, MC; Long, H; Wang, S; Wu, YB; Zhang, BH; Yan, ZF; Yu, FH; Cui, SZ				Ba, Ming-Chen; Long, Hui; Wang, Shuai; Wu, Yin-Bing; Zhang, Bo-Huo; Yan, Zhao-Fei; Yu, Fei-Hong; Cui, Shu-Zhong			Hyperthermia enhances radiosensitivity of colorectal cancer cells through ROS inducing autophagic cell death	JOURNAL OF CELLULAR BIOCHEMISTRY			English	Article						autophagy; cvolorectal cancer; hyperthermia; radiotherapy; ROS	INTRAPERITONEAL CHEMOTHERAPY; OXIDATIVE-STRESS; MILD HYPERTHERMIA; DOWN-REGULATION; RECTAL-CANCER; BREAST-CANCER; APOPTOSIS; SENSITIVITY; THERAPY; MODULATION	Hyperthermia (HT) enhances the anti-cancer effects of radiotherapy (RT), but the precise biochemical mechanisms involved are unclear. This study was aim to investigate if mild HT sensitizes colorectal cancer cells to RT through reactive oxygen species (ROS)-inducing autophagic cell death in a mice model of HCT116 human colorectal cancer. HCT116 mice model were randomly divided into five groups: mock group, hyperthermia group (HT), radiotherapy group (RT), HT+RT group, and HT+RT +N-acetyl L-cysteine (NAC) group (HT+CT+NAC). After four weeks of treatment, cancer growth inhibition, rate and mitochondrial membrane potential were measured with MTT and JC-1 assays, respectively, while ROS were estimated fluorimetrically. The relationship of these parameters to expressions of autophagy-related genes Beclin1, LC3B, and mTOR was analyzed. Gene expression was measured by Real-Time polymerase chain reaction (RT-PCR). There were significant increases in ROS levels and mitochondrial membrane potential in the HT+RT group. ROS levels in the HT+RT group increased more significantly than in any other group. In contrast, ROS levels in the HT+RT+NAC group were significantly decreased relative to the HT+RT group. The number of autophagic bodies in HT+RT group was higher than that of mock group. There were significant increases in the expression of Beclin1 and LC3B genes, while mTOR expression was significantly decreased in the HT+CT group. Treatment with NAC reversed the pattern of these changes. These results indicate that HT enhances the radiosensitivity of colorectal cancer cells to RT through ROS inducing autophagic cell death.	[Ba, Ming-Chen; Wang, Shuai; Wu, Yin-Bing; Zhang, Bo-Huo; Yan, Zhao-Fei; Yu, Fei-Hong; Cui, Shu-Zhong] Guangzhou Med Univ, Canc Hosp & Inst, Intracelom Hypertherm Perfus Therapy Ctr, Guangzhou, Guangdong, Peoples R China; [Long, Hui] Guangzhou Dermatol Inst, Dept Pharm, Guangzhou 510095, Guangdong, Peoples R China		Long, H (corresponding author), Guangzhou Dermatol Inst, Dept Pharm, Guangzhou 510095, Guangdong, Peoples R China.; Ba, MC (corresponding author), Guangzhou Med Univ, Canc Hosp, Intracelom Hypertherm Perfus Therapy Ctr, 78 Hengzhigang Rd, Guangzhou 510095, Guangdong, Peoples R China.	medbamc@126.com; bil368@163.com			Guangzhou Key Medical Discipline Construction Project [2006Z1-E6041]; Guangdong Science and Technology Plan Project [2009A030301013]; Guangzhou Science Technology and Innovation Commission [2014Y2-00152, 2014Y2-00548]	Guangzhou Key Medical Discipline Construction Project, Grant number: 2006Z1-E6041; Guangdong Science and Technology Plan Project, Grant number: 2009A030301013; Guangzhou Science Technology and Innovation Commission, Grant numbers: 2014Y2-00152, 2014Y2-00548	Aladag I, 2016, J LARYNGOL OTOL, V130, P440, DOI 10.1017/S0022215116000992; ARMOUR EP, 1993, CANCER RES, V53, P2740; Atkinson RL, 2010, SCI TRANSL MED, V2, DOI 10.1126/scitranslmed.3001447; Baratti D, 2014, DIS COLON RECTUM, V57, P858, DOI 10.1097/DCR.0000000000000149; Barsukov YA, 2013, COLORECTAL DIS, V15, P1107, DOI 10.1111/codi.12281; Cao Y, 2016, HEMATOLOGY, V21, P613, DOI 10.1080/10245332.2016.1165446; Chen F, 2008, CELL BIOL INT, V32, P715, DOI 10.1016/j.cellbi.2008.02.010; Chen WQ, 2015, CHINESE J CANCER RES, V27, P2, DOI 10.3978/j.issn.1000-9604.2015.01.06; Cho YY, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0057172; Choi J, 2013, HISTOPATHOLOGY, V62, P275, DOI 10.1111/his.12002; Cui K, 2004, PROG NEURO-PSYCHOPH, V28, P771, DOI 10.1016/j.pnpbp.2004.05.023; Devun F, 2014, RADIOLOGY, V270, P736, DOI 10.1148/radiol.13130805; Dickinson BC, 2011, NAT CHEM BIOL, V7, P504, DOI [10.1038/NCHEMBIO.607, 10.1038/nchembio.607]; Failli A, 2009, TUMORI J, V95, P343; Falk MH, 2001, INT J HYPERTHER, V17, P1, DOI 10.1080/02656730150201552; Fleury C, 2002, BIOCHIMIE, V84, P131, DOI 10.1016/S0300-9084(02)01369-X; HOCKENBERY DM, 1993, CELL, V75, P241, DOI 10.1016/0092-8674(93)80066-N; Imaoka T, 2016, INT J RADIAT BIOL, V92, P289, DOI 10.3109/09553002.2016.1152413; Jabs T, 1999, BIOCHEM PHARMACOL, V57, P231, DOI 10.1016/S0006-2952(98)00227-5; Kang MR, 2009, J PATHOL, V217, P702, DOI 10.1002/path.2509; Kattan Z, 2008, BREAST CANCER RES TR, V108, P203, DOI 10.1007/s10549-007-9597-5; Klaver YLB, 2013, STRAHLENTHER ONKOL, V189, P256, DOI 10.1007/s00066-012-0282-1; Lehmann K, 2012, ANN SURG, V256, P730, DOI 10.1097/SLA.0b013e3182737517; Lemasters JJ, 1998, BBA-BIOENERGETICS, V1366, P177, DOI 10.1016/S0005-2728(98)00112-1; Lock R, 2011, MOL BIOL CELL, V22, P165, DOI 10.1091/mbc.E10-06-0500; Ma GX, 2016, CHEM-BIOL INTERACT, V253, P1, DOI 10.1016/j.cbi.2016.04.028; Masunaga S, 1997, JPN J CANCER RES, V88, P770, DOI 10.1111/j.1349-7006.1997.tb00449.x; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Nicco C, 2005, BIOMED PHARMACOTHER, V59, P169, DOI 10.1016/j.biopha.2005.03.009; Pelicano H, 2004, DRUG RESIST UPDATE, V7, P97, DOI 10.1016/j.drup.2004.01.004; Reggiori F, 2002, EUKARYOT CELL, V1, P11, DOI 10.1128/EC.01.1.11-21.2002; Renschler MF, 2004, EUR J CANCER, V40, P1934, DOI 10.1016/j.ejca.2004.02.031; Scherz-Shouval R, 2007, EMBO J, V26, P1749, DOI 10.1038/sj.emboj.7601623; Scherz-Shouval R, 2011, TRENDS BIOCHEM SCI, V36, P30, DOI 10.1016/j.tibs.2010.07.007; Schroeder C, 2012, INT J HYPERTHER, V28, P707, DOI 10.3109/02656736.2012.722263; Senturker S, 1997, FEBS LETT, V416, P286, DOI 10.1016/S0014-5793(97)01226-X; Siegel EM, 2014, DIS COLON RECTUM, V57, P941, DOI 10.1097/DCR.0000000000000160; Thannickal VJ, 2000, AM J PHYSIOL-LUNG C, V279, pL1005; Torre LA, 2015, CA-CANCER J CLIN, V65, P87, DOI 10.3322/caac.21262; Toth S, 2002, CELL TISSUE RES, V309, P409, DOI 10.1007/s00441-001-0506-7; Vurusaner B, 2012, FREE RADICAL BIO MED, V52, P7, DOI 10.1016/j.freeradbiomed.2011.09.035; Wang CC, 2007, SURGERY, V142, P384, DOI 10.1016/j.surg.2007.03.013; Wu WKK, 2012, ONCOGENE, V31, P939, DOI 10.1038/onc.2011.295; Yang L, 2011, W INDIAN MED J, V60, P107; Yorimitsu T, 2007, TRENDS CELL BIOL, V17, P279, DOI 10.1016/j.tcb.2007.04.005; Zhang J, 2015, BIO-MED MATER ENG, V26, pS2259, DOI 10.3233/BME-151532; Zhou WH, 2012, AUTOPHAGY, V8, P389, DOI 10.4161/auto.18641; Zhu JJ, 2016, LIFE SCI, V151, P115, DOI 10.1016/j.lfs.2016.02.014	48	5	5	1	27	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0730-2312	1097-4644		J CELL BIOCHEM	J. Cell. Biochem.	APR	2018	119	4					3763	3774		10.1002/jcb.26615			12	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	FX6IO	WOS:000426187500072	29240246				2022-04-25	
J	Yu, ZY; Wang, Z; Lee, KY; Yuan, P; Ding, J				Yu, Zhao-Yan; Wang, Zi; Lee, Ke-Yue; Yuan, Ping; Ding, Jie			Effect of silencing colon cancer-associated transcript 2 on the proliferation, apoptosis and autophagy of gastric cancer BGC-823 cells	ONCOLOGY LETTERS			English	Article						gastric cancer; long non-coding RNA; colon cancer-associated transcript 2; POU domain class 5 transcription factor 1B; apoptosis; autophagy	NONCODING RNA CCAT2; POOR-PROGNOSIS; SUSCEPTIBILITY; METAANALYSIS; METASTASIS; BECLIN-1; PATHWAY; GROWTH; 8Q24	The role of long non-coding RNAs (lncRNAs) in the carcinogenesis and progression of tumors has been receiving increasing attention. Colon cancer-associated transcript 2 (CCAT2), a type of oncogenic lncRNA, is regarded as a novel biomarker of poor prognosis and metastasis in various types of cancer. However, the molecular contributions of CCAT2 to gastric cancer (GC) progression remain largely unclear. The aim of the present study was to demonstrate the effect of silencing CCAT2 on the biological behavior of GC BGC-823 cells and illustrate the potential underlying molecular mechanisms. A short hairpin RNA interference plasmid pRNAT-U6.1-CCAT2 targeting CCAT2 was successfully constructed. At 48 h after transfection with the interference plasmid, the survival rate of BGC-823 cells was significantly decreased, as determined by the MTT assay. In addition, RT-qPCR results revealed that CCAT2 gene expression was effectively suppressed by the transfection, while POU domain class 5 transcription factor 1B (POU5F1B) gene expression was significantly decreased. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay further revealed that the apoptotic index was significantly higher in the interference group. Western blot analysis also demonstrated that the expression of beclin-1 protein was significantly increased, whereas the expression levels of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) proteins were downregulated in the interference group. In conclusion, CCAT2 was able to positively regulate the expression of POU5F1B gene. Furthermore, silencing of CCAT2 gene inhibited the proliferation of BGC-823 cells, as well as induced apoptosis and autophagy in BGC-823 cells, by suppression of the PI3K/mTOR signaling pathways.	[Yu, Zhao-Yan; Yuan, Ping; Ding, Jie] Guizhou Prov Peoples Hosp, Dept Gen Surg, 83 East Zhongshan Rd, Guiyang 550002, Guizhou, Peoples R China; [Wang, Zi] Guizhou Prov Peoples Hosp, Dept Oncol, Guiyang 550002, Guizhou, Peoples R China; [Lee, Ke-Yue] Guizhou Prov Peoples Hosp, Dept Hepatobiliary Surg, Guiyang 550002, Guizhou, Peoples R China		Ding, J (corresponding author), Guizhou Prov Peoples Hosp, Dept Gen Surg, 83 East Zhongshan Rd, Guiyang 550002, Guizhou, Peoples R China.	djofgzsy@163.com			Guizhou Provincial Fund Project of Science and Technology [(2015)2095]; Science and Technology Fund Projects of Guizhou Provincial Health and Family Planning Commission [gzwjkj2015-1-019]; Joint Fund Project of Guizhou Provincial Science and Technology Agency [(2015)7170]	This study was supported by grants from the Guizhou Provincial Fund Project of Science and Technology [grant no. (2015)2095], the Science and Technology Fund Projects of Guizhou Provincial Health and Family Planning Commission (grant no. gzwjkj2015-1-019), and the Joint Fund Project of Guizhou Provincial Science and Technology Agency [grant no. (2015)7170].	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Lett.	MAR	2018	15	3					3127	3132		10.3892/ol.2017.7677			6	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GD9FK	WOS:000430818300055	29435046	Green Published, gold			2022-04-25	
J	Soria, NGC; Aga, DS; Atilla-Gokcumen, GE				Soria, N. G. Chavez; Aga, D. S.; Atilla-Gokcumen, G. E.			Lipidomics reveals insights on the biological effects of copper oxide nanoparticles in a human colon carcinoma cell line	MOLECULAR OMICS			English	Article							SPECTROMETRY-BASED METABOLOMICS; CUO NANOPARTICLES; TOXICITY; TRIACYLGLYCEROLS; MECHANISM; AUTOPHAGY; BEHAVIOR; LIPIDS	Engineered nanomaterials have unique properties compared to their bulk counterparts. Copper oxide nanoparticles (CuO NPs) are one example of nanomaterials used in a wide range of consumer products due to their conductivity and biocidal properties. While CuO NPs can induce toxicity in various organisms, their interactions with different organisms and how they affect cellular homeostasis is yet to be fully understood. In this work, the toxicity of CuO NPs was evaluated in different human cell lines (colorectal carcinoma, cervical cancer, embryonic kidney, and lung fibroblast), showing a dose-dependent toxicity. An untargeted lipidomics approach using liquid chromatography-quadrupole time of flight mass spectrometry was employed in a human colon carcinoma cell line to investigate the impact of CuO NP exposure at the cellular level. A 24 h CuO NP exposure at 2.5 and 5 mu g mL(-1) resulted in upregulation of different metabolites: triacylglycerols, phosphatidylcholines, and ceramides accumulated. The most profound increase in a dose-dependent manner was observed in ceramides, specifically in C18:0, C18:1, and C22:0 species, with up to similar to 10 fold accumulations. Further experiments suggested that activation of autophagy and oxidative stress could be responsible for the toxicity observed in these cell lines. Increases in the level of glutathione oxide (similar to 7 fold) also supported the activation of oxidative stress upon CuO NP treatment. Based on the changes in different metabolites induced by CuO NP exposure and previous studies from our laboratory, we propose that autophagy and oxidative stress could play a role in CuO NP-induced toxicity.	[Soria, N. G. Chavez; Aga, D. S.; Atilla-Gokcumen, G. E.] SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA		Aga, DS; Atilla-Gokcumen, GE (corresponding author), SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA.	dianaaga@buffalo.edu; ekinatil@buffalo.edu		Aga, Diana/0000-0001-6512-7713; Chavez Soria, Nita/0000-0003-2303-6914	National Science FoundationNational Science Foundation (NSF) [CHE1506295, CHE-0959565, MCB1817468]	We acknowledge the support from the National Science Foundation grant CHE1506295 (to D. S. A.) and MCB1817468 (to G. E. A.-G.). We would like to thank the Instrument Center, specifically Dr Valerie Frerichs (UB, Department of Chemistry). This work utilized Inductively Coupled Plasma Mass Spectrometry instrument that was purchased with funding from National Science Foundation (CHE-0959565). We also would like to thank Yueling Qin (UB, Department of Chemistry) for his help with TEM.	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K, 2014, OXIDE NANOSTRUCTURES; Storck EM, 2018, ANNU REV BIOCHEM, V87, P839, DOI 10.1146/annurev-biochem-062917-012448; Sun TT, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0043442; Tautenhahn R, 2012, NAT BIOTECHNOL, V30, P826, DOI 10.1038/nbt.2348; TUKEY JW, 1949, BIOMETRICS, V5, P99, DOI 10.2307/3001913; Wongrakpanich A, 2016, ENVIRON SCI-NANO, V3, P365, DOI 10.1039/c5en00271k; Xia T, 2008, ACS NANO, V2, P2121, DOI 10.1021/nn800511k; Zhu ZJ, 2013, NAT PROTOC, V8, P451, DOI 10.1038/nprot.2013.004	42	13	15	2	21	ROYAL SOC CHEMISTRY	CAMBRIDGE	THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND		2515-4184		MOL OMICS	Mol. Omics	FEB 1	2019	15	1					30	38		10.1039/c8mo00162f			9	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	HM6HN	WOS:000459574900009	30560257				2022-04-25	
J	Holloway, KR; Calhoun, TN; Saxena, M; Metoyer, CF; Kandler, EF; Rivera, CA; Pruitt, K				Holloway, Kimberly R.; Calhoun, Tara N.; Saxena, Madhurima; Metoyer, Cheynita F.; Kandler, Ethan F.; Rivera, Chantal A.; Pruitt, Kevin			SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA			English	Article						breast cancer; colon cancer; cambinol; beta-catenin; sirtuin 2	BONE MORPHOGENETIC PROTEIN-4; BETA-CATENIN; CANCER-CELLS; COLORECTAL-CANCER; PATHWAY ACTIVATION; PROSTATE-CANCER; COLON-CANCER; LUNG-CANCER; DNA-DAMAGE; CYCLIN D1	Sirtuin 1 (SIRT1) is a class III histone deacetylase that deacetylates histone and nonhistone proteins to regulate gene transcription and protein function. Because SIRT1 regulates very diverse responses such as apoptosis, insulin sensitivity, autophagy, differentiation, and stem cell pluripotency, it has been a challenge to reconcile how it orchestrates such pleiotropic effects. Here we show that SIRT1 serves as an important regulator of Wnt signaling. We demonstrate that SIRT1 loss of function leads to a significant decrease in the levels of all three Dishevelled (Dvl) proteins. Furthermore, we demonstrate that SIRT1 and Dvl proteins complex in vivo and that inhibition of SIRT1 leads to changes in gene expression of Wnt target genes. Finally, we demonstrate that Wnt-stimulated cell migration is inhibited by a SIRT1 inhibitor. Because the three mammalian Dvl proteins serve as key messengers for as many as 19 Wnt ligands, SIRT1-mediated regulation of Dvl proteins may explain the diverse physiological responses observed in different cellular contexts. Previously, SIRT1 had only been shown to mediate the epigenetic silencing of Wnt antagonists. In contrast, here we report that SIRT1 regulates Dvl protein levels and Wnt signaling in several cellular contexts. These findings demonstrate that SIRT1 is a regulator of transient and constitutive Wnt signaling.	[Holloway, Kimberly R.; Calhoun, Tara N.; Saxena, Madhurima; Kandler, Ethan F.; Rivera, Chantal A.; Pruitt, Kevin] Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA; [Holloway, Kimberly R.; Calhoun, Tara N.; Saxena, Madhurima; Metoyer, Cheynita F.; Kandler, Ethan F.; Rivera, Chantal A.; Pruitt, Kevin] Louisiana State Univ, Hlth Sci Ctr, Sch Med, Shreveport, LA 71130 USA; [Pruitt, Kevin] Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, Shreveport, LA 71130 USA		Pruitt, K (corresponding author), Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA.	kpruit@lsuhsc.edu			Feist-Weiller Cancer Center	Our research was supported by an intramural grant to K.P. from the Feist-Weiller Cancer Center.	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Natl. Acad. Sci. U. S. A.	MAY 18	2010	107	20					9216	9221		10.1073/pnas.0911325107			6	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	598GH	WOS:000277822600037	20439735	Green Published			2022-04-25	
J	Sun, X; Shu, YH; Yan, PY; Huang, HL; Gao, RL; Xu, MT; Lu, LQ; Tian, JK; Huang, DS; Zhang, JB				Sun, Xin; Shu, Yuhan; Yan, Peiyi; Huang, Hongliang; Gao, Ruilan; Xu, Mengting; Lu, Liqin; Tian, Jingkui; Huang, Dongsheng; Zhang, Jianbin			Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib	CELL DEATH & DISEASE			English	Article							MOLECULAR-CLONING; NUCLEAR-PROTEIN; PHASE-II; AUTOPHAGY; MTORC1; MULTICENTER; DEGRADATION; EXPRESSION; CANCER; TRIAL	Anlotinib is a receptor tyrosine kinase inhibitor with potential anti-neoplastic and anti-angiogenic activities. It has been approved for the treatment of non-small-cell lung cancer. Lysosomes are acidic organelles and have been implicated in various mechanisms of cancer therapeutics. However, the effect of anlotinib on lysosomal function has not been investigated. In the present study, anlotinib induces apoptosis in human colon cancer cells. Through transcriptome sequencing, we found for the first time that anlotinib treatment upregulates ATP6V0E2 (ATPase H(+)Transporting V0 Subunit E2) and other lysosome-related genes expression in human colon cancer. In human colon cancer, we validated that anlotinib activates lysosomal function and enhances the fusion of autophagosomes and lysosomes. Moreover, anlotinib treatment is shown to inhibit mTOR (mammalian target of rapamycin) signaling and the activation of lysosomal function by anlotinib is mTOR dependent. Furthermore, anlotinib treatment activates TFEB, a key nuclear transcription factor that controls lysosome biogenesis and function. We found that anlotinib treatment promotes TFEB nuclear translocation and enhances its transcriptional activity. When TFEB or ATP6V0E2 are knocked down, the enhanced lysosomal function and autophagy by anlotinib are attenuated. Finally, inhibition of lysosomal function enhances anlotinib-induced cell death and tumor suppression, which may be attributed to high levels of ROS (reactive oxygen species). These findings suggest that the activation of lysosomal function protects against anlotinib-mediated cell apoptosis via regulating the cellular redox status. Taken together, our results provide novel insights into the regulatory mechanisms of anlotinib on lysosomes, and this information could facilitate the development of potential novel cancer therapeutic agents that inhibit lysosomal function.	[Sun, Xin; Lu, Liqin; Zhang, Jianbin] Hangzhou Med Coll, Zhejiang Prov Peoples Hosp, Dept Oncol, Peoples Hosp, Hangzhou, Peoples R China; [Shu, Yuhan; Xu, Mengting; Tian, Jingkui] Zhejiang Univ, Coll Biomed Engn & Instrument Sci, Hangzhou, Peoples R China; [Yan, Peiyi] Shanghai Putuo Dist Peoples Hosp, Dept Clin Lab, Shanghai, Peoples R China; [Huang, Hongliang] Guangdong Pharmaceut Univ, Sch Biosci & Biopharmaceut, Guangzhou, Peoples R China; [Huang, Hongliang] Guangdong Pharmaceut Univ, Ctr Bioresources & Drug Discovery, Guangzhou, Peoples R China; [Gao, Ruilan] Zhejiang Chinese Med Univ, Inst Hematol Res, Affiliated Hosp 1, Hangzhou, Peoples R China; [Huang, Dongsheng; Zhang, Jianbin] Hangzhou Med Coll, Clin Res Inst, Key Lab Tumor Mol Diag & Individualized Med Zheji, Peoples Hosp, Hangzhou, Peoples R China		Zhang, JB (corresponding author), Hangzhou Med Coll, Zhejiang Prov Peoples Hosp, Dept Oncol, Peoples Hosp, Hangzhou, Peoples R China.; Tian, JK (corresponding author), Zhejiang Univ, Coll Biomed Engn & Instrument Sci, Hangzhou, Peoples R China.; Huang, DS; Zhang, JB (corresponding author), Hangzhou Med Coll, Clin Res Inst, Key Lab Tumor Mol Diag & Individualized Med Zheji, Peoples Hosp, Hangzhou, Peoples R China.	tjk@zju.edu.cn; dshuang@zju.edu.cn; zhangjianbin@hmc.edu.cn			Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LR18H160002]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31701199, 81703907]; Traditional Chinese Medicine Scientific Research Fund Project of Zhejiang Province [2018ZB010]; Zhejiang Provincial Program in Medicine and Health Sciences and Technology [2018253645]; Zhejiang Provincial Outstanding Talent Project of Ten Thousand Talents Program, Zhejiang Provincial Qianjiang Talents Program	This work was supported by research grants from Zhejiang Provincial Natural Science Foundation of China (LR18H160002), National Natural Science Foundation of China (31701199), Traditional Chinese Medicine Scientific Research Fund Project of Zhejiang Province (2018ZB010), Zhejiang Provincial Program in Medicine and Health Sciences and Technology (2018253645), Zhejiang Provincial Outstanding Talent Project of Ten Thousand Talents Program, Zhejiang Provincial Qianjiang Talents Program to Z.J. and National Natural Science Foundation of China (81703907) to S.X.	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AUG 24	2020	11	8							702	10.1038/s41419-020-02904-0			15	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	NK8MF	WOS:000566984200002	32839434	gold, Green Published			2022-04-25	
J	Zhao, J; Dong, JN; Wang, HG; Zhao, M; Sun, J; Zhu, WM; Zuo, LG; Gong, JF; Li, Y; Gu, LL; Li, N; Li, JS				Zhao, Jie; Dong, Jian-Ning; Wang, Hong-Gang; Zhao, Mingli; Sun, Jing; Zhu, Wei-Ming; Zuo, Lu-Gen; Gong, Jian-Feng; Li, Yi; Gu, Li-Li; Li, Ning; Li, Jie-Shou			Docosahexaenoic Acid Attenuated Experimental Chronic Colitis in Interleukin 10-Deficient Mice by Enhancing Autophagy Through Inhibition of the mTOR Pathway	JOURNAL OF PARENTERAL AND ENTERAL NUTRITION			English	Article						Crohn's disease; interleukin 10-deficient mice; docosahexaenoic acid; autophagy; mTOR pathway	INFLAMMATORY BOWEL DISEASES; POLYUNSATURATED FATTY-ACIDS; CROHNS-DISEASE; EICOSAPENTAENOIC ACID; CELLS; CANCER; APOPTOSIS; IMMUNITY; OMEGA-3-FATTY-ACIDS; MODULATION	Background: In the battle against Crohn's disease, autophagy stimulation is a promising therapeutic optionone both new and newly rediscovered. In experimental models, docosahexaenoic acid (DHA)a long-chain polyunsaturated fatty acidhas been demonstrated to be useful in the treatment of inflammatory bowel disease through inhibition of the nuclear factor-B pathway. However, the impact of DHA on autophagy in the colon remains unclear. Methods: Mice were divided into 3 groups: wild type (placebo), the interleukin 10 knockout group (IL-10(-/-), placebo), and the DHA group (IL-10(-/-), DHA). DHA was administered to IL-10(-/-) mice by gavage at a dosage of 35.5 mg/kg/d for 2 weeks. The severity of colitis, expression of proinflammatory cytokines, expression/distribution of LC3B, and mTOR signaling pathway were evaluated in the proximal colon tissues collected from all mice at the end of the experiment. Results: DHA administration ameliorated experimental colitis in the IL-10(-/-) mice, as demonstrated by decreased proinflammatory cytokines (TNF- and IFN-), reduced infiltration of inflammatory cells, and lowered histologic scores of the proximal colon mucosa. Moreover, in the DHA-treated mice, enhanced autophagy was observed to be associated with (1) increased expression and restoration of the distribution integrity of LC3B in the colon and (2) inhibition of the mTOR signaling pathway. Conclusion: This study showed that DHA therapy could attenuate experimental chronic colitis in IL-10(-/-) mice by triggering autophagy via inhibition of the mTOR pathway.	[Zhao, Jie; Dong, Jian-Ning; Wang, Hong-Gang; Zhao, Mingli; Sun, Jing; Zhu, Wei-Ming; Zuo, Lu-Gen; Gong, Jian-Feng; Li, Yi; Gu, Li-Li; Li, Ning; Li, Jie-Shou] Nanjing Univ, Sch Med, Jinling Hosp, Dept Gen Surg, 305 East Zhongshan Rd, Nanjing 210002, Jiangsu, Peoples R China		Zhu, WM (corresponding author), Nanjing Univ, Sch Med, Jinling Hosp, Dept Gen Surg, 305 East Zhongshan Rd, Nanjing 210002, Jiangsu, Peoples R China.	zhuweimingtg@163.com			National Ministry of Health for Digestive Disease [201002020]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81200263, 81170365, 81270006]; Jiangsu Provincial Special Program of Medical Science [BL2012006]	This work was supported in part by funding from the National Ministry of Health for Digestive Disease (grant 201002020), the National Natural Science Foundation of China (grants 81200263, 81170365, 81270006), and Jiangsu Provincial Special Program of Medical Science (BL2012006).	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Parenter. Enter. Nutr.	JUL	2017	41	5					824	829		10.1177/0148607115609308			6	Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Nutrition & Dietetics	FC1WU	WOS:000406629400012	26407598				2022-04-25	
J	Wu, JC; Wang, FZ; Tsai, ML; Lo, CY; Badmaev, V; Ho, CT; Wang, YJ; Pan, MH				Wu, Jia-Ching; Wang, Fang-Zong; Tsai, Mei-Ling; Lo, Chih-Yu; Badmaev, Vladimir; Ho, Chi-Tang; Wang, Ying-Jan; Pan, Min-Hsiung			Se-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal adenocarcinoma cells	MOLECULAR NUTRITION & FOOD RESEARCH			English	Article						Autophagy; DNA methylation; Epigenetic; Se-allylselenocysteine; PCDH17	DNA METHYLTRANSFERASE 1; SELENOAMINO ACIDS; CANCER PREVENTION; TUMOR-SUPPRESSOR; GASTRIC-CANCER; SELENIUM; DEATH; APOPTOSIS; METHYLATION; ACTIVATION	Scope: Selenium ( Se)-conjugated compounds have been established as anti-carcinogenic compounds. The use of chemicals as cancer chemotherapeutic agents to induce programmed cell death (PCD) involves genetic and epigenetic modifications. In this study, we investigated the underlying molecular mechanisms of Se-allylselenocysteine (ASC)-induced PCD and protocadherin 17 (PCDH17) expression in HT-29 cells. Methods and results: Cell viability analysis indicated that the ability of ASC to induce cancer cell death was greater than that of Se-methylselenocysteine in colorectal cancer cells. ASC also decreased global DNA methylation levels via downregulation of DNA methyltransferase 1 expression. The autophagic cell death is the cause in ASC-induced cytotoxicity that was inhibited by pretreatment with autophagy inhibitor. At the molecular level, ASC induced PCDH17 expression through decreased PCDH17 promoter hypermethylation. PCDH17 is also an important role in ASC-induced autophagy by HT-29 transfected with PCDH17 shRNA or expression plasmid. Our western blot analysis showed that ASC significantly induced autophagy via the AMPK/mTOR pathway that was also regulated PCDH17 expression. Additionally, we used the HT-29 tumor xenograft models to confirm the ability of ASC inhibited tumor growth. Conclusion: These results reveal that ASC is an effective inducer of autophagy through regulating the AMPK/mTOR and PCDH17 expression via epigenetic modification.	[Wu, Jia-Ching; Wang, Ying-Jan] Natl Cheng Kung Univ, Coll Med, Dept Environm & Occupat Hlth, Tainan 70101, Taiwan; [Wang, Fang-Zong; Tsai, Mei-Ling] Natl Kaohsiung Marine Univ, Dept Seafood Sci, Kaohsiung, Taiwan; [Lo, Chih-Yu] Natl Chiayi Univ, Dept Food Sci, Chiayi 60004, Taiwan; [Badmaev, Vladimir] Amer Med Holdings Inc, New York, NY USA; [Ho, Chi-Tang] Rutgers State Univ, Dept Food Sci, New Brunswick, NJ 08903 USA; [Wang, Ying-Jan] Asia Univ, Dept Biomed Informat, Taichung, Taiwan; [Wang, Ying-Jan; Pan, Min-Hsiung] China Med Univ, China Med Univ Hosp, Dept Med Res, Taichung, Taiwan; [Pan, Min-Hsiung] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung, Taiwan; [Pan, Min-Hsiung] Natl Taiwan Univ, Inst Food Sci & Technol, Taipei 10764, Taiwan		Pan, MH (corresponding author), China Med Univ, China Med Univ Hosp, Dept Med Res, Taichung, Taiwan.	mhpan@ntu.edu.tw	Pan, Min-Hsiung/AAT-8865-2021	Pan, Min-Hsiung/0000-0002-5188-7030	National Taiwan UniversityNational Taiwan University [NTU-104R7777]; Ministry of Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [101-2628-B-022-001-MY4, 102-2628-B-002-053-MY3]	This study was supported by the National Taiwan University NTU-104R7777; Ministry of Science and Technology101-2628-B-022-001-MY4, 102-2628-B-002-053-MY3	Aryal P, 2014, FEBS J, V281, P4644, DOI 10.1111/febs.12969; CAI XJ, 1995, J AGR FOOD CHEM, V43, P1754, DOI 10.1021/jf00055a002; Cheishvili D, 2015, BRIT J PHARMACOL, V172, P2705, DOI 10.1111/bph.12885; Cheng YC, 2015, EXP BIOL MED, V240, P467, DOI 10.1177/1535370214553772; Coffin JC, 2000, TOXICOL SCI, V58, P243, DOI 10.1093/toxsci/58.2.243; Commandeur JNM, 2001, ADV EXP MED BIOL, V500, P105; Elmore S, 2007, TOXICOL PATHOL, V35, P495, DOI 10.1080/01926230701320337; Feldman J.P., 2009, J APPL QUANT METHODS, V4, P455; Ganther HE, 1999, CARCINOGENESIS, V20, P1657, DOI 10.1093/carcin/20.9.1657; Haruki S, 2010, CARCINOGENESIS, V31, P1027, DOI 10.1093/carcin/bgq053; Hu XT, 2013, J PATHOL, V229, P62, DOI 10.1002/path.4093; Ip C, 1999, ANTICANCER RES, V19, P2875; Jia Y, 2013, CHIN J CANCER, V32, P21, DOI 10.5732/cjc.011.10245; Jiang WQ, 2001, CANCER LETT, V162, P167, DOI 10.1016/S0304-3835(00)00647-9; Joseph J, 2013, NUTRIENTS, V5, P340, DOI 10.3390/nu5020340; Klionsky DJ, 2012, AUTOPHAGY, V8, P445, DOI 10.4161/auto.19496; Larsen EH, 2001, J ANAL ATOM SPECTROM, V16, P1403, DOI 10.1039/b106355n; Larsen EH, 2006, ANAL BIOANAL CHEM, V385, P1098, DOI 10.1007/s00216-006-0535-x; Liu Man, 2013, Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, V29, P809; Mathew R, 2007, NAT REV CANCER, V7, P961, DOI 10.1038/nrc2254; Michalska-Kacymirow M, 2014, ANAL BIOANAL CHEM, V406, P3717, DOI 10.1007/s00216-014-7742-7; Mihaylova MM, 2011, NAT CELL BIOL, V13, P1016, DOI 10.1038/ncb2329; Mukhtar E, 2012, CURR DRUG TARGETS, V13, P1831, DOI 10.2174/138945012804545489; Ouyang L, 2012, CELL PROLIFERAT, V45, P487, DOI 10.1111/j.1365-2184.2012.00845.x; Pan MH, 2008, CHEM SOC REV, V37, P2558, DOI 10.1039/b801558a; Pan MH, 2011, MOL NUTR FOOD RES, V55, P723, DOI 10.1002/mnfr.201000481; Qu YP, 2013, CLIN CHIM ACTA, V424, P53, DOI 10.1016/j.cca.2013.05.002; Ren J, 2011, CELL SIGNAL, V23, P1082, DOI 10.1016/j.cellsig.2011.02.003; Sadikovic B, 2008, CURR GENOMICS, V9, P394, DOI 10.2174/138920208785699580; Sanmartin C, 2012, INT J MOL SCI, V13, P9649, DOI 10.3390/ijms13089649; Sheng Y, 2013, BIOCHEM BIOPH RES CO, V432, P5, DOI 10.1016/j.bbrc.2013.01.106; Shi WY, 2012, CELL DEATH DIS, V3, DOI 10.1038/cddis.2012.13; Sui XB, 2012, MOL BIOL REP, V39, P1105, DOI 10.1007/s11033-011-0837-8; Sun H, 2013, ANTI-CANCER AGENT ME, V13, P1048, DOI 10.2174/18715206113139990130; 't Hoen PAC, 2002, BIOCHEM PHARMACOL, V63, P1843, DOI 10.1016/S0006-2952(02)00987-5; Tanida I, 2012, AUTOPHAGY, V8, P88, DOI 10.4161/auto.8.1.18339; van Eersel J, 2010, P NATL ACAD SCI USA, V107, P13888, DOI 10.1073/pnas.1009038107; Walczak M, 2013, AUTOPHAGY, V9, P424, DOI 10.4161/auto.22931; Wang Juan, 2008, Ai Zheng, V27, P119; Wang XB, 2014, J INT MED RES, V42, P292, DOI 10.1177/0300060513504364; Wu JC, 2011, MOL NUTR FOOD RES, V55, P1646, DOI 10.1002/mnfr.201100454; Wu SB, 2014, BBA-GEN SUBJECTS, V1840, P1331, DOI 10.1016/j.bbagen.2013.10.034; Yang YQ, 2012, HISTOL HISTOPATHOL, V27, P217, DOI 10.14670/HH-27.217; Yie YY, 2015, MOL CELL BIOCHEM, V402, P63, DOI 10.1007/s11010-014-2314-x; Zhang YX, 2012, NUCLEIC ACIDS RES, V40, P4850, DOI 10.1093/nar/gks159; Zhao SY, 2015, J CELL MOL MED, V19, P630, DOI 10.1111/jcmm.12476	46	21	21	1	15	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	1613-4125	1613-4133		MOL NUTR FOOD RES	Mol. Nutr. Food Res.	DEC	2015	59	12					2511	2522		10.1002/mnfr.201500373			12	Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology	DA3WJ	WOS:000367730600015	26395119				2022-04-25	
J	Lin, S; Wang, HB; Yang, WJ; Wang, AG; Geng, C				Lin, Sen; Wang, Hongbo; Yang, Wenjuan; Wang, Aiguang; Geng, Chao			Silencing of Long Non-Coding RNA Colon Cancer-Associated Transcript 2 Inhibits the Growth and Metastasis of Gastric Cancer Through Blocking mTOR Signaling	ONCOTARGETS AND THERAPY			English	Article						colon cancer-associated transcript 2; gastric cancer; mammalian target of rapamycin; apoptosis; autophagy	PROMOTES CELL-PROLIFERATION; CCAT2 PROMOTES; THERAPEUTIC TARGET; AUTOPHAGY; EXPRESSION; APOPTOSIS	Purpose: This study aimed to evaluate the specific role of colon cancer-associated transcript 2 (CCAT2) on gastric cancer (GC), and reveal the potential regulatory mechanism relating to mammalian target of rapamycin (mTOR) signaling. Methods: The expression of CCAT2 was detected in GC tissues and cells by quantitative real-time PCR (qRT-PCR), and its relation with the pathologic characteristics of GC patients was analyzed. HGC-27 and SGC-7901 cells were transfected with siRNA-CCAT2 to silence CCAT2, and HGC-27 cells were then treated with an mTOR agonist Leucine (Leu) to activate mTOR signaling. The cell proliferation was evaluated by cell viability and colony formation. The cell cycle and apoptosis, and the migration and invasion abilities were detected by Flow cytometry, and Transwell assay, respectively. The expression of PCNA (proliferation marker), Snail, N-cadherin, E-cadherin (invasion markers), P53, Caspase-8, Bcl-2 (apoptosis markers), LC3-II/LC3-I, ATG3, p62 (autophagy makers), phosphorylated mTOR (p-mTOR), p-AKT, and p-p70S6K (mTOR signaling markers) were detected by Western blot. Results: CCAT2 was upregulated in GC tissues and cells, and positively associated with the maximum tumor diameter, lymphatic metastasis, TNM staging, and low overall survival rate (P < 0.05). siRNA-CCAT2 transfection significantly inhibited the viability, colony formation, and migration and invasion abilities, blocked the cell cycle in G0/G1 phase, and promoted the apoptosis and autophagy of SGC-7901 and HGC-27 cells (P < 0.05). In addition, siRNA-CCAT2 transfection significantly upregulated P53, Caspase-8, LC3-II/LC3-I and ATG3, and downregulated PCNA, Bcl-2, p62, p-mTOR, p-AKT and p-p70S6K in SGC-7901 and HGC-27 cells (P < 0.05). siRNA-CCAT2 reversed the tumor-promoting effect of mTOR signaling activation on HGC-27 cells (P < 0.05). Conclusion: Silencing of CCAT2 inhibited the proliferation, migration and invasion, and promoted the apoptosis and autophagy of GC cells through blocking mTOR signaling.	[Lin, Sen; Wang, Hongbo] Shandong Univ, Hosp 2, Dept Gastroenterol, 247 Beiyuan St, Jinan 250033, Shandong, Peoples R China; [Yang, Wenjuan] Jinan Cent Hosp, Dept Nursing, Jinan 250013, Shandong, Peoples R China; [Wang, Aiguang] Qianfoshan Hosp Shandong Prov, Dept Oncol, Jinan 250014, Shandong, Peoples R China; [Geng, Chao] Shouguang Peoples Hosp, Dept Gastroenterol, Shouguang City 262799, Shandong, Peoples R China		Lin, S (corresponding author), Shandong Univ, Hosp 2, Dept Gastroenterol, 247 Beiyuan St, Jinan 250033, Shandong, Peoples R China.	linsen334@163.com					Al-Batran SE, 2012, INT J CANCER, V130, P491, DOI 10.1002/ijc.26396; An JY, 2010, INT J CANCER, V126, P2904, DOI 10.1002/ijc.24872; Chang TK, 2013, NAT CELL BIOL, V15, P1067, DOI 10.1038/ncb2804; Deng X, 2017, BIOMED PHARMACOTHER, V91, P1160, DOI 10.1016/j.biopha.2017.05.030; Gozuacik D, 2017, FRONT ONCOL, V7, DOI 10.3389/fonc.2017.00065; Gu Y, 2015, FUTURE ONCOL, V11, P2427, DOI 10.2217/fon.15.175; Hewitt G, 2016, AUTOPHAGY, V12, P1917, DOI 10.1080/15548627.2016.1210368; Huang JY, 2013, ANN SURG ONCOL, V20, P3927, DOI 10.1245/s10434-013-3021-7; Ichimura Y, 2010, SEMIN IMMUNOPATHOL, V32, P431, DOI 10.1007/s00281-010-0220-1; Jemal A, 2011, CA-CANCER J CLIN, V61, P69, DOI [10.3322/caac.20107, 10.3322/caac.20115]; Kaur A, 2017, INFLAMMOPHARMACOLOGY, V25, P293, DOI 10.1007/s10787-017-0336-1; Kui W, 2011, AUTOPHAGY, V7, P13, DOI [10.4161/auto.7.5.14845, DOI 10.4161/AUTO.7.5.14845]; Lee HW, 2014, BMB REP, V47, P697, DOI 10.5483/BMBRep.2014.47.12.069; Li Z, 2016, CELL PROLIFERAT, V49, P471, DOI 10.1111/cpr.12269; Ling H, 2013, GENOME RES, V23, P1446, DOI 10.1101/gr.152942.112; Liu J, 2011, BMC CANCER, V11, DOI 10.1186/1471-2407-11-183; Liu K, 2016, AUTOPHAGY, V12, P2000, DOI 10.1080/15548627.2016.1212786; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Murayama T, 2009, BRIT J CANCER, V100, P782, DOI 10.1038/sj.bjc.6604915; Ruan R, 2018, EUR REV MED PHARMACO, V22, P2978, DOI 10.26355/eurrev_201805_15053; Schlafli AM, 2016, ONCOTARGET, V7, P39544, DOI 10.18632/oncotarget.9647; Schmitt AM, 2016, CANCER CELL, V29, P452, DOI 10.1016/j.ccell.2016.03.010; Schuler M, 2001, BIOCHEM SOC T, V29, P684, DOI 10.1042/BST0290684; Tanida Isei, 2008, V445, P77, DOI 10.1007/978-1-59745-157-4_4; Wang BD, 2018, ONCOL LETT, V15, P3369, DOI 10.3892/ol.2017.7669; Wang CY, 2015, INT J CLIN EXP PATHO, V8, P779; Wang YJ, 2016, AM J CANCER RES, V6, P2651; Wu SW, 2017, MINERVA MED, V108, P317, DOI 10.23736/S0026-4806.17.04703-6; Wu YouXing, 2016, Chinese Journal of Cancer Biotherapy, V23, P52; Wu ZJ, 2017, EUR REV MED PHARMACO, V21, P706; Xie P, 2017, CANCER BIOMARK, P1; Xin Y, 2017, CELL PROLIFERAT, V50, DOI 10.1111/cpr.12342; Yamashita K, 2011, WORLD J GASTROENTERO, V17, P3390, DOI 10.3748/wjg.v17.i29.3390; Ye YW, 2011, J SURG ONCOL, V104, P76, DOI 10.1002/jso.21896; Yi JH, 2017, ONCOTARGET, V8, P96656, DOI 10.18632/oncotarget.3750; Yu ZY, 2018, ONCOL LETT, V15, P3127, DOI 10.3892/ol.2017.7677	36	9	10	1	3	DOVE MEDICAL PRESS LTD	ALBANY	PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND	1178-6930			ONCOTARGETS THER	OncoTargets Ther.		2020	13						337	349		10.2147/OTT.S220302			13	Biotechnology & Applied Microbiology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Oncology	KC7ZB	WOS:000507390200001	32021279	Green Published, gold			2022-04-25	
J	Zeng, XL; Chen, SZ; Yang, Y; Ke, Z				Zeng, Xianliang; Chen, Sizeng; Yang, Yang; Ke, Zhao			Acylated and unacylated ghrelin inhibit atrophy in myotubes co-cultured with colon carcinoma cells	ONCOTARGET			English	Article						cancer cachexia; ghrelin; co-culture; calpain; myotube	SKELETAL-MUSCLE ATROPHY; CALPAIN INHIBITORS; MYOSTATIN; DEGRADATION; PROTEOLYSIS; PATHWAY; DIFFERENTIATION; MECHANISM; AUTOPHAGY; MODEL	Cancer cachexia is a result of increased protein degradation and decreased protein synthesis. The multifunctional circulating hormone ghrelin promotes synthesis and inhibits degradation of muscle protein, but its mechanism of action is not fully understood. Here, we investigated whether co-culturing C2C12 myotubes with CT26 colon carcinoma cells induces myotube atrophy, and whether acylated ghrelin (AG) and unacylated ghrelin (UnAG) had anti-atrophic effects. We found that co-culture induced myotube atrophy and increased tumor necrosis factor-alpha (TNF-alpha) and myostatin concentrations in the culture medium. Moreover, co-culture down-regulated myogenin and MyoD expression, inhibited the Akt signaling, up-regulated ubiquitin E3 ligase expression, and activated the calpain system and autophagy in myotubes. Both AG and UnAG inhibited these changes. Our study describes a novel in vitro model that can be employed to investigate cancer cachexia, and our findings suggest a possible use for AG and UnAG in treating cancer cachexia.	[Zeng, Xianliang; Chen, Sizeng; Yang, Yang; Ke, Zhao] Fujian Med Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, Fuzhou 350005, Fujian, Peoples R China		Chen, SZ (corresponding author), Fujian Med Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, Fuzhou 350005, Fujian, Peoples R China.	chensz04871@hotmail.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81272465]	This work was supported by the National Natural Science Foundation of China (No. 81272465).	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J	Zhou, WJ; Xu, G; Wang, YQ; Xu, Z; Liu, XF; Xu, X; Ren, GJ; Tian, KL				Zhou, Wenjing; Xu, Gang; Wang, Yunqiu; Xu, Ziao; Liu, Xiaofei; Xu, Xia; Ren, Guijie; Tian, Keli			Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells	CELL CYCLE			English	Article						autophagy; Colorectal cancer; co-culture; metabolism; oxidative stress; NAC; 3-MA	CARCINOMA-ASSOCIATED FIBROBLASTS; BREAST-CANCER; TUMOR MICROENVIRONMENT; STROMAL FIBROBLASTS; PHENOTYPE; GROWTH; CHEMOTHERAPY; CAVEOLIN-1; THERAPY	Tumors are comprised of malignant cancer cells and stromal cells which constitute the tumor microenvironment (TME). Previous studies have shown that cancer associated fibroblast (CAF) in TME is an important promoter of tumor initiation and progression. However, the underlying molecular mechanisms by which CAFs influence the growth of colorectal cancer cells (CRCs) have not been clearly elucidated. In this study, by using a non-contact co-culture system between human colorectal fibroblasts (CCD-18-co) and CRCs (LoVo, SW480, and SW620), we found that fibroblasts existing in tumor microenvironment positively influenced the metabolism of colorectal cancer cells, through its autophagy and oxidative stress pathway which were initially induced by neighboring tumor cells. Therefore, our data provided a novel possibility to develop fibroblasts as a potential target to treat CRC.	[Zhou, Wenjing; Wang, Yunqiu; Liu, Xiaofei; Xu, Xia; Ren, Guijie; Tian, Keli] Shandong Univ, Sch Med, Dept Biochem & Mol Biol, Jinan, Shandong, Peoples R China; [Zhou, Wenjing] Shandong Univ, Qilu Hosp, Dept Neurosurg, Jinan, Peoples R China; [Zhou, Wenjing] Shandong Univ, Brain Sci Res Inst, Jinan, Peoples R China; [Xu, Gang] PLA, Hosp 456, Dept Gastroenterol, Jinan, Shandong, Peoples R China; [Xu, Ziao] Anhui Med Univ, Affiliated Hosp 1, Hefei, Anhui, Peoples R China		Tian, KL (corresponding author), Shandong Univ, Sch Med, Dept Biochem & Mol Biol, Jinan, Shandong, Peoples R China.	tiankeli@sdu.edu.cn	Zhou, Wenjing/O-5814-2018	Zhou, Wenjing/0000-0002-4932-9312	Natural Science Foundation of Shandong ProvinceNatural Science Foundation of Shandong Province [ZR2014HM087]	This work was supported by the Natural Science Foundation of Shandong Province (ZR2014HM087). 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	Susmi, TF; Rahman, A; Khan, MMR; Yasmin, F; Islam, MS; Nasif, O; Alharbi, SA; Batiha, GE; Hossain, MU				Susmi, Tasmina Ferdous; Rahman, Atikur; Khan, Md. Moshiur Rahman; Yasmin, Farzana; Islam, Md. Shariful; Nasif, Omaima; Alharbi, Sulaiman Ali; Batiha, Gaber El-Saber; Hossain, Mohammad Uzzal			Prognostic and clinicopathological insights of phosphodiesterase 9A gene as novel biomarker in human colorectal cancer	BMC CANCER			English	Article						PDE9A gene; Colorectal cancer; Methylation; Pathways; Biomarker	DOWN-REGULATION; MESSENGER-RNA; EXPRESSION; CGMP; DATABASE; SURVIVAL; FAMILY; HYPERMETHYLATION; IDENTIFICATION; PROLIFERATION	Background PDE9A (Phosphodiesterase 9A) plays an important role in proliferation of cells, their differentiation and apoptosis via intracellular cGMP (cyclic guanosine monophosphate) signaling. The expression pattern of PDE9A is associated with diverse tumors and carcinomas. Therefore, PDE9A could be a prospective candidate as a therapeutic target in different types of carcinoma. The study presented here was designed to carry out the prognostic value as a biomarker of PDE9A in Colorectal cancer (CRC). The present study integrated several cancer databases with in-silico techniques to evaluate the cancer prognosis of CRC. Results The analyses suggested that the expression of PDE9A was significantly down-regulated in CRC tissues than in normal tissues. Moreover, methylation in the DNA promoter region might also manipulate PDE9A gene expression. The Kaplan-Meier curves indicated that high level of expression of PDE9A gene was associated to higher survival in OS, RFS, and DSS in CRC patients. PDE9A demonstrated the highest positive correlation for rectal cancer recurrence with a marker gene CEACAM7. Furtheremore, PDE9A shared consolidated pathways with MAPK14 to induce survival autophagy in CRC cells and showed interaction with GUCY1A2 to drive CRPC. Conclusions Overall, the prognostic value of PDE9A gene could be used as a potential tumor biomarker for CRC.	[Susmi, Tasmina Ferdous; Rahman, Atikur; Khan, Md. Moshiur Rahman; Yasmin, Farzana] Jashore Univ Sci & Technol, Fac Biol Sci & Technol, Dept Genet Engn & Biotechnol, Jashore 7408, Bangladesh; [Rahman, Atikur] Jiangnan Univ, Sch Biotechnol, Dept Fermentat Engn, Wuxi, Jiangsu, Peoples R China; [Islam, Md. Shariful] Hokkaido Univ, Grad Sch Life Sci, Dept Reprod & Dev Biol, Sapporo,5 Chome Kita 8 Jonishi, Sapporo, Hokkaido 0600808, Japan; [Islam, Md. Shariful] Univ Kentucky, Dept Biol, 101 TH Morgan Bldg, Lexington, KY 40506 USA; [Nasif, Omaima] King Saud Univ, King Khalid Univ Hosp, Coll Med, Dept Physiol, POB 2925, Riyadh 11461, Saudi Arabia; [Alharbi, Sulaiman Ali] King Saud Univ, Coll Sci, Dept Bot & MicroBiol, POB 2455, Riyadh 11451, Saudi Arabia; [Batiha, Gaber El-Saber] Damanhour Univ, Fac Vet Med, Dept Pharmacol & Therapeut, Damanhour 22511, Albeheira, Egypt; [Hossain, Mohammad Uzzal] Natl Inst Biotechnol, Bioinformat Div, Dhaka 1349, Bangladesh		Islam, MS (corresponding author), Hokkaido Univ, Grad Sch Life Sci, Dept Reprod & Dev Biol, Sapporo,5 Chome Kita 8 Jonishi, Sapporo, Hokkaido 0600808, Japan.; Islam, MS (corresponding author), Univ Kentucky, Dept Biol, 101 TH Morgan Bldg, Lexington, KY 40506 USA.	sharifbge@uky.edu		Susmi, Tasmina Ferdous/0000-0002-2628-2371; Rahman, Atikur/0000-0002-2022-711X	King Saud University (KSU)King Saud University [RSP-2020/257]; King Saud University, Riyadh, Saudi ArabiaKing Saud University	This study is supported by King Saud University (KSU), Researchers Supporting Project number (RSP-2020/257), King Saud University, Riyadh, Saudi Arabia.	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J	Chiacchiera, F; Simone, C				Chiacchiera, Fulvio; Simone, Cristiano			Inhibition of p38 alpha unveils an AMPK-FoxO3A axis linking autophagy to cancer-specific metabolism	AUTOPHAGY			English	Article						p38 alpha; FoxO3A; ATG transcription; AMPK; HIF1 alpha; colorectal cancer	CELL-DEATH; DISEASE	Autophagy is an essential process for the maintenance of cellular and metabolic homeostasis. Indeed, it is required for the recovery of ATP-generating substrates in cells subjected to different types of stress insults. Thus, the activity of the autophagic machinery strongly depends on the metabolic status of the cell.(1) It has been proposed that this principle applies not only to normal, but also to cancer cells,(2) despite the profound differences in their metabolism. Cancer cells predominantly produce ATP through the constitutive activation of aerobic glycolysis, a process that generally relies on the stabilization and activation of the transcription factor HIF1 alpha, which regulates the expression of glycolytic genes.(3) We recently showed that p38 alpha is required to sustain the expression of HIF1 alpha target genes, and that its inhibition causes a rapid drop in ATP levels in colorectal cancer cells (CRCs). This acute energy need triggers AMPK-dependent nuclear accumulation of FoxO3A and subsequent activation of its transcriptional program, leading to sequential induction of autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38 alpha has both a cytostatic and cytotoxic effect on colorectal neoplasms, associated with nuclear enrichment of FoxO3A and expression of its target genes p21 and PTEN.(4) Our data suggest that CRCs impaired in their glycolytic metabolism trigger autophagy as a reversible recovery mechanism and undergo cell cycle arrest; however, the persistence of the stress insults inevitably leads to cell death.	[Chiacchiera, Fulvio; Simone, Cristiano] Consorzio Mario Negri Sud, Lab Signal Dependent Transcript, Dept Translat Pharmacol, I-66030 Santa Maria Imbaro, Ch, Italy		Simone, C (corresponding author), Consorzio Mario Negri Sud, Lab Signal Dependent Transcript, Dept Translat Pharmacol, I-66030 Santa Maria Imbaro, Ch, Italy.	simone@negrisud.it	Simone, Cristiano/K-3452-2018; Chiacchiera, Fulvio/K-6740-2016; Chiacchiera, Fulvio/ABD-6137-2020	Simone, Cristiano/0000-0002-2628-7658; Chiacchiera, Fulvio/0000-0003-3830-2090; 	IRC (Italian Foundation for Cancer Research) fellowship; 'My First Grant'; Italian Association for Cancer ResearchFondazione AIRC per la ricerca sul cancro	We thank Dr. Francesco Paolo Jori for his helpful discussion during the preparation of the manuscript and editorial assistance; Dr. Francesca Demarchi and Dr. Tamara Copetti (C.I.B., Trieste, Italy) for providing the MAP1LC3 antisera. Dr. Chiacchiera is supported by a FIRC (Italian Foundation for Cancer Research) fellowship. This work was partially supported by a 'My First Grant' (to C.S.) from the Italian Association for Cancer Research.	CHIACCHIERA F, 2009, CELL DEATH IN PRESS; Comes F, 2007, CELL DEATH DIFFER, V14, P693, DOI 10.1038/sj.cdd.4402076; Gatenby RA, 2004, NAT REV CANCER, V4, P891, DOI 10.1038/nrc1478; Jin SK, 2008, AUTOPHAGY, V4, P563, DOI 10.4161/auto.5830; Klionsky DJ, 2008, AUTOPHAGY, V4, P151, DOI 10.4161/auto.5338; Kroemer G, 2009, CELL DEATH DIFFER, V16, P3, DOI 10.1038/cdd.2008.150; Kroemer G, 2008, CANCER CELL, V13, P472, DOI 10.1016/j.ccr.2008.05.005; Levine B, 2008, CELL, V132, P27, DOI 10.1016/j.cell.2007.12.018; Levine B, 2007, NATURE, V446, P745, DOI 10.1038/446745a; Mammucari C, 2007, CELL METAB, V6, P458, DOI 10.1016/j.cmet.2007.11.001; Meijer AJ, 2009, AUTOPHAGY, V5, P3, DOI 10.4161/auto.5.1.7207; Mizushima N, 2008, NATURE, V451, P1069, DOI 10.1038/nature06639; Simone C, 2007, AUTOPHAGY, V3, P468, DOI 10.4161/auto.4319; Zhao J, 2007, CELL METAB, V6, P472, DOI 10.1016/j.cmet.2007.11.004	14	63	64	1	4	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	1554-8627	1554-8635		AUTOPHAGY	Autophagy	OCT 1	2009	5	7					1030	1033		10.4161/auto.5.7.9252			4	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	531TH	WOS:000272691100013	19587525	Green Published, Bronze			2022-04-25	
J	Khan, A; Wani, MY; Al-Bogami, AS; Subramanian, K; Kandhavelu, J; Ruff, P; Penny, C				Khan, Amber; Wani, Mohmmad Younus; Al-Bogami, Abdullah Saad; Subramanian, Kumar; Kandhavelu, Jeyalakshmi; Ruff, Paul; Penny, Clement			Anticancer Activity of Novel Gabexate Mesilate Mimetics in Colorectal Cancer Cells	CHEMISTRYSELECT			English	Article						Antitumor agents; Cell cycle; Colorectal cancer; Gabexate mesilate; High mobility group box 1	COLON-CANCER; HMGB1; AUTOPHAGY; SURVIVORSHIP; THERAPY; PATHWAY	Despite there being significant advances in colorectal cancer (CRC) treatments, recurrence and chemoresistance remain a challenge in the treatment of patients. During the process of autophagy, cancer cells acquire anoikis resistance and escape chemotherapy. High Mobility Group Box 1 (HMGB1) protein is a key mediator of autophagy and can be exploited to develop effective targeted anticancer therapies. Gabexate mesilate (GM) used in the treatment of pancreatitis is both a synthetic inhibitor of HMGB1 and of metastasis. Structural analogues of GM hold promise to suppress HMGB1 functionality to arrest cancer growth, recurrence and resistance mechanisms. We synthesized structural GM mimetics (GMMs) and evaluated their anticancer activity. Considering the critical role of HMGB1 in the cell cycle, we analyzed cell cycle response to active GMMs in CRC cells in a Muse flow cell analyzer. Docking studies were further performed to predict the binding modes and affinity of active GMM for HMGB1. A total of thirteen GMMs were synthesized and their anticancer activity was evaluated on each of the SW480, HT29 and DLD1 CRC cell lines. Of the 13-novel synthetic GMMs assessed, A1, A2, A3 and A6 were found to be the most active, with anticancer inhibitory concentrations (IC80) of 250-500 mu g/mL. Treatment with active GMMs resulted in CRC cells being arrested mainly in preparatory phases of the cell cycle. Docking studies established that the active GMMs possessed specific binding affinity with the target, compared to the inactive GMM.	[Khan, Amber; Subramanian, Kumar; Kandhavelu, Jeyalakshmi; Ruff, Paul; Penny, Clement] Univ Witwatersrand, Dept Internal Med, Fac Hlth Sci, 7 York Rd, ZA-2193 Johannesburg, South Africa; [Wani, Mohmmad Younus; Al-Bogami, Abdullah Saad] Univ Jeddah, Chem Dept, Fac Sci, POB 80327, Jeddah 21589, Saudi Arabia		Penny, C (corresponding author), Univ Witwatersrand, Dept Internal Med, Fac Hlth Sci, 7 York Rd, ZA-2193 Johannesburg, South Africa.	clempenny@yahoo.co.uk	Wani, Mohammad Younus/E-3909-2018; Wani, Mohmmad Younus/AAJ-5016-2020; Kandhavelu, Jeyalakshmi/AAL-8279-2020; Al-Bogami, Abdullah S/H-7774-2012	Wani, Mohammad Younus/0000-0002-1838-1337; Wani, Mohmmad Younus/0000-0002-1838-1337; Kandhavelu, Jeyalakshmi/0000-0003-3511-3040	Medical Research Council (MRC) of South AfricaUK Research & Innovation (UKRI)Medical Research Council UK (MRC); National Research Foundation (NRF) of South AfricaNational Research Foundation - South Africa [99554]; Wits Faculty of Health Sciences Griffin Trust Fund	The study was supported by funding from the Medical Research Council (MRC) of South Africa to the Wits/MRC Common Epithelial Cancer Research Centre. AK is grateful to the National Research Foundation (NRF) of South Africa [Grant number: 99554] for research funding and bursary and to the Wits Faculty of Health Sciences Griffin Trust Fund for financial assistance.	Brandi G, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0041347; DESCHNER EE, 1987, PREV MED, V16, P580, DOI 10.1016/0091-7435(87)90075-2; EINCK L, 1985, EXP CELL RES, V156, P295, DOI 10.1016/0014-4827(85)90539-7; Frick MA, 2017, CANCER-AM CANCER SOC, V123, P1860, DOI 10.1002/cncr.30527; Guglielmi V, 2017, EUR REV MED PHARMACO, V21, P5268, DOI 10.26355/eurrev_201711_13851; Haggar Fatima A, 2009, Clin Colon Rectal Surg, V22, P191, DOI 10.1055/s-0029-1242458; Hidaka S, 2011, J SURG RES, V165, P142, DOI 10.1016/j.jss.2009.05.039; Ke SB, 2015, INT J ONCOL, V46, P1051, DOI 10.3892/ijo.2014.2793; Lee H, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0034318; Li QL, 2014, ONCOTARGET, V5, P6387, DOI 10.18632/oncotarget.2201; Liu WJ, 2015, CANCER BIOL THER, V16, P511, DOI 10.1080/15384047.2015.1017691; Livesey KM, 2012, AUTOPHAGY, V8, P846, DOI 10.4161/auto.19891; Makhoul R, 2015, CLIN COLON RECT SURG, V28, P262, DOI 10.1055/s-0035-1564435; Musumeci D, 2014, PHARMACOL THERAPEUT, V141, P347, DOI 10.1016/j.pharmthera.2013.11.001; Nishiyama T, 2012, AM J EMERG MED, V30, P1219, DOI 10.1016/j.ajem.2011.06.003; Ozeki T, 2010, INT J CLIN EXP PATHO, V3, P710; Poznic M, 2009, J BIOSCIENCES, V34, P305, DOI 10.1007/s12038-009-0034-2; Scaffidi P, 2002, NATURE, V418, P191, DOI 10.1038/nature00858; Schwartz D, 1998, SEMIN CANCER BIOL, V8, P325, DOI 10.1006/scbi.1998.0095; Smolarczyk R, 2012, POSTEP HIG MED DOSW, V66, P913, DOI 10.5604/17322693.1021108; Sun XF, 2014, AUTOPHAGY, V10, P1873, DOI 10.4161/auto.32184; Thorburn A, 2014, MOL PHARMACOL, V85, P830, DOI 10.1124/mol.114.091850; Torre LA, 2015, CA-CANCER J CLIN, V65, P87, DOI 10.3322/caac.21262; Trott O, 2010, J COMPUT CHEM, V31, P455, DOI 10.1002/jcc.21334; Waki K, 2016, CANCER SCI, V107, P1721, DOI 10.1111/cas.13084; White E, 2015, CLIN CANCER RES, V21, P5037, DOI 10.1158/1078-0432.CCR-15-0490; Wu TY, 2016, ONCOTARGET, V7, P50417, DOI 10.18632/oncotarget.10413; Yamaguchi H, 2012, BIOINFORMATION, V8, P1147, DOI 10.6026/97320630081147; Yang H, 2015, MOL MED, V21, pS6, DOI 10.2119/molmed.2015.00087; Yoon WH, 2004, CLIN CANCER RES, V10, P4517, DOI 10.1158/1078-0432.CCR-04-0084; Zhang ZX, 2015, J EXP CLIN CANC RES, V34, DOI 10.1186/s13046-015-0166-1; Zhao XL, 2017, J PATHOL, V243, P376, DOI 10.1002/path.4958	32	0	0	0	5	WILEY-V C H VERLAG GMBH	WEINHEIM	POSTFACH 101161, 69451 WEINHEIM, GERMANY	2365-6549			CHEMISTRYSELECT	ChemistrySelect	JUN 29	2018	3	24					6942	6948		10.1002/slct.201800629			7	Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry	GL0RT	WOS:000436798700033					2022-04-25	
J	Xie, RY; Wang, J; Liu, XH; Wu, LQ; Zhang, H; Tang, WM; Li, YQ; Xiang, L; Peng, Y; Huang, XT; Bai, Y; Liu, GN; Li, AM; Wang, YD; Chen, Y; Ren, YX; Li, GX; Gong, W; Liu, SD; Wang, JD				Xie, Ruyi; Wang, Jing; Liu, Xuehua; Wu, Liqing; Zhang, Hui; Tang, Weimei; Li, Yueqiao; Xiang, Li; Peng, Ying; Huang, Xiaoting; Bai, Yang; Liu, Guangnan; Li, Aimin; Wang, Yadong; Chen, Ye; Ren, Yuexin; Li, Guoxin; Gong, Wei; Liu, Side; Wang, Jide			RUFY3 interaction with FOXK1 promotes invasion and metastasis in colorectal cancer	SCIENTIFIC REPORTS			English	Article							DOMAIN-CONTAINING PROTEIN; FYVE-FINGER; RUN DOMAIN; EFFECTOR; IDENTIFICATION; TUMORIGENESIS; EXPRESSION; AUTOPHAGY; COMPLEX; RABIP4	RUFY3 is highly expressed in brain tissue and has a role in neuronal development. Transcriptional factor FOXK1 is involved in cell growth and metabolism. We knew that RUFY3 or FOXK1 has been correlated with the malignant of tumor cells. However, the role of these molecules in colorectal cancer (CRC) progression remains unknown. We investigated the protein expression levels by Western blot, immunofluorescence and immunohistochemistry analyses. The migration and invasive abilities of CRC cells were assessed using shRNA-mediated inhibition in vitro and in vivo. We showed that RUFY3 expression was up-regulated in CRC compared with its expression in a normal human colon cell line (FHC). RUFY3 suppression inhibited anchorage independent cell tumorigenesis. RUFY3 induced elevated expression of eight major oncogenes. Moreover, RUFY3 physically interacts with FOXK1 in CRC. A positive correlation was observed between the expression patterns of RUFY3 and FOXK1. Furthermore, RUFY3 and FOXK1 expression were correlated with tumor progression and represented significant predictors of overall survival in CRC patients. SiRNA-mediated repression of FOXK1 in RUFY3-overexpressing cells reversed the epithelial-mesenchymal transition (EMT) and metastatic phenotypes. In vivo, FOXK1 promoted RUFY3-mediated metastasis via orthotopic implantation. These findings suggest that the RUFY3-FOXK1 axis might promote the development and progression of human CRC.	[Xie, Ruyi; Wang, Jing; Liu, Xuehua; Wu, Liqing; Zhang, Hui; Tang, Weimei; Li, Yueqiao; Xiang, Li; Peng, Ying; Huang, Xiaoting; Bai, Yang; Liu, Guangnan; Li, Aimin; Wang, Yadong; Chen, Ye; Ren, Yuexin; Gong, Wei; Liu, Side; Wang, Jide] Southern Med Univ, Nanfang Hosp, Dept Gastroenterol, Guangdong Prov Key Lab Gastroenterol, Guangzhou 510515, Guangdong, Peoples R China; [Liu, Xuehua] First Peoples Hosp Shunde, Dept Gastroenterol, Foshan 528300, Peoples R China; [Zhang, Hui] Southern Med Univ, Hexian Mem Affiliated Hosp, Dept Gastroenterol, Guangzhou 511400, Guangdong, Peoples R China; [Xiang, Li] Longgang Dist Peoples Hosp, Dept Gastroenterol, Shenzhen 518172, Peoples R China; [Li, Guoxin] Southern Med Univ, Nanfang Hosp, Dept Gen Surg, Guangzhou 510515, Guangdong, Peoples R China		Liu, SD; Wang, JD (corresponding author), Southern Med Univ, Nanfang Hosp, Dept Gastroenterol, Guangdong Prov Key Lab Gastroenterol, Guangzhou 510515, Guangdong, Peoples R China.	liuside@163.com; jidewang55@163.com			National Natural Science Funds of ChinaNational Natural Science Foundation of China (NSFC) [81672875, 81272761]; President Foundation of Nanfang Hospital, Southern Medical University [2012B009, 2013Z007]; high-level topic-matching funds of Nanfang Hospital [201347, G201227]; Guangzhou Pilot Project of Clinical and Translational Research Center (early gastrointestinal cancer) [7415696196402]	This study was supported by grants from the National Natural Science Funds of China (81672875 & 81272761), 'President Foundation of Nanfang Hospital, Southern Medical University' (2012B009, 2013Z007), and high-level topic-matching funds of Nanfang Hospital (201347 and G201227). Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University; Guangzhou Pilot Project of Clinical and Translational Research Center (early gastrointestinal cancer, No. 7415696196402).	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J	Islam, F; Gopalan, V; Law, S; Tang, JCO; Lam, AKY				Islam, Farhadul; Gopalan, Vinod; Law, Simon; Tang, Johnny Cheuk-on; Lam, Alfred King-yin			FAM134B promotes esophageal squamous cell carcinoma in vitro and its correlations with clinicopathologic features	HUMAN PATHOLOGY			English	Article						Esophagus; FAM134B; JK1; RETREG1; Squamous cell carcinoma	COLORECTAL-CANCER; COLON-CANCER; OVEREXPRESSION; EXPRESSION; JK1; MUTATIONS; GENE	Family with sequence similarity 134, member B (FAM134B) is an autophagy regulator of endoplasmic reticulum first discovered to be involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC). The present study examined the functional behavior of FAM134B in cancer cells and the association of FAM134B expression with clinicopathologic factors in patients with ESCC. Expression at both the mRNA and protein levels was investigated using real-time polymerase chain reaction and immunohistochemistry. The results were correlated with the clinical and pathological features of the patients. In addition, in vitro functional assays were used to investigate the roles of FAM134B in ESCC cells in response to gene silencing with shRNA lentiviral particles. Overexpression of FAM134B mRNA and protein was present in 31.2% (n = 29/93) and 36.6% (n = 41/112), respectively, in tumors, whereas downregulation occurred in 39.8% (n = 37/93) and 63.4% (n = 71/112), respectively. Expression of FAM134B protein in ESCC correlated with histologic grade (P =.002) and pathologic stage (P =.012). In vitro suppression of FAM134B in ESCC induced significant reductions of cell proliferation and colony formation (P <.05). In addition, suppression of FAM134B caused reduction of wound healing, migration, and invasion capacities of ESCC. To conclude, FAM134B could play crucial roles in the initiation and progression of ESCC, and FAM134B protein expression has potential predictive value. Therefore, development of strategies targeting FAM134B could have therapeutic value in the management of patients with ESCC. (C) 2019 Elsevier Inc. All rights reserved.	[Islam, Farhadul; Gopalan, Vinod; Lam, Alfred King-yin] Griffith Univ, Sch Med, Dept Canc Mol Pathol, Gold Coast, Qld, Australia; [Islam, Farhadul] Univ Rajshahi, Dept Biochem & Mol Biol, Rajshahi 6205, Bangladesh; [Law, Simon] Univ Hong Kong, Dept Surg, Hong Kong, Peoples R China; [Tang, Johnny Cheuk-on] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, Lo Ka Chung Ctr Nat Anticanc Drug Dev, State Key Lab Chirosci, Hong Kong, Peoples R China		Tang, JCO (corresponding author), Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, 11 Yuk Choi Rd, Hong Kong, Peoples R China.; Lam, AKY (corresponding author), Griffith Med Sch, Gold Coast Campus, Gold Coast, Qld 4222, Australia.	bccotang@polyu.edu.hk; a.lam@griffith.edu.au	Lam, Alfred/C-1652-2008; Law, Simon/C-4324-2009; Tang, Johnny Cheuk-on/W-7214-2019; Tang, Johnny C. O./M-9639-2014; Islam, Farhadul/R-5643-2017	Lam, Alfred/0000-0003-2771-564X; Law, Simon/0000-0002-6518-5806; Tang, Johnny Cheuk-on/0000-0002-4261-3206; Tang, Johnny C. O./0000-0002-4261-3206; Islam, Farhadul/0000-0001-5262-4702	Griffith UniversityGriffith University; Menzies Health Institute Queensland, Gold Coast, Queensland, Australia	This project was supported by a student scholarship from Griffith University and funding from Menzies Health Institute Queensland (Chamier's family donation), Gold Coast, Queensland, Australia.	Chan D, 2013, WORLD J GASTROENTERO, V19, P2772, DOI 10.3748/wjg.v19.i18.2772; Dai W, 2017, J PATHOL, V242, P500, DOI 10.1002/path.4925; Dai XF, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-07189-6; Fatima S, 2006, INT J MOL MED, V17, P159; Gopalan V, 2016, EXP CELL RES, V348, P146, DOI 10.1016/j.yexcr.2016.09.010; Hamilton S. 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Gastroenterol., V40, P256, DOI 10.1590/S0004-28032003000400011; Rice T.W., 2017, AJCC CANC STAGING SY, P185; Saremi N, 2018, METHODS MOL BIOL, V1756, P105, DOI 10.1007/978-1-4939-7734-5_10; SHIMADA Y, 1992, CANCER, V69, P277, DOI 10.1002/1097-0142(19920115)69:2<277::AID-CNCR2820690202>3.0.CO;2-C; Tang JCO, 2001, CLIN CANCER RES, V7, P1539; Tang WK, 2007, INT J MOL MED, V19, P915; Wahab R, 2018, EXP MOL PATHOL, V104, P71, DOI 10.1016/j.yexmp.2018.01.004; Xu WW, 2015, ONCOTARGET, V6, P1790, DOI 10.18632/oncotarget.2781	35	16	16	0	3	W B SAUNDERS CO-ELSEVIER INC	PHILADELPHIA	1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA	0046-8177	1532-8392		HUM PATHOL	Hum. Pathol.	MAY	2019	87						1	10		10.1016/j.humpath.2018.11.033			10	Pathology	Science Citation Index Expanded (SCI-EXPANDED)	Pathology	IA4GX	WOS:000469523100001	30794892	Green Accepted			2022-04-25	
J	Zajac, J; Kostrhunova, H; Novohradsky, V; Vrana, O; Raveendran, R; Gibson, D; Kasparkova, J; Brabec, V				Zajac, Juraj; Kostrhunova, Hana; Novohradsky, Vojtech; Vrana, Oldrich; Raveendran, Raji; Gibson, Dan; Kasparkova, Jana; Brabec, Viktor			Potentiation of mitochondrial dysfunction in tumor cells by conjugates of metabolic modulator dichloroacetate with a Pt(IV) derivative of oxaliplatin	JOURNAL OF INORGANIC BIOCHEMISTRY			English	Article						Platinum-dichloroacetate conjugates; Mitochondrial dysfunction; Glucose metabolism; Autophagy; 5-Fluorouracil; Cancer therapy	IN-VITRO CYTOTOXICITY; PLATINUM(IV) COMPLEXES; INCREASES SENSITIVITY; ANTITUMOR-ACTIVITY; COLORECTAL-CANCER; MOLECULAR-BASIS; HUMAN COLON; CISPLATIN; 5-FLUOROURACIL; RESISTANCE	The molecular and cellular mechanisms of enhanced toxic effects in tumor cells of the Pt(IV) derivatives of antitumor oxaliplatin containing axial dichloroacetate (DCA) ligands were investigated. DCA ligands were chosen because DCA has shown great potential as an apoptosis sensitizer and anticancer agent reverting the Wartburg effect. In addition, DCA reverses mitochondrial changes in a wide range of cancers, promoting tumor cell apoptosis in a mitochondrial-dependent pathway. We demonstrate that (i) the transformation of oxaliplatin to its Pt(IV) derivatives containing axial DCA ligands markedly enhances toxicity in cancer cells and helps overcome inherent and acquired resistance to cisplatin and oxaliplatin; (ii) a significant fraction of the intact molecules of DCA conjugates with Pt(IV) derivative of oxaliplatin accumulates in cancer cells where it releases free DCA; (iii) mechanism of biological action of the Pt(IV) derivatives of oxaliplatin containing DCA ligands is connected with the effects of DCA released in cancer cells from the Pt(IV) prodrugs on mitochondria and metabolism of glucose; (iv) treatments with the Pt(IV) derivatives of oxaliplatin containing DCA ligands activate an autophagic response in human colorectal cancer cells; (v) the toxic effects in cancer cells of the Pt(IV) derivatives of oxaliplatin containing DCA ligands can be potentiated if cells are treated with these prodrugs in combination with 5-fluorouracil. These properties of the Pt(IV) derivatives of oxaliplatin containing DCA ligands provide opportunities for further development of new platinum-based agents with the capability of killing cancer cells resistant to conventional antitumor platinum drugs used in the clinic. (C) 2015 Elsevier Inc. All rights reserved.	[Zajac, Juraj; Kostrhunova, Hana; Novohradsky, Vojtech; Vrana, Oldrich; Brabec, Viktor] Acad Sci Czech Republ, Inst Biophys, Vvi, Kralovopolska 135, CZ-61265 Brno, Czech Republic; [Zajac, Juraj; Kasparkova, Jana] Palacky Univ, Fac Sci, Dept Biophys, 17 Listopadu 12, CZ-77146 Olomouc, Czech Republic; [Raveendran, Raji; Gibson, Dan] Hebrew Univ Jerusalem, Sch Pharm, Inst Drug Res, IL-91120 Jerusalem, Israel		Brabec, V (corresponding author), Acad Sci Czech Republ, Inst Biophys, Vvi, Kralovopolska 135, CZ-61265 Brno, Czech Republic.	brabec@ibp.cz	Brabec, Viktor/H-1946-2014; Kostrhunová, Hana/H-1934-2014	Brabec, Viktor/0000-0002-8233-1393; Kostrhunová, Hana/0000-0003-2706-6491	Czech Science FoundationGrant Agency of the Czech Republic [14-21053S]; Ministry of Education, Youth and Sports of the Czech RepublicMinistry of Education, Youth & Sports - Czech Republic [LH14317, LD14019]; Palack University (IGAPrF) [2015 025]; Israel Science foundationIsrael Science Foundation [1332/10]	This work was supported by the Czech Science Foundation (Grant 14-21053S) and the Ministry of Education, Youth and Sports of the Czech Republic (Grant LH14317). J.Z. and J.K. also acknowledge the support from the Ministry of Education, Youth and Sports of the Czech Republic (Grant LD14019) and from the student project of Palack University (IGAPrF 2015 025). D.G. acknowledges the support of the Israel Science foundation (grant 1332/10). The authors also acknowledge that their participation in the EU COST Action CM1105 enabled them to exchange regularly the most recent ideas in the field of platinum anticancer drugs with several European colleagues.	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Inorg. Biochem.	MAR	2016	156						89	97		10.1016/j.jinorgbio.2015.12.003			9	Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	DE6UP	WOS:000370769400010	26780576				2022-04-25	
J	Li, B; Shi, C; Li, B; Zhao, JM; Wang, L				Li, Bai; Shi, Chong; Li, Bo; Zhao, Jing-Ming; Wang, Lei			The effects of Curcumin on HCT-116 cells proliferation and apoptosis via the miR-491/PEG10 pathway	JOURNAL OF CELLULAR BIOCHEMISTRY			English	Article						cell apoptosis; cell proliferation; Curcumin; miR-491; PEG10	MICRORNA EXPRESSION; IMPRINTED GENE; CANCER; PEG10; AUTOPHAGY; INVOLVEMENT; SURVIVAL	Paternally expressed gene-10 (PEG10) could participate in several carcinomas and might be regulated by miR-491. To now, miR-491 was found to play an important role in the sensitivity and mechanism of drug usage in the treatment of colorectal cancer, and drug resistance is a key factor to affect the disease healing. In this study, miR-491, PEG10, Wnt1, and -catenin expression levels and their correlation with colorectal cancer were assessed in cancer tissues and adjacent parts. And the target relationship between PEG10 and miR-491 was verified. Meanwhile, the impaction of Curcumin on miR-491, PEG10, and Wnt/-catenin signaling pathway were analyzed in HCT-116 cells. The effects of PEG10 and Curcumin on human HCT-116 cells proliferation and apoptosis were investigated by MTT and flow cytometry assay. Results showed that the expression of miR-491 in colon cancer tissues was decreased, but PEG10, Wnt1, and -catenin were higher than that in adjacent tissues. The PEG10 gene 3 UTR could combine with miR-491 seed sequence and miR-491 overexpression could cause a decrease in PEG10, Wnt1, and -catenin levels in human HCT-116 cells. Furthermore, PEG10 overexpression increased the expression levels of Wnt1 and -catenin, thereby promoting cell proliferation and inhibiting apoptosis. In addition, Curcumin could up-regulate miR-491, inhibit PEG10, and Wnt/-catenin signaling pathway. Consequently, Curcumin reduced HCT-116 cells proliferation and promoted cells apoptosis via the miR-491/PEG10 pathway. In conclusion, PEG10 was a target gene of miR-491, miR-491/PEG10 strengthen the sensitivity of Curcumin in HCT-116 cells proliferation and apoptosis, which might act as an ideal diagnostic biomarker treatment methods.	[Li, Bai; Wang, Lei] Jilin Univ, Affiliated Hosp 1, Dept Colorectal & Anal Surg, 71 Xinmin St, Changchun, Jilin, Peoples R China; [Shi, Chong; Zhao, Jing-Ming] Changchun Univ Chinese Med, Afflicted Hosp, Dept Anorectal Surg, Changchun, Jilin, Peoples R China; [Li, Bo] Jilin Univ, China Japan Union Hosp, Dept Gastrointestinal Colorectal & Anal Surg, Changchun, Jilin, Peoples R China		Wang, L (corresponding author), Jilin Univ, Affiliated Hosp 1, Dept Colorectal & Anal Surg, 71 Xinmin St, Changchun, Jilin, Peoples R China.	leiwang_jlu@163.com	Li, Bo/AAA-8968-2020	Li, Bo/0000-0002-7294-6888; Jingming, Zhao/0000-0002-1019-1029			Calin GA, 2004, P NATL ACAD SCI USA, V101, P2999, DOI 10.1073/pnas.0307323101; Calin GA, 2006, NAT REV CANCER, V6, P857, DOI 10.1038/nrc1997; Chen TL, 2011, MOL CELL PROTEOMICS, V10, DOI 10.1074/mcp.M110.004945; Cimmino A, 2005, P NATL ACAD SCI USA, V102, P13944, DOI 10.1073/pnas.0506654102; Cummins JM, 2006, P NATL ACAD SCI USA, V103, P3687, DOI 10.1073/pnas.0511155103; Gupta SC, 2012, CLIN EXP PHARMACOL P, V39, P283, DOI 10.1111/j.1440-1681.2011.05648.x; Hamano R, 2011, CLIN CANCER RES, V17, P3029, DOI 10.1158/1078-0432.CCR-10-2532; He L, 2005, NATURE, V435, P828, DOI 10.1038/nature03552; Huang ST, 2017, SCI REP-UK, V7, DOI 10.1038/srep40382; Ip WK, 2007, CANCER LETT, V250, P284, DOI 10.1016/j.canlet.2006.10.012; Johnson SM, 2005, CELL, V120, P635, DOI 10.1016/j.cell.2005.01.014; Kim JY, 2012, ARCH ORAL BIOL, V57, P1018, DOI 10.1016/j.archoralbio.2012.04.005; Kumar MS, 2007, NAT GENET, V39, P673, DOI 10.1038/ng2003; Lee HC, 2006, FRONT BIOSCI-LANDMRK, V11, P1901, DOI 10.2741/1933; Lee YJ, 2011, KOREAN J PHYSIOL PHA, V15, P1, DOI 10.4196/kjpp.2011.15.1.1; Lewis BP, 2005, CELL, V120, P15, DOI 10.1016/j.cell.2004.12.035; Li B, 2013, INT J GYNECOL CANCER, V23, P803, DOI 10.1097/IGC.0b013e31828c9581; Liu SG, 2013, ONCOL LETT, V5, P1639, DOI 10.3892/ol.2013.1251; Lu J, 2005, NATURE, V435, P834, DOI 10.1038/nature03702; Nakano H, 2010, INT J CANCER, V127, P1072, DOI 10.1002/ijc.25143; O'Connell JB, 2004, DIS COLON RECTUM, V47, P2064, DOI 10.1007/s10350-004-0738-1; Okabe H, 2003, CANCER RES, V63, P3043; Ono R, 2001, GENOMICS, V73, P232, DOI 10.1006/geno.2001.6494; Safe S, 2016, PHYTOTHER RES, V30, P1723, DOI 10.1002/ptr.5669; Sahu PK, 2016, EUR J MED CHEM, V121, P510, DOI 10.1016/j.ejmech.2016.05.037; Siegel R, 2013, CA-CANCER J CLIN, V63, P11, DOI 10.3322/caac.21166; Tsou AP, 2003, J BIOMED SCI, V10, P625, DOI 10.1159/000073528; Ventura A, 2009, CELL, V136, P586, DOI 10.1016/j.cell.2009.02.005; Volinia S, 2006, P NATL ACAD SCI USA, V103, P2257, DOI 10.1073/pnas.0510565103; Voorhoeve PM, 2006, CELL, V124, P1169, DOI 10.1016/j.cell.2006.02.037; Voortman J, 2010, CANCER RES, V70, P8288, DOI 10.1158/0008-5472.CAN-10-1348; Wang YW, 2016, JALA-J LAB AUTOM, V21, P723, DOI 10.1177/2211068216655524; Wilken R, 2011, MOL CANCER, V10, DOI 10.1186/1476-4598-10-12; Xiao K, 2013, J PHARMACOL SCI, V123, P102, DOI 10.1254/jphs.13085FP; Yoshibayashi H, 2007, ONCOL REP, V17, P549; Zhuang WZ, 2012, CANCER SCI, V103, P684, DOI 10.1111/j.1349-7006.2011.02198.x	36	27	29	0	18	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0730-2312	1097-4644		J CELL BIOCHEM	J. Cell. Biochem.	APR	2018	119	4					3091	3098		10.1002/jcb.26449			8	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	FX6IO	WOS:000426187500010	29058812				2022-04-25	
J	Le, XF; Bast, RC				Le, Xiao-Feng; Bast, Robert C., Jr.			Src family kinases and paclitaxel sensitivity	CANCER BIOLOGY & THERAPY			English	Review						Src; SFK; paclitaxel; dasatinib; ovarian cancer; drug sensitivity; resistance	GROWTH-FACTOR RECEPTOR; MICROTUBULE-ASSOCIATED PROTEIN; BETA-TUBULIN GENE; OVARIAN-CANCER CELLS; HUMAN BREAST-CANCER; C-SRC; TYROSINE KINASE; MULTIDRUG-RESISTANCE; LUNG-CANCER; FYN KINASE	Src-family Kinases (SFKs) participate in the regulation of proliferation, differentiation, apoptosis, autophagy, adhesion, migration, invasion and angiogenesis in normal and cancer cells. Abnormal expression of SFKs has been documented in cancers that arise in breast, colon, ovary, melanocyte, gastric mucosa, head and neck, pancreas, lung and brain. Targeting SFKs in cancer cells has been shown to be a promising therapeutic strategy in solid tumors, particularly in ovarian, colon and breast cancers. Paclitaxel is one of most widely used chemotherapeutic agents for the management of ovarian, breast, lung and head and neck cancers. As a microtubule-stabilizing agent, paclitaxel possesses both mitosis-dependent and mitosis-independent activities against cancer cells. A variety of mechanisms such as deregulation of P-glycoprotein, alteration of tubulin isotypes, alteration of microtubule-regulatory proteins, deregulation of apoptotic signaling pathways, mutation of tubulins and overexpression of copper transporters have been implicated in the development of primary or secondary resistance to paclitaxel. By affecting cancer cell survival, proliferation, autophagy, microtubule stability, motility, and/or angiogenesis, SFKs interact with mechanisms that regulate paclitaxel sensitivity. Inhibition of SFKs can potentiate the anti-tumor activity of paclitaxel by enhancing apoptosis, autophagy and microtubule stability. Based on pre-clinical observations, administration of SFK inhibitors in combination with paclitaxel could improve treatment for ovarian, breast, lung and head and neck cancers. Identification and validation of predictive biomarkers could also permit personalization of the therapy.	[Le, Xiao-Feng; Bast, Robert C., Jr.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA		Le, XF (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA.	xfle@mdanderson.org; rbast@mdanderson.org	Bast, Robert C/E-6585-2011	Bast, Robert C/0000-0003-4621-8462	Anne and Henry Zarrow Foundation; National Foundation for Cancer Research; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P50 CA83639, CCSG P30 CA16672]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016672, P50CA083639] Funding Source: NIH RePORTER	We are grateful to the Anne and Henry Zarrow Foundation, Mr. and Mrs. Stuart Zarrow, the National Foundation for Cancer Research, the MD Anderson SPORE in Ovarian Cancer NCI P50 CA83639 and the MD Anderson NCI CCSG P30 CA16672 for their support in preparing this review.	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J	Khorsandi, L; Saki, G; Bavarsad, N; Mombeini, M				Khorsandi, L.; Saki, G.; Bavarsad, N.; Mombeini, M.			Silymarin induces a multi-targeted cell death process in the human colon cancer cell line HT-29	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Necroptosis; Apoptosis; Autophagy; Silymarin; Colon cancer	REACTIVE OXYGEN; STEM-CELLS; AUTOPHAGY; APOPTOSIS; NECROPTOSIS; INHIBITION; SILIBININ; DIFFERENTIATION; NANOPARTICLES; CURCUMIN	This study investigated the Silymarin (SM) effects on growth of HT-29 human colon cancer cell line and its cellular death mechanism. HT-29 cells were treated by 25 mM/ml of SM for 48 h. HT-29 cells were also pretreated with 10 mmol zVAD (apoptosis inhibitor), 10 mmol 3-MA (autophagy inhibitor) and 3 mmol Nec (necroptosis inhibitor) for evaluation cell death induced by apoptosis, outophagy and necroptosis. MTT and clonogenicity assays revealed that the SM without inhibitors induced a significant decrease in cell viability and proliferation of HT-29 cells (p < 0.05). SM in presence of Nec and 3-MA significantly decreased viability and proliferation of HT-29 cells. Apoptotic indexes were significantly increased compare to other groups. SM in presence of zVAD and 3-MA significantly decreased viability and proliferation of HT-29 cells, and expression of RIPK1 and RIPK3 in compare to absence the inhibitors. Necroptotic index was also increased. zVAD could not completely blocked apoptosis. This indicate that SM may stimulate both caspase-dependent and caspase-independent apoptotic pathways. SM in presence of zVAD and Nec significantly decreased cell viability and proliferation of HT-29 cells in compare to control and other experimental groups. LC3-II positive cells were significantly increased in this group in compare to the control and SM without inhibitors treatment. Our results revealed that the high SM toxicity to HT-29 cells depends on multiple cell death pathways, which involved mainly autophagy. (C) 2017 Elsevier Masson SAS. All rights reserved.	[Khorsandi, L.; Saki, G.] Ahvaz Jundishapur Univ Med Sci, Cell & Mol Res Ctr, POB 61335, Ahvaz, Iran; [Khorsandi, L.; Saki, G.; Mombeini, M.] Ahvaz Jundishapur Univ Med Sci, Fac Med, Dept Anat Sci, Ahvaz, Iran; [Bavarsad, N.] Ahvaz Jundishapur Univ Med Sci, Dept Pharmaceut, Fac Med, Nanotechnol Res Ctr, Ahvaz, Iran		Khorsandi, L (corresponding author), Ahvaz Jundishapur Univ Med Sci, Cell & Mol Res Ctr, POB 61335, Ahvaz, Iran.	khorsandi_cmrc@yahoo.com	Khorsandi, Layasadat/R-3901-2017; saki, ghasem/M-3341-2018; Bavarsad, Neda/P-8663-2015	Khorsandi, Layasadat/0000-0002-3391-3055; saki, ghasem/0000-0001-5268-8407; Bavarsad, Neda/0000-0002-7872-0273	research council of Ahvaz Jundishapur University of Medical sciences [CMRC-95034]	This paper is a part Ms. C thesis of Maryam Mombeini and was supported by a Grant (CMRC-95034) from the research council of Ahvaz Jundishapur University of Medical sciences.	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C., 2016, AUTOPHAGY, V12, P659	45	9	10	0	7	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.	OCT	2017	94						890	897		10.1016/j.biopha.2017.08.015			8	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	FP6MU	WOS:000417741000100	28810529				2022-04-25	
J	Verdoodt, B; Vogt, M; Schmitz, I; Liffers, ST; Tannapfel, A; Mirmohammadsadegh, A				Verdoodt, Berlinda; Vogt, Markus; Schmitz, Inge; Liffers, Sven-Thorsten; Tannapfel, Andrea; Mirmohammadsadegh, Alireza			Salinomycin Induces Autophagy in Colon and Breast Cancer Cells with Concomitant Generation of Reactive Oxygen Species	PLOS ONE			English	Article							DEATH; APOPTOSIS; KINASE; RESISTANCE; ROLES; ROS; METASTASIS; ACTIVATION; EXPRESSION; CROSSTALK	Background: Salinomycin is a polyether ionophore antibiotic that has recently been shown to induce cell death in human cancer cells displaying multiple mechanisms of drug resistance. The underlying mechanisms leading to cell death after salinomycin treatment have not been well characterized. We therefore investigated the role of salinomycin in caspase dependent and independent cell death in colon cancer (SW480, SW620, RKO) and breast cancer cell lines (MCF-7, T47D, MDA-MB-453). Methodology/Principal Findings: We detected features of apoptosis in all cell lines tested, but the executor caspases 3 and 7 were only strongly activated in RKO and MDA-MB-453 cells. MCF-7 and SW620 cells instead presented features of autophagy such as cytoplasmic vacuolization and LC3 processing. Caspase proficient cell lines activated autophagy at lower salinomycin concentrations and before the onset of caspase activation. Salinomycin also led to the formation of reactive oxygen species (ROS) eliciting JNK activation and induction of the transcription factor JUN. Salinomycin mediated cell death could be partially inhibited by the free radical scavenger N-acetyl-cysteine, implicating ROS formation in the mechanism of salinomycin toxicity. Conclusions: Our data indicate that, in addition to its previously reported induction of caspase dependent apoptosis, the initiation of autophagy is an important and early effect of salinomycin in tumor cells.	[Verdoodt, Berlinda; Vogt, Markus; Schmitz, Inge; Liffers, Sven-Thorsten; Tannapfel, Andrea; Mirmohammadsadegh, Alireza] Ruhr Univ Bochum, Inst Pathol, Bochum, Germany		Mirmohammadsadegh, A (corresponding author), Ruhr Univ Bochum, Inst Pathol, Univ Str 150, Bochum, Germany.	alireza.mirmohammadsadegh@rub.de			Ministry for Innovation, Science and Research of Nordrhein-Westfalen; Protein Research Unit Ruhr within Europe, PURE	This work was funded by the Ministry for Innovation, Science and Research of Nordrhein-Westfalen, and by the Protein Research Unit Ruhr within Europe, PURE. 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	Sun, WL				Sun, Wei-Liang			Ambra1 in autophagy and apoptosis: Implications for cell survival and chemotherapy resistance (Review)	ONCOLOGY LETTERS			English	Review						activating molecule in beclin 1-regulated autophagy protein 1; autophagy; apoptosis; chemotherapy; resistance	BREAST-CANCER CELLS; BECLIN 1; COLON-CANCER; HEPATOCELLULAR-CARCINOMA; REGULATES AUTOPHAGY; MULTIDRUG-RESISTANCE; THERAPEUTIC TARGET; INHIBITS AUTOPHAGY; DEATH; 5-FLUOROURACIL	Increasing studies suggest that autophagy has a protective role in cancer treatment and may even be involved in chemotherapy resistance. Nevertheless, the mechanism of autophagy in cancer treatment and drug resistance has not yet been established. There is a complex association between autophagy and apoptosis. Accordingly, these two processes can mutually regulate and transform to determine the fate of a cell, depending on the context. Activating molecule in Beclin 1-regulated autophagy protein 1 (Ambra1) is an important factor at the crossroad between autophagy and apoptosis. The expression level and intracellular distributions of Ambra1 may control the balance and conversion between autophagy and apoptosis, and modify the effectiveness of chemotherapy. Therefore, Ambra1 may provide a novel target for cancer treatment, particularly for overcoming anticancer drug resistance. The present review focuses on the role of Ambra1 in autophagy and apoptosis and assesses the implications for cell survival and chemotherapy resistance.	[Sun, Wei-Liang] Guangxi Med Univ, Dept Internal Med Oncol, Affiliated Hosp 1, 6 Shuangyong Rd, Nanning 530021, Guangxi, Peoples R China		Sun, WL (corresponding author), Guangxi Med Univ, Dept Internal Med Oncol, Affiliated Hosp 1, 6 Shuangyong Rd, Nanning 530021, Guangxi, Peoples R China.	swl20022001@hotmail.com			National Natural Science Foundation of China (Beijing, China)National Natural Science Foundation of China (NSFC) [81360340]; Wu Jieping Medical Foundation clinical research special fund (Beijing, China) [320.6750.12689]	The present study is supported by grants front the National Natural Science Foundation of China (Beijing, China; grant no. 81360340) and the Wu Jieping Medical Foundation clinical research special fund (Beijing, China; grant no. 320.6750.12689).	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Lett.	JUL	2016	12	1					367	374		10.3892/ol.2016.4644			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	DR5RN	WOS:000379960200062	27347152	Green Published, gold			2022-04-25	
J	Mosieniak, G; Adamowicz, M; Alster, O; Jaskowiak, H; Szczepankiewicz, AA; Wilczynski, GM; Ciechomska, IA; Sikora, E				Mosieniak, Grazyna; Adamowicz, Marek; Alster, Olga; Jaskowiak, Hubert; Szczepankiewicz, Andrzej A.; Wilczynski, Grzegorz M.; Ciechomska, Iwona A.; Sikora, Ewa			Curcumin induces permanent growth arrest of human colon cancer cells: Link between senescence and autophagy	MECHANISMS OF AGEING AND DEVELOPMENT			English	Article						Senescence; Autophagy; Curcumin; p53; Polyploidy	NF-KAPPA-B; CELLULAR SENESCENCE; MITOTIC CATASTROPHE; DNA FRAGMENTATION; APOPTOTIC PATHWAY; DOWN-REGULATION; TUMOR-CELLS; IN-VITRO; P53; EXPRESSION	Curcumin, a natural polyphenol derived from the rhizome of Curcuma longa, is a potent anticancer agent, which restricts tumor cell growth both in vitro and in vivo. Thus far curcumin was shown to induce death of cancer cells. This study reports the induction of cellular senescence of human colon cancer cells HCT116 upon curcumin treatment. The SA-beta-galactosidase activation was observed both in p53+/+ and p53-/- cells, however the latter ones were less sensitive to the prosenescent activity of curcumin. Upregulation of p53 and p21 proteins was observed in p53+/+ HCT116, while p53-independent induction of p21 was noticed in p53-/- HCT116. Moreover, the senescence of HCT116 cells was accompanied by autophagy, that was confirmed by electron microscopy observations of autophagosomes in the curcumin-treated cells as well as LC3-II expression, punctue staining of LC3 and increased content of acidic vacuoles. Inhibition of autophagy, due to the diminished expression of ATG5 by RNAi decreased the number of senescent cells induced by curcumin, but did not lead to increased cell death. Altogether, we demonstrated a new antitumor activity of curcumin leading to cancer cell senescence and revealed the presence of a functional link between senescence and autophagy in curcumin-treated cells. (C) 2012 Elsevier Ireland Ltd. All rights reserved.	[Mosieniak, Grazyna; Adamowicz, Marek; Alster, Olga; Jaskowiak, Hubert; Sikora, Ewa] PAS, Nencki Inst Expt Biol, Lab Mol Bases Aging, PL-02093 Warsaw, Poland; [Szczepankiewicz, Andrzej A.; Wilczynski, Grzegorz M.] PAS, Nencki Inst Expt Biol, Lab Mol & Syst Neuromotphol, PL-02093 Warsaw, Poland; [Ciechomska, Iwona A.] PAS, Nencki Inst Expt Biol, Lab Transcript Regulat, PL-02093 Warsaw, Poland		Mosieniak, G (corresponding author), PAS, Nencki Inst Expt Biol, Lab Mol Bases Aging, PL-02093 Warsaw, Poland.	g.mosieniak@nencki.gov.pl	Ciechomksa, Iwona/R-4706-2016	Ciechomksa, Iwona/0000-0002-8068-0020; Mosieniak, Grazyna/0000-0001-7957-1241; Sikora, Ewa/0000-0002-1111-1748; Wilczynski, Grzegorz/0000-0001-6667-0291; Szczepankiewicz, Andrzej/0000-0002-1502-3147	Ministry of Science and Higher EducationMinistry of Science and Higher Education, PolandEuropean Commission [N301 008 32/0549]; National Center of ScienceNational Science Centre, Poland [2011/01/M/NZ1/01597]	This work was supported by the Ministry of Science and Higher Education (grant N301 008 32/0549) and by National Center of Science (grant 2011/01/M/NZ1/01597).	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Ageing Dev.	JUN	2012	133	6					444	455		10.1016/j.mad.2012.05.004			12	Cell Biology; Geriatrics & Gerontology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Geriatrics & Gerontology	978SE	WOS:000306765300008	22613224				2022-04-25	
J	Xu, JL; Yuan, L; Tang, YC; Xu, ZY; Xu, HD; Cheng, XD; Qin, JJ				Xu, Jing-Li; Yuan, Li; Tang, Yan-Cheng; Xu, Zhi-Yuan; Xu, Han-Dong; Cheng, Xiang-Dong; Qin, Jiang-Jiang			The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?	FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY			English	Review						gastric cancer; autophagy; chemoresistance; ncRNAs; natural products; inhibitor and activator	CELL-CYCLE PROGRESSION; MESENCHYMAL TRANSITION; SUPPRESSES AUTOPHAGY; COLON-CANCER; APOPTOSIS; MIGRATION; RESISTANCE; INVASION; PATHWAY; DEATH	Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.	[Xu, Jing-Li; Yuan, Li; Xu, Zhi-Yuan; Xu, Han-Dong; Cheng, Xiang-Dong; Qin, Jiang-Jiang] Chinese Acad Sci, Inst Canc & Basic Med, Hangzhou, Peoples R China; [Xu, Jing-Li; Yuan, Li; Xu, Zhi-Yuan; Xu, Han-Dong; Cheng, Xiang-Dong; Qin, Jiang-Jiang] Univ Chinese Acad Sci, Zhejiang Canc Hosp, Canc Hosp, Hangzhou, Peoples R China; [Xu, Jing-Li; Yuan, Li; Xu, Han-Dong] Zhejiang Chinese Med Univ, Clin Med Coll 1, Hangzhou, Peoples R China; [Tang, Yan-Cheng] Hong Kong Baptist Univ, Sch Chinese Med, Kowloon Tsai, Hong Kong, Peoples R China		Cheng, XD; Qin, JJ (corresponding author), Chinese Acad Sci, Inst Canc & Basic Med, Hangzhou, Peoples R China.; Cheng, XD; Qin, JJ (corresponding author), Univ Chinese Acad Sci, Zhejiang Canc Hosp, Canc Hosp, Hangzhou, Peoples R China.	chengxd516@126.com; zylysjtu@hotmail.com	Qin, Jiangjiang/AAM-9553-2020	Qin, Jiangjiang/0000-0002-8559-616X; Cheng, Xiangdong/0000-0003-1470-2831; yuan, li/0000-0002-6245-9437	Natural Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province [LY18H290006]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81903842, 81973634]; Program of Zhejiang Provincial TCM Sci-tech Plan [2018ZY006, 2020ZZ005]	This study was supported by Natural Science Foundation of Zhejiang Province (LY18H290006), National Natural Science Foundation of China (81903842 and 81973634), and Program of Zhejiang Provincial TCM Sci-tech Plan (2018ZY006 and 2020ZZ005).	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Cell. Dev. Biol.	DEC 3	2020	8								621428	10.3389/fcell.2020.621428			17	Cell Biology; Developmental Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Developmental Biology	PF8JS	WOS:000599294500001	33344463	Green Published, gold			2022-04-25	
J	Chen, Y; Fu, LL; Wen, X; Liu, B; Huang, J; Wang, JH; Wei, YQ				Chen, Y.; Fu, L. L.; Wen, X.; Liu, B.; Huang, J.; Wang, J. H.; Wei, Y. Q.			Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy	APOPTOSIS			English	Article						Apoptosis; Autophagy; Oncogenic microRNA; Tumor suppressive microRNA	LUNG ADENOCARCINOMA CELLS; DOWN-REGULATION; UP-REGULATION; REGULATES AUTOPHAGY; PROMOTES APOPTOSIS; BREAST-CANCER; INHIBITS AUTOPHAGY; INDUCE APOPTOSIS; COLON-CANCER; EXPRESSION	MicroRNAs (miRNAs), small and non-coding endogenous RNAs similar to 22 nucleotides (nt) in length, have been known to regulate approximately 30 % of human gene expression at the post-transcriptional and translational levels. Accumulating data have demonstrated that certain miRNAs could exert an oncogenic and/or tumor suppressive function and might play essential roles in the regulation of apoptosis and autophagy in cancer. In this review, we summarize that certain oncogenic and tumor suppressive miRNAs could modulate apoptotic pathways in different types of cancer. Subsequently, we demonstrate that other miRNAs might play regulatory roles in the autophagic pathways of cancer. A limited number of oncogenic/tumor suppressive miRNAs could regulate apoptosis and autophagy, respectively, and cooperatively. Taken together, these findings would provide a new clue to elucidate more apoptotic and/or autophagic mechanisms of miRNAs for designing potential novel therapeutic strategies in cancer.	[Chen, Y.; Wen, X.; Liu, B.; Wei, Y. Q.] Sichuan Univ, West China Hosp, Dept Gastrointestinal Surg, State Key Lab Biotherapy, Chengdu 610041, Peoples R China; [Fu, L. L.] Sichuan Univ, Coll Life Sci, Chengdu 610064, Peoples R China; [Huang, J.] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Shenyang 110016, Peoples R China; [Wang, J. H.] Xinjiang Med Univ, Coll Pharm, Urumqi 830011, Peoples R China		Liu, B (corresponding author), Sichuan Univ, West China Hosp, Dept Gastrointestinal Surg, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.	liubo2400@163.com; 13504051049@163.com	Wen, Xin/ADT-4758-2022	Wen, Xin/0000-0001-6513-8623	National 973 Basic Research Program of ChinaNational Basic Research Program of China [2010CB529900]; Key Projects of the National Science and Technology Pillar Program [2012BAI30B02]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81160543, 81260628, 81303270, 81172374]; West China Hospital-Chengdu Science and Technology Department Translational Medicine Innovation Foundation [ZH13039]; Shenyang Pharmaceutical University Scientific Research Fund [ZCJJ2013407]	We thank Dr. Yan Cheng (Pennsylvania State University) for her critical review on this manuscript. We are also grateful to the revision of this manuscript by Elsevier Webshop. This work was supported by grants from the National 973 Basic Research Program of China (No. 2010CB529900), the Key Projects of the National Science and Technology Pillar Program (No. 2012BAI30B02), the National Natural Science Foundation of China (Nos. 81160543, 81260628, 81303270 and 81172374), the West China Hospital-Chengdu Science and Technology Department Translational Medicine Innovation Foundation (No. ZH13039), and the Shenyang Pharmaceutical University Scientific Research Fund (No. ZCJJ2013407).	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J	Deng, Z; Liu, Q; Wang, MM; Wei, HK; Peng, J				Deng, Zhao; Liu, Qi; Wang, Miaomiao; Wei, Hong-Kui; Peng, Jian			GPA Peptide-Induced Nur77 Localization at Mitochondria Inhibits Inflammation and Oxidative Stress through Activating Autophagy in the Intestine	OXIDATIVE MEDICINE AND CELLULAR LONGEVITY			English	Article							FISH SKIN GELATIN; BOWEL-DISEASE; EXPERIMENTAL COLITIS; EPITHELIAL-CELLS; IMMUNITY; UBIQUITINATION; PATHOGENESIS; THERAPY; CANCER; GENE	Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. Nur77, belongs to the NR4A subfamily of nuclear hormone receptors, plays a critical role in controlling the pathology of colitis. The aim of this study is to investigate the protection effect and mechanism of Gly-Pro-Ala (GPA) peptide, isolated from fish skin gelatin hydrolysate, in a mouse model of dextran sulfate sodium- (DSS-) induced colitis and intestinal epithelial cells (IECs) stimulated by lipopolysaccharide (LPS). In vivo, GPA treatment alleviates DSS-induced weight loss, disease activity index (DAI) increase, colon length shortening, and colonic pathological damage. Production of proinflammatory cytokines, ROS, and MDA is significantly decreased by GPA treatment. In vitro, GPA significantly inhibits proinflammatory cytokine production, cytotoxicity, ROS, and MDA in IECs. Furthermore, GPA induces autophagy to suppress inflammation and oxidative stress. GPA promotes Nur77 translocation from the nucleus to mitochondria where it facilitates Nur77 interaction with TRAF6 and p62, leading to the induction of autophagy. In addition, GPA contributed to the maintenance of tight junction architecture in vivo and in vitro. Taken together, GPA, as a Nur77 modulator, could exert anti-inflammatory and antioxidant effects by inducing autophagy in IECs, suggesting that GPA may be promising for the prevention of colitis.	[Deng, Zhao; Liu, Qi; Wang, Miaomiao; Wei, Hong-Kui; Peng, Jian] Huazhong Agr Univ, Coll Anim Sci & Technol, Dept Anim Nutr & Feed Sci, Wuhan 430070, Peoples R China; [Wei, Hong-Kui; Peng, Jian] Cooperat Innovat Ctr Sustainable Pig Prod, Wuhan 430070, Hubei, Peoples R China		Wei, HK; Peng, J (corresponding author), Huazhong Agr Univ, Coll Anim Sci & Technol, Dept Anim Nutr & Feed Sci, Wuhan 430070, Peoples R China.; Wei, HK; Peng, J (corresponding author), Cooperat Innovat Ctr Sustainable Pig Prod, Wuhan 430070, Hubei, Peoples R China.	weihongkui@mail.hzau.edu.cn; pengjian@mail.hzau.edu.cn	deng, zhao/AAK-6182-2021	deng, zhao/0000-0002-7025-4976	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31972578]; Hubei Province Technology Innovation Special Major Project [2019ABA081]; Modern Agricultural Industry Technology System [CARS-35]; Basic Scientific Research Operating Expenses of Central Universities [2662017PY017]	We thank the Department of Animal Nutrition and Feed Science (Huazhong Agricultural University) for their help. This research was supported by the National Natural Science Foundation of China (31972578), the Hubei Province Technology Innovation Special Major Project (2019ABA081), the Modern Agricultural Industry Technology System (CARS-35), and the Basic Scientific Research Operating Expenses of Central Universities (2662017PY017).	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J	Izdebska, M; Zielinska, W; Halas-Wisniewska, M; Grzanka, A				Izdebska, Magdalena; Zielinska, Wioletta; Halas-Wisniewska, Marta; Grzanka, Alina			Involvement of Actin in Autophagy and Autophagy-Dependent Multidrug Resistance in Cancer	CANCERS			English	Review						autophagy; actin; cancer; multidrug resistance	CELL-DEATH; ARP2/3 COMPLEX; COLON-CANCER; INDEPENDENT FUNCTIONS; MAMMALIAN AUTOPHAGY; INHIBITS AUTOPHAGY; REQUIRE AUTOPHAGY; LIR MOTIF; IN-VITRO; MEMBRANE	Currently, autophagy in the context of cancer progression arouses a lot of controversy. It is connected with the possibility of switching the nature of this process from cytotoxic to cytoprotective and vice versa depending on the treatment. At the same time, autophagy of cytoprotective character may be one of the factors determining multidrug resistance, as intensification of the process is observed in patients with poorer prognosis. The exact mechanism of this relationship is not yet fully understood; however, it is suggested that one of the elements of the puzzle may be a cytoskeleton. In the latest literature reports, more and more attention is paid to the involvement of actin in the autophagy. The role of this protein is linked to the formation of autophagosomes, which are necessary element of the process. However, based on the proven effectiveness of manipulation of the actin pool, it seems to be an attractive alternative in breaking autophagy-dependent multidrug resistance in cancer.	[Izdebska, Magdalena; Zielinska, Wioletta; Halas-Wisniewska, Marta; Grzanka, Alina] Nicolaus Copernicus Univ Torun, Coll Med Bydgoszcz, Fac Med, Dept Histol & Embryol, PL-85092 Bydgoszcz, Poland		Izdebska, M (corresponding author), Nicolaus Copernicus Univ Torun, Coll Med Bydgoszcz, Fac Med, Dept Histol & Embryol, PL-85092 Bydgoszcz, Poland.	mizdebska@cm.umk.pl	Hałas-Wiśniewska, Marta/AAI-4961-2020	Halas-Wisniewska, Marta/0000-0002-1264-0481; Zielinska, Wioletta/0000-0002-3065-0931; Izdebska, Magdalena/0000-0002-9395-0886	Nicolaus Copernicus University in Torun, Faculty of Medicine, Collegium Medicum in Bydgoszcz [163]	The present study was co supported via research tasks within the framework of statutory activities no. 163 (Nicolaus Copernicus University in Torun, Faculty of Medicine, Collegium Medicum in Bydgoszcz).	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J	Xie, X; Zhao, Y; Ma, CY; Xu, XM; Zhang, YQ; Wang, CG; Jin, J; Shen, X; Gao, JL; Li, N; Sun, ZJ; Dong, DL				Xie, Xin; Zhao, Yu; Ma, Chun-Yan; Xu, Xiao-Ming; Zhang, Yan-Qiu; Wang, Chen-Guang; Jin, Jing; Shen, Xin; Gao, Jin-Lai; Li, Na; Sun, Zhi-Jie; Dong, De-Li			Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway	BRITISH JOURNAL OF PHARMACOLOGY			English	Article							PERMEABILITY TRANSITION PORE; NRF2 ANTIOXIDANT PATHWAY; MYELOID-LEUKEMIA CELLS; GLUTATHIONE DEPLETION; COLORECTAL-CANCER; ACID-ESTERS; IN-VITRO; APOPTOSIS RESISTANCE; DRUG-RESISTANCE; DEATH	Background and PurposeDimethyl fumarate (DMF) is a newly approved drug for the treatment of relapsing forms of multiple sclerosis and relapsing-remitting multiple sclerosis. Here, we investigated the effects of DMF and its metabolites mono-methylfumarate (MMF and methanol) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms involved. Experimental ApproachCell viability was measured by the MTT or CCK8 assay. Protein expressions were measured by Western blot analysis. LDH release, live- and dead-cell staining, intracellular GSH levels, and mitochondrial membrane potential were examined by using commercial kits. Key ResultsDMF but not MMF induced cell necroptosis, as demonstrated by the pharmacological tool necrostatin-1, transmission electron microscopy, LDH and HMGB1 release in CT26 cells. The DMF-induced decrease in cellular GSH levels as well as cell viability and increase in reactive oxygen species (ROS) were inhibited by co-treatment with GSH and N-acetylcysteine (NAC) in CT26 cells. DMF activated JNK, p38 and ERK MAPKs in CT26 cells and JNK, p38 and ERK inhibitors partially reversed the DMF-induced decrease in cell viability. GSH or NAC treatment inhibited DMF-induced JNK, p38, and ERK activation in CT26 cells. DMF but not MMF increased autophagy responses in SGC-7901, HCT116, HT29 and CT26 cancer cells, but autophagy inhibition did not prevent the DMF-induced decrease in cell viability. Conclusion and ImplicationsDMF but not its metabolite MMF induced necroptosis in colon cancer cells through a mechanism involving the depletion of GSH, an increase in ROS and activation of MAPKs.	[Xie, Xin; Zhao, Yu; Ma, Chun-Yan; Xu, Xiao-Ming; Zhang, Yan-Qiu; Wang, Chen-Guang; Jin, Jing; Shen, Xin; Gao, Jin-Lai; Li, Na; Dong, De-Li] Harbin Med Univ, Dept Pharmacol, State Prov Key Labs Biomed Pharmaceut China, Key Lab Cardiovasc Res,Minist Educ, Harbin 150086, Heilongjiang, Peoples R China; [Sun, Zhi-Jie] Harbin Engn Univ, Ctr Biomed Mat & Engn, Harbin, Peoples R China		Dong, DL (corresponding author), Harbin Med Univ, Dept Pharmacol, Baojian Rd 157, Harbin 150086, Heilongjiang, Peoples R China.	dongdeli@ems.hrbmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81373406, 81421063]	This work was supported by the National Natural Science Foundation of China (Grant No. 81373406, 81421063).	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J. Pharmacol.	AUG	2015	172	15					3929	3943		10.1111/bph.13184			15	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	CM8LN	WOS:000357952500018	25953698	Green Published, Bronze			2022-04-25	
J	Nkune, NW; Kruger, CA; Abrahamse, H				Nkune, Nkune W.; Kruger, Cherie A.; Abrahamse, Heidi			Possible Enhancement of Photodynamic Therapy (PDT) Colorectal Cancer Treatment when Combined with Cannabidiol	ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY			English	Review						Colorectal Cancer (CRC); combinative treatment; Cannabis sativa; Cannabidiol (CBD); Photodynamic Therapy (PDT); targeted therapy	COLON-CANCER; INDUCED APOPTOSIS; DRUG-DELIVERY; ZINC PHTHALOCYANINE; RADIATION-THERAPY; TARGETED THERAPY; RECTAL-CANCER; STAGE-II; NANOPARTICLES; AUTOPHAGY	Colorectal Cancer (CRC) has a high mortality rate and is one of the most difficult diseases to manage due to tumour resistance and metastasis. The treatment of choice for CRC is reliant on the phase and time of diagnosis. Despite several conventional treatments available to treat CRC (surgical excision, chemo-, radiation and immune-therapy), resistance is a major challenge, especially if it has metastasized. Additionally, these treatments often cause unwanted adverse side effects and so it remains imperative to investigate alternative combination therapies. Photodynamic Therapy (PDT) is a promising treatment modality for the primary treatment of CRC, since it is non-invasive, has few side effects and selectively damages only cancerous tissues, leaving adjacent healthy structures intact. PDT involves three fundamentals: a Photosensitizer (PS) drug localized in tumour tissues, oxygen, and light. Upon PS excitation using a specific wavelength of light, an energy transfer cascade occurs, that ultimately yields cytotoxic species, which in turn induces cell death. Cannabidiol (CBD) is a cannabinoid compound derived from the Cannabis sativa plant, which has shown to exert anticancer effects on CRC through different pathways, inducing apoptosis and so inhibiting tumour metastasis and secondary spread. This review paper highlights current conventional treatment modalities for CRC and their limitations, as well as discusses the necessitation for further investigation into unconventional active nanoparticle targeting PDT treatments for enhanced primary CRC treatment. This can be administered in combination with CBD, to prevent CRC secondary spread and enhance the synergistic efficacy of CRC treatment outcomes, with less side effects.	[Nkune, Nkune W.; Kruger, Cherie A.; Abrahamse, Heidi] Univ Johannesburg, Fac Hlth Sci, Laser Res Ctr, Johannesburg, South Africa		Kruger, CA (corresponding author), Univ Johannesburg, Fac Hlth Sci, Dept Laser Res Ctr, POB 17011, Johannesburg, South Africa.	cherier@uj.ac.za	Nkune, Nkune Williams/AAK-1713-2021; ABRAHAMSE, HEIDI/U-7763-2019; Kruger, Cherie Ann/H-2004-2016	Nkune, Nkune Williams/0000-0003-3746-707X; ABRAHAMSE, HEIDI/0000-0001-5002-827X; Kruger, Cherie Ann/0000-0002-4556-9132	South African Research Chairs Initiative of the Department of Science and Technology; South African Research Chairs Initiative of the National Research Foundation of South Africa [98337]; National Research Foundation Thuthuka Fund [TTK180409318735]; Cancer Association of South Africa (CANSA) Research Funding Grant; University of Johannesburg; National Laser Centre; National Research Foundation of South Africa (CSIR-DST); CSIR-DST InterBursary Programme	This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98337), National Research Foundation Thuthuka Fund (Grant No TTK180409318735) and Cancer Association of South Africa (CANSA) Research Funding Grant. The authors sincerely thank the University of Johannesburg, the National Laser Centre and the National Research Foundation of South Africa (CSIR-DST) for their financial grant support, as well as the CSIR-DST InterBursary Programme for postgraduate student monetary support.	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Chem.		2021	21	2					137	148		10.2174/1871520620666200415102321			12	Oncology; Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	QK4KN	WOS:000620356100003	32294046	hybrid			2022-04-25	
J	Zhou, W; Liu, LB; Xue, YX; Zheng, J; Liu, XB; Ma, J; Li, Z; Liu, YH				Zhou, Wei; Liu, Libo; Xue, Yixue; Zheng, Jian; Liu, Xiaobai; Ma, Jun; Li, Zhen; Liu, Yunhui			Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR-590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway	FRONTIERS IN MOLECULAR NEUROSCIENCE			English	Article						EMAP-II; TMZ; GSCs; autophagy; microRNAs; MiR-590-3p; MACC1	EPITHELIAL-MESENCHYMAL TRANSITION; GLIOMA-CELLS; CANCER-CELLS; HEPATOCELLULAR-CARCINOMA; PANCREATIC-CANCER; IN-VITRO; REGULATES AUTOPHAGY; COLORECTAL-CANCER; MACC1 EXPRESSION; EMAP II	This study aims to investigate the effect of Endothelial-Monocyte-Activating Polypeptide-II (EMAP-II) combined with temozolomide (TMZ) upon glioblastoma stem cells (GSCs) and its possible molecular mechanisms. In this study, combination of EMAP-II with TMZ inhibited cell viability, migration and invasion in GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) and chloroquine (CQ) partly reverse the anti-proliferative effect of the combination treatment. Autophagic vacuoles were formed in GSCs after the combination therapy, accompanied with the up-regulation of LC3-II and Beclin-1 as well as the down-regulation of p62/SQSTM1. Further, miR-590-3p was up-regulated and Metastasis-associated in colon cancer 1 (MACC1) was down-regulated by the combination treatment in GSCs; MiR-590-3p overexpression and MACC1 knockdown up-regulated LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1 in GSCs; MACC1 was identified as a direct target of miR-590-3p, mediating the effects of miR-590-3p in the combination treatment. Furthermore, the combination treatment and MACC1 knockdown decreased p-PI3K, p-Akt, p-mTOR, p-S6 and p-4EBP in GSCs; PI3K/Akt agonist insulin-like growth factor-1(IGF-1) partly blocked the effect of the combination treatment. Moreover, in vivo xenograft models, the mice given stable overexpressed miR-590-3p cells and treated with EMAP-II and TMZ had the smallest tumor sizes, besides, miR-590-3p + EMAP-II + TMZ up-regulated the expression level of miR-590-3p, LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1. In conclusion, these results elucidated anovel molecular mechanism of EMAP-II in combination with TMZ suppressed malignant biological behaviors of GSCs via miR-590-3p/MACC1 inhibiting PI3K/AKT/mTOR signaling pathway, and might provide potential therapeutic approaches for human GSCs.	[Zhou, Wei; Zheng, Jian; Liu, Xiaobai; Li, Zhen; Liu, Yunhui] China Med Univ, Dept Neurosurg, Shengjing Hosp, Shenyang, Peoples R China; [Zhou, Wei; Zheng, Jian; Liu, Xiaobai; Li, Zhen; Liu, Yunhui] Liaoning Res Ctr Translat Med Nervous Syst Dis, Shenyang, Peoples R China; [Liu, Libo; Xue, Yixue; Ma, Jun] China Med Univ, Dept Neurobiol, Coll Basic Med, Shenyang, Peoples R China; [Liu, Libo; Xue, Yixue; Ma, Jun] China Med Univ, Minist Publ Hlth China, Key Lab Cell Biol, Shenyang, Peoples R China; [Liu, Libo; Xue, Yixue; Ma, Jun] China Med Univ, Minist Educ China, Key Lab Med Cell Biol, Shenyang, Peoples R China		Liu, YH (corresponding author), China Med Univ, Dept Neurosurg, Shengjing Hosp, Shenyang, Peoples R China.; Liu, YH (corresponding author), Liaoning Res Ctr Translat Med Nervous Syst Dis, Shenyang, Peoples R China.	liuyh_cmuns@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672511, 81372484, 81402573, 81573010]; Liaoning Science and Technology Plan Project [2015225007]; Shenyang Science and Technology Plan Projects [F15-199-1-30, F15-199-1-57]; outstanding scientific fund of Shengjing hospital [201304]	This work is supported by grants from the National Natural Science Foundation of China (81672511, 81372484, 81402573 and 81573010), Liaoning Science and Technology Plan Project (No. 2015225007), Shenyang Science and Technology Plan Projects (Nos. F15-199-1-30 and F15-199-1-57) and outstanding scientific fund of Shengjing hospital (No. 201304).	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Molec. Neurosci.	MAR 13	2017	10								68	10.3389/fnmol.2017.00068			17	Neurosciences	Science Citation Index Expanded (SCI-EXPANDED)	Neurosciences & Neurology	EN5RD	WOS:000396062300001	28348518	gold, Green Published, Green Submitted			2022-04-25	
J	Lin, PL; Tang, HH; Wu, SY; Shaw, NS; Su, CL				Lin, Pin-Lun; Tang, Han-Hsuan; Wu, Shan-Ying; Shaw, Ning-Sing; Su, Chun-Li			Saponin Formosanin C-Induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells	ANTIOXIDANTS			English	Article						formosanin C; hepatocellular carcinoma; ferroptosis; autophagy; ferritinophagy	COLORECTAL-CANCER CELLS; NF-KAPPA-B; IRON HOMEOSTASIS; AUTOPHAGY; APOPTOSIS; DEGRADATION; DEATH; ACSL4; CYTOTOXICITY; ACTIVATION	Ferroptosis, a recently discovered form of iron-dependent cell death, requires an increased level of lipid-reactive oxygen species (ROS). Ferritinophagy, a ferritin degradation pathway, depends on a selective autophagic cargo receptor (NCOA4). By screening various types of natural compounds, formosanin C (FC) was identified as a novel ferroptosis inducer, characterized by attenuations of FC-induced viability inhibition and lipid ROS formation in the presence of ferroptosis inhibitor. FC also induced autophagic flux, evidenced by preventing autophagic marker LC3-II degradation and increasing yellow LC3 puncta in tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) transfected cells when combined with autophagic flux inhibitor. It is noteworthy that FC-induced ferroptosis and autophagic flux were stronger in HepG2 cells expressing higher NCOA4 and lower ferritin heavy chain 1 (FTH1) levels, agreeing with the results of gene expression analysis using CTRP and PRISM, indicating that FTH1 expression level exhibited a significant negative correlation with the sensitivity of the cells to a ferroptosis inducer. Confocal and electron microscopy confirmed the pronounced involvement of ferritinophagy in FC-induced ferroptosis in the cells with elevated NCOA4. Since ferroptosis is a non-apoptotic form of cell death, our data suggest FC has chemotherapeutic potential against apoptosis-resistant HCC with a higher NCOA4 expression via ferritinophagy.	[Lin, Pin-Lun; Su, Chun-Li] Natl Taiwan Normal Univ, Dept Human Dev & Family Studies, Taipei 106, Taiwan; [Tang, Han-Hsuan; Wu, Shan-Ying; Su, Chun-Li] Natl Taiwan Normal Univ, Sch Life Sci, Grad Program Nutr Sci, Taipei 106, Taiwan; [Wu, Shan-Ying] Taipei Med Univ, Sch Med, Dept Microbiol & Immunol, Coll Med, Taipei 110, Taiwan; [Shaw, Ning-Sing] Natl Taiwan Univ, Dept Biochem Sci & Technol, Coll Life Sci, Taipei 106, Taiwan		Su, CL (corresponding author), Natl Taiwan Normal Univ, Dept Human Dev & Family Studies, Taipei 106, Taiwan.; Su, CL (corresponding author), Natl Taiwan Normal Univ, Sch Life Sci, Grad Program Nutr Sci, Taipei 106, Taiwan.; Shaw, NS (corresponding author), Natl Taiwan Univ, Dept Biochem Sci & Technol, Coll Life Sci, Taipei 106, Taiwan.	sp940921@gate.sinica.edu.tw; 60751001s@ntnu.edu.tw; shanyingwu@tmu.edu.tw; nsshaw@ntu.edu.tw; chunlisu@ntnu.edu.tw		Tang, Han-Hsuan/0000-0002-9034-3597; Lin, Pin-lun/0000-0001-5313-7180; Su, Chun-Li/0000-0001-7617-2077	Ministry of Science and Technology, TaiwanMinistry of Science and Technology, Taiwan [MOST 105-2320-B-003-003, 105-2514-S-003-006, 106-2320-B-003-006-MY3, 106-2514-S-003-006]; National Taiwan Normal University, Taiwan [10502, 10602]	This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 105-2320-B-003-003, 105-2514-S-003-006, 106-2320-B-003-006-MY3, and 106-2514-S-003-006) and National Taiwan Normal University, Taiwan (10502 and 10602).	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J	Zhang, MY; Gou, WF; Zhao, S; Mao, XY; Zheng, ZH; Takano, Y; Zheng, HC				Zhang, Mei-Ying; Gou, Wen-Feng; Zhao, Shuang; Mao, Xiao-Yun; Zheng, Zhi-Hong; Takano, Yasuo; Zheng, Hua-Chuan			Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						colorectal carcinoma; Beclin 1; tumorigenesis; pathogenesis; prognosis	TUMOR-SUPPRESSOR; HEPATOCELLULAR-CARCINOMA; PROGNOSTIC-SIGNIFICANCE; PROTEIN EXPRESSION; REDUCED EXPRESSION; CERVICAL-CANCER; AUTOPHAGY GENE; APOPTOSIS; TUMORIGENESIS; CHEMOTHERAPY	Beclin 1 participates in development, autophagy, differentiation, anti-apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH) were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05). According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM) than adenoma and carcinoma (p < 0.05). Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05). Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05), but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM) staging, differentiation or serum carcinoembryonic antigen (CEA) concentration (p > 0.05). Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05). Cox's model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05). It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma.	[Zhang, Mei-Ying; Zheng, Zhi-Hong] China Med Univ, Lab Anim Ctr, Shenyang 110001, Peoples R China; [Gou, Wen-Feng; Zhao, Shuang; Zheng, Hua-Chuan] China Med Univ, Coll Basic Med, Dept Biochem & Mol Biol, Shenyang 110001, Peoples R China; [Mao, Xiao-Yun] China Med Univ, Affiliated Hosp 1, Dept Surg Oncol, Shenyang 110001, Peoples R China; [Takano, Yasuo] Kanagawa Canc Ctr, Clin Res Inst, Yokohama, Kanagawa 2410815, Japan		Zheng, HC (corresponding author), China Med Univ, Coll Basic Med, Dept Biochem & Mol Biol, Shenyang 110001, Peoples R China.	zhmeiying@hotmail.com; xiaogouaeiou@163.com; zhaoshuang1235@163.com; maoxiaoyun@126.com; zhihongzheng@163.com; ytakano@gancen.asahi.yokohama.jp; zheng_huachuan@hotmail.com			Shenyang Outstanding Talent Foundation of China; Shenyang Science and Technology Grant [F10-149-9-25, F11-264-1-10]; Liaoning Science and Technology Grant; National Natural Scientific Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81172371, 81201886]; Ministry of Education, Culture, Sports and Technology of JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [23659958]	This study was supported by: Shenyang Outstanding Talent Foundation of China; Shenyang Science and Technology Grant (F10-149-9-25; F11-264-1-10); Liaoning Science and Technology Grant; National Natural Scientific Foundation of China (81172371; 81201886) and Grant-in aid for Scientific Research from the Ministry of Education, Culture, Sports and Technology of Japan (23659958).	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J. Mol. Sci.	AUG	2014	15	8					14372	14385		10.3390/ijms150814372			14	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	AO7GD	WOS:000341519600073	25196438	Green Published, gold, Green Submitted			2022-04-25	
J	Talbert, E; Metzger, G; He, W; Guttridge, D				Talbert, Erin E.; Metzger, Gregory A.; He, Wei A.; Guttridge, Denis C.			Modeling human cancer cachexia in colon 26 tumor-bearing adult mice	JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE			English	Article						Muscle wasting; Ubiquitin ligases; Autophagy; Muscle regeneration	SKELETAL-MUSCLE; WEIGHT-LOSS; ADENOCARCINOMA; REJUVENATION; CHEMOTHERAPY; DYSFUNCTION	Muscle wasting is a profound side effect of advanced cancer. Cancer-induced cachexia decreases patient quality of life and is associated with poor patient survival. Currently, no clinical therapies exist to treat cancer-induced muscle wasting. Although cancers commonly associated with cachexia occur in older individuals, the standard animal models used to elucidate the causes of cachexia rely on juvenile mice. In an effort to better model human cancer cachexia, we determined whether cachectic features seen in young mice could be achieved in adult, pre-sarcopenic mice following colon 26 (C-26) tumor cell inoculation. Both young and adult mice developed similar-sized tumors and progressed to cachexia with similar kinetics, as evidenced by losses in body mass, and adipose and skeletal muscle tissues. Proteolytic signaling, including proteasome and autophagy genes, was also increased in muscles from both young and adult tumor-bearing animals. Furthermore, tumor-associated muscle damage and activation of Pax7 progenitor cells was induced in both young and adult mice. Although cancer cachexia generally occurs in older individuals, these data suggest that the phenotype and underlying mechanisms can be effectively modeled using the currently accepted protocol in juvenile mice.	[Talbert, Erin E.; Metzger, Gregory A.; He, Wei A.; Guttridge, Denis C.] Ohio State Univ, Coll Med, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, Columbus, OH 43210 USA; [Talbert, Erin E.; Metzger, Gregory A.; He, Wei A.; Guttridge, Denis C.] Ohio State Univ, Coll Med, Arthur G James Comprehens Canc Ctr, Columbus, OH 43210 USA		Guttridge, D (corresponding author), Ohio State Univ, Coll Med, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, 460 W 12th Ave, Columbus, OH 43210 USA.	erin.talbert@osumc.edu; gregory.metzger@osumc.edu; wei.he@osumc.edu; denis.guttridge@osumc.edu	He, Wei/J-6275-2016; Talbert, Erin/AAM-5535-2020	Talbert, Erin/0000-0003-4587-0950; Guttridge, Denis/0000-0002-7276-6609	Ohio State Comprehensive Cancer Center; Ohio State Cancer Genetics NIH T32 training grant [T32 CA106196]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 CA180057]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA180057] Funding Source: NIH RePORTER	We thank Katherine Ladner for technical assistance and The Ohio State Comprehensive Cancer Center for support for this project. EET is Weiss Postdoctoral Fellow and is supported by the Ohio State Cancer Genetics NIH T32 training grant, T32 CA106196. Further support was provided by an NIH grant, R01 CA180057 to DCG.	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Cachexia Sarcopenia Muscle	DEC	2014	5	4					321	328		10.1007/s13539-014-0141-2			8	Geriatrics & Gerontology; Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	Geriatrics & Gerontology; General & Internal Medicine	AU1WC	WOS:000345407100010	24668658	gold, Green Published			2022-04-25	
J	Qiao, XR; Wang, XF; Shang, Y; Li, Y; Chen, SZ				Qiao, Xinran; Wang, Xiaofei; Shang, Yue; Li, Yi; Chen, Shu-zhen			Azithromycin enhances anticancer activity of TRAIL by inhibiting autophagy and up-regulating the protein levels of DR4/5 in colon cancer cells in vitro and in vivo	CANCER COMMUNICATIONS			English	Article						Azithromycin; TRAIL; Apoptosis; Autophagy; Colon cancer	INDUCED APOPTOSIS; DOWN-REGULATION; DEATH; CHLOROQUINE; INDUCTION; CLARITHROMYCIN; ANTIBIOTICS; BORTEZOMIB; RESISTANCE; CELECOXIB	Background: Azithromycin is a member of macrolide antibiotics, and has been reported to inhibit the proliferation of cancer cells. However, the underlying mechanisms are not been fully elucidated. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively targets tumor cells without damaging healthy cells. In the present study, we examined whether azithromycin is synergistic with TRAIL, and if so, the underlying mechanisms in colon cancers. Methods: HCT-116, SW480, SW620 and DiFi cells were treated with azithromycin, purified TRAIL, or their combination. A sulforhoddamine B assay was used to examine cell survival. Apoptosis was examined using annexin V-FITC/PI staining, and autophagy was observed by acridine orange staining. Western blot analysis was used to detect protein expression levels. In mechanistic experiments, siRNAs were used to knockdown death receptors (DR4, DR5) and LC-3B. The anticancer effect of azithromycin and TRAIL was also examined in BALB/c nude mice carrying HCT-116 xenografts. Results: Azithromycin decreased the proliferation of HCT-116 and SW480 cells in a dose-dependent manner. Combination of azithromycin and TRAIL inhibited tumor growth in a manner that could not be explained by additive effects. Azithromycin increased the expressions of DR4, DR5, p62 and LC-3B proteins and potentiated induction of apoptosis by TRAIL. Knockdown of DR4 and DR5 with siRNAs increased cell survival rate and decreased the expression of cleaved-PARP induced by the combination of azithromycin and TRAIL. LC-3B siRNA and CQ potentiated the anti-proliferation activity of TRAIL alone, and increased the expressions of DR4 and DR5. Conclusion: The synergistic antitumor effect of azithromycin and TRAIL mainly relies on the up-regulations of DR4 and DR5, which in turn result from LC-3B-involved autophagy inhibition.	[Chen, Shu-zhen] Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China; Peking Union Med Coll, Beijing 100050, Peoples R China		Chen, SZ (corresponding author), Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China.	bjcsz@imb.pumc.edu.cn		Chen, Shu-zhen/0000-0003-4881-0558; , xinran/0000-0003-0909-7155; qiao, xinran/0000-0002-0354-3364	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81373437, 81621064]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2016-I2M-02-002]	The manuscript was supported by grants from the National Natural Science Foundation of China (81373437 and 81621064) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-02-002).	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JUL 3	2018	38								43	10.1186/s40880-018-0309-9			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	GM7HG	WOS:000438353700001	29970185	Green Published, gold			2022-04-25	
J	Huang, XM; Yang, ZJ; Xie, Q; Zhang, ZK; Zhang, H; Ma, JY				Huang, Xuan-mei; Yang, Zhi-jie; Xie, Qing; Zhang, Zi-kang; Zhang, Hua; Ma, Jun-ying			Natural products for treating colorectal cancer: A mechanistic review	BIOMEDICINE & PHARMACOTHERAPY			English	Review						Natural products; Colorectal cancer; Anti-cancer effects; Molecular mechanisms; Regulation networks	CELL-CYCLE ARREST; FLUOROURACIL PLUS LEUCOVORIN; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; EPITHELIAL-MESENCHYMAL TRANSITION; ENHANCED ANTITUMOR-ACTIVITY; FACTOR-KAPPA-B; COLON-CANCER; PHASE-II; INDUCE APOPTOSIS; ANTIPROLIFERATIVE ACTIVITY	Colorectal cancer (CRC) is one of the most common types of cancers in humans and is closely linked to the global cancer-related mortalities worldwide. Molecular pathological epidemiology studies can reveal the risk factors of CRC and contribute to biomarker research and precision medicine. The current clinical treatment for CRC mainly involves surgery and chemotherapy. However, because of the occurrence of side effects and the emergence of drug resistance, there is an urgent need to find new and more effective drugs for CRC treatment. An increasing number of studies have demonstrated that many natural products possess effective anti-CRC effects and may serve as alternative chemotherapy agents for CRC treatment. In this review, we summarize the natural products with anti-CRC effects from different sources based on the chemical structures such as alkaloids, polysaccharides, polyphenols, terpenoid, unsaturated fatty acids, and discuss the natural product-derived drugs used clinically for colorectal cancer treatment. Furthermore, natural products of marine origin are also discussed for their enormous potential to serve as the candidate drugs. Notably, we generalize the experiment-based molecular mechanisms and the regulatory networks whereby natural products exert anticancer effects on cell proliferation, metastasis, apoptosis, autophagy, and angiogenesis.	[Huang, Xuan-mei; Xie, Qing; Zhang, Zi-kang; Zhang, Hua] Guangdong Med Univ, Marine Biomed Res Inst, Inst Lab Med, Guangdong Prov Key Lab Med Mol Diagnost, Dongguan 523808, Peoples R China; [Yang, Zhi-jie; Ma, Jun-ying] Chinese Acad Sci, South China Sea Inst Oceanol, RNAM Ctr Marine Microbiol, CAS Key Lab Trop Marine Bioresources & Ecol,Guang, Guangzhou 510301, Guangdong, Peoples R China		Zhang, H (corresponding author), Guangdong Med Univ, Marine Biomed Res Inst, Inst Lab Med, Guangdong Prov Key Lab Med Mol Diagnost, Dongguan 523808, Peoples R China.; Ma, JY (corresponding author), Chinese Acad Sci, South China Sea Inst Oceanol, RNAM Ctr Marine Microbiol, CAS Key Lab Trop Marine Bioresources & Ecol,Guang, Guangzhou 510301, Guangdong, Peoples R China.	1837766853@qq.com; yzjie6@126.com; 1048271414@qq.com; 1119129766@qq.com; huazhang@gdmu.edu.cn; majunying@scsio.ac.cn	Zhang, Hua/AAF-3999-2020; Zhang, Hua/AAA-2164-2022	Zhang, Hua/0000-0001-9731-2737; Ma, Junying/0000-0002-0641-7291	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31870046, 81741166]; Natural Science Foundation of Guangdong ProvinceNational Natural Science Foundation of Guangdong Province [2016A030312014, 2018A0303130005, 2015A03313528]; Special Support Program for Training High-Level Talents in Guangdong [201528018]; Fund of the School of Laboratory Medicine of Guangdong Medical University	This work was supported by the National Natural Science Foundation of China (31870046 and 81741166), the Natural Science Foundation of Guangdong Province (2016A030312014, 2018A0303130005 and 2015A03313528), the Special Support Program for Training High-Level Talents in Guangdong (201528018) and Fund of the School of Laboratory Medicine of Guangdong Medical University.	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Pharmacother.	SEP	2019	117								109142	10.1016/j.biopha.2019.109142			13	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	IM2EA	WOS:000477804500082	31238258	gold			2022-04-25	
J	Xiang, XC; Tian, YH; Hu, JN; Xiong, R; Bautista, M; Deng, L; Yue, QJ; Li, YQ; Kuang, W; Li, JF; Liu, K; Yu, CL; Feng, G				Xiang, Xiaocong; Tian, Yunhong; Hu, Jiani; Xiong, Rong; Bautista, Matthew; Deng, Li; Yue, Qiuju; Li, Yuqi; Kuang, Wei; Li, Junfeng; Liu, Kang; Yu, Chunlei; Feng, Gang			Fangchinoline exerts anticancer effects on colorectal cancer by inducing autophagy via regulation AMPK/mTOR/ULK1 pathway	BIOCHEMICAL PHARMACOLOGY			English	Article						Fangchinoline; Autophagy; Apoptosis; AMPK; Colorectal cancer	LETHAL; MTOR	Autophagy has become a promising target for cancer therapy. Fangchinoline (Fan) has been shown to exert anticancer effects in some types of cancers. However, the anticancer effects on colorectal cancer (CRC) and the underlying mechanisms have never been elucidated. More specifically, regulation of autophagy in CRC by Fan has never been reported before. In the present study, Fan was found to induce apoptosis and autophagic flux in the CRC cell lines HT29 and HCT116, which was reflected by the enhanced levels of LC3-II protein and p62 degradation, and the increased formation of autophagosomes and puncta formation by LC3-II. Meanwhile, combination with the early-stage autophagy inhibitor 3-methyladenine (3-MA) but not the late-stage autophagy inhibitor chloroquine (CQ) further increased Fan-induced cell death, which suggested the cytoprotective function of autophagy induced by Fan in both HT29 and HCT116 cells. Moreover, Fan treatment demonstrated a dose- and time-dependently increase in the phosphorylation of AMPK and decrease in the phosphorylation of mammalian target of rapamycin (mTOR) and ULK1, leading to the activation of the AMPK/mTOR/ULK1 signaling pathway. Furthermore, in the HT29 xenograft model, Fan inhibited tumor growth in vivo. These results indicate that Fan inhibited CRC cell growth both in vitro and in vivo and revealed a new molecular mechanism involved in the anticancer effect of Fan on CRC, suggesting that Fan is a potent autophagy inducer and might be a promising anticancer agent.	[Xiang, Xiaocong; Xiong, Rong; Deng, Li; Yue, Qiuju; Liu, Kang; Feng, Gang] Nanchong Nanchong Cent Hosp, Clin Med Coll 2, North Sichuan Med Coll, Inst Tissue Engn & Stem Cells,Canc Biotherapy Key, Nanchong 637000, Peoples R China; [Li, Yuqi; Kuang, Wei; Yu, Chunlei] North Sichuan Med Coll, Sch Pharm, Inst Mat Med, Nanchong 637000, Peoples R China; [Tian, Yunhong] Nanchong Cent Hosp, Clin Med Coll 2, North Sichuan Med Coll, Dept Gen Surg, Nanchong 637000, Peoples R China; [Li, Junfeng] Nanchong Cent Hosp, Clin Med Coll 2, North Sichuan Med Coll, Dept Cardiothorac Surg, Nanchong 637000, Peoples R China; [Hu, Jiani; Bautista, Matthew] Wayne State Univ, Dept Radiol, Detroit, MI 48201 USA		Feng, G (corresponding author), Nanchong Nanchong Cent Hosp, Clin Med Coll 2, North Sichuan Med Coll, Inst Tissue Engn & Stem Cells,Canc Biotherapy Key, Nanchong 637000, Peoples R China.; Yu, CL (corresponding author), North Sichuan Med Coll, Sch Pharm, Inst Mat Med, Nanchong 637000, Peoples R China.	yuchunlei@nsmc.edu.cn; fenggang@nsmc.edu.cn		Bautista, Matthew/0000-0002-4510-2719	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81903026]; Science and Technology Department of Sichuan Province Foundation [20YYJC2624]; Ministry of Education "Chunhui Plan" cooperative scientific research project [12]; Bureau of Science and Technology and Intellectual Property of Nanchong [19SXHZ0304, 18SXHZ0375]; Scientific Research Project of the Health Commission of Sichuan Province [19PJ224]	This study was supported by the National Natural Science Foundation of China (No. 81903026) , the Science and Technology Department of Sichuan Province Foundation (No. 20YYJC2624) , The Ministry of Education "Chunhui Plan" cooperative scientific research project (No. 12) , the Bureau of Science and Technology and Intellectual Property of Nanchong (No. 19SXHZ0304 and No. 18SXHZ0375) and the Scientific Research Project of the Health Commission of Sichuan Province (No. 19PJ224) .	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Pharmacol.	APR	2021	186								114475	10.1016/j.bcp.2021.114475		MAR 2021	15	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	RN5UA	WOS:000640416200005	33609560	hybrid			2022-04-25	
J	Zeng, CJ; Matsuda, K; Jia, WH; Chang, J; Kweon, SS; Xiang, YB; Shin, AS; Jee, SH; Kim, DH; Zhang, B; Cai, QY; Guo, XY; Long, JR; Wang, N; Courtney, R; Pan, ZZ; Wu, C; Takahashi, A; Shin, MH; Matsuo, K; Matsuda, F; Gao, YT; Oh, JH; Kim, S; Jung, KJ; Ahn, YO; Ren, ZF; Li, HL; Wu, J; Shi, JJ; Wen, WQ; Yang, G; Li, BS; Ji, BT; Brenner, H; Schoen, RE; Kury, S; Gruber, SB; Schumacher, FR; Stenzel, SL; Casey, G; Hopper, JL; Jenkins, MA; Kim, HR; Jeong, JY; Park, JW; Tajima, K; Cho, SH; Kubo, M; Shu, XO; Lin, DX; Zeng, YX; Zheng, W				Zeng, Chenjie; Matsuda, Koichi; Jia, Wei-Hua; Chang, Jiang; Kweon, Sun-Seog; Xiang, Yong-Bing; Shin, Aesun; Jee, Sun Ha; Kim, Dong-Hyun; Zhang, Ben; Cai, Qiuyin; Guo, Xingyi; Long, Jirong; Wang, Nan; Courtney, Regina; Pan, Zhi-Zhong; Wu, Chen; Takahashi, Atsushi; Shin, Min-Ho; Matsuo, Keitaro; Matsuda, Fumihiko; Gao, Yu-Tang; Oh, Jae Hwan; Kim, Soriul; Jung, Keum Ji; Ahn, Yoon-Ok; Ren, Zefang; Li, Hong-Lan; Wu, Jie; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Li, Bingshan; Ji, Bu-Tian; Brenner, Hermann; Schoen, Robert E.; Kuery, Sebastien; Gruber, Stephen B.; Schumacher, Fredrick R.; Stenzel, Stephanie L.; Casey, Graham; Hopper, John L.; Jenkins, Mark A.; Kim, Hyeong-Rok; Jeong, Jin-Young; Park, Ji Won; Tajima, Kazuo; Cho, Sang-Hee; Kubo, Michiaki; Shu, Xiao-Ou; Lin, Dongxin; Zeng, Yi-Xin; Zheng, Wei		GECCO; Colorectal Transdisciplinary; CCFR	Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk	GASTROENTEROLOGY			English	Article						Epidemiology; Single Nucleotide Polymorphisms; Colon Cancer; eQTL	GENOME-WIDE ASSOCIATION; SOCS BOX; SCAN; METAANALYSIS; AUTOPHAGY; VARIANTS; TFEB; DYSREGULATION; RAD21; MITF	BACKGROUND & AIMS: Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. METHODS: This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. RESULTS: We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 x 10(-8) to 1.24 x 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. CONCLUSIONS: We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.	[Zeng, Chenjie; Zhang, Ben; Cai, Qiuyin; Guo, Xingyi; Long, Jirong; Wang, Nan; Courtney, Regina; Wu, Jie; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA; [Matsuda, Koichi] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Genome Technol, Tokyo, Japan; [Jia, Wei-Hua; Pan, Zhi-Zhong; Zeng, Yi-Xin] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China; [Chang, Jiang; Wu, Chen; Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing 100730, Peoples R China; [Chang, Jiang; Wu, Chen; Lin, Dongxin] Peking Union Med Coll, Beijing 100021, Peoples R China; [Kweon, Sun-Seog; Shin, Min-Ho] Chonnam Natl Univ, Dept Prevent Med, Sch Med, Gwangju, South Korea; [Kweon, Sun-Seog] Chonnam Natl Univ, Jeonnam Reg Canc Ctr, Hwasun Hosp, Hwasun, South Korea; [Xiang, Yong-Bing; Gao, Yu-Tang; Li, Hong-Lan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China; [Shin, Aesun] Natl Canc Ctr, Mol Epidemiol Branch, Goyang Si, South Korea; [Shin, Aesun; Ahn, Yoon-Ok] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea; [Jee, Sun Ha; Kim, Soriul; Jung, Keum Ji] Yonsei Univ, Grad Sch Publ Hlth, Dept Epidemiol & Hlth Promot, Inst Hlth Promot, Seoul 120749, South Korea; [Kim, Dong-Hyun; Jeong, Jin-Young] Hallym Univ, Coll Med, Dept Social & Prevent Med, Okcheon Dong, South Korea; [Wang, Nan] Fourth Mil Med Univ, Tangdu Hosp, Gen Dept, Xian, Shaanxi, Peoples R China; [Takahashi, Atsushi; Kubo, Michiaki] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan; [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan; [Matsuda, Fumihiko] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan; [Oh, Jae Hwan; Park, Ji Won] Natl Canc Ctr, Ctr Colorectal Canc, Goyang Si, South Korea; [Ren, Zefang] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China; [Li, Bingshan] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37203 USA; [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA; [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany; [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Div Prevent Oncol, Heidelberg, Germany; [Brenner, Hermann] German Canc Res Ctr, Heidelberg, Germany; [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany; [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA; [Kuery, Sebastien] CHU Nantes, Gen Med Serv, F-44035 Nantes 01, France; [Gruber, Stephen B.; Schumacher, Fredrick R.; Stenzel, Stephanie L.; Casey, Graham] Univ So Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA; [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia; [Jenkins, Mark A.] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia; [Kim, Hyeong-Rok] Chonnam Natl Univ, Sch Med, Dept Surg, Gwangju, South Korea; [Park, Ji Won] Seoul Natl Univ Hosp, Dept Surg, Seoul 110744, South Korea; [Tajima, Kazuo] Mie Univ, Grad Sch Med, Dept Publ Hlth & Occupat Med, Tsu, Mie, Japan; [Cho, Sang-Hee] Chonnam Natl Univ, Sch Med, Dept Hematooncol, Gwangju, South Korea		Zheng, W (corresponding author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA.	wei.zheng@vanderbilt.edu	Kweon, Sun-Seog/AAZ-4732-2021; Schmit, Stephanie/AAW-8980-2020; Brenner, Hermann/ABE-6383-2020; Schumacher, Fredrick/R-6043-2019; Brenner, Hermann/B-4627-2017; Hoffmeister, Michael/T-7187-2019; Gallinger, Steven/E-4575-2013; Shin, Aesun/E-9145-2014; Zheng, Wei/O-3351-2013; Jenkins, Mark/P-7803-2015; Matsuo, Keitaro/H-6758-2019; Schmit, Stephanie L./AAC-5916-2019; KÜRY, Sébastien/G-5971-2015; Moreno, Victor/A-1697-2010; Matsuda, Koichi/D-4597-2011	Kweon, Sun-Seog/0000-0003-2378-8550; Brenner, Hermann/0000-0002-6129-1572; Schumacher, Fredrick/0000-0002-3073-7463; Brenner, Hermann/0000-0002-6129-1572; Hoffmeister, Michael/0000-0002-8307-3197; Shin, Aesun/0000-0002-6426-1969; Zheng, Wei/0000-0003-1226-070X; Jenkins, Mark/0000-0002-8964-6160; Matsuo, Keitaro/0000-0003-1761-6314; Schmit, Stephanie L./0000-0001-5931-1194; KÜRY, Sébastien/0000-0001-5497-0465; SHI, JIAJUN/0000-0001-5194-0009; Harrison, Tabitha/0000-0002-4173-7530; Caan, Bette/0000-0002-5803-310X; Long, Jirong/0000-0002-7433-9766; Zeng, Chenjie/0000-0002-0149-5661; Wu, Chen/0000-0003-4954-1011; Lin, Dongxin/0000-0002-8723-8868; Moreno, Victor/0000-0002-2818-5487; Jung, Keum Ji/0000-0003-4993-0666; Jee, Sun Ha/0000-0001-9519-3068; Matsuda, Koichi/0000-0001-7292-2686	US National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA188214, R37CA070867, R01CA124558, P50CA095103, R01CA148667]; Vanderbilt University School of Medicine; Vanderbilt-Ingram Cancer Center [P30CA068485]; Shanghai Women's Health Study (US NIH) [R37CA070867, UM1CA182910]; Shanghai Men's Health Study (US NIH) [R01CA082729, UM1CA173640]; Shanghai Breast and Endometrial Cancer Studies (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA064277, R01CA092585]; Shanghai Colorectal Cancer Study 3 (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA188214, R37CA070867]; Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project) [2011ZX09307-001-04;]; Guangzhou Colorectal Cancer Study (National Basic Research Program) [2011CB504303]; Guangzhou Colorectal Cancer Study (Natural Science Foundation of China)National Natural Science Foundation of China (NSFC) [81072383]; Japan BioBank Colorectal Cancer Study (Ministry of Education, Culture, Sports, Science and Technology of the Japanese government)Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer (HCES-CRC) [HCRI15011-1]; Japanese Ministry of Education, Culture, Sports, Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [17015018, 221S0001]; Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea [2010-0010276, 2013R1A1A2A10008260]; National Cancer Center Korea [0910220]; KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control [1220180]; KCPS-II Colorectal Cancer Study (Seoul RD Program) [10526]; GECCO; CORECT; GECCO (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U01CA137088, R01CA059045]; DALS (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA048998]; DACHS (German Federal Ministry of Education and Research) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404, 01ER0814]; HPFS [P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993, P50 CA127003]; NHS [R01 CA137178, R01 CA151993, P50 CA127003, UM1 CA186107, P01 CA87969]; OFCCR (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U01CA074783]; PMH (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA076366]; PHS (US NIH) [R01CA042182]; VITAL (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K05CA154337]; WHI (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; PLCO (US NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [Z01CP 010200, U01HG004446, U01HG 004438]; National Cancer Institute as part of the GAME-ON consortium (US NIH) [U19CA148107]; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA81488, P30CA014089]; National Human Genome Research Institute at the US NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [T32HG000040]; National Institute of Environmental Health Sciences at the US NIH [T32ES013678]; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI); US NIH under RFAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA-95-011]; National Cancer Institute grant (US NIH) [U01CA122839]; Ontario Research Fund; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research through Ontario Ministry of Economic Development and Innovation; Regional Hospital Clinical Research Program (PHRC); Regional Council of Pays de la LoireRegion Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte Contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); US NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [Z01CP 010200, U01HG004446, U01HG 004438]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA074783, U01CA097735, R01CA188214, UM1CA167551, R01CA076366, UM1CA167552, P30CA014089, R01CA151993, P01CA055075, R01CA148667, U01CA074794, Z01CP010200, U01CA074799, U01CA137088, R01CA124558, U01CA122839, P50CA095103, P50CA127003, UM1CA173640, U01CA074800, UM1CA186107, U01CA164930, U19CA148107, R01CA081488, U01CA074806, P30CA071789, P30CA068485, R01CA082729, P01CA087969, R37CA070867, UM1CA182910, R01CA042182, K05CA154337, R01CA064277, R01CA048998, R01CA137178, R01CA059045, R01CA092585] Funding Source: NIH RePORTER; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [U01HG004438, U01HG004446, T32HG000040] 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) [T32ES013678] Funding Source: NIH RePORTER; 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) [25293168] Funding Source: KAKEN	The work at the Vanderbilt University School of Medicine was supported by US National Institutes of Health grants R01CA188214, R37CA070867, R01CA124558, P50CA095103, and R01CA148667, as well as Ingram Professorship and Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. The Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH, R37CA070867, UM1CA182910), Shanghai Men's Health Study (US NIH, R01CA082729, UM1CA173640), Shanghai Breast and Endometrial Cancer Studies (US NIH, R01CA064277 and R01CA092585; contributing only controls), Shanghai Colorectal Cancer Study 3 (US NIH, R37CA070867, R01CA188214 and Ingram Professorship funds), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04; National Basic Research Program, 2011CB504303, contributing only controls; Natural Science Foundation of China, 81072383, contributing only controls), Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). The Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, 17015018 and 221S0001), Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276 and 2013R1A1A2A10008260; National Cancer Center Korea, 0910220), and the KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control, 1220180; Seoul R&D Program, 10526).; Participating studies (grant support) in the GECCO, CORECT, and CCFR GWAS meta-analysis are GECCO (US NIH, U01CA137088 and R01CA059045), DALS (US NIH, R01CA048998), DACHS (German Federal Ministry of Education and Research, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404 and 01ER0814), HPFS (P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993 and P50 CA127003), NHS (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003), OFCCR (US NIH, U01CA074783), PMH (US NIH, R01CA076366), PHS (US NIH, R01CA042182), VITAL (US NIH, K05CA154337), WHI (US NIH, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C), and PLCO (US NIH, Z01CP 010200, U01HG004446 and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH, U19CA148107) with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, US NIH under RFA CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01CA097735), Familial Colorectal Neoplasia Collaborative Group (US NIH, U01CA074799) (University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01CA074783), Seattle Colorectal Cancer Family Registry (US NIH, U01CA074794). and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The GWAS work was supported by a National Cancer Institute grant (US NIH, U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J. Hudson and B.W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through support from the Ontario Ministry of Economic Development and Innovation. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte Contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). PLCO data sets were accessed with approval through dbGaP (CGEMS prostate cancer scan, phs000207.v1.p1 (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645-649); CGEMS pancreatic cancer scan, phs000206.v4.p3 (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41:986-990, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 2010; 42: 224-228); and GWAS of Lung Cancer and Smoking, phs000093.v2.p2 (Landi MT, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 2009;85:679-691), which was funded by Z01CP 010200, U01HG004446 and U01HG 004438 from the US NIH).	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J	Greene, LM; Wang, S; O'Boyle, NM; Bright, SA; Reid, JE; Kelly, P; Meegan, MJ; Zisterer, DM				Greene, Lisa M.; Wang, Shu; O'Boyle, Niamh M.; Bright, Sandra A.; Reid, Jane E.; Kelly, Patrick; Meegan, Mary J.; Zisterer, Daniela M.			Combretazet-3 a novel synthetic cis-stable combretastatin A-4-azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer	ONCOLOGY REPORTS			English	Article						combretastatin A-4; azetidinone (beta-lactam); colon cancer	TARGETING AGENT COMBRETASTATIN-A4; VASCULAR DISRUPTING AGENTS; BETA-LACTAM ANALOG; MULTIDRUG-RESISTANCE; SOLID TUMORS; A-4; CELLS; DERIVATIVES; PHOSPHATE; AUTOPHAGY	In recent years an extensive series of synthetic combretastatin A-4 (CA-4)-azetidinone (beta-lactam) hybrids were designed and synthesised with a view to improve the stability, therapeutic efficacy and aqueous solubility of CA-4. Lead compounds containing a 3,4,5-trimethoxy aromatic ring at position 1 and a variety of substitution patterns at positions 3 and 4 of the beta-lactam ring were screened in three adenocarcinoma-derived colon cancer cell lines (CT-26, Caco-2 and the CA-4 resistant cell line, HT-29). In both CT-26 and Caco-2 cells all P-lactam analogues analysed displayed potent therapeutic efficacy within the nanomolar range. Substitution of the ethylene bridge of CA-4 with the beta-lactam ring together with the aforementioned aryl substitutions improved the therapeutic efficacy of CA-4 up to 300-fold in the combretastatin refractory HT-29 cells. The lead compound combretazet-3 (CAZ-3); chemical name [4-(3-hydroxy-4-methoxyphenyl)-3-(4-hydroxy phenyl)-1-(3,4,5-tri methoxy phenyl)azetidin-2-one] demonstrated improved chemical stability together with enhanced therapeutic efficacy as compared with CA-4 whilst maintaining the natural biological properties of CA-4. Furthermore, CAZ-3 demonstrated significant tumour inhibition in a murine model of colon cancer. Our results suggest that combretastatin-azetidinone hybrids represent an effective novel therapy for the treatment of combretastatin resistant carcinomas.	[Greene, Lisa M.; Bright, Sandra A.; Reid, Jane E.; Zisterer, Daniela M.] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland; [Wang, Shu; O'Boyle, Niamh M.; Kelly, Patrick; Meegan, Mary J.] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Pharm & Pharmaceut Sci, Dublin 2, Ireland		Greene, LM (corresponding author), Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, 152-160 Pearse St, Dublin 2, Ireland.	greeneli@tcd.ie		Zisterer, Daniela/0000-0001-5005-1023; Reid, Jane/0000-0002-5196-8121; O'Boyle, Niamh/0000-0001-5660-4944	Health Research Board Ireland	We would like to thank Health Research Board Ireland for funding the project. We would also like to thank Sally Lee at Cyprotex Discovery, Ltd., (Macclesfield, UK) for carrying out the microsomal stability studies.	Beale TM, 2010, MEDCHEMCOMM, V1, P202, DOI 10.1039/c0md00095g; Carr M, 2010, EUR J MED CHEM, V45, P5752, DOI 10.1016/j.ejmech.2010.09.033; Delmonte A, 2009, EXPERT OPIN INV DRUG, V18, P1541, DOI 10.1517/13543780903213697; Dowlati A, 2002, CANCER RES, V62, P3408; Eikesdal HP, 2000, INT J RADIAT ONCOL, V46, P645, DOI 10.1016/S0360-3016(99)00451-4; Greene LM, 2012, BIOCHEM PHARMACOL, V84, P612, DOI 10.1016/j.bcp.2012.06.005; Greene LM, 2011, INT J MOL MED, V27, P715, DOI 10.3892/ijmm.2011.633; Greene LM, 2010, J PHARMACOL EXP THER, V335, P302, DOI 10.1124/jpet.110.170415; Hinnen P, 2007, BRIT J CANCER, V96, P1159, DOI 10.1038/sj.bjc.6603694; Lee HY, 2011, J MED CHEM, V54, P8517, DOI 10.1021/jm201031f; Leslie EM, 2001, TOXICOLOGY, V167, P3, DOI 10.1016/S0300-483X(01)00454-1; Marrelli M, 2011, CURR MED CHEM, V18, P3035, DOI 10.2174/092986711796391642; O'Boyle NM, 2011, EUR J MED CHEM, V46, P4595, DOI 10.1016/j.ejmech.2011.07.039; O'Boyle NM, 2011, BIOORGAN MED CHEM, V19, P2306, DOI 10.1016/j.bmc.2011.02.022; O'Boyle NM, 2010, J MED CHEM, V53, P8569, DOI 10.1021/jm101115u; Ohsumi K, 1998, J MED CHEM, V41, P3022, DOI 10.1021/jm980101w; Patterson DM, 2012, CLIN CANCER RES, V18, P1415, DOI 10.1158/1078-0432.CCR-11-2414; PETTIT GR, 1989, EXPERIENTIA, V45, P209, DOI 10.1007/BF01954881; Romagnoli R, 2012, J MED CHEM, V55, P475, DOI 10.1021/jm2013979; Rubinsztein DC, 2012, NAT REV DRUG DISCOV, V11, P709, DOI 10.1038/nrd3802; Rustin GJS, 2003, J CLIN ONCOL, V21, P2815, DOI 10.1200/JCO.2003.05.185; Schobert R, 2011, INT J CLIN PHARM TH, V49, P71, DOI 10.5414/CPP49071; Shan Y, 2011, CURR MED CHEM, V18, P523, DOI 10.2174/092986711794480221	23	21	21	0	14	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1021-335X			ONCOL REP	Oncol. Rep.	JUN	2013	29	6					2451	2458		10.3892/or.2013.2379			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	148GO	WOS:000319232800051	23564200	Bronze			2022-04-25	
J	Tang, Y; Ren, F; Cong, X; Kong, Y; Tian, YX; Xu, YF; Fan, JH				Tang, Ying; Ren, Feng; Cong, Xi; Kong, Ying; Tian, Yuxiang; Xu, Yuefei; Fan, Jianhui			Overexpression of ribonuclease inhibitor induces autophagy in human colorectal cancer cells via the Akt/mTOR/ULK1 pathway	MOLECULAR MEDICINE REPORTS			English	Article						ribonuclease inhibitor; colorectal cancer; autophagy; signal pathway	TO-MESENCHYMAL TRANSITION; SIGNALING PATHWAY; PROTEIN; PHOSPHORYLATION; METASTASIS; STATISTICS; ANGIOGENIN; MTOR; AMPK	Ribonuclease inhibitor (RI), also termed angiogenin inhibitor, acts as the inhibitor of ribonucleolytic activity of RNase A and angiogenin. The expression of RI has been investigated in melanoma and bladder cancer cells. However, the precise role of RI in tumorigenesis, in addition to RI-induced autophagy, remains poorly understood. In the present study, it was demonstrated that RI positively regulated autophagy in human colorectal cancer (CRC) cells as indicated by an increase in light chain 3 (LC3)-II levels. Furthermore, RI regulated cell survival in HT29 cells. In addition, autophagy-associated proteins, including beclin-1 and autophagy-related protein 13, were increased in response to RI-induced autophagy, and the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR)/Unc-51 like autophagy activating kinase (ULK1) pathway may be involved in the activation of autophagy induced by RI overexpression. Taken together, the evidence of the present study indicated that the overexpression of RI induced ATG-dependent autophagy in CRC cells via the Akt/mTOR/ULK1 pathway, suggesting that the upregulation of RI activity may constitute a novel approach for the treatment of human colorectal carcinoma.	[Tang, Ying] Dalian Med Univ, Affiliated Hosp 2, Dept Pathol, Dalian 116023, Liaoning, Peoples R China; [Ren, Feng; Cong, Xi; Kong, Ying; Tian, Yuxiang; Xu, Yuefei; Fan, Jianhui] Dalian Med Univ, Dept Biochem & Mol Biol, 9 Sout Lvshun Rd Western Sect, Dalian 116044, Liaoning, Peoples R China		Fan, JH (corresponding author), Dalian Med Univ, Dept Biochem & Mol Biol, 9 Sout Lvshun Rd Western Sect, Dalian 116044, Liaoning, Peoples R China.	fanjh@dlmedu.edu.cn			National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31400687]	This study was supported by a grant from the National Science Foundation of China (grant no. 31400687).	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Med. Rep.	MAY	2019	19	5					3519	3526		10.3892/mmr.2019.10030			8	Oncology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Research & Experimental Medicine	HV3DH	WOS:000465868800016	30896869	Green Published, Green Submitted, hybrid			2022-04-25	
J	Le, YC; Zhang, SL; Ni, JH; You, Y; Luo, KJ; Yu, YQ; Shen, XY				Le, Yunchen; Zhang, Sulin; Ni, Jiahui; You, Yan; Luo, Kejing; Yu, Yunqiu; Shen, Xiaoyan			Sorting nexin 10 controls mTOR activation through regulating amino-acid metabolism in colorectal cancer	CELL DEATH & DISEASE			English	Article							CHAPERONE-MEDIATED AUTOPHAGY; TUMOR-SUPPRESSOR; METABOLOMICS; DISEASE; TARGET; LAMP2A; DEGRADATION; SUFFICIENCY; PROGRESSION; MECHANISMS	Amino-acid metabolism plays a vital role in mammalian target of rapamycin (mTOR) signaling, which is the pivot in colorectal cancer (CRC). Upregulated chaperone-mediated autophagy (CMA) activity contributes to the regulation of metabolism in cancer cells. Previously, we found that sorting nexin 10 (SNX10) is a critical regulator in CMA activation. Here we investigated the role of SNX10 in regulating amino-acid metabolism and mTOR signaling pathway activation, as well as the impact on the tumor progression of mouse CRC. Our results showed that SNX10 deficiency promoted colorectal tumorigenesis in male FVB mice and CRC cell proliferation and survival. Metabolic pathway analysis of gas chromatography-mass spectrometry (GC-MS) data revealed unique changes of amino-acid metabolism by SNX10 deficiency. In HCT116 cells, SNX10 knockout resulted in the increase of CMA and mTOR activation, which could be abolished by chloroquine treatment or reversed by SNX10 overexpression. By small RNA interference (siRNA), we found that the activation of mTOR was dependent on lysosomal-associated membrane protein type-2A (LAMP-2A), which is a limiting factor of CMA. Similar results were also found in Caco-2 and SW480 cells. Ultra-high-performance liquid chromatography-quadrupole time of flight (UHPLC-QTOF) and GC-MS-based untargeted metabolomics revealed that 10 amino-acid metabolism in SNX10-deficient cells were significantly upregulated, which could be restored by LAMP-2A siRNA. All of these amino acids were previously reported to be involved in mTOR activation. In conclusion, this work revealed that SNX10 controls mTOR activation through regulating CMA-dependent amino-acid metabolism, which provides potential target and strategy for treating CRC.	[Le, Yunchen; Zhang, Sulin; Ni, Jiahui; You, Yan; Luo, Kejing; Yu, Yunqiu; Shen, Xiaoyan] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China		Yu, YQ; Shen, XY (corresponding author), Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China.	yqyu@shmu.edu.cn; shxiaoy@fudan.edu.cn		Le, Yunchen/0000-0003-4440-5854	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773744, 81573441]	This study was funded by National Natural Science Foundation of China (No. 81773744 and 81573441).	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JUN 4	2018	9								666	10.1038/s41419-018-0719-2			14	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	GH9XW	WOS:000434024500002	29867114	Green Published, gold			2022-04-25	
J	Chiacchiera, F; Simone, C				Chiacchiera, Fulvio; Simone, Cristiano			Signal-dependent regulation of gene expression as a target for cancer treatment: Inhibiting p38 alpha in colorectal tumors	CANCER LETTERS			English	Review						colorectal cancer; chromatin-associated kinase; p38; signal-dependent gene expression; autophagy	ACTIVATED PROTEIN-KINASE; AUTOPHAGIC CELL-DEATH; MALIGNANT GLIOMA-CELLS; NITRIC-OXIDE; HOG1 KINASE; CYCLIN-E; P38; TRANSCRIPTION; COMPLEX; MUTATIONS	In the last year, several evidences indicated that pharmacological manipulation of relevant signaling pathways could selectively affect gene expression to influence cell fate. These findings render of extreme importance the elucidation of how external stimuli are transduced to mediate chromatin modifications, resulting in a permissive or repressive environment for gene expression. These signaling cascades activate or repress the function of chromatin binding proteins that represent attractive pharmacological targets for human diseases. Actually, the closer the target is to chromatin, the more the transcriptional effect will be selective. Recent studies suggest that pharmacological manipulation of signaling pathways to modulate cell fate is indeed possible and that chromatin-associated kinases could represent an optimal target. The p38 MAPK is the prototype of this class of enzymes and its central role in the transcription process is evolutionary conserved. In this review we will focus on the possibility to inhibit p38 alpha in colorectal cancer to arrest tumor progression and induce autophagic cell death. (C) 2008 Elsevier Ireland Ltd. All rights reserved.	[Chiacchiera, Fulvio; Simone, Cristiano] Consorzio Mario Negri Sud, Lab Signaldependent Transcript, DTP, I-66030 Santa Maria Imbaro, Chieti, Italy		Simone, C (corresponding author), Consorzio Mario Negri Sud, Lab Signaldependent Transcript, DTP, Via Nazl 8-A, I-66030 Santa Maria Imbaro, Chieti, Italy.	simone@negrisud.it	Chiacchiera, Fulvio/ABD-6137-2020; Simone, Cristiano/K-3452-2018; Chiacchiera, Fulvio/K-6740-2016	Simone, Cristiano/0000-0002-2628-7658; Chiacchiera, Fulvio/0000-0003-3830-2090	Associazione Italiana per la Ricerca sul CancroFondazione AIRC per la ricerca sul cancro Funding Source: Custom		Abeliovich H, 2000, J CELL BIOL, V151, P1025, DOI 10.1083/jcb.151.5.1025; Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Alepuz PM, 2003, EMBO J, V22, P2433, DOI 10.1093/emboj/cdg243; Alepuz PM, 2001, MOL CELL, V7, P767, DOI 10.1016/S1097-2765(01)00221-0; Amaravadi R, 2005, J CLIN INVEST, V115, P2618, DOI 10.1172/JCI26273; Arico S, 2001, J BIOL CHEM, V276, P35243, DOI 10.1074/jbc.C100319200; 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JUN 28	2008	265	1					16	26		10.1016/j.canlet.2008.02.061			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	313GX	WOS:000256730200002	18395970				2022-04-25	
J	Li, YF; Shi, LJ; Wang, P; Wang, JW; Shi, GY; Lee, SC				Li, Yuan Fei; Shi, Lin Jie; Wang, Pu; Wang, Jia Wen; Shi, Guang Yi; Lee, Shao Chin			Binding between ROCK1 and DCTN2 triggers diabetes-associated centrosome amplification in colon cancer cells	ONCOLOGY REPORTS			English	Article						centrosome amplification; type 2 diabetes; Rho-associated protein kinase 1; dynactin subunit 2; colon cancer cells; functional proteomics	DNA-DAMAGE; COLORECTAL-CANCER; PROGNOSTIC VALUE; EXPRESSION; TUMORIGENESIS; AUTOPHAGY; PHASE; ROS	Type 2 diabetes increases the risk various types of cancer and is associated with a poor prognosis therein. There is also evidence that the disease is associated with cancer metastasis. Centrosome amplification can initiate tumorigenesis with metastasis in vivo and increase the invasiveness of cancer cells in vitro. Our previous study reported that type 2 diabetes promotes centrosome amplification via the upregulation and centrosomal translocation of Rho-associated protein kinase 1 (ROCK1), which suggests that centrosome amplification is a candidate biological link between type 2 diabetes and cancer development. In the present study, functional proteomics analysis was used to further investigate the molecular pathways underlying centrosome amplification by targeting ROCK1 binding partners. High glucose, insulin and palmitic acid were used to induce centrosome amplification, and immunofluorescent staining was employed to visualize centrosomal alterations. Combined with immunoprecipitation, mass spectrometry-based proteomics analysis was used to identify ROCK1 binding proteins, and protein complex disruption was achieved by siRNA-knockdown. In total, 1,148 ROCK1 binding proteins were identified, among which 106 proteins were exclusively associated with the treated samples, 193 were only associated with the control samples, and 849 were found in both the control and treated samples. Of the proteins with evidence of centrosomal localization, Dynactin subunit 2 (DCTN2) was confirmed to be localized to the centrosomes. Treating the cells with high glucose, insulin and palmitic acid increased the protein levels of ROCK1 and DCTN2, promoted their binding with each other, and triggered centrosome amplification. Disruption of the protein complex by knocking down ROCK1 or DCTN2 expression partially attenuated centrosome amplification, while simultaneous knockdown of both proteins completely inhibited centrosome amplification. These results suggested ROCK1-DCTN2 binding as a signal for the regulation of centrosome homeostasis, which is key for diabetes-associated centrosome amplification, and enriches our knowledge of centrosome biology. Therefore, the ROCK1-DCTN2 complex may serve as a target for inhibiting centrosome amplification both in research or future therapeutic development.	[Li, Yuan Fei; Shi, Lin Jie] Shanxi Med Univ, First Hosp, Dept Oncol, 85 Jiefang South Rd, Taiyuan 030001, Shanxi, Peoples R China; [Shi, Lin Jie] Shaanxi Prov Canc Hosp, Intens Care Unit, Xian 710000, Shaanxi, Peoples R China; [Wang, Pu] Changzhi Med Univ, Changzhi 030001, Shanxi, Peoples R China; [Wang, Jia Wen; Shi, Guang Yi; Lee, Shao Chin] Jiangsu Normal Univ, Inst Biomed Sci, Sch Life Sci, 101 Shanghai Rd, Xuzhou 221116, Jiangsu, Peoples R China		Li, YF (corresponding author), Shanxi Med Univ, First Hosp, Dept Oncol, 85 Jiefang South Rd, Taiyuan 030001, Shanxi, Peoples R China.; Lee, SC (corresponding author), Jiangsu Normal Univ, Inst Biomed Sci, Sch Life Sci, 101 Shanghai Rd, Xuzhou 221116, Jiangsu, Peoples R China.	liyflinda@163.com; lee_shao@hotmail.com			Shanxi Health Commission Research Project [09509]; Jiangsu Normal University [9212418102]; Department of Science and Technology of the Jiangsu Province [BX2019029]	The present study was supported by grants from the Shanxi Health Commission Research Project (grant no. 09509) and Jiangsu Normal University (grant no. 9212418102), as well as the Department of Science and Technology of the Jiangsu Province (grant no. BX2019029).	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Rep.	JUL	2021	46	1							151	10.3892/or.2021.8102			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	SO5QV	WOS:000659027600001	34080666	hybrid, Green Published			2022-04-25	
J	El-Gowily, AH; Abosheasha, MA				El-Gowily, Afnan H.; Abosheasha, Mohammed A.			Differential mechanisms of autophagy in cancer stem cells: Emphasizing gastrointestinal cancers	CELL BIOCHEMISTRY AND FUNCTION			English	Review						autophagy; gastrointestinal cancer; stem cells; tumour microenvironment	TARGETING NOTCH; SELF-RENEWAL; TUMOR-GROWTH; COLON-CANCER; THERAPEUTIC TARGET; EMERGING ROLE; SOLID TUMORS; PROMOTES; SURVIVAL; HEDGEHOG	Gastrointestinal (GI) cancers are one of the most common forms of malignancies and still are the most important cause of cancer-related mortality worldwide. Autophagy is a conserved catabolic pathway involving lysosomal degradation and recycling of whole cellular components, which is essential for cellular homeostasis. For instance, it acts as a pivotal intracellular quality control and repair mechanism but also implicated in cell reformation during cell differentiation and development. Indeed, GI cancer stem cells (CSCs) are thought to be responsible for tumour initiation, traditional therapies resistance, metastasis and tumour recurrence. Molecular mechanisms of autophagy in normal vs CSCs gain great interest worldwide. Here, we shed light on the role of autophagy in normal stem cells differentiation for embryonic progression and its role in maintaining the activity and self-renewal capacity of CSCs which offer novel viewpoints on promising cancer therapeutic strategies based on the differential roles of autophagy in CSCs.	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Funct.	MAR	2021	39	2					162	173		10.1002/cbf.3552		MAY 2020	12	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	QT0WO	WOS:000535923500001	32468609				2022-04-25	
J	Guaman-Ortiz, LM; Romero-Benavides, JC; Suarez, AI; Torres-Aguilar, S; Castillo-Veintimilla, P; Samaniego-Romero, J; Ortiz-Diaz, K; Bailon-Moscoso, N				Guaman-Ortiz, Luis M.; Romero-Benavides, Juan C.; Suarez, Alirica I.; Torres-Aguilar, Stephania; Castillo-Veintimilla, Paola; Samaniego-Romero, Jimmy; Ortiz-Diaz, Kevin; Bailon-Moscoso, Natalia			Cytotoxic Property of Grias neuberthii Extract on Human Colon Cancer Cells: A Crucial Role of Autophagy	EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article							MOLECULAR-MECHANISMS; MEDICINAL-PLANTS; DEATH; DERIVATIVES; LUPEOL; P62	Traditional herbal medicine has become an important alternative in the treatment of various cancer types, including colon cancer, which represents one of the main health problems around the world. Therefore, the search for new therapies to counteract this disease is very active. Grias neuberthii is an endemic plant located in the Ecuadorian Amazon region, which has been used in traditional medicine for its pharmacological properties, including its ability to inhibit tumor cell growth, although scientific studies are limited. We have analyzed the effect of this plant on two colon carcinoma cell lines, that is, RKO (normal p53) and SW613-B3 (mutated p53) cells. Among several extracts obtained from various parts of G. neuberthii plant, we identified the extract with the greatest cytotoxic potential, derived from the stem bark. The cytotoxic effect was similar on both cell lines, thus indicating that it is independent of the status of p53. However, significant differences were observed after the analysis of colony formation, with RKO cells being more sensitive than SW613-B3. No evidence for apoptotic markers was recorded; nevertheless, both cell lines showed signs of autophagy after the treatment, including increased Beclin-1 and LC3-II and decreased p62. Finally, three chemical compounds, possibly responsible for the effect observed in both cell lines, were identified: lupeol (1), 3 '-O-methyl ellagic acid 4-O-beta-D-rhamnopyranoside (2), and 19-alpha-hydroxy-asiatic acid monoglucoside (3).	[Guaman-Ortiz, Luis M.; Torres-Aguilar, Stephania; Samaniego-Romero, Jimmy; Ortiz-Diaz, Kevin; Bailon-Moscoso, Natalia] Univ Tecn Particular Loja, Dept Ciencias Salud, Loja 1101608, Ecuador; [Romero-Benavides, Juan C.; Suarez, Alirica I.; Castillo-Veintimilla, Paola] Univ Tecn Particular Loja, Dept Quim & Ciencias Exactas, Loja 1101608, Ecuador; [Suarez, Alirica I.] Univ Cent Venezuela, Fac Farm, Caracas 1050, Venezuela; [Castillo-Veintimilla, Paola] Inst Nacl Invest Salud Publ LIP, Programa Nacl Abordaje Multidisciplinario Parasit, Guayaquil 3961, Ecuador		Bailon-Moscoso, N (corresponding author), Univ Tecn Particular Loja, Dept Ciencias Salud, Loja 1101608, Ecuador.	lmguaman@utpl.edu.ec; jcromerob@utpl.edu.ec; alirica1@yahoo.es; sdtorres1@utpl.edu.ec; pmcastillo@utpl.edu.ec; jpsamaniego2@utpl.edu.ec; koortiz@utpl.edu.ec; ncbailon@utpl.edu.ec	Bailon-Moscoso, Natalia/Z-1548-2019; Romero-Benavides, Juan Carlos/Q-9855-2018	Romero-Benavides, Juan Carlos/0000-0003-1660-1217; Guaman Ortiz, Luis Miguel/0000-0003-2919-4905; Bailon Moscoso, Natalia/0000-0003-2754-1328	International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy [ECU1601 EC]; Universidad Tecnica Particular de Loja (UTPL), Loja, Ecuador [PROY_CCSAL_1266]	This work was supported by International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy (ECU1601 EC) and Universidad Tecnica Particular de Loja (UTPL), Loja, Ecuador (PROY_CCSAL_1266). The authors want to thank Dr. A. Ivana Scovassi for her support in the observations and analysis of experimental results and reviewing the English version.	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Med.	APR 1	2020	2020								1565306	10.1155/2020/1565306			11	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	LE8GK	WOS:000526961900001	32328120	Green Published, gold			2022-04-25	
J	Sun, J; Feng, Y; Wang, Y; Ji, Q; Cai, G; Shi, L; Wang, YY; Huang, Y; Zhang, J; Li, Q				Sun, Jian; Feng, Yu; Wang, Yan; Ji, Qing; Cai, Gang; Shi, Lei; Wang, Yiyi; Huang, Yan; Zhang, Jue; Li, Qi			alpha -hederin induces autophagic cell death in colorectal cancer cells through reactive oxygen species dependent AMPK/mTOR signaling pathway activation	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						colorectal cancer; alpha-hederin; autophagy; reactive oxygen species; AMP-activated protein kinase; mechanistic target of rapamycin signaling	INDUCED APOPTOSIS; NIGELLA-SATIVA; ANTICANCER ACTIVITY; ROS; SAPONIN; THYMOQUINONE; CONSTITUENTS; HEDERAGENIN; INHIBITION; GENERATION	alpha-hederin, a monodesmosidic triterpenoid saponin, had previously demonstrated strong anticancer effects. In the current study, the pharmacological mechanism of autophagic cell death induced by alpha-hederin was investigated in human colorectal cancer cells. First, through cell counting kit-8 and colony formation assays, it was demonstrated that alpha-hederin could inhibit the proliferation of HCT116 and HCT8 cell. Results of flow cytometry using fluorescein isothiocyanate Annexin V/propidium iodide and Hoechst 33258 staining indicated that alpha-hederin could induce apoptosis. Western blotting demonstrated that alpha-hederin could activate mitochondrial apoptosis signal pathway. Then, using light chain 3 lentiviral and electron microscope assay, it was demonstrated that alpha-hederin could induce autophagy in colorectal cancer cells. In addition, immunohistochemistry results from in vivo experiments also demonstrated that alpha-hederin could induce autophagy. AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling was demonstrated to be activated by alpha-hederin, which could be blocked by reactive oxygen species (ROS) inhibitor NAC. Furthermore, NAC could inhibit apoptosis and autophagy induced by alpha-hederin. Finally, 3-MA (autophagy inhibitor) reduced the inhibition of alpha-hederin on cell activity, but it had no significant effect on apoptosis. In conclusion, alpha-hederin triggered apoptosis through ROS-activated mitochondrial signaling pathway and autophagic cell death through ROS dependent AMPK/mTOR signaling pathway activation in colorectal cancer cells.	[Sun, Jian; Shi, Lei; Wang, Yiyi; Huang, Yan; Zhang, Jue] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Clin Lab, Shanghai 201203, Peoples R China; [Feng, Yu; Wang, Yan; Ji, Qing; Cai, Gang; Li, Qi] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, 528 Zhangheng Rd, Shanghai 201203, Peoples R China		Li, Q (corresponding author), Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, 528 Zhangheng Rd, Shanghai 201203, Peoples R China.	zhangjue425@hotmail.com		Li, Qi/0000-0003-2004-6885; Sun, Jian/0000-0001-9645-4741	International Cooperation Key Project of the National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81520108031]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81473478]; Shanghai Academic Research Leader [16XD1403600]; Shanghai Rising-Star Program [16QA1403700]; Municipal Human Resources Development Program for Outstanding Leaders in Medical Disciplines in Shanghai [2017BR031]; Shanghai University of Traditional Chinese Medicine [18LK042]	The present study was supported by the International Cooperation Key Project of the National Natural Science Foundation of China (grant no. 81520108031), the National Natural Science Foundation of China (grant no. 81473478), Shanghai Academic Research Leader (grant no. 16XD1403600), Shanghai Rising-Star Program (grant no. 16QA1403700), Municipal Human Resources Development Program for Outstanding Leaders in Medical Disciplines in Shanghai (grant no. 2017BR031) and Shanghai University of Traditional Chinese Medicine (grant no. 18LK042).	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J. Oncol.	MAY	2019	54	5					1601	1612		10.3892/ijo.2019.4757			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	HS5GM	WOS:000463899800010	30896843	Green Published, hybrid, Green Submitted			2022-04-25	
J	Carew, JS; Medina, EC; Esquivel, JA; Mahalingam, D; Swords, R; Kelly, K; Zhang, H; Huang, P; Mita, AC; Mita, MM; Giles, FJ; Nawrocki, ST				Carew, Jennifer S.; Medina, Ernest C.; Esquivel, Juan A., II; Mahalingam, Devalingam; Swords, Ronan; Kelly, Kevin; Zhang, Hui; Huang, Peng; Mita, Alain C.; Mita, Monica M.; Giles, Francis J.; Nawrocki, Steffan T.			Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation	JOURNAL OF CELLULAR AND MOLECULAR MEDICINE			English	Article						apoptosis; autophagy; bortezomib; proteasome; aggresome; chloroquine; histone deacetylase; superoxide; cancer	HISTONE DEACETYLASE INHIBITORS; MALIGNANT GLIOMA-CELLS; REGULATES AGGRESOME FORMATION; PANCREATIC-CANCER CELLS; MULTIPLE-MYELOMA; LEUKEMIA-CELLS; THERAPY; DEATH; PROTEASOME; BORTEZOMIB	Autophagy is an evolutionarily conserved cell survival pathway that enables cells to recoup ATP and other critical biosynthetic molecules during nutrient deprivation or exposure to hypoxia, which are hallmarks of the tumour microenvironment. Autophagy has been implicated as a potential mechanism of resistance to anticancer agents as it can promote cell survival in the face of stress induced by chemotherapeutic agents by breaking down cellular components to generate alternative sources of energy. Disruption of autophagy with chloroquine (CQ) induces the accumulation of ubiquitin-conjugated proteins in a manner similar to the proteasome inhibitor bortezomib (BZ). However, CQ-induced protein accumulation occurs at a slower rate and is localized to lysosomes in contrast to BZ, which stimulates rapid buildup of ubiquitinated proteins and aggresome formation in the cytosol. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) blocked BZ-induced aggresome formation, but promoted CQ-mediated ubiquitinated protein accumulation. Disruption of autophagy with CQ strongly enhanced VOR-mediated apoptosis in colon cancer cells. Accordingly, knockdown of the essential autophagy gene Atg7 also sensitized cells to VOR-induced apoptosis. Knockdown of HDAC6 greatly enhanced BZ-induced apoptosis, but only marginally sensitized cells to CQ. Subsequent studies determined that the CQ/VOR combination promoted a large increase in superoxide generation that was required for ubiquitinated protein accumulation and cell death. Finally, treatment with the CQ/VOR combination significantly reduced tumour burden and induced apoptosis in a colon cancer xenograft model. Collectively, our results establish that inhibition of autophagy with CQ induces ubiquitinated protein accumulation and VOR potentiates CQ-mediated aggregate formation, superoxide generation and apoptosis.	[Carew, Jennifer S.; Medina, Ernest C.; Esquivel, Juan A., II; Mahalingam, Devalingam; Swords, Ronan; Kelly, Kevin; Mita, Alain C.; Mita, Monica M.; Giles, Francis J.; Nawrocki, Steffan T.] Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78245 USA; [Zhang, Hui; Huang, Peng] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA		Nawrocki, ST (corresponding author), Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, 14960 Omicron Dr, San Antonio, TX 78245 USA.	nawrocki@uthscsa.edu			NIH Cancer CenterUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA054174]; AT&T Endowed Chair at The Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, TX, USA; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA054174] Funding Source: NIH RePORTER	This work was supported by the NIH Cancer Center Core Grant CA054174 and funds provided by the AT&T Endowed Chair at The Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, TX, USA.	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Cell. Mol. Med.	OCT	2010	14	10					2448	2459		10.1111/j.1582-4934.2009.00832.x			12	Cell Biology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Research & Experimental Medicine	672OS	WOS:000283596400011	19583815	Green Accepted, Green Published, Bronze			2022-04-25	
J	Yadav, SS; Kumar, M; Varshney, A; Yadava, PK				Yadav, Suresh Singh; Kumar, Manoj; Varshney, Akhil; Yadava, Pramod Kumar			KLF4 sensitizes the colon cancer cell HCT-15 to cisplatin by altering the expression of HMGB1 and hTERT	LIFE SCIENCES			English	Article						KLF4; Cisplatin; And chemo-resistance	STEM-CELLS; COLORECTAL-CANCER; DOWN-REGULATION; PROMOTES CHEMORESISTANCE; 1ST-LINE TREATMENT; DRUG-RESISTANCE; AUTOPHAGY; ARREST; CYCLE; FLUOROURACIL	Aims: Insensitivity of cancer cells to therapeutic drugs is the most daunting challenge in cancer treatment. The mechanism of developing chemo-resistance is only partly understood to date. In continuation of some earlier reports, we hypothesize that KLF4, a key transcription factors that also has a crucial role in maintaining the stemness in cancer cells, may offer a basis for chemo-resistance. Main methods: Sensitivity of cells to cisplatin was analyzed by cell proliferation, colony formation, and cell growth assay. Cell cycle analysis and immunophenotyping were used to measure cell cycle arrest and level of reactive oxygen species respectively. Immunoblotting was used to analyze the change in expression hTERT and HMGB1 involved in KLF4 mediated cisplatin resistance. Key findings: We found that KLF4 expression sensitizes cancer cell to cisplatin cytotoxicity. Further, KLF4 promotes the cisplatin-mediated G2/M cell cycle arrest while KLF4 knocked down induces cisplatin-mediated S-phase arrest compared to control. Decreased level of reactive oxygen species (ROS) in cisplatin-treated and KLF4 knocked down HCT-15 cells compared to vector control, accounting for increased cell survival. Immuno-blotting showed that KLF4 positively regulates expression of the survival proteins hTERT and HMGB1 while in presence of cisplatin, expression of HMGB1 and hTERT is negatively regulated by KLF4. Significance: This study suggests the involvement of KLF4-HMGB1/hTERT signaling in offering the basis for chemo-resistance in colon cancer cells and KLF4 overexpression as a probable strategy for sensitizing drug-resistant cancer cells to chemotherapy. The present study opens up new avenues for cancer research and therapeutics.	[Yadav, Suresh Singh] Weizmann Inst Sci, Herzl St 234, IL-76100 Rehovot, Israel; [Varshney, Akhil] Univ Virginia, Ctr Adv Vis Sci, 415 Lane Rd, Charlottesville, VA 22908 USA; [Kumar, Manoj; Yadava, Pramod Kumar] Jawaharlal Nehru Univ, Sch Life Sci, Appl Mol Biol Lab, New Delhi 110067, India; [Kumar, Manoj] IISER, Berhampur 760010, Odisha, India		Yadava, PK (corresponding author), Jawaharlal Nehru Univ, Sch Life Sci, Appl Mol Biol Lab, New Delhi 110067, India.	pky0200@mail.jnu.ac.in		Varshney, Akhil/0000-0003-0759-0982; Yadava, Pramod/0000-0003-2395-1274	University grant commission (UGC) IndiaUniversity Grants Commission, India; Jawaharlal Nehru University, New Delhi	We acknowledge the University grant commission (UGC) India for the post-doctoral fellowship and contingency to SSY. We also acknowledge the Jawaharlal Nehru University, New Delhi for providing the working space and financial assistance.	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MAR 1	2019	220						169	176		10.1016/j.lfs.2019.02.005			8	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	HL0RF	WOS:000458400900019	30716337				2022-04-25	
J	Ke, P; Shao, BZ; Xu, ZQ; Chen, XW; Liu, C				Ke, Ping; Shao, Bo-Zong; Xu, Zhe-Qi; Chen, Xiong-Wen; Liu, Chong			Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease	FRONTIERS IN IMMUNOLOGY			English	Article						autophagy; Paneth cell; macrophage; goblet cell; inflammatory bowel disease; immune reaction	ENDOPLASMIC-RETICULUM STRESS; GENOME-WIDE ASSOCIATION; AMELIORATES EXPERIMENTAL COLITIS; CHAPERONE-MEDIATED AUTOPHAGY; COLORECTAL-CANCER CELLS; PREVENTS MUCOSAL INJURY; AMBIENT AIR-POLLUTION; NF-KAPPA-B; CROHNS-DISEASE; VITAMIN-D	Intestinal mucosal barrier, mainly composed of the intestinal mucus layer and the epithelium, plays a critical role in nutrient absorption as well as protection from pathogenic microorganisms. It is widely acknowledged that the damage of intestinal mucosal barrier or the disturbance of microorganism balance in the intestinal tract contributes greatly to the pathogenesis and progression of inflammatory bowel disease (IBD), which mainly includes Crohn's disease and ulcerative colitis. Autophagy is an evolutionarily conserved catabolic process that involves degradation of protein aggregates and damaged organelles for recycling. The roles of autophagy in the pathogenesis and progression of IBD have been increasingly studied. This present review mainly describes the roles of autophagy of Paneth cells, macrophages, and goblet cells in IBD, and finally, several potential therapeutic strategies for IBD taking advantage of autophagy.	[Ke, Ping; Shao, Bo-Zong; Xu, Zhe-Qi; Chen, Xiong-Wen; Liu, Chong] Second Mil Med Univ, Dept Pharmacol, Shanghai, Peoples R China		Chen, XW; Liu, C (corresponding author), Second Mil Med Univ, Dept Pharmacol, Shanghai, Peoples R China.	xchen001@gmail.com; wanlc2004@aliyun.com	Chen, Xiongwen/D-5988-2012	Chen, Xiongwen/0000-0002-3829-5815	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81670260]; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL088243] Funding Source: NIH RePORTER	This work was supported by a grant from the National Natural Science Foundation of China (81670260).	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Immunol.	JAN 9	2017	7								695	10.3389/fimmu.2016.00695			14	Immunology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology	EG9HC	WOS:000391368500001	28119697	Green Published, gold			2022-04-25	
J	Miao, YF; Zhang, YW; Chen, YL; Chen, LB; Wang, FY				Miao, Yufeng; Zhang, Youwei; Chen, Yonglin; Chen, Longbang; Wang, Fangyu			GABARAP is Overexpressed in Colorectal Carcinoma and Correlates with Shortened Patient Survival	HEPATO-GASTROENTEROLOGY			English	Article						gamma-aminobutyric acid type A (GABAA) receptor-associated protein; Autophagy; Colorectal cancer	ACTIVATED PROTEIN-KINASE; AUTOPHAGY; CANCER; CELLS; EXPRESSION; GATE-16; SYSTEM; HEALTH; LC3	Background/Aims: gamma-aminobutyric acid type A (GABAA) receptor associated protein (GABARAP), the mammalian homologue of yeast Atg8, is involved in autophagosome formation during autophagy. The aim of this study is to explore the expression and its prognostic significance in comparison with various clinicopathological predictors of survival. Methodology: GABARAP protein expression was determined by immunohistochemistry in 103 colorectal cancers. Cytoplasmic immunoreactivity was scored semiquantitatively. The results were analyzed in correlation with various clinicopathological variables, including patient survival. Chi-square test and Kaplan-Meier survival analysis were applied. Results: The expression of GABARAP was significantly higher in colorectal cancers than that in adjacent matched nontumor tissues (51.5% vs 33.0%, p<0.01). Increased expression of GABARAP expression in colorectal cancers was significantly correlated with a low grade of differentiation and shortened overall survival (p<0.05). There were no significant differences between the expression of GABARAP and age, gender, stage, tumor size, location of primary tumor, and lymph node invasion. Conclusions: Our data demonstrated that GABARAP is frequently expressed in colorectal cancer. Overexpression of GABARAP is a new independent prognostic marker, which is associated with poor differentiation as well as shortened overall survival.	[Miao, Yufeng; Wang, Fangyu] Nanjing Univ, Sch Med, Jinling Hosp, Dept Med Oncol, Nanjing 210002, Peoples R China; [Miao, Yufeng; Zhang, Youwei; Chen, Longbang] Nanjing Univ, Sch Med, Jinling Hosp, Dept Gastroenterol & Hepatol, Nanjing 210002, Peoples R China; [Chen, Yonglin] Lanzhou Univ, Sch Basic Med Sci, Dept Pathol, Lanzhou 730000, Peoples R China		Wang, FY (corresponding author), Nanjing Univ, Sch Med, Jinling Hosp, Dept Med Oncol, Nanjing 210002, Peoples R China.	wangfy65@gmail.com			Nanjing Military Command [07M076]	This work was supported by the Science and Technology Innovation Program of Nanjing Military Command (No. 07M076).	Chen N, 2009, BBA-MOL CELL RES, V1793, P1516, DOI 10.1016/j.bbamcr.2008.12.013; Cuervo AM, 2004, TRENDS CELL BIOL, V14, P70, DOI 10.1016/j.tcb.2003.12.002; Degenhardt K, 2006, CANCER CELL, V10, P51, DOI 10.1016/j.ccr.2006.06.001; Essrich C, 1998, NAT NEUROSCI, V1, P563, DOI 10.1038/2798; Hector S, 2009, BBA-REV CANCER, V1795, P117, DOI 10.1016/j.bbcan.2008.12.002; Hemelaar J, 2003, J BIOL CHEM, V278, P51841, DOI 10.1074/jbc.M308762200; Hoyer-Hansen M, 2007, AUTOPHAGY, V3, P381, DOI 10.4161/auto.4240; Kato K, 2002, ONCOGENE, V21, P6082, DOI 10.1038/sj.onc.1205737; Kirkegaard K, 2004, NAT REV MICROBIOL, V2, P301, DOI 10.1038/nrmicro865; Klebig C, 2005, CANCER RES, V65, P394; Kneussel M, 2000, TRENDS NEUROSCI, V23, P429, DOI 10.1016/S0166-2236(00)01627-1; 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; McLeod HL, 1999, BRIT J CANCER, V79, P191, DOI 10.1038/sj.bjc.6690033; Meijer Alfred J., 2006, Molecular Aspects of Medicine, V27, P411, DOI 10.1016/j.mam.2006.08.002; Moreno-Sanchez R, 2007, FEBS J, V274, P1393, DOI 10.1111/j.1742-4658.2007.05686.x; OgierDenis E, 1996, J BIOL CHEM, V271, P28593, DOI 10.1074/jbc.271.45.28593; Peto J, 2001, NATURE, V411, P390, DOI 10.1038/35077256; Pouyssegur J, 2006, NATURE, V441, P437, DOI 10.1038/nature04871; Roberts SS, 2004, J CLIN ONCOL, V22, P4127, DOI 10.1200/JCO.2004.02.032; Roberts SS, 2009, PATHOL ONCOL RES, V15, P645, DOI 10.1007/s12253-009-9165-x; Scriven P, 2007, J MOL MED, V85, P331, DOI 10.1007/s00109-006-0150-5; Sou Y, 2006, J BIOL CHEM, V281, P3017, DOI 10.1074/jbc.M505888200; Tanida I, 2004, INT J BIOCHEM CELL B, V36, P2503, DOI 10.1016/j.biocel.2004.05.009; White A, 2007, CHEM WORLD-UK, V4, P34	25	26	27	0	2	H G E UPDATE MEDICAL PUBLISHING S A	ATHENS	PO BOX 17257, ATHENS GR-10024, GREECE	0172-6390			HEPATO-GASTROENTEROL	Hepato-Gastroenterol.	MAR-APR	2010	57	98					257	261					5	Gastroenterology & Hepatology; Surgery	Science Citation Index Expanded (SCI-EXPANDED)	Gastroenterology & Hepatology; Surgery	612XD	WOS:000278938200015	20583424				2022-04-25	
J	Ji, S; Tang, SN; Li, K; Li, ZW; Liang, WF; Qiao, X; Wang, Q; Yu, SW; Ye, M				Ji, Shuai; Tang, Shunan; Li, Kai; Li, Ziwei; Liang, Wenfei; Qiao, Xue; Wang, Qi; Yu, Siwang; Ye, Min			Licoricidin inhibits the growth of SW480 human colorectal adenocarcinoma cells in vitro and in vivo by inducing cycle arrest, apoptosis and autophagy	TOXICOLOGY AND APPLIED PHARMACOLOGY			English	Article						Licoricidin; Colorectal cancer; Cycle arrest; Apoptosis; Autophagy; AMPK	GLYCYRRHIZA-URALENSIS; ETHANOL EXTRACT; ISOLIQUIRITIGENIN; DEATH; YEAST; ROOT	Licorice (Glycyrrhiza uralensis Fisch.) possesses significant anti-cancer activities, but the active ingredients and underlying mechanisms have not been revealed. By screening the cytotoxic activities of 122 licorice compounds against SW480 human colorectal adenocarcinoma cells, we found that licoricidin (LCD) inhibited SW480 cell viability with an IC50 value of 7.2 mu M. Further studies indicated that LCD significantly induced G1/S cell cycle arrest and apoptosis in SW480 cells, accompanied by inhibition of cyclins/CDK1 expression and activation of caspase-dependent pro-apoptotic signaling. Meanwhile, LCD promoted autophagy in SW480 cells, and activated AMPK signaling and inhibited Akt/mTOR pathway. Overexpression of a dominant-negative AMPK alpha 2 abolished LCD-induced inhibition of Akt/mTOR, autophagic and pro-apoptotic signaling pathways, and significantly reversed loss of cell viability, suggesting activation of AMPK is essential for the anti-cancer activity of LCD. In vivo anti-tumor experiments indicated that LCD (20 mg/kg, i.p.) significantly inhibited the growth of SW480 xenografts in nude mice with an inhibitory rate of 43.5%. In addition, we obtained the glycosylated product LCDG by microbial transformation, and found that glycosylation slightly enhanced the in vivo anti-cancer activities of LCD. This study indicates that LCD could inhibit SW480 cells by inducing cycle arrest, apoptosis and autophagy, and is a potential chemopreventive or chemotherapeutic agent against colorectal cancer. (C) 2017 Elsevier Inc. All rights reserved.	[Ji, Shuai; Tang, Shunan; Li, Kai; Li, Ziwei; Liang, Wenfei; Qiao, Xue; Wang, Qi; Yu, Siwang; Ye, Min] Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, 38 Xueyuan Rd, Beijing 100191, Peoples R China; [Ji, Shuai] Xuzhou Med Univ, Sch Pharm, Jiangsu Key Lab New Drug Res & Clin Pharm, 209 Tongshan Rd, Xuzhou 221004, Peoples R China		Yu, SW; Ye, M (corresponding author), Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, 38 Xueyuan Rd, Beijing 100191, Peoples R China.	swang_yu@bjmu.edu.cn; yemin@bjmu.edu.cn	yu, Siwang/AAL-8059-2020	Qiao, Xue/0000-0002-8771-7877; Yu, Siwang/0000-0002-3336-202X	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81173644, 81222054, 81472657]	This work was supported by National Natural Science Foundation of China (No. 81173644, No. 81222054, No. 81472657).	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Appl. Pharmacol.	JUL 1	2017	326						25	33		10.1016/j.taap.2017.04.015			9	Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Toxicology	EW6BH	WOS:000402589700004	28416456				2022-04-25	
J	Luo, Y; Chihara, Y; Fujimoto, K; Sasahira, T; Kuwada, M; Fujiwara, R; Fujii, K; Ohmori, H; Kuniyasu, H				Luo, Yi; Chihara, Yoshitomo; Fujimoto, Kiyohide; Sasahira, Tomonori; Kuwada, Masaomi; Fujiwara, Rina; Fujii, Kiyomu; Ohmori, Hitoshi; Kuniyasu, Hiroki			High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy	EUROPEAN JOURNAL OF CANCER			English	Article						HMGB1; Necrosis; Apoptosis; TLR4; RAGE	GLYCATION END-PRODUCTS; COLON-CANCER; COLORECTAL-CANCER; REGULATES AUTOPHAGY; HMGB PROTEINS; LINOLEIC-ACID; EXPRESSION; AMPHOTERIN; RECEPTOR; GROWTH	The role of the high mobility group box 1 (HMGB1) protein in chemotherapy-induced cell death was examined. CT26 mouse colon cancer cells were treated with trichostatin A (TSA; apoptosis inducer) or doxorubicin (DXR; necrosis inducer). DXR increased HMGB1 concentration in CT26 cell culture medium, whereas TSA did not. In a CT26 bilateral subcutaneous tumour model, DXR or TSA was injected in a single tumour. After injection, serum HMGB1 concentration in DXR-treated mice was 10 times higher than that in TSA-treated mice. After DXR treatment, the contralateral and remnant tumours showed more pronounced growth than did those treated with TSA. In mouse models, lung and liver metastasis was enhanced by DXR but not by TSA. DXR-enhanced metastasis was abrogated by anti-HMGB1 antibody treatment. In a cancer dormancy model, DXR induced regrowth of quiescent CT26 cells. HMGB1 induced tumour necrosis factor-a secretion via Toll-like receptor (TLR) 4 in U937 monocytes; however, HMGB1 decreased the number of U937 cells, resulting in restriction of immune activation via receptor for advanced glycation endproducts (RAGE). RAGE showed a more pronounced effect on nuclear factor kappa B activation than did TLR4 in CT26 cells. These findings suggest that HMGB1 released from necrotic cancer cells treated with a necrosis inducer enhances regrowth and metastasis of remnant cancer cells via RAGE activation. (C) 2012 Elsevier Ltd. All rights reserved.	[Luo, Yi; Chihara, Yoshitomo; Sasahira, Tomonori; Fujiwara, Rina; Fujii, Kiyomu; Ohmori, Hitoshi; Kuniyasu, Hiroki] Nara Med Univ, Dept Mol Pathol, Kashihara, Nara 6348521, Japan; [Chihara, Yoshitomo; Fujimoto, Kiyohide; Kuwada, Masaomi] Nara Med Univ, Dept Urol, Kashihara, Nara 6348521, 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 Science, JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science; Ministry of Health, Labour and Welfare, JapanMinistry of Health, Labour and Welfare, Japan	This work was supported in part by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, Japan, and Grant-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare, Japan.	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J	de Bruin, EC; Mederna, JP				de Bruin, Elza C.; Mederna, Jan Paul			Apoptosis and non-apoptotic deaths in cancer development and treatment response	CANCER TREATMENT REVIEWS			English	Review						Apoptosis; Autophagy; Mitotic catastrophe; Necrosis; Tumorigenesis; Treatment response; Radiotherapy	NECROTIC CELL-DEATH; TUMOR-NECROSIS-FACTOR; RADIATION-INDUCED AUTOPHAGY; PROTEIN CONJUGATION SYSTEM; FLICE-INHIBITORY PROTEIN; MALIGNANT GLIOMA-CELLS; RECTAL-CANCER; COLORECTAL-CARCINOMA; MITOTIC CATASTROPHE; DNA-DAMAGE	Resistance to apoptosis is closely linked to tumorigenesis, as it enables malignant cells to expand even in a stressful environment. Celts resistant to apoptosis are also assumed to be resistant to anti-cancer therapies. Apoptosis has therefore taken a central position in cell death research. However, its contribution to treatment success is highly debated for solid tumors. It becomes more and more clear that cells can also die by non-apoptotic mechanisms, such as autophagy, mitotic catastrophe and necrosis. In this review, we summarize the current knowledge regarding the molecular pathways that underlie these apoptotic and non-apoptotic death pathways, and discuss the clinical data that have now accumulated to evaluate their rotes in tumor development and cancer treatment. (C) 2008 Elsevier Ltd. All. rights reserved.	[de Bruin, Elza C.; Mederna, Jan Paul] Univ Amsterdam, Acad Med Ctr, Ctr Expt Mol Med, Lab Expt Oncol & Radiobiol, NL-1105 AZ Amsterdam, Netherlands		Mederna, JP (corresponding author), Univ Amsterdam, Acad Med Ctr, Ctr Expt Mol Med, Lab Expt Oncol & Radiobiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.	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Rev.	DEC	2008	34	8					737	749		10.1016/j.ctrv.2008.07.001			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	386EW	WOS:000261866100008	18722718				2022-04-25	
J	Liang, HH; Huang, CY; Chou, CW; Makondi, PT; Huang, MT; Wei, PL; Chang, YJ				Liang, Hung-Hua; Huang, Chien-Yu; Chou, Ching-Wen; Makondi, Precious Takondwa; Huang, Ming-Te; Wei, Po-Li; Chang, Yu-Jia			Heat shock protein 27 influences the anti-cancer effect of curcumin in colon cancer cells through ROS production and autophagy activation	LIFE SCIENCES			English	Article						Colorectal cancer; Resistance; Curcumin; HSP27; Apoptosis; Autophagy; Reactive oxygen species	METASTATIC COLORECTAL-CANCER; RANDOMIZED CONTROLLED-TRIAL; PERSONALIZED MEDICINE; PROSTATE-CANCER; CYCLE ARREST; APOPTOSIS; HSP27; SURVIVAL; ANTIOXIDANT; RADIOSENSITIVITY	The problem of therapeutic resistance and chemotherapeutic efficacy is tricky and critical in the management of colorectal cancer (CRC). Curcumin is a promising anti-cancer agent. Heat shock protein 27 (HSP27) is correlated with CRC progression and is said to affect CRC response to different therapies. However, the role of HSP27 on the therapeutic efficacy of curcumin remains unknown. HSP27 was silenced using small hairpin RNA (shRNA) technique. The cytotoxic and apoptotic effects of curcumin were assessed by sulforhodamine B (SRB) colorimetric assay, flow cytometric cell cycle analysis, and annexin V/propidium iodide (PI) double-labeling assays. Total reactive oxygen species (ROS)/superoxide and autophagy detection were performed, and the levels of apoptosis-related proteins were examined by Western blotting. It was found that the silencing of HSP27 (HSP27-KD) resulted in increased treatment resistance to curcumin in CRC cells. In addition, cell cycle analysis showed that the curcumin treatment caused cell cycle arrest at the G2/M phase in the control group, and apoptosis was reduced in the HSP27-KD group. Curcumin treatment also resulted in a decrease in anti-apoptotic proteins, p-Akt, Akt, Bcl-2 and p-Bad, and increase in pro-apoptotic proteins Bad and c-PARP levels in the control cells but not in the HSP27-KD cells. This was also followed by low reactive oxygen/nitrogen species (ROS/RNS), superoxide and autophagy induction levels in the HSP27-KD cells as compared to the control cells. Therefore, as silencing of HSP27 increases curcumin resistance by reducing apoptosis and reactive oxidative stress production, HSP27 is a potential selective target for curcumin treatment in CRC.	[Liang, Hung-Hua; Chou, Ching-Wen; Chang, Yu-Jia] Taipei Med Univ, Coll Med, Grad Inst Clin Med, Taipei, Taiwan; [Huang, Chien-Yu; Wei, Po-Li] Taipei Med Univ, Coll Med, Sch Med, Dept Surg, Taipei, Taiwan; [Huang, Chien-Yu; Huang, Ming-Te] Taipei Med Univ, Shuang Ho Hosp, Div Gen Surg, Dept Surg, Taipei, Taiwan; [Makondi, Precious Takondwa] Taipei Med Univ, Coll Med, Int PhD Program Med, Taipei, Taiwan; [Wei, Po-Li] Taipei Med Univ, Wan Fang Hosp, Div Colorectal Surg, Dept Surg, Taipei, Taiwan; [Wei, Po-Li] Taipei Med Univ, Taipei Med Univ Hosp, Dept Med Res, Canc Res Ctr, Taipei, Taiwan; [Wei, Po-Li] Taipei Med Univ, Taipei Med Univ Hosp, Dept Med Res, Translat Lab, Taipei, Taiwan; [Wei, Po-Li] Taipei Med Univ, Taipei Med Univ Hosp, Div Colorectal Surg, Dept Surg, Taipei, Taiwan; [Wei, Po-Li] Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan		Huang, CY; Chang, YJ (corresponding author), 250 Wu Xing St, Taipei, Taiwan.	b8501133@tmu.edu.tw; cyh@tmu.edu.tw; b101102137@tmu.edu.tw; mthuant@tmu.edu.tw; poliwei@tmu.edu.tw; r5424012@tmu.edu.tw			Taipei Medical University [TMU106-AE1-B03]	This work was funded by Taipei Medical University (TMU106-AE1-B03)	Aggarwal BB, 2007, ADV EXP MED BIOL, V595, P1; Andre F, 2013, PHARMACOGENOMICS, V14, P931, DOI [10.2217/PGS.13.79, 10.2217/pgs.13.79]; Andre T, 2015, J CLIN ONCOL, V33, P4176, DOI 10.1200/JCO.2015.63.4238; Binefa G, 2014, WORLD J GASTROENTERO, V20, P6786, DOI 10.3748/wjg.v20.i22.6786; Bosset JF, 2006, NEW ENGL J MED, V355, P1114, DOI 10.1056/NEJMoa060829; Chang YJ, 2015, TUMOR BIOL, V36, P633, DOI 10.1007/s13277-014-2640-3; Chang YJ, 2011, ANN SURG ONCOL, V18, P2395, DOI 10.1245/s10434-011-1597-3; Chen W, 2018, J CELL MOL MED, V22, P2283, DOI 10.1111/jcmm.13510; Chen X, 2016, MOL MED REP, V13, P689, DOI 10.3892/mmr.2015.4600; Ciocca DR, 2005, CELL STRESS CHAPERON, V10, P86, DOI 10.1379/CSC-99r.1; Des Guetz G, 2010, COCHRANE DB SYST REV, DOI 10.1002/14651858.CD007046.pub2; Diaz Z, 2013, MODERN PATHOL, V26, P1413, DOI 10.1038/modpathol.2013.81; 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SEP 15	2018	209						43	51		10.1016/j.lfs.2018.07.047			9	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	GS5SE	WOS:000443730000006	30056019				2022-04-25	
J	Marchal, JA; Carrasco, E; Ramirez, A; Jimenez, G; Olmedo, C; Peran, M; Agil, A; Conejo-Garcia, A; Cruz-Lopez, O; Campos, JM; Garcia, MA				Antonio Marchal, Juan; Carrasco, Esther; Ramirez, Alberto; Jimenez, Gema; Olmedo, Carmen; Peran, Macarena; Agil, Ahmad; Conejo-Garcia, Ana; Cruz-Lopez, Olga; Maria Campos, Joaquin; Angel Garcia, Maria			Bozepinib, a novel small antitumor agent, induces PKR-mediated apoptosis and synergizes with IFN alpha triggering apoptosis, autophagy and senescence	DRUG DESIGN DEVELOPMENT AND THERAPY			English	Article						seven-member heterocycles; purines; IC50; interferon cytokine; cell death; breast and colon cancer cells	BREAST-CANCER CELLS; INTERFERON-ALPHA; ANTICANCER ACTIVITY; PROTEIN-KINASE; WILD-TYPE; DEATH; P53; MELANOMA; IMMUNOTHERAPY; CHLOROQUINE	Bozepinib [(RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin- 3-yl]-9H-purine] is a potent antitumor compound that is able to induce apoptosis in breast cancer cells. In the present study, we show that bozepinib also has antitumor activity in colon cancer cells, showing 50% inhibitory concentration (IC50) values lower than those described for breast cancer cells and suggesting great potential of this synthetic drug in the treatment of cancer. We identified that the double-stranded RNA-dependent protein kinase (PKR) is a target of bozepinib, being upregulated and activated by the drug. However, p53 was not affected by bozepinib, and was not necessary for induction of apoptosis in either breast or colon cancer cells. In addition, the efficacy of bozepinib was improved when combined with the interferon-alpha (IFN alpha) cytokine, which enhanced bozepinib-induced apoptosis with involvement of protein kinase PKR. Moreover, we report here, for the first time, that in combined therapy, IFNa induces a clear process of autophagosome formation, and prior treatment with chloroquine, an autophagy inhibitor, is able to significantly reduce IFN alpha/bozepinib-induced cell death. Finally, we observed that a minor population of caspase 3-deficient MCF-7 cells persisted during long-term treatment with lower doses of bozepinib and the bozepinib/IFN alpha combination. Curiously, this population showed beta-galactosidase activity and a percentage of cells arrested in S phase, that was more evident in cells treated with the bozepinib/IFN alpha combination than in cells treated with bozepinib or IFNa alone. Considering the resistance of some cancer cells to conventional chemotherapy, combinations enhancing the diversity of the cell death outcome might succeed in delivering more effective and less toxic chemotherapy.	[Antonio Marchal, Juan; Carrasco, Esther; Ramirez, Alberto; Jimenez, Gema; Olmedo, Carmen; Peran, Macarena] Univ Granada, Ctr Biomed Res, Biopathol & Regenerat Med Inst, Granada, Spain; [Antonio Marchal, Juan; Jimenez, Gema] Univ Granada, Fac Med, Dept Human Anat & Embryol, Granada, Spain; [Ramirez, Alberto; Peran, Macarena] Univ Jaen, Dept Hlth Sci, Jaen, Spain; [Olmedo, Carmen; Angel Garcia, Maria] Virgen de las Nieves Univ Hosp, Expt Surg Res Unit, E-18012 Granada, Spain; [Agil, Ahmad] Univ Granada, Fac Med, Dept Pharmacol, Granada, Spain; [Agil, Ahmad] Univ Granada, Fac Med, Ctr Neurosci, Granada, Spain; [Conejo-Garcia, Ana; Cruz-Lopez, Olga; Maria Campos, Joaquin] Univ Granada, Fac Pharm, Dept Pharmaceut & Organ Chem, Granada, Spain; [Angel Garcia, Maria] Virgen de las Nieves Univ Hosp, Dept Oncol, E-18012 Granada, Spain		Garcia, MA (corresponding author), Hosp Univ Virgen de las Nieves, E-18012 Granada, Spain.	jmarchal@ugr.es; mangelgarcia@ugr.es	Cruz-Lopez, Olga/F-3060-2017; Marchal, Juan Antonio/M-4305-2014; Agil, Ahmad/D-9620-2014; Peran, Macarena/I-5225-2016; Garcia, Maria Angel MA/I-5116-2016; Rosa, Joaquín/L-8436-2014; García, Ana Conejo/I-5087-2018; Jiménez, Gema/O-7778-2017	Marchal, Juan Antonio/0000-0002-4996-8261; Peran, Macarena/0000-0001-7562-2347; Garcia, Maria Angel MA/0000-0003-2003-3769; Rosa, Joaquín/0000-0002-9035-8123; García, Ana Conejo/0000-0001-5776-7315; Jiménez, Gema/0000-0002-9803-879X; Agil, Ahmad/0000-0003-0164-9648; Ramirez Rivera, Alberto/0000-0002-7661-6974; Cruz-Lopez, Olga/0000-0002-9807-4061	Instituto de Salud Carlos III (Fondo de Investigacion Sanitaria FEDER funds [CP08/0063, PI10/02295, PI10/00592]	We gratefully acknowledge Jaime Lazuen for providing excellent technical assistance with the cytometry studies and Manuela Exposito for statistical assistance. We also thank staff from the Experimental Surgery Research Unit, and Pablo Bueno for support with equipment. This work was supported in part by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitaria FEDER funds, CP08/0063, PI10/02295, and PI10/00592).	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Dev. Ther.		2013	7						1301	1313		10.2147/DDDT.S51354			13	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	241FH	WOS:000326151300001	24194639	Green Published, gold, Green Submitted			2022-04-25	
J	Jeong, YK; Oh, JY; Yoo, JK; Lim, SH; Kim, EH				Jeong, Youn Kyoung; Oh, Ju Yeon; Yoo, Jae Kuk; Lim, Sun Ha; Kim, Eun Ho			The Biofunctional Effects of Mesima as a Radiosensitizer for Hepatocellular Carcinoma	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						mesima; HCC; radiation; radiosensitivity	PHELLINUS-LINTEUS; APOPTOSIS; POLYSACCHARIDE; METASTASIS; MUSHROOMS; INVASION; GROWTH; ARREST; CELLS	The tropical basidiomycete fungus Phellinus linteus (Mesima) exhibits anti-tumor, anti-angiogenic, and immunomodulatory properties in various cancers including prostate, colon, and lung cancer along with melanoma by, for example, inducing apoptosis or cell cycle arrest. However, whether medina also facilitates treatment of hepatocellular carcinoma (HCC), the third global cause of cancer deaths, remains unknown. Here, we examined its potential as a radiosensitizer in HCC radiotherapy using human HCC Hep3B and HepG2 cell lines and xenograft tumors. Mesima pretreatment significantly enhanced HCC cell radiosensitivity in vitro and the combination of mesima + radiation treatment significantly reduced xenograft tumor growth and size in vivo compared to those with single treatments. Mechanistically, mesima significantly enhanced radiotherapy efficiency by inhibiting tumor cell survival through inducing apoptosis (assessed via annexin V), impairing cell cycle regulation (shown by flow cytometry), and reducing radiation-induced DNA damage repair (measured via gamma-H2AX foci). Combination treatment also facilitated autophagic cell death beyond that from single treatments (assessed by quantifying stained acidic vesicular organelles), and diminished tumor cell metastatic potentials (shown by wound and Transwell assays). These findings support the synergistic anti-tumor effects of mesima combined with radiation and suggest scientific evidence for mesima as a radiosensitizer in HCC.	[Jeong, Youn Kyoung] Korea Inst Radiol & Med Sci, Radiat Nonclin Ctr, Seoul 01812, South Korea; [Oh, Ju Yeon] Korea Univ, Sch Life Sci & Biotechnol, Lab Biochem, Seoul 136701, South Korea; [Yoo, Jae Kuk] Han Kook Shin Yak Pharmaceut Co Ltd, Nonsan 33023, South Korea; [Lim, Sun Ha; Kim, Eun Ho] Daegu Catholic Univ, Sch Med, Dept Biochem, 33,17 Gil, Daegu 705718, South Korea		Kim, EH (corresponding author), Daegu Catholic Univ, Sch Med, Dept Biochem, 33,17 Gil, Daegu 705718, South Korea.	amy3523@kirams.re.kr; ojo5295@naver.com; yjk125@daum.net; sunha112@cu.ac.kr; eh140149@cu.ac.kr			Korea Institute of Radiological and Medical Sciences (KIRAMS) [51313-2017, 51314-2019]	This study was supported by private contract project (51313-2017, 51314-2019) from the Korea Institute of Radiological and Medical Sciences (KIRAMS).	Borchers AT, 1999, P SOC EXP BIOL MED, V221, P281, DOI 10.1046/j.1525-1373.1999.d01-86.x; Bruix J, 2005, HEPATOLOGY, V42, P1208, DOI 10.1002/hep.20933; CHICHARA G, 1969, NATURE, V222, P687, DOI 10.1038/222687a0; Collett NP, 2010, SEMIN ONCOL, V37, P258, DOI 10.1053/j.seminoncol.2010.06.014; Collins L, 2006, BRIT J CANCER, V95, P282, DOI 10.1038/sj.bjc.6603277; El-Serag HB, 2007, GASTROENTEROLOGY, V132, P2557, DOI 10.1053/j.gastro.2007.04.061; Franken NAP, 2006, NAT PROTOC, V1, P2315, DOI 10.1038/nprot.2006.339; Guo JJ, 2007, MOL CARCINOGEN, V46, P144, DOI 10.1002/mc.20275; Han SB, 1999, IMMUNOPHARMACOLOGY, V41, P157, DOI 10.1016/S0162-3109(98)00063-0; Jackson SP, 2002, CARCINOGENESIS, V23, P687, DOI 10.1093/carcin/23.5.687; Kim EH, 2016, ONCOTARGET, V7, P65125, DOI 10.18632/oncotarget.11372; Leber MF, 2009, INT J ONCOL, V34, P881, DOI 10.3892/ijo_00000214; Lee HJ, 2005, BIOL PHARM BULL, V28, P27, DOI 10.1248/bpb.28.27; Li G, 2004, CANCER LETT, V216, P175, DOI 10.1016/j.canlet.2004.07.014; Los M, 2002, MOL BIOL CELL, V13, P978, DOI 10.1091/mbc.01-05-0272; McIlwain DR, 2013, CSH PERSPECT BIOL, V5, DOI 10.1101/cshperspect.a008656; Parkin DM, 2001, LANCET ONCOL, V2, P533, DOI 10.1016/S1470-2045(01)00486-7; Pawlik TM, 2004, INT J RADIAT ONCOL, V59, P928, DOI 10.1016/j.ijrobp.2004.03.005; Psaila B, 2009, NAT REV CANCER, V9, P285, DOI 10.1038/nrc2621; Sliva D, 2010, EXP THER MED, V1, P407, DOI 10.3892/etm_00000063; Song KS, 1995, CHEM PHARM BULL, V43, P2105, DOI 10.1248/cpb.43.2105; Song KS, 2011, BMC CANCER, V11, DOI 10.1186/1471-2407-11-307; Wasser SP, 2002, APPL MICROBIOL BIOT, V60, P258, DOI 10.1007/s00253-002-1076-7	23	5	5	2	4	MDPI	BASEL	ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND		1422-0067		INT J MOL SCI	Int. J. Mol. Sci.	FEB	2020	21	3							871	10.3390/ijms21030871			14	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	KY4PQ	WOS:000522551603025	32013255	Green Published, gold			2022-04-25	
J	Al-Bari, MAA; Xu, PY				Al-Bari, Md Abdul Alim; Xu, Pingyong			Molecular regulation of autophagy machinery by mTOR-dependent and -independent pathways	ANNALS OF THE NEW YORK ACADEMY OF SCIENCES			English	Review						macroautophagy; autophagy regulation; mTOR signaling; amino acid sensing; calcium channel; TRPML; miRNA	ACTIVATED PROTEIN-KINASE; ER CA2+ DEPLETION; CELL-DEATH; CANCER CELLS; ENDOPLASMIC-RETICULUM; AMINO-ACIDS; AMPK PHOSPHORYLATION; COLORECTAL-CANCER; RAG GTPASES; ION-CHANNEL	Macroautophagy is a lysosomal degradative pathway or recycling process that maintains cellular homeostasis. This autophagy involves a series of sequential processing events, such as initiation; elongation and nucleation of the isolation membrane; cargo recruitment and maturation of the autophagosome (AP); transport of the AP; docking and fusion of the AP with a late endosome or lysosome; and regeneration of the lysosome by the autophagic lysosomal reformation cycle. These events are critically coordinated by the action of a set of several key components, including autophagy-related proteins (Atg), and regulated by intricate networks, such as mechanistic target of rapamycin (mTOR), a master regulator of autophagy, as well as mTOR-independent signaling pathways. Among mTOR-independent pathways, the transient receptor potential (TRP) calcium ion channel TRPML (mucolipin) subfamily is emerging as an important signaling channel to modulate lysosomal biogenesis and autophagy. This review discusses the recent advances in elucidating the molecular mechanisms and regulation of the autophagy process. Understanding these mechanisms may ultimately allow scientists and clinicians to control this process in order to improve human health.	[Al-Bari, Md Abdul Alim] Univ Rajshahi, Dept Pharm, Rajshahi 6205, Bangladesh; [Xu, Pingyong] Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Beijing, Peoples R China; [Xu, Pingyong] Chinese Acad Sci, Inst Biophys, Beijing Key Lab Noncoding RNA, Beijing, Peoples R China		Al-Bari, MAA (corresponding author), Univ Rajshahi, Dept Pharm, Rajshahi 6205, Bangladesh.	alimalbari347@ru.ac.bd	Al-Bari, Abdul Alim/AAT-4301-2020; Al-Bari, Md. Abdul Alim/C-2946-2018	Al-Bari, Md. 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J	Duarte, D; Cardoso, A; Vale, N				Duarte, Diana; Cardoso, Armando; Vale, Nuno			Synergistic Growth Inhibition of HT-29 Colon and MCF-7 Breast Cancer Cells with Simultaneous and Sequential Combinations of Antineoplastics and CNS Drugs	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						colorectal cancer; breast cancer; drug synergism; antineoplastic drugs; drug repurposing; CNS drugs; combination therapy	VALPROIC ACID; ANTICANCER ACTIVITY; IN-VITRO; IMIPRAMINE BLUE; P-GLYCOPROTEIN; 5-FLUOROURACIL; AUTOPHAGY; VIVO; TRIFLUOPERAZINE; CHEMOTHERAPY	Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.	[Duarte, Diana; Vale, Nuno] Ctr Hlth Technol & Serv Res CINTESIS, OncoPharma Res Grp, Rua Doutor Placido da Costa, P-4200450 Porto, Portugal; [Duarte, Diana] Univ Porto, Fac Pharm, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto, Portugal; [Cardoso, Armando] Ctr Hlth Technol & Serv Res CINTESIS, NeuroGen Res Grp, Rua Doutor Placido da Costa, P-4200450 Porto, Portugal; [Cardoso, Armando] Univ Porto, Fac Med, Dept Biomed, Unit Anat, Alameda Prof Hernani Monteiro, P-4200319 Porto, Portugal; [Vale, Nuno] Univ Porto, Fac Med, Dept Community Med Hlth Informat & Decis MEDCIDS, Alameda Prof Hernani Monteiro, P-4200319 Porto, Portugal		Vale, N (corresponding author), Ctr Hlth Technol & Serv Res CINTESIS, OncoPharma Res Grp, Rua Doutor Placido da Costa, P-4200450 Porto, Portugal.; Vale, N (corresponding author), Univ Porto, Fac Med, Dept Community Med Hlth Informat & Decis MEDCIDS, Alameda Prof Hernani Monteiro, P-4200319 Porto, Portugal.	dianaduarte29@gmail.com; cardosoa@med.up.pt; nunovale@med.up.pt	Duarte, Diana/ABA-2082-2020; Cardoso, Armando/H-9733-2013	Duarte, Diana/0000-0003-1420-5042; Vale, Nuno/0000-0002-1283-1042; Cardoso, Armando/0000-0002-2967-6990	FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020; Portuguese funds through Fundacao para a Ciencia e a Tecnologia (FCT) [IF/00092/2014/CP1255/CT0004]	This research was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through Fundacao para a Ciencia e a Tecnologia (FCT) in the framework of the project IF/00092/2014/CP1255/CT0004.	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J. Mol. Sci.	JUL	2021	22	14							7408	10.3390/ijms22147408			39	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	TN6ZN	WOS:000676380700001	34299028	gold, Green Published			2022-04-25	
J	Li, LC; Wang, HY; Qian, J; Wei, GL; Ding, R; Hu, CH; Fang, D; Jiang, ZY; Bi, L; Song, J; Ma, J; Qin, FX; Huang, XF; Cao, M; Huo, JG				Li, Lingchang; Wang, Haiyan; Qian, Jun; Wei, Guoli; Ding, Rong; Hu, Canhong; Fang, Dong; Jiang, Ziyu; Bi, Lei; Song, Jie; Ma, Jun; Qin, Fengxia; Huang, Xiaofei; Cao, Meng; Huo, Jiege			FuFangChangTai Decoction Activates Macrophages via Inducing Autophagy	EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE			English	Article							T-CELLS; IL-6; EXPRESSION; APOPTOSIS; PATHWAYS; ROLES; CD80	The traditional Chinese medicine decoction FuFangChangTai (FFCT) has been used in the therapy of colon cancer clinically, yielding alleviated toxicity and enhanced immunity. In our previous study, FFCT exerted its antitumor activity not only by inducing apoptosis but also by activating autophagy to eliminate tumor cells. However, its mechanism is not well understood. The purpose of this study was to investigate the relationship between macrophages activation and FFCT-induced autophagy. Results showed that FFCT could induce autophagy in colon cancer, as demonstrated by increased level of intracellular autophagy marker LC3 II in CT26.WT cells by fluorescence microscope and western blot assay. FFCT also facilitated numbers of vesicular bodies with bilayer membrane in CT26.WT cells, which were indicative of autophagosomes formation. Autophagosomes secreted by FFCT-treated CT26.WT cells can activate M1 type macrophages, accompanied with increased expression of costimulatory molecules CD86 and CD40 on the surface of RAW264.7 cells, and more inflammatory cytokines secretion, such as TNF-, IL-6, MCP-1, and IL-1. mRNA expressions of M2 macrophages markers, such as IL-10, CD206, Arg-1, and FIZZ-1, were downregulated. And this process helps regulate the polarization of macrophages and promote the immune response. These findings support a mechanism of FFCT-induced autophagy and provide novel evidence demonstrating that macrophages are involved in FFCT-induced autophagy progression.	[Li, Lingchang; Wei, Guoli; Ding, Rong; Hu, Canhong; Jiang, Ziyu; Song, Jie; Qin, Fengxia; Huang, Xiaofei; Cao, Meng; Huo, Jiege] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing, Jiangsu, Peoples R China; [Li, Lingchang; Qian, Jun; Bi, Lei] Nanjing Univ Chinese Med, Nanjing, Jiangsu, Peoples R China; [Wang, Haiyan] Xuzhou Tongshan Dist Hosp Tradit Chinese Med, Xuzhou, Jiangsu, Peoples R China; [Fang, Dong] Zhenjiang Hosp Chinese Tradit & Western Med, Zhenjiang, Jiangsu, Peoples R China; [Ma, Jun] Nanjing Univ Chinese Med, Huaian Affiliated Hosp, Huaian, Jiangsu, Peoples R China		Cao, M; Huo, JG (corresponding author), Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing, Jiangsu, Peoples R China.	mcao1979@163.com; huojiege@jsatcm.com	Li, Lingchang/AAL-4850-2021	Li, Lingchang/0000-0001-5520-7023	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81503574, 81673945, 81873055, 81873219]; Natural Science Foundation of Jiangsu Province of ChinaNatural Science Foundation of Jiangsu Province [BK20151605]; Jiangsu Provincial TCM Leading Talent Project [SLJ0211]; Jiangsu Provincial Clinical Research Project [BL2014099]; Open subject of Jiangsu Branch of Chinese Academy of Chinese Medical Sciences [FY201803]	This study received Grants from National Natural Science Foundation of China (81503574, 81673945, 81873055, and 81873219); Natural Science Foundation of Jiangsu Province of China (BK20151605); Jiangsu Provincial TCM Leading Talent Project (SLJ0211); Jiangsu Provincial Clinical Research Project (BL2014099); Open subject of Jiangsu Branch of Chinese Academy of Chinese Medical Sciences (FY201803).	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Med.		2019	2019								5657035	10.1155/2019/5657035			10	Integrative & Complementary Medicine	Science Citation Index Expanded (SCI-EXPANDED)	Integrative & Complementary Medicine	IF3RW	WOS:000473001700001	31308853	Green Published, Green Submitted, gold			2022-04-25	
J	Yu, HI; Shen, HC; Chen, SH; Lim, YP; Chuang, HH; Tai, TS; Kung, FP; Lu, CH; Hou, CY; Lee, YR				Yu, Hui-, I; Shen, Hui-Ching; Chen, Shu-Hsin; Lim, Yun-Ping; Chuang, Hsiang-Hsun; Tai, Tsai-Sung; Kung, Fang-Ping; Lu, Chieh-Hsiang; Hou, Chia-Yi; Lee, Ying-Ray			Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Article						aloperine; thyroid cancer; autophagy	CYCLE ARREST; IN-VITRO; DERIVATIVES; APOPTOSIS; EVOLUTION; DISCOVERY; INJURY	Aloperine, an alkaloid isolated from Sophoraalopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma; colon, breast, and prostate cancers; and osteosarcoma. Cell cycle arrest, apoptosis induction, and tumorigenesis suppression have been demonstrated following aloperine treatment. In a previous study, we demonstrated antitumor effects of aloperine on human thyroid cancer cells through anti-tumorigenesis and caspase-dependent apoptosis induction via the Akt signaling pathway. In the present study, we demonstrated the modulation of the autophagy mechanism following the incubation of multidrug-resistant papillary and anaplastic human thyroid cancer cells with aloperine; we also illustrate the underlying mechanisms, including AMPK, Erk, JNK, p38, and Akt signaling pathways. Further investigation revealed the involvement of the Akt signaling pathway in aloperine-modulated autophagy in human thyroid cancer cells. These results indicate a previously unappreciated function of aloperine in autophagy modulation in human thyroid cancer cells.	[Yu, Hui-, I; Chuang, Hsiang-Hsun; Tai, Tsai-Sung; Kung, Fang-Ping; Lu, Chieh-Hsiang] Chiayi Christian Hosp, Ditmanson Med Fdn, Dept Internal Med, Div Endocrinol & Metab, Chiayi 600, Taiwan; [Shen, Hui-Ching; Hou, Chia-Yi] Chi Mei Med Ctr, Dept Clin Pathol, Liouying 736, Taiwan; [Chen, Shu-Hsin; Lee, Ying-Ray] Chiayi Christian Hosp, Ditmanson Med Fdn, Dept Med Res, Chiayi 600, Taiwan; [Lim, Yun-Ping] China Med Univ, Coll Pharm, Dept Pharm, Taichung 404, Taiwan		Lee, YR (corresponding author), Chiayi Christian Hosp, Ditmanson Med Fdn, Dept Med Res, Chiayi 600, Taiwan.	04490@cych.org.tw; huiching0105@gmail.com; 10472@cych.org.tw; limyp@mail.cmu.edu.tw; 04486@cych.org.tw; 04015@cych.org.tw; 07266@cych.org.tw; 02602@cych.org.tw; 960360@mail.chimei.org.tw; yingray.lee@gmail.com		Lee, Ying-Ray/0000-0002-0349-0960	Ministry of Science and Technology of the Republic of China, TaiwanMinistry of Science and Technology, Taiwan [MOST 108-2314-B-705-001]; Ditmanson Medical Foundation Chiayi Christian Hospital [R107-24]; Chi Mei Medical Center [CLFHR10836]	This work was supported by the grants from the Ministry of Science and Technology of the Republic of China, Taiwan (MOST 108-2314-B-705-001), Ditmanson Medical Foundation Chiayi Christian Hospital (Grant R107-24) and Chi Mei Medical Center (CLFHR10836). We thank Myron for the critical review of the manuscript.	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J. Mol. Sci.	NOV	2019	20	21							5315	10.3390/ijms20215315			15	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	JQ4VU	WOS:000498946100073	31731481	Green Published, gold			2022-04-25	
J	O'Donovan, TR; Rajendran, S; O'Reilly, S; O'Sullivan, GC; McKenna, SL				O'Donovan, Tracey R.; Rajendran, Simon; O'Reilly, Seamus; O'Sullivan, Gerald C.; McKenna, Sharon L.			Lithium Modulates Autophagy in Esophageal and Colorectal Cancer Cells and Enhances the Efficacy of Therapeutic Agents In Vitro and In Vivo	PLOS ONE			English	Article							TUMOR STROMA MODEL; ISCHEMIA/REPERFUSION INJURY; MEMBRANE PERMEABILIZATION; CARDIOMYOCYTE DEATH; OXIDATIVE STRESS; FLOW-CYTOMETRY; INHIBITION; DEGRADATION; GROWTH; DRUG	Many epithelial cancers, particularly gastrointestinal tract cancers, remain poor prognosis diseases, due to resistance to cytotoxic therapy and local or metastatic recurrence. We have previously shown that apoptosis incompetent esophageal cancer cells induce autophagy in response to chemotherapeutic agents and this can facilitate their recovery. However, known pharmacological inhibitors of autophagy could not enhance cytotoxicity. In this study, we have examined two well known, clinically approved autophagy inducers, rapamycin and lithium, for their effects on chemosensitivity in apoptosis incompetent cancer cells. Both lithium and rapamycin were shown to induce autophagosomes in esophageal and colorectal cancer cells by western blot analysis of LC3 isoforms, morphology and FACS quantitation of Cyto-ID or mCherry-GFP-LC3. Analysis of autophagic flux indicates inefficient autophagosome processing in lithium treated cells, whereas rapamycin treated cells showed efficient flux. Viability and recovery was assessed by clonogenic assays. When combined with the chemotherapeutic agent 5-fluorouracil, rapamycin was protective. In contrast, lithium showed strong enhancement of non-apoptotic cell death. The combination of lithium with 5-fluorouracil or oxaliplatin was then tested in the syngenic mouse (balb/c) colorectal cancer model-CT26. When either chemotherapeutic agent was combined with lithium a significant reduction in tumor volume was achieved. In addition, survival was dramatically increased in the combination group (p < 0.0001), with > 50% of animals achieving long term cure without re-occurrence (> 1 year tumor free). Thus, combination treatment with lithium can substantially improve the efficacy of chemotherapeutic agents in apoptosis deficient cancer cells. Induction of compromised autophagy may contribute to this cytotoxicity.	[O'Donovan, Tracey R.; Rajendran, Simon; O'Sullivan, Gerald C.; McKenna, Sharon L.] Natl Univ Ireland Univ Coll Cork, Leslie C Quick Lab, Cork Canc Res Ctr, BioSci Inst, Cork, Ireland; [O'Reilly, Seamus] Cork Univ Hosp, Dept Med Oncol, Cork, Ireland		McKenna, SL (corresponding author), Natl Univ Ireland Univ Coll Cork, Leslie C Quick Lab, Cork Canc Res Ctr, BioSci Inst, Cork, Ireland.	s.mckenna@ucc.ie	McKenna, Sharon/AAD-9432-2020	McKenna, Sharon/0000-0002-6764-6274	Health Research Board [HRA_POR/2011/55]	Funding was provided by Health Research Board HRA_POR/2011/55.	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Vidal F, 2011, INT J ONCOL, V38, P1365, DOI 10.3892/ijo.2011.955; Voss V, 2010, MOL CANCER RES, V8, P1002, DOI 10.1158/1541-7786.MCR-09-0562; Weiner LM, 2012, NEW ENGL J MED, V366, P1156, DOI 10.1056/NEJMcibr1114526; Wiersma VR, 2015, AUTOPHAGY, V11, P1373, DOI 10.1080/15548627.2015.1063767; Xie M, 2014, CIRCULATION, V129, P1139, DOI 10.1161/CIRCULATIONAHA.113.002416; Yao XF, 2014, FOOD CHEM TOXICOL, V67, P96, DOI 10.1016/j.fct.2014.02.017; Yazlovitskaya EM, 2006, CANCER RES, V66, P11179, DOI 10.1158/0008-5472.CAN-06-2740; Yue W, 2013, AUTOPHAGY, V9, P714, DOI 10.4161/auto.23997; Zhou HY, 2012, CHIN J CANCER, V31, P8, DOI 10.5732/cjc.011.10281; Zhou J, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0087161; Zhou ST, 2012, CANCER LETT, V323, P115, DOI 10.1016/j.canlet.2012.02.017	69	25	31	0	16	PUBLIC LIBRARY SCIENCE	SAN FRANCISCO	1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA	1932-6203			PLOS ONE	PLoS One	AUG 6	2015	10	8							e0134676	10.1371/journal.pone.0134676			26	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	CO3MQ	WOS:000359062300058	26248051	gold, Green Published, Green Submitted			2022-04-25	
J	Zhao, S; Chen, SR; Yang, XF; Shen, DF; Takano, Y; Su, RJ; Zheng, HC				Zhao, Shuang; Chen, Shu-rui; Yang, Xue-feng; Shen, Dao-fu; Takano, Yasuo; Su, Rong-jian; Zheng, Hua-chuan			BTG1 might be employed as a biomarker for carcinogenesis and a target for gene therapy in colorectal cancers	ONCOTARGET			English	Article						colorectal cancer; BTG1; carcinogenesis; aggressive phenotypes; gene therapy	CELL TRANSLOCATION GENE-1; PROGNOSTIC MARKER; TUMOR-METASTASIS; GASTRIC-CANCER; EXPRESSION; CARCINOMA; APOPTOSIS; LEUKEMIA; PATHOGENESIS; IDENTIFICATION	Here, BTG1 overexpression inhibited proliferation, induced differentiation, autophagy, and apoptosis in colorectal cancer cells (p<0.05). BTG1 overexpression reduced mitochondrial membrane potential and caused senescence in HCT-116 transfectants (p<0.05). BTG1-induced G(2) arrest might be related to Cyclin B1 and Cdc25B hypoexpression in HCT-15 transfectants, while G(1) arrest in HCT-116 transfectants overexpressing p21 and p27. BTG1 overexpression decreased the expression of Bcl-2, Bcl-xL, XIAP, Akt1 or survivin and increased the expression of Bax or p53 in colorectal cancer cells. BTG1-induced autophagy was dependent on Beclin-1 expression. BTG1 overexpression might weaken beta-catenin pathway in colorectal cancer cells. The chemosensitivity of BTG1 transfectants to paclitaxel, cisplatin, MG132 or SAHA was positively correlated with its apoptotic induction. There was a lower expression level of BTG1 in cancer than matched non-neoplastic mucosa by RT-PCR (p<0.05), while versa for Western blot and immunohistochemical data (p<0.05). BTG1 overexpression significantly suppressed the growth of HCT-15 and HCT-116 via inhibiting proliferation, inducing apoptosis and autophagy in nude mice. Up-regulated BTG1 expression plays an important role in colorectal carcinogenesis as a potential biomarker. BTG1 expression might reverse aggressive phenotypes, so it might be employed as a target of gene therapy for colorectal cancer.	[Zhao, Shuang; Yang, Xue-feng; Shen, Dao-fu; Zheng, Hua-chuan] Jinzhou Med Univ, Canc Ctr, Key Lab Brain & Spinal Cord Injury Liaoning Prov, Affiliated Hosp 1, Jinzhou, Peoples R China; [Zhao, Shuang; Yang, Xue-feng; Shen, Dao-fu; Zheng, Hua-chuan] Jinzhou Med Univ, Affiliated Hosp 1, Anim Ctr, Jinzhou, Peoples R China; [Chen, Shu-rui] Jinzhou Med Univ, Dept Sci & Technol, Jinzhou, Peoples R China; [Takano, Yasuo] Tokyo Univ Technol, Sch Hlth Sci, Ohta Ku, Tokyo, Japan; [Su, Rong-jian; Zheng, Hua-chuan] Jinzhou Med Univ, Life Sci Inst, Jinzhou, Peoples R China		Zheng, HC (corresponding author), Jinzhou Med Univ, Canc Ctr, Key Lab Brain & Spinal Cord Injury Liaoning Prov, Affiliated Hosp 1, Jinzhou, Peoples R China.; Zheng, HC (corresponding author), Jinzhou Med Univ, Affiliated Hosp 1, Anim Ctr, Jinzhou, Peoples R China.; Zheng, HC (corresponding author), Jinzhou Med Univ, Life Sci Inst, Jinzhou, Peoples R China.	zheng_huachuan@hotmail.com			President Fund of Jinzhou Medical University [XZJJ20140201, XZJJ20140203]; Liaoning BaiQianWan Talents Program; Scientific Research Fund of Liaoning Provincial Education Department [LJQ2014093]; Key Scientific and Technological Project of Liaoning Province [2015408001]; National Natural Scientific Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472544]	We thank Dr. Xin-lu Wang (Shengjing Hospital, China Medical University) for her assistance of ultrasonic examination. This study was supported by President Fund of Jinzhou Medical University (XZJJ20140201; XZJJ20140203), Liaoning BaiQianWan Talents Program, A Project Supported by Scientific Research Fund of Liaoning Provincial Education Department (LJQ2014093), a Key Scientific and Technological Project of Liaoning Province (2015408001) and National Natural Scientific Foundation of China (81472544).	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J	Huang, W; Zeng, C; Liu, J; Yuan, L; Liu, WD; Wang, L; Zhu, HC; Xu, Y; Luo, Y; Xie, D; Jiang, XJ; Ren, CP				Huang, Wei; Zeng, Chong; Liu, Jie; Yuan, Li; Liu, Weidong; Wang, Lei; Zhu, Hecheng; Xu, Yang; Luo, Yi; Xie, Dan; Jiang, Xingjun; Ren, Caiping			Sodium butyrate induces autophagic apoptosis of nasopharyngeal carcinoma cells by inhibiting AKT/mTOR signaling	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Nasopharyngeal carcinoma; Sodium butyrate; Autophagy; Apoptosis; AKT/mTOR	COLORECTAL-CANCER; PI3K/AKT/MTOR PATHWAY; HDAC INHIBITORS; DUAL ROLE; DEATH; INVOLVEMENT; ACTIVATION; CROSSTALK; LIFE; AMPK	Previously, we confirmed the anti-tumor effects of sodium butyrate (NaBu) in nasopharyngeal carcinoma (NPC). However, its molecular mechanisms have not be fully elucidated. In this study, we studied the effects of NaBu on autophagy and explored the relation between NaBu associated autophagy and apoptosis in NPC cells. EGFP-LC3 plasmids were introduced into NPC cells to observed the effects of NaBu on autophagy flux with or without chloroquine (CQ) addition. Autophagy markers were also detected by Western blot. Under NaBu treatment, autophagy and apoptosis markers were detected simultaneously at different time. Then, to explore the roles of autophagy in NaBu induced apoptosis, the effects of autophagy inhibition, via specific inhibitor treatment or key gene knockdown, were analyzed. At last, the upstream signaling and its roles in NaBu induced autophagy and apoptosis were also analyzed. Increased LC3 dots and LC3-II accumulation indicated that NaBu can promote autophagy flux in NPC cells. LC3-II accumulation was earlier than cleaved PARP increment suggesting autophagy activation is prior to apoptosis activation, which was validated by flow cytometry mediated apoptosis analysis. Moreover, autophagy inhibition, achieved by 3-MA treatment or BECN1 knockdown, can antagonize NaBu induced apoptosis reflecting by re-deregulated cPARP and apoptotic rates. Furthermore, NaBu treatment inhibited the AKT/mTOR axis indicated by deregulated p-AKT(S473) and p-mTOR(S2448) and ectopic AKT expression both suppressed NaBu induced autophagy and apoptosis. At last, Western blot showed that HDAC6 dependent EGFR deregulation may account for the NaBu associated AKT/mTOR inhibition. NaBu can induce autophagic apoptosis via suppressing AKT/mTOR axis in NPC cells. Our results suggest that combination of autophagy inhibitors and deacetylase inhibitors may not be recommended in NPC clinical treatment. (C) 2019 Published by Elsevier Inc.	[Huang, Wei; Liu, Weidong; Wang, Lei; Ren, Caiping] Cent S Univ, Key Lab Carcinogenesis, Chinese Minist Hlth, Xiangya Hosp, Changsha 410008, Hunan, Peoples R China; [Huang, Wei; Liu, Weidong; Wang, Lei; Ren, Caiping] Cent S Univ, Key Lab Carcinogenesis & Canc Invas, Chinese Minist Educ, Changsha 410008, Hunan, Peoples R China; [Huang, Wei; Liu, Weidong; Wang, Lei; Ren, Caiping] Cent S Univ, Sch Basic Med Sci, Collaborat Innovat Ctr Canc Med, Canc Res Inst, Changsha, Hunan, Peoples R China; [Huang, Wei] Xiangya Hosp, Res Ctr Carcinogenesis & Targeted Therapy, Changsha, Hunan, Peoples R China; [Zeng, Chong] Hunan Rongjun Hosp, Dept Resp Med & Neurol, Changsha, Hunan, Peoples R China; [Liu, Jie] Changsha Cent Hosp, Dept Pathol, Changsha, Hunan, Peoples R China; [Yuan, Li] Cent S Univ, Xiangya Hosp 3, Dept Nucl Med, Changsha, Hunan, Peoples R China; [Zhu, Hecheng; Xu, Yang; Luo, Yi] Changsha Kexin Canc Hosp, Changsha, Hunan, Peoples R China; [Xie, Dan] Sun Yat Sen Univ, Canc Ctr, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Guangzhou, Guangdong, Peoples R China; [Jiang, Xingjun] Cent S Univ, Xiangya Hosp, Dept Neurosurg, Changsha 410008, Hunan, Peoples R China		Ren, CP (corresponding author), Cent S Univ, Key Lab Carcinogenesis, Chinese Minist Hlth, Xiangya Hosp, Changsha 410008, Hunan, Peoples R China.; Ren, CP (corresponding author), Cent S Univ, Key Lab Carcinogenesis & Canc Invas, Chinese Minist Educ, Changsha 410008, Hunan, Peoples R China.; Jiang, XJ (corresponding author), Cent S Univ, Xiangya Hosp, Dept Neurosurg, Changsha 410008, Hunan, Peoples R China.	jiangxj@csu.edu.cn; rencaiping@csu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773179, 81702924, 81272972]; Natural Science Foundation of Hunan Province of ChinaNatural Science Foundation of Hunan Province [2016JJ2172, 2018JJ3811]; National Basic Research Program of ChinaNational Basic Research Program of China [2010CB833605]; Open-End Fund for the Valuable and Precision Instruments of Central South University	The present study was supported by the National Natural Science Foundation of China (nos. 81773179, 81702924, 81602686and 81272972), the Natural Science Foundation of Hunan Province of China (nos. 2016JJ2172, 2018JJ3811), the National Basic Research Program of China(2010CB833605), and the Open-End Fund for the Valuable and Precision Instruments of Central South University.	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Biophys. Res. Commun.	JUN 18	2019	514	1					64	70		10.1016/j.bbrc.2019.04.111			7	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	IA2QS	WOS:000469406800010	31023529				2022-04-25	
J	Rodrigues, BLC; Lallo, MA; Perez, EC				Colhado Rodrigues, Bridilla Luiza; Lallo, Maria Anete; Perez, Elizabeth Cristina			The Controversial Role of Autophagy in Tumor Development: A Systematic Review	IMMUNOLOGICAL INVESTIGATIONS			English	Review						Autophagocytosis; cancer; cell death; homeostasis; ATG proteins; PI3K; AKT; mTOR intracellular signaling pathway	CELL-DEATH; CANCER; SURVIVAL	Autophagy is a natural regulatory mechanism of the cell that eliminates unnecessary and dysfunctional cellular components to maintain homeostasis. Several authors have demonstrated that this mechanism can be induced by pathological conditions as cancer. However, their role in tumor development is still a controversial issue in cancer research. Here, we discussed the most relevant findings concerning autophagy in tumor development. In this critical review performed with studies published between 2002 and 2018, we found that the main pathway involved in the autophagy process is the PI3K/AKT/mTOR intracellular signaling pathway. Regarding their role in cancer development, breast cancer is the main study target, followed by lung, prostate and colon cancer. In these issues, 46% of the works consulted suggesting that autophagy inhibits tumor progression by favor a better antitumor response, 4% suggest that favors growth and tumor progression and, 50% of the authors failed to establish whether autophagy inhibits or favors tumor development. Herein, we concluded that depending on the study model, autophagy may favor or inhibits growth and cancer progression.	[Colhado Rodrigues, Bridilla Luiza; Lallo, Maria Anete; Perez, Elizabeth Cristina] Univ Paulista, Programa Posgrad Patol Ambiental & Expt, Rua Doutor Bacelar 1212,4th Floor, BR-04026002 Sao Paulo, SP, Brazil; [Colhado Rodrigues, Bridilla Luiza] Inst Butantan, Lab Imunogenet, Sao Paulo, SP, Brazil		Perez, EC (corresponding author), Univ Paulista, Programa Posgrad Patol Ambiental & Expt, Rua Doutor Bacelar 1212,4th Floor, BR-04026002 Sao Paulo, SP, Brazil.	elicristin@hotmail.com	Lallo, Maria A/D-5976-2012	Lallo, Maria Anete/0000-0003-3578-3087; Colhado Rodrigues, Bridilla Luiza/0000-0003-4819-429X	Banco Santander, grant for undergraduate student [2016/2107]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESPFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2017/04176-7]	This work was supported by Banco Santander, grant for undergraduate student 2016/2107; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP grant #2017/04176-7.	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Invest.	MAY 18	2020	49	4					386	396		10.1080/08820139.2019.1682600		NOV 2019	11	Immunology	Science Citation Index Expanded (SCI-EXPANDED)	Immunology	LE0ON	WOS:000496602400001	31726897				2022-04-25	
J	Mena, S; Rodriguez, ML; Ponsoda, X; Estrela, JM; Jaattela, M; Ortega, AL				Mena, Salvador; Rodriguez, Maria L.; Ponsoda, Xavier; Estrela, Jose M.; Jaattela, Marja; Ortega, Angel L.			Pterostilbene-Induced Tumor Cytotoxicity: A Lysosomal Membrane Permeabilization-Dependent Mechanism	PLOS ONE			English	Article							INDUCED CELL-DEATH; CANCER-CELLS; B16 MELANOMA; DOWN-REGULATION; CATHEPSIN-D; RESVERATROL; AUTOPHAGY; APOPTOSIS; THERAPY; ARREST	The phenolic phytoalexin resveratrol is well known for its health-promoting and anticancer properties. Its potential benefits are, however, limited due to its low bioavailability. Pterostilbene, a natural dimethoxylated analog of resveratrol, presents higher anticancer activity than resveratrol. The mechanisms by which this polyphenol acts against cancer cells are, however, unclear. Here, we show that pterostilbene effectively inhibits cancer cell growth and stimulates apoptosis and autophagosome accumulation in cancer cells of various origins. However, these mechanisms are not determinant in cell demise. Pterostilbene promotes cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 (HSP70) content, a known stabilizer of lysosomal membranes. A375 melanoma and A549 lung cancer cells with low levels of HSP70 showed high susceptibility to pterostilbene, whereas HT29 colon and MCF7 breast cancer cells with higher levels of HSP70 were more resistant. Inhibition of HSP70 expression increased susceptibility of HT29 colon and MCF7 breast cancer cells to pterostilbene. Our data indicate that lysosomal membrane permeabilization is the main cell death pathway triggered by pterostilbene.	[Mena, Salvador; Estrela, Jose M.; Ortega, Angel L.] Green Mol, Valencia, Spain; [Rodriguez, Maria L.; Estrela, Jose M.; Ortega, Angel L.] Univ Valencia, Dept Physiol, E-46100 Burjassot, Spain; [Ponsoda, Xavier] Univ Valencia, Dept Cell Biol, E-46100 Burjassot, Spain; [Jaattela, Marja] Danish Canc Soc, Inst Canc Biol, Apoptosis Dept, Copenhagen, Denmark; [Jaattela, Marja] Danish Canc Soc, Inst Canc Biol, Ctr Genotox Stress Response, Copenhagen, Denmark		Mena, S (corresponding author), Green Mol, Valencia, Spain.	angel.ortega@uv.es	Estrela, Jose/H-4449-2015; Mena, Salvador/F-6696-2016; Ortega, Angel L./A-4113-2014; Jäättelä, Marja/AAT-7932-2021; Rodriguez, Maria/A-8510-2016; Mena, Salvador/L-8780-2014; Ponsoda, Xavier/L-8272-2014	Estrela, Jose/0000-0002-2540-9190; Ortega, Angel L./0000-0002-9901-3383; Jäättelä, Marja/0000-0001-5950-7111; Mena, Salvador/0000-0002-6423-4741; Ponsoda, Xavier/0000-0002-4051-4458	MICINNSpanish GovernmentEuropean Commission [JC2008-00282, SAF2009-07729, IPT-010000-2010-21]; GV-Conselleria d'Educacio [GVPRE/2008/272]; Danish Cancer SocietyDanish Cancer Society; Danish Medical CouncilDanish Medical Research Council; Danish National Research FoundationDanmarks Grundforskningsfond	This research was supported by grants from the MICINN (JC2008-00282 ALO SAF2009-07729 and IPT- 010000-2010-21 to JME), the GV-Conselleria d'Educacio (GVPRE/2008/272 to ALO), the Danish Cancer Society (to MJ), the Danish Medical Council (to MJ) and the Danish National Research Foundation (to MJ). 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	Booth, L; Roberts, JL; Rais, R; Cutler, RE; Diala, I; Lalani, AS; Hancock, JF; Poklepovic, A; Dent, P				Booth, Laurence; Roberts, Jane L.; Rais, Rumeesa; Cutler, Richard E., Jr.; Diala, Irmina; Lalani, Alshad S.; Hancock, John F.; Poklepovic, Andrew; Dent, Paul			Neratinib augments the lethality of [regorafenib plus sildenafil]	JOURNAL OF CELLULAR PHYSIOLOGY			English	Article						autophagy; DNA damage; HDAC	K-RAS; BETA-CATENIN; INHIBITORS; ENHANCE; COMPLEX	Regorafenib is approved for the treatment of colorectal cancer and hepatocellular carcinoma. In the trial NCT02466802, we have discovered that regorafenib can be safely combined with the phosphodiesterase 5 inhibitor sildenafil in advanced solid tumor patients. The present studies determined whether the approved ERBB1/2/4 and RAS downregulating drug neratinib, could enhance the lethality of [regorafenib+sildenafil]. Neratinib enhanced [regorafenib+sildenafil] lethality in a greater than additive fashion in colon cancer cells. The drug combination reduced the expression of mutant K-RAS and of multiple histone deacetylase (HDAC) proteins that required autophagosome formation. It caused green fluorescent protein or red fluorescent protein-tagged forms of K-RAS V12 to localize into large intracellular vesicles. Compared with [regorafenib+sildenafil], the three-drug combination caused greater and more prolonged activation of the ATM-AMPK-ULK-1 pathway and caused a greater suppression and prolonged inactivation of mammalian target of rapamycin, AKT, and p70 S6K. Approximately 70% of enhanced lethality caused by neratinib required ataxia-telangiectasia-mutated (ATM)-AMP-dependent protein kinase (AMPK) signaling whereas knockdown of Beclin1, ATG5, FADD, and CD95 completely prevented the elevated killing effect. Exposure of cells to [regorafenib+sildenafil] reduced the expression of the checkpoint immunotherapy biomarkers programmed death-ligand 1, ornithine decarboxylase, and indoleamine 2,3-dioxygenase-1 and increased the expression of major histocompatibility complex A (MHCA), which also required autophagosome formation. Knockdown of specific HDAC proteins recapitulated the effects observed using chemical agents. In vivo, using mouse cancer models, neratinib significantly enhanced the antitumor efficacy of [regorafenib+sildenafil]. Our data support performing a new three drug Phase I trial combining regorafenib, sildenafil, and neratinib.	[Booth, Laurence; Roberts, Jane L.; Rais, Rumeesa; Dent, Paul] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Biochem, Richmond, VA USA; [Booth, Laurence; Roberts, Jane L.; Rais, Rumeesa; Dent, Paul] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Mol Biol, Richmond, VA USA; [Poklepovic, Andrew] Virginia Commonwealth Univ, Med, Richmond, VA USA; [Cutler, Richard E., Jr.; Diala, Irmina; Lalani, Alshad S.] Puma Biotechnol Inc, Los Angeles, CA USA; [Cutler, Richard E., Jr.; Diala, Irmina; Lalani, Alshad S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA; [Hancock, John F.] Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA		Dent, P (corresponding author), Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Massey Canc Ctr, POB 980035, Richmond, VA 23298 USA.	paul.dent@vcuhealth.org		Hancock, John/0000-0003-0542-4710	National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01 CA192613]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA192613] Funding Source: NIH RePORTER	National Cancer Institute, Grant/Award Number: R01 CA192613	Booth L, 2018, CANCER BIOL THER, V19, P132, DOI 10.1080/15384047.2017.1394556; Booth L, 2017, ONCOTARGET, V8, P90262, DOI 10.18632/oncotarget.21660; Booth L, 2017, CANCER BIOL THER, V18, P705, DOI 10.1080/15384047.2017.1362511; Booth L, 2017, ONCOTARGET, V8, P1449, DOI 10.18632/oncotarget.13640; Booth L, 2016, ONCOTARGET, V7, P40398, DOI 10.18632/oncotarget.9752; Booth L, 2016, ONCOTARGET, V7, P12975, DOI 10.18632/oncotarget.7349; Booth L, 2014, MOL PHARMACOL, V85, P408, DOI 10.1124/mol.113.090043; Carr BI, 2013, J CELL PHYSIOL, V228, P1344, DOI 10.1002/jcp.24291; Cho KJ, 2016, MOL CELL BIOL, V36, P3086, DOI 10.1128/MCB.00365-16; CROSS DAE, 1995, NATURE, V378, P785, DOI 10.1038/378785a0; DENT P, 1990, NATURE, V348, P302, DOI 10.1038/348302a0; Echavarria I, 2017, EXPERT REV ANTICANC, V17, P669, DOI 10.1080/14737140.2017.1338954; Fiedler M, 2011, P NATL ACAD SCI USA, V108, P1937, DOI 10.1073/pnas.1017063108; Gottardi CJ, 2008, STRUCTURE, V16, P336, DOI 10.1016/j.str.2008.02.005; Kimelman D, 2006, ONCOGENE, V25, P7482, DOI 10.1038/sj.onc.1210055; Liu J, 2006, J MOL BIOL, V360, P133, DOI 10.1016/j.jmb.2006.04.064; MacDonald BT, 2009, DEV CELL, V17, P9, DOI 10.1016/j.devcel.2009.06.016; Markowitz SD, 2009, NEW ENGL J MED, V361, P2449, DOI 10.1056/NEJMra0804588; Qi XM, 2014, ONCOTARGET, V5, P4269, DOI 10.18632/oncotarget.2001; Skarderud MR, 2018, CANCER TREAT REV, V62, P61, DOI 10.1016/j.ctrv.2017.10.011; Tavallai M, 2015, J CELL PHYSIOL, V230, P2281, DOI 10.1002/jcp.24961; Zhang QJ, 2009, J PHYSIOL-LONDON, V587, P3911, DOI 10.1113/jphysiol.2009.172916	22	24	24	1	19	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0021-9541	1097-4652		J CELL PHYSIOL	J. Cell. Physiol.	APR	2019	234	4					4874	4887		10.1002/jcp.27276			14	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	HK0TE	WOS:000457613700143	30203445	Green Accepted			2022-04-25	
J	Janji, B; Hasmim, M; Parpal, S; Berchem, G; Noman, MZ				Janji, Bassam; Hasmim, Meriem; Parpal, Santiago; Berchem, Guy; Noman, Muhammad Zaeem			Firing up the cold tumors by targeting Vps34	ONCOIMMUNOLOGY			English	Article						Autophagy; VPS34; cold; hot tumors; proinflammatory cytokines; CCL5; CXCL10; immune landscape; NK cells; T CD8 lymphocytes; cancer immunotherapy; anti-PD-1; PD-L1; melanoma; colon cancer	AUTOPHAGY; GROWTH	Cancer immunotherapy based on anti-PD-1/PD-L1 blockade is particularly effective in responding to patients with hot tumors. These tumors are characterized by the accumulation of proinflammatory cytokines and T cell infiltration. In our recent report published inScience Advances, we demonstrate that targeting the autophagy-related protein Vps34 switched cold immune desert tumors into hot inflamed immune-infiltrated tumors and enhanced the efficacy of anti-PD-1/PD-L1. Our study provides the preclinical rationale to set up combination immunotherapy clinical trials using selective Vps34 inhibitors and immune checkpoint blockers in melanoma and CRC.	[Janji, Bassam; Hasmim, Meriem; Noman, Muhammad Zaeem] Luxembourg Inst Hlth LIH, Dept Oncol, Tumor Immunotherapy & Microenvironm TIME Grp, Luxembourg, Luxembourg; [Parpal, Santiago] Sprint Biosci, Stockholm, Sweden; [Parpal, Santiago] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden; [Berchem, Guy] Ctr Hosp Luxembourg, Dept Hematooncol, Luxembourg, Luxembourg		Janji, B (corresponding author), Luxembourg Inst Hlth, Tumor Immunotherapy & Microenvironm TIME Grp, Dept Oncol, L-1526 Luxembourg, Luxembourg.	bassam.janji@lih.lu; muhammadzaeem.noman@lih.lu	Berchem, Guy/C-9364-2014; NOMAN, Muhammmad Zaeem/AAJ-1466-2021; NOMAN, Muhammmad Zaeem/AAJ-1465-2021	Berchem, Guy/0000-0003-0157-2257; NOMAN, Muhammmad Zaeem/0000-0002-1837-3097; NOMAN, Muhammmad Zaeem/0000-0002-1837-3097; JANJI, Bassam/0000-0002-9763-0943	Luxembourg National Research FundLuxembourg National Research Fund [C18/BM/12670304/COMBATIC]; Action LIONS Vaincre le Cancer Luxembourg; Fondation Cancer Luxembourg [FC/2018/06]; Kriibskrank Kanner Foundation [2016-08-15]; Janssen Cilag Pharma; Roche pharma	This work was supported by grants from Luxembourg National Research Fund C18/BM/12670304/COMBATIC; Roche pharma and Action LIONS Vaincre le Cancer Luxembourg; Fondation Cancer Luxembourg (FC/2018/06); Kriibskrank Kanner Foundation (2016-08-15); Janssen Cilag Pharma.	Baginska J, 2013, P NATL ACAD SCI USA, V110, P17450, DOI 10.1073/pnas.1304790110; Harlin H, 2009, CANCER RES, V69, P3077, DOI 10.1158/0008-5472.CAN-08-2281; Marsh T, 2015, NAT CELL BIOL, V17, P1, DOI 10.1038/ncb3089; Mgrditchian T, 2017, P NATL ACAD SCI USA, V114, pE9271, DOI 10.1073/pnas.1703921114; Noman MZ, 2020, SCI ADV, V6, DOI 10.1126/sciadv.aax7881; Noman MZ, 2011, CANCER RES, V71, P5976, DOI 10.1158/0008-5472.CAN-11-1094; Poillet-Perez L, 2018, NATURE, V563, P569, DOI 10.1038/s41586-018-0697-7; Smyth MJ, 2016, NAT REV CLIN ONCOL, V13, P143, DOI 10.1038/nrclinonc.2015.209; Tumeh PC, 2014, NATURE, V515, P568, DOI 10.1038/nature13954; Yang AN, 2018, CANCER DISCOV, V8, P276, DOI 10.1158/2159-8290.CD-17-0952	10	8	8	0	1	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	2162-402X			ONCOIMMUNOLOGY	OncoImmunology		2020	9	1							1809936	10.1080/2162402X.2020.1809936			2	Oncology; Immunology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Immunology	NL0ZW	WOS:000567155100001	32939326	Green Published, gold			2022-04-25	
J	Schmukler, E; Grinboim, E; Schokoroy, S; Amir, A; Wolfson, E; Kloog, Y; Pinkas-Kramarski, R				Schmukler, Eran; Grinboim, Efrat; Schokoroy, Sari; Amir, Adva; Wolfson, Eya; Kloog, Yoel; Pinkas-Kramarski, Ronit			Ras inhibition enhances autophagy, which partially protects cells from death	ONCOTARGET			English	Article						autophagy; Ras; transformation; signal transduction	COLON-CANCER CELLS; TUMOR-GROWTH; FARNESYLTHIOSALICYLIC ACID; UNANSWERED QUESTIONS; ONCOGENIC RAS; IN-VITRO; DEGRADATION; ANTAGONIST; PATHWAY; ACTIVATION	Autophagy, a process of regulated turnover of cellular constituents, is essential for normal growth control but may be defective under pathological conditions. The Ras/PI3K/mTOR signaling pathway negatively regulates autophagy. Ras signaling has been documented in a large number of human cancers. In this in-vitro study we examined the effect of the Ras inhibitor Salirasib (S-trans, trans-farnesylthiosalicylic acid; FTS) on autophagy induction and cell viability. We show that Ras inhibition by FTS induced autophagy in several cell lines, including mouse embryonic fibroblasts and the human cancer cell lines HeLa, HCT-116 and DLD-1. The autophagy induced by FTS seems to inhibit the cell death induced by FTS, since in the absence of autophagy the death of FTS-treated cells was enhanced. Therefore, inhibition of autophagy may promote the inhibition of tumor cell growth and the cell death mediated by FTS.	[Schmukler, Eran; Grinboim, Efrat; Schokoroy, Sari; Amir, Adva; Wolfson, Eya; Kloog, Yoel; Pinkas-Kramarski, Ronit] Tel Aviv Univ, Dept Neurobiol, Ramat Aviv, Israel		Pinkas-Kramarski, R (corresponding author), Tel Aviv Univ, Dept Neurobiol, Ramat Aviv, Israel.	lironit@post.tau.ac.il		Pinkas-Kramarski, Ronit/0000-0002-1000-369X	Israel Science FoundationIsrael Science Foundation [848/12]; Kauffman Prostate Cancer Research Fund	This work was supported by the Israel Science Foundation (Grant no. 848/12) and by the Kauffman Prostate Cancer Research Fund.	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J	de la Cruz-Morcillo, MA; Valero, MLL; Callejas-Valera, JL; Arias-Gonzalez, L; Melgar-Rojas, P; Galan-Moya, EM; Garcia-Gil, E; Garcia-Cano, J; Sanchez-Prieto, R				de la Cruz-Morcillo, M. A.; Valero, M. L. L.; Callejas-Valera, J. L.; Arias-Gonzalez, L.; Melgar-Rojas, P.; Galan-Moya, E. M.; Garcia-Gil, E.; Garcia-Cano, J.; Sanchez-Prieto, R.			P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance	ONCOGENE			English	Article						5-fluorouracil; p38MAPK; autophagy; resistance; p53; apoptosis	ACTIVATED PROTEIN-KINASE; P38 MAP KINASE; COLORECTAL-CANCER CELLS; CISPLATIN-BASED THERAPY; DNA-DAMAGE; GENE-EXPRESSION; COLON-CANCER; CHEMOTHERAPEUTIC-AGENTS; P53-DEPENDENT APOPTOSIS; THYMIDYLATE SYNTHASE	5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPK alpha by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy. Oncogene (2012) 31, 1073-1085; doi:10.1038/onc.2011.321; published online 15 August 2011	[de la Cruz-Morcillo, M. A.; Valero, M. L. L.; Callejas-Valera, J. L.; Arias-Gonzalez, L.; Melgar-Rojas, P.; Galan-Moya, E. M.; Garcia-Gil, E.; Garcia-Cano, J.; Sanchez-Prieto, R.] UCLM, Oncol Mol Lab, CRIB, PCYTA, Albacete 02006, Spain		Sanchez-Prieto, R (corresponding author), UCLM, Oncol Mol Lab, CRIB, PCYTA, C Almansa 14, Albacete 02006, Spain.	ricardo.sanchez@uclm.es	Romo, José A./J-3024-2012; Sanchez-Prieto, Ricardo/AAY-4271-2021; Prieto, Ricardo/AAZ-7221-2021; Sanchez-Prieto, Ricardo/B-6877-2008; Arias-González, Laura/D-9517-2016; García-Cano, Jesús/AAA-9257-2020; Galan-Moya, Eva M/I-2912-2015	Romo, José A./0000-0003-2907-580X; Sanchez-Prieto, Ricardo/0000-0003-0882-9780; Sanchez-Prieto, Ricardo/0000-0003-0882-9780; Arias-González, Laura/0000-0003-2132-9350; García-Cano, Jesús/0000-0002-8312-2622; Galan-Moya, Eva M/0000-0001-5758-7592; Garcia Gil, Elena/0000-0002-8952-0306; de la Cruz-Morcillo, Miguel Angel/0000-0002-6674-1333	Fundacion Leticia Castillejo Castillo; Ministerio de Ciencia e InnovacionInstituto de Salud Carlos IIISpanish GovernmentEuropean Commission [SAF2009-07329]; European CommunityEuropean Commission	This work was supported by grants from Fundacion Leticia Castillejo Castillo and Ministerio de Ciencia e Innovacion (SAF2009-07329) to RSP. RSP Research Institute, and the work carried out in his laboratory, received support from the European Community through the regional development funding program (FEDER). We appreciate the comments and suggestions of Drs G Almazan, E de la Casa-Esperon, S Gutkind, D Arango, A Cuenda, A Vazquez, I Sanchez and D Garcia-Olmo.	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Oncology; Cell Biology; Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity	901EW	WOS:000300945900001	21841826	Bronze			2022-04-25	
J	Qiao, XR; Wang, C; Wang, WD; Shang, Y; Li, Y; Ni, J; Chen, SZ				Qiao, Xinran; Wang, Chen; Wang, Wendie; Shang, Yue; Li, Yi; Ni, Jun; Chen, Shu-zhen			Levamisole enhances DR4-independent apoptosis induced by TRAIL through inhibiting the activation of JNK in lung cancer	LIFE SCIENCES			English	Article						Levamisole; TRAIL; Cell cycle arrest; DR4; LC3B; Erk; cJUN	COLORECTAL-CANCER; COLON-CANCER; PHASE-III; STAGE-II; EXPRESSION; CELLS; AUTOPHAGY; PATHWAY	The headings aims: Levamisole has anti-parasite and antitumor activities, but the anti-lung cancer mechanism has not been studied. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a promising drug because of the ability to selectively target cancer cells. However, the tolerance of cancer cells to TRAIL limits its antitumor activity. Other drugs combined with TRAIL need to be explored to enhance its antitumor activity. Based on the adjuvant anticancer effect of levamisole on anticancer drugs activity, the antitumor activity of levamisole combined with TRAIL will be investigated. Materials and methods: In vitro and in vivo experiments were employed to investigate the anti-tumor activity. Flow-cytometry analysis, western blotting and siRNA transfection were used to explore the molecular mechanism. Key findings: Levamisole decreased the proliferation of lung cancer cells in vitro and in vivo and induced cell cycle arrest in G0/G1 phase. Besides, levamisole also enhanced TRAIL-induced DR4-independent apoptosis by inhibiting the phosphorylation of cJUN. A new cellular protective pathway LC3B-DR4/Erk was also disclosed, in which levamisole only increased the expression of LC3B and then activated the phosphorylation of Erk and increased the expression of DR4, while p-Erk and DR4 inter-regulated. Significance: Levamisole may be used as an adjuvant of TRAIL in treating lung cancer. The discovery of LC3BDR4/Erk as a new protective pathway provides a new direction for sensitizing lung cancer cells to TRAIL.	[Qiao, Xinran; Wang, Chen; Wang, Wendie; Shang, Yue; Li, Yi; Ni, Jun; Chen, Shu-zhen] Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotehnol, Beijing, Peoples R China		Chen, SZ (corresponding author), 1 Tiantan Xili, Beijing 100050, Peoples R China.	bjcsz@imb.pumc.edu.cn		Chen, Shu-zhen/0000-0003-4881-0558	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81621064, 81702934]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2016-I2M-02-002, 2019-I2M-1-003]; "Significant New Drug Development" Major Science and Technology Development Projects of China [2018ZX09711001-007-002]	The manuscript was supported by grants from the National Natural Science Foundation of China (81621064, 81702934), CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-02-002, 2019-I2M-1-003), and "Significant New Drug Development" Major Science and Technology Development Projects of China (no. 2018ZX09711001-007-002).	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SEP 15	2020	257								118034	10.1016/j.lfs.2020.118034			11	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	NN3TU	WOS:000568714500014	32621923				2022-04-25	
J	Tsai, DH; Chung, CH; Lee, KT				Tsai, Dai-Hua; Chung, Cheng-Han; Lee, Kung-Ta			Antrodia cinnamomea induces autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway in colorectal cancer cells	SCIENTIFIC REPORTS			English	Article							ENDOPLASMIC-RETICULUM STRESS; ER STRESS; CAMPHORATA MYCELIA; INDUCED APOPTOSIS; FRUITING BODIES; EXPRESSION; CHOP; GENE; INHIBITION; INDUCTION	Antrodia cinnamomea, a well-known traditional medicine used in Taiwan, is a potent anticancer drug for colorectal cancer, but the upstream molecular mechanism of its anticancer effects remains unclear. In this study, A. cinnamomea extracts showed cytotoxicity in HCT116, HT29, SW480, Caco-2 and, Colo205 colorectal cancer cells. Whole-genome expression profiling of A. cinnamomea extracts in HCT116 cells was performed. A. cinnamomea extracts upregulated the expression of the endoplasmic reticulum stress marker CHOP and its downstream gene TRB3. Moreover, dephosphorylation of Akt and mTOR as well as autophagic cell death were observed. Gene expression and autophagic cell death were reversed by the knockdown of CHOP and TRB3. Autophagy inhibition but not apoptosis inhibition reversed A. cinnamomea-induced cell death. Finally, we demonstrated that A. cinnamomea extracts significantly suppressed HCT116 tumour growth in nude mice. Our findings suggest that autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway may represent a new mechanism of anti-colorectal cancer action by A. cinnamomea. A. cinnamomea is a new CHOP activator and potential drug that can be used in colorectal cancer treatment.	[Tsai, Dai-Hua; Lee, Kung-Ta] Natl Taiwan Univ, Dept Biochem Sci & Technol, Taipei 10617, Taiwan; [Chung, Cheng-Han] Yong Teng Biotechnol Co Ltd, New Taipei 22180, Taiwan		Lee, KT (corresponding author), Natl Taiwan Univ, Dept Biochem Sci & Technol, Taipei 10617, Taiwan.	ktlee@ntu.edu.tw					Garcia MA, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0023887; Averous J, 2004, J BIOL CHEM, V279, P5288, DOI 10.1074/jbc.M311862200; B'chir W, 2013, NUCLEIC ACIDS RES, V41, P7683, DOI 10.1093/nar/gkt563; Chan YY, 2010, J ETHNOPHARMACOL, V127, P652, DOI 10.1016/j.jep.2009.12.008; Chang CW, 2013, EVID-BASED COMPL ALT, V2013, DOI 10.1155/2013/946451; Chen LY, 2011, J AGR FOOD CHEM, V59, P11255, DOI 10.1021/jf2024215; Dabkeviciene D, 2015, MED ONCOL, V32, DOI 10.1007/s12032-015-0703-y; Demain AL, 2011, MICROB BIOTECHNOL, V4, P687, DOI 10.1111/j.1751-7915.2010.00221.x; Esche C, 2005, J INVEST DERMATOL, V125, P615, DOI 10.1111/j.0022-202X.2005.23841.x; Ferlay J, 2015, INT J CANCER, V136, pE359, DOI 10.1002/ijc.29210; Fribley A, 2009, METHODS MOL BIOL, V559, P191, DOI 10.1007/978-1-60327-017-5_14; Geethangili M, 2011, EVID-BASED COMPL ALT, V2011, P1, DOI 10.1093/ecam/nep108; GUJULUVA CN, 1994, ONCOGENE, V9, P1819; Ha H, 2017, THERANOSTICS, V7, P1543, DOI 10.7150/thno.15625; Hansen TE, 2011, BMC BIOL, V9, DOI 10.1186/1741-7007-9-39; Hseu YC, 2007, FOOD CHEM TOXICOL, V45, P1107, DOI 10.1016/j.fct.2006.12.012; Hsiao G, 2003, J AGR FOOD CHEM, V51, P3302, DOI 10.1021/jf021159t; Hsin IL, 2012, TOXICOL APPL PHARM, V263, P330, DOI 10.1016/j.taap.2012.07.005; Hsu YL, 2007, FOOD CHEM TOXICOL, V45, P1249, DOI 10.1016/j.fct.2007.01.005; Huang GJ, 2010, J AGR FOOD CHEM, V58, P7445, DOI 10.1021/jf1013764; Huang L., 2013, OA ALTERNAT MED, V1, P7; Itatani Y, 2016, INT J MOL SCI, V17, DOI 10.3390/ijms17050643; Itoh Y, 2005, CYTOKINE, V29, P275, DOI 10.1016/j.cyto.2004.11.005; Jiang W, 2008, BMC SYST BIOL, V2, DOI 10.1186/1752-0509-2-72; Jing GJ, 2012, EXP DIABETES RES, DOI 10.1155/2012/589589; Kuo MC, 2008, J ETHNOPHARMACOL, V120, P196, DOI 10.1016/j.jep.2008.08.011; Lai Chiao-I, 2016, J Tradit Complement Med, V6, P48, DOI 10.1016/j.jtcme.2014.11.026; Langmead B, 2012, NAT METHODS, V9, P357, DOI [10.1038/NMETH.1923, 10.1038/nmeth.1923]; Li B, 2011, BMC BIOINFORMATICS, V12, DOI 10.1186/1471-2105-12-323; Li CC, 2012, BIOMEDICINE-TAIWAN, V2, P10, DOI 10.1016/j.biomed.2012.02.002; Li YM, 2014, ACTA BIOCH BIOPH SIN, V46, P629, DOI 10.1093/abbs/gmu048; LIEN HM, 2011, EVID-BASED COMPL ALT, DOI DOI 10.1093/ECAM/NEP230; Lin HC, 2017, J AGR FOOD CHEM, V65, P51, DOI 10.1021/acs.jafc.6b04101; Lu MC, 2009, ARCH TOXICOL, V83, P121, DOI 10.1007/s00204-008-0337-3; Mann J, 2002, NAT REV CANCER, V2, P143, DOI 10.1038/nrc723; Marciniak SJ, 2004, GENE DEV, V18, P3066, DOI 10.1101/gad.1250704; Mitra S., 2018, EVID-BASED COMPL ALT, V2018; Ohoka N, 2005, EMBO J, V24, P1243, DOI 10.1038/sj.emboj.7600596; Pan-Hammarstrom Q, 2006, J INTERF CYTOK RES, V26, P628, DOI 10.1089/jir.2006.26.628; Park DK, 2013, J MED FOOD, V16, P681, DOI 10.1089/jmf.2012.2605; Rashid HO, 2015, AUTOPHAGY, V11, P1956, DOI 10.1080/15548627.2015.1091141; Robinson MD, 2010, BIOINFORMATICS, V26, P139, DOI 10.1093/bioinformatics/btp616; RON D, 1992, GENE DEV, V6, P439, DOI 10.1101/gad.6.3.439; Salazar M, 2009, J CLIN INVEST, V119, P1359, DOI 10.1172/JCI37948; Sarvaiya PJ, 2013, ONCOTARGET, V4, P2171, DOI 10.18632/oncotarget.1426; Sheu F, 2009, J AGR FOOD CHEM, V57, P4130, DOI 10.1021/jf900469a; Song TY, 2003, J AGR FOOD CHEM, V51, P1571, DOI 10.1021/jf0209701; Sturm A, 2005, CYTOKINE, V29, P42, DOI 10.1016/j.cyto.2004.09.007; Su Yu-Cheng, 2012, J Tradit Complement Med, V2, P312; Torre LA, 2016, CANCER EPIDEM BIOMAR, V25, P16, DOI 10.1158/1055-9965.EPI-15-0578; Tsai Z. T., 1985, USE EFFECT GANODERMA, V116; Tu SH, 2012, J AGR FOOD CHEM, V60, P3612, DOI 10.1021/jf300221g; Verfaillie T., 2010, INT J CELL BIOL, V2010, DOI [10.1155/2010/93050920145727, DOI 10.1155/2010/930509]; Wang DZ, 2009, CURR OPIN PHARMACOL, V9, P688, DOI 10.1016/j.coph.2009.08.003; Wen ZN, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0018278; Wu H, 2006, PROTEOMICS, V6, P826, DOI 10.1002/pmic.200401341; Xiao YC, 2015, CANCER LETT, V361, P22, DOI 10.1016/j.canlet.2015.02.021; Yamaguchi H, 2004, J BIOL CHEM, V279, P45495, DOI 10.1074/jbc.M406933200; Yan WH, 2014, CELL PHYSIOL BIOCHEM, V33, P823, DOI 10.1159/000358655; Yu CC, 2012, J NUTR BIOCHEM, V23, P900, DOI 10.1016/j.jnutbio.2011.04.015; Zinszner H, 1998, GENE DEV, V12, P982, DOI 10.1101/gad.12.7.982; Zou CG, 2009, ENDOCRINOLOGY, V150, P277, DOI 10.1210/en.2008-0794	62	16	18	4	13	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	2045-2322			SCI REP-UK	Sci Rep	NOV 27	2018	8								17424	10.1038/s41598-018-35780-y			12	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	HB8DO	WOS:000451315600011	30479369	gold, Green Published			2022-04-25	
J	Shen, B; Tan, MY; Mu, XY; Qin, Y; Zhang, F; Liu, Y; Fan, Y				Shen, Bing; Tan, Mingyue; Mu, Xinyu; Qin, Yan; Zhang, Fang; Liu, Yong; Fan, Yu			Upregulated SMYD3 promotes bladder cancer progression by targeting BCLAF1 and activating autophagy	TUMOR BIOLOGY			English	Article						SMYD3; BCLAF1; Autophagy; Bladder cancer; Histone methyltransferases	HEPATOCELLULAR-CARCINOMA; TUMOR-SUPPRESSOR; PROSTATE-CANCER; GASTRIC-CANCER; COLON-CANCER; HISTONE; OVEREXPRESSION; PROLIFERATION; METASTASIS; SURVIVAL	The recent discovery of a large number of histone methyltransferases reveals important roles of these enzymes in regulating tumor development and progression. SMYD3, a histone methyltransferase, is associated with poor prognosis of patients with prostate and gastric cancer. In the study, we attempted to investigate its putative oncogenic role on bladder cancer. Here, we report that SMYD3 frequently amplified in bladder cancer is correlated with bladder cancer progression and poor prognosis. Overexpression of SMYD3 promotes bladder cancer cell proliferation and invasion, whereas SMYD3 knockdown inhibits cancer cell growth and invasion. Mechanically, SMYD3 positively regulates the expression of BCL2-associated transcription factor 1 (BCLAF1). SMYD3 physically interacts with the promoter of BCLAF1 and upregulates its expression by accumulating di- and trimethylation of H3K4 at the BCLAF1 locus. We further show that SMYD3 overexpression in bladder cancer cells promotes autophagy activation, whereas BCLAF1 depletion inhibits SMYD3-induced autophagy. Finally, we demonstrate that SMYD3 promotes bladder cancer progression, at least in part by increasing BCLAF1 expression and activating autophagy. Our results establish a function for SMYD3 in autophagy activation and bladder cancer progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of bladder cancer.	[Shen, Bing; Tan, Mingyue; Mu, Xinyu; Qin, Yan; Zhang, Fang; Liu, Yong; Fan, Yu] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Dept Renal Transplantat & Urol, 100 Haining Rd, Shanghai 200080, Peoples R China		Fan, Y (corresponding author), Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Dept Renal Transplantat & Urol, 100 Haining Rd, Shanghai 200080, Peoples R China.	fanyu1965@163.com			National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81402086]	This work was funded by National Science Foundation of China (Grant No. 81402086).	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JUN	2016	37	6					7371	7381		10.1007/s13277-015-4410-2			11	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	DM6LT	WOS:000376464700035	26676636				2022-04-25	
J	Ortiz, LMG; Tillhon, M; Parks, M; Dutto, I; Prosperi, E; Savio, M; Arcamone, AG; Buzzetti, F; Lombardi, P; Scovassi, AI				Guaman Ortiz, Luis Miguel; Tillhon, Micol; Parks, Michael; Dutto, Ilaria; Prosperi, Ennio; Savio, Monica; Arcamone, Andrea G.; Buzzetti, Franco; Lombardi, Paolo; Scovassi, Anna Ivana			Multiple Effects of Berberine Derivatives on Colon Cancer Cells	BIOMED RESEARCH INTERNATIONAL			English	Article							NATURAL ALKALOID BERBERINE; LUNG-CANCER; IN-VITRO; APOPTOSIS; MITOCHONDRIAL; DEATH; BINDING; GROWTH; P53; PERSPECTIVES	The pharmacological use of the plant alkaloid berberine is based on its antibacterial and anti-inflammatory properties; recently, anticancer activity has been attributed to this compound. To exploit this interesting feature, we synthesized three berberine derivatives, namely, NAX012, NAX014, and NAX018, and we tested their effects on two human colon carcinoma cell lines, that is, HCT116 and SW613-B3, which are characterized by wt and mutated p53, respectively. We observed that cell proliferation is more affected by cell treatment with the derivatives than with the lead compound; moreover, the derivatives proved to induce cell cycle arrest and cell death through apoptosis, thus suggesting that they could be promising anticancer drugs. Finally, we detected typical signs of autophagy in cells treated with berberine derivatives.	[Guaman Ortiz, Luis Miguel; Tillhon, Micol; Parks, Michael; Dutto, Ilaria; Prosperi, Ennio; Scovassi, Anna Ivana] CNR, Ist Genet Mol, I-27100 Pavia, Italy; [Guaman Ortiz, Luis Miguel] Univ Tecn Particular Loja, Dept Ciencias Salud, Loja 1101608, Ecuador; [Savio, Monica] Univ Pavia, Dept Mol Med, Immunol & Gen Pathol Unit, I-27100 Pavia, Italy; [Arcamone, Andrea G.; Buzzetti, Franco; Lombardi, Paolo] Naxospharma Srl, I-20026 Novate Milanese, Italy		Scovassi, AI (corresponding author), CNR, Ist Genet Mol, I-27100 Pavia, Italy.	scovassi@igm.cnr.it	Prosperi, Ennio/A-3439-2014; Ortiz, Luis Miguel Guaman/X-9496-2019; dutto, Ilaria/AAX-9097-2020; Tillhon, Micol/AAQ-6994-2020	Prosperi, Ennio/0000-0001-5391-5157; Ortiz, Luis Miguel Guaman/0000-0003-2919-4905; Scovassi, Anna Ivana/0000-0003-3484-9881; Dutto, Ilaria/0000-0002-6987-6647; Parks, Michael/0000-0001-8240-0603; Lombardi, Paolo/0000-0002-7971-7404	Regione Lombardia, ItalyRegione Lombardia [13810040]; SENESCYT (Quito, Ecuador); Universidad Tecnica Particular de Loja (Loja, Ecuador); Italian AIRCFondazione AIRC per la ricerca sul cancro	The research was partly supported by Regione Lombardia, Italy (Project Plant Cell, Grant no. 13810040 to Anna Ivana Scovassi and Naxospharma). Luis Miguel Guaman Ortiz is a Ph.D. student (Dottorato in Genetica, Biologia Cellulare e Molecolare, University of Pavia, Italy) supported by SENESCYT (Quito, Ecuador) and Universidad Tecnica Particular de Loja (Loja, Ecuador); Micol Tillhon is a Postdoc supported by Italian AIRC; Ilaria Dutto is a Ph.D. student from IUSS, Pavia, Italy. Thanks are due to Dr. Francesca Aredia for the experiments with 3MA. The authors kindly acknowledge the reviewers for stimulating to improve the paper.	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Int.		2014	2014								924585	10.1155/2014/924585			12	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	AK0JP	WOS:000338099100001	25045712	Green Published, gold, Green Submitted			2022-04-25	
J	Li, MX; Luo, T; Huang, Y; Su, JY; Li, D; Chen, XH; Zhang, YF; Huang, LH; Li, SX; Jiao, CW; Li, WZ; Xie, YZ; Li, WD				Li, Muxia; Luo, Ting; Huang, Yong; Su, Jiyan; Li, Dan; Chen, Xiaohong; Zhang, Yifan; Huang, Longhua; Li, Shunxian; Jiao, Chunwei; Li, Wenzhi; Xie, Yizhen; Li, Wende			Polysaccharide from Pycnoporus sanguineus ameliorates dextran sulfate sodium-induced colitis via helper T cells repertoire modulation and autophagy suppression	PHYTOTHERAPY RESEARCH			English	Article						autophagy; epithelium barrier; helper T cells; inflammatory bowel disease; Pycnoporus sanguineus	INFLAMMATORY-BOWEL-DISEASE; CANCER; PROLIFERATION; SULFASALAZINE; INHIBITION; PREVALENCE; MUSHROOM; COLON; MICE	Inflammatory bowel disease (IBD) is a chronic autoimmune disease associated with various risk factors. Pycnoporus sanguineus (L.) Murrill is a saprotrophic fungus used worldwide for its industrial and medical purposes. Here, polysaccharide from P. sanguineus (PPS) was explored for its antiinflammatory potential in a murine colitis model of IBD induced by dextran sulfate sodium (DSS). PPS ameliorated the colitis as manifested by the lowered disease activity index (DAI), prolonged colon, and reduced serum lipopolysaccharide (LPS). PPS recovered the histological lesion by upregulating the expressions of Zonula occludens-1 (ZO-1), E-cadherin, and proliferating cell nuclear antigen (PCNA). PPS inhibited the helper T cells (Th)-mediated immune response by decreasing the proportions of Th cells (including Th2 cells, Th17 cells, and regulatory T cells), which was accompanied with reductions on myeloperoxidase (MPO) activity and releases of several interleukins and chemokines within the colon. Moreover, PPS exhibited an evident inhibition on autophagy, in which the ratio of light chain 3 (LC3) II/I was declined, while the expression of p62 and Beclin-1 was increased. The present study highlighted important clinical implications for the treatment application of PPS against IBD, which relies on the regulation of Th cells repertoire and autophagy suppression to restore epithelium barrier.	[Li, Muxia; Li, Dan; Chen, Xiaohong] Guangzhou Univ Chinese Med, Math Engn Acad Chinese Med, Guangdong Prov Key Lab New Drug Dev & Res Chinese, Guangzhou, Guangdong, Peoples R China; [Li, Muxia; Su, Jiyan; Li, Dan; Chen, Xiaohong; Zhang, Yifan; Huang, Longhua; Xie, Yizhen] Guangdong Acad Sci, Guangdong Inst Microbiol, Guangdong Prov Key Lab Microbial Culture Collect, State Key Lab Appl Microbiol Southern China,Guang, Guangzhou, Guangdong, Peoples R China; [Luo, Ting] Jinan Univ, Guangzhou, Guangdong, Peoples R China; [Luo, Ting; Li, Wende] Guangdong Prov Key Lab Lab Anim, Guangdong Lab Anim Monitoring Inst, 11 Fengxin Rd, Guangzhou 510663, Guangdong, Peoples R China; [Huang, Yong] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Gastrointestinal Surg, Guangzhou, Guangdong, Peoples R China; [Li, Dan; Chen, Xiaohong; Li, Shunxian; Jiao, Chunwei; Xie, Yizhen] Guangdong Yuewei Edible Fungi Technol Co Ltd, Guangzhou, Guangdong, Peoples R China; [Li, Wenzhi] Infinitus China Co Ltd, Guangzhou, Guangdong, Peoples R China		Li, WD (corresponding author), Guangdong Prov Key Lab Lab Anim, Guangdong Lab Anim Monitoring Inst, 11 Fengxin Rd, Guangzhou 510663, Guangdong, Peoples R China.; Xie, YZ (corresponding author), Guangdong Inst Microbiol, Guangdong Prov Key Lab Microbial Culture Collect, State Key Lab Appl Microbiol Southern China, 100 Xianlie Zhong Rd, Guangzhou 510070, Guangdong, Peoples R China.	xyzgdim@sina.com; lwd@gdlami.com			GDAS' Special Project of Science and Technology Development [2019GDASYL-0105002]; Guangdong Province Innovation Team Construction Program on Modern Agriculture Industrial technology system [2019KJ103]; Guangdong Province Science and Technology Innovation Strategy Special Fund [2018B020205001]; Guangzhou Science and Technology Plan Project [201604016051]; High-level Leading Talent Introduction Program of GDAS [2016GDASRC-0102]; Natural Science Foundation of Guangdong ProvinceNational Natural Science Foundation of Guangdong Province [2018A0303130102, 2018A030313887]; Pearl River S&T Nova Program of Guangzhou [201806010078]; Provincial-level Major Scientific Research Projects in Regular Universities of Guangdong Province [2017KZDXM017]; Science and Technology Planning Project of Guangdong Province [2017B030314171, 2018B030317001]; Science and Technology Planning Project of Guangzhou [201707020022]; Nanyue Microbial Talents Cultivation Fund of Guangdong Institute of Microbiology [GDIMYET20150203]	GDAS' Special Project of Science and Technology Development, Grant/Award Number: 2019GDASYL-0105002; Guangdong Province Innovation Team Construction Program on Modern Agriculture Industrial technology system, Grant/Award Number: 2019KJ103; Guangdong Province Science and Technology Innovation Strategy Special Fund, Grant/Award Number: 2018B020205001; Guangzhou Science and Technology Plan Project, Grant/Award Number: 201604016051; High-level Leading Talent Introduction Program of GDAS, Grant/Award Number: 2016GDASRC-0102; Natural Science Foundation of Guangdong Province, Grant/Award Numbers: 2018A0303130102, 2018A030313887; Pearl River S&T Nova Program of Guangzhou, Grant/Award Number: 201806010078; Provincial-level Major Scientific Research Projects in Regular Universities of Guangdong Province, Grant/Award Number: 2017KZDXM017; Science and Technology Planning Project of Guangdong Province, Grant/Award Numbers: 2017B030314171, 2018B030317001; Science and Technology Planning Project of Guangzhou, Grant/Award Number: 201707020022; the Nanyue Microbial Talents Cultivation Fund of Guangdong Institute of Microbiology, Grant/Award Number: GDIMYET20150203	Baumgart DC, 2007, LANCET, V369, P1641, DOI 10.1016/S0140-6736(07)60751-X; Baumgart DC, 2012, LANCET, V380, P1590, DOI 10.1016/S0140-6736(12)60026-9; Boukes GJ, 2017, S AFR J BOT, V113, P62, DOI 10.1016/j.sajb.2017.07.010; Brest P, 2010, CURR MOL MED, V10, P486, DOI 10.2174/156652410791608252; Brown GD, 2005, CELL MICROBIOL, V7, P471, DOI 10.1111/j.1462-5822.2005.00505.x; Brown GD, 2003, IMMUNITY, V19, P311, DOI 10.1016/S1074-7613(03)00233-4; Butera A, 2018, FRONT IMMUNOL, V9, DOI 10.3389/fimmu.2018.02511; Cabrera S, 2013, AUTOPHAGY, V9, P1188, DOI 10.4161/auto.24797; COLLIER HOJ, 1976, PROSTAGLANDINS, V11, P219, DOI 10.1016/0090-6980(76)90145-3; Correa E, 2006, PHYTOTHER RES, V20, P497, DOI 10.1002/ptr.1890; 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Szanto A, 2008, IMMUNOBIOLOGY, V213, P789, DOI 10.1016/j.imbio.2008.07.015; Ueno A, 2018, J AUTOIMMUN, V87, P38, DOI 10.1016/j.jaut.2017.12.004; Wells CL, 1996, GASTROENTEROLOGY, V110, P1429, DOI 10.1053/gast.1996.v110.pm8613048; Wittkopf N, 2012, CLIN DEV IMMUNOL, DOI 10.1155/2012/278059; Wlodarska M, 2014, CELL, V156, P1045, DOI 10.1016/j.cell.2014.01.026; Xie CC, 2016, AUTOPHAGY, V12, P410, DOI 10.1080/15548627.2015.1132134; Zheng J., 2017, MOLECULES, V23, DOI 10.3390/molecules23010051	59	4	5	4	27	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0951-418X	1099-1573		PHYTOTHER RES	Phytother. Res.	OCT	2020	34	10					2649	2664		10.1002/ptr.6695		APR 2020	16	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	OC4MU	WOS:000526020700001	32281697				2022-04-25	
J	Quah, SY; Wong, CC; Wong, HC; Ho, KL; Manan, NA; Deb, PK; Sagineedu, SR; Stanslas, J				Quah, Shun Ying; Wong, Charng Choon; Wong, Hui Chyn; Ho, Kok Lian; Manan, Nizar Abdul; Deb, Pran Kishore; Sagineedu, Sreenivasa Rao; Stanslas, Johnson			Microarray-based identification of differentially expressed genes associated with andrographolide derivatives-induced resistance in colon and prostate cancer cell lines	TOXICOLOGY AND APPLIED PHARMACOLOGY			English	Article						Chemoresistance; SRJ09; SRJ23; Microarray analysis; Gene expression	FIBROBLAST-GROWTH-FACTOR; FACTOR RECEPTOR 4; HEME OXYGENASE-1; DRUG-RESISTANCE; IN-VITRO; BREAST-CANCER; STEM-CELLS; HEPATOCELLULAR-CARCINOMA; PROMOTES PROGRESSION; INDUCED APOPTOSIS	Chemoresistance poses a major hurdle to cancer treatments. Andrographolide-derived SRJ09 and SRJ23 were reported to exhibit potent, selective inhibitory activities against colon and prostate cancer cells, respectively. In this study, previously developed resistant colon (HCT-116rst09) and prostate (PC-3rst23) cancer cell lines were used to elucidate the molecular mechanisms contributing to chemoresistance. Cytotoxic effects of SRJ09 and SRJ23 on both parental and resistant cells were investigated. Cell cycle distributions in HCT-116rst09 cells following SRJ09 treatment were analysed using flow cytometry. Whole-genome microarray analysis was performed on both parental and resistant cells to obtain differential gene expression profiles. Microarray data were subjected to protein-protein interaction network, functional enrichment, and pathway analyses. Reverse transcription-polymerase chain reaction (RT-PCR) was used to validate the changes in expression levels of selected genes. Besides morphological changes, HCT-116rst09 cells showed 7.0-fold resistance to SRJ09 while PC3rst23 cells displayed a 5.5-fold resistance to SRJ23, as compared with their respective parental cells. G0/G1-phase cell cycle arrest was observed in HCT-116rst09 cells upon SRJ09 treatment. Collectively, 77 and 21 genes were found differentially modulated in HCT-116rst09 and PC-3rst23 cells, respectively. Subsequent bioinformatics analysis revealed several genes associated with FGFR4 and PI3K pathways, and cancer stemness, were chemoresistance mediators in HCT-116rst09 cells. RT-PCR confirmed the HMOX1 upregulation and ATG12 downregulation protected the PC-3rst23 cells from SRJ23 cytotoxicity. In conclusion, acquired chemoresistance to SRJ09 and SRJ23 in colon and prostate cancer cells, respectively, could be attributed to the alterations in the expression of genes such as those related to PI3K and autophagy pathways.	[Quah, Shun Ying; Wong, Charng Choon; Wong, Hui Chyn; Stanslas, Johnson] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Med, Pharmacotherapeut Unit, Serdang 43400, Selangor, Malaysia; [Ho, Kok Lian] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Pathol, Serdang 43400, Selangor, Malaysia; [Manan, Nizar Abdul] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Human Anat, Serdang 43400, Selangor, Malaysia; [Deb, Pran Kishore] Philadelphia Univ, Fac Pharm, POB 1, Amman 19392, Jordan; [Sagineedu, Sreenivasa Rao] Int Med Univ, Sch Pharm, Dept Pharmaceut Chem, Kuala Lumpur 57000, Malaysia		Stanslas, J (corresponding author), Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Med, Pharmacotherapeut Unit, Serdang 43400, Selangor, Malaysia.	rcxjs@upm.edu.my		Quah, Shun Ying/0000-0002-0621-7169	Universiti Putra Malaysia, Malaysia through Research University Grant Scheme [04-01-09-0713RU, 04-02-12-2017RU]	This work was supported by the Universiti Putra Malaysia, Malaysia through Research University Grant Scheme [grant numbers 04-01-09-0713RU and 04-02-12-2017RU] to J. Stanslas.	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Appl. Pharmacol.	AUG 15	2021	425								115605	10.1016/j.taap.2021.115605		JUN 2021	15	Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Toxicology	SV9LE	WOS:000664138800004	34087331				2022-04-25	
J	Li, B; Wu, GL; Dai, W; Wang, G; Su, HY; Shen, XP; Zhan, R; Xie, JM; Wang, Z; Qin, ZH; Gao, QG; Shen, GH				Li, Bin; Wu, Guo-liang; Dai, Wei; Wang, Gang; Su, Hao-yuan; Shen, Xue-ping; Zhan, Rui; Xie, Jia-ming; Wang, Zhong; Qin, Zheng-hong; Gao, Quan-gen; Shen, Gen-hai			Aescin-induced reactive oxygen species play a pro-survival role in human cancer cells via ATM/AMPK/ULK1-mediated autophagy	ACTA PHARMACOLOGICA SINICA			English	Article						aescin; ROS; autophagy; apoptosis; human hepatocellular carcinoma HepG2 cells; human colon carcinoma HCT 116 cells; 3-MA; NAC; KU-55933	FACTOR-KAPPA-B; BETA-ESCIN; APOPTOSIS; ROS; STRESS; INHIBITION; ACTIVATION; MECHANISMS; AMPK	Aescin, a natural mixture of triterpene saponins, has been reported to exert anticancer effect. Recent studies show that aescin increases intracellular reactive oxygen species (ROS) levels. However, whether the increased ROS play a role in the anticancer action of aescin remains to be explored. In this study, we demonstrated that aescin (20-80 mu g/mL) dose-dependently induced apoptosis and activated mammalian target of rapamycin (mTOR)-independent autophagy in human hepatocellular carcinoma HepG2 cells and colon carcinoma Ha 116 cells. The activation of autophagy favored cancer cell survival in response to aescin, as suppression of autophagy with ATG5 siRNAs or 3-methyladenine (3-MA), a selective inhibitor of autophagy, promoted aescin-induced apoptosis in vitro, and significantly enhanced the anticancer effect of aescin in vivo. Meanwhile, aescin dose-dependently elevated intracellular ROS levels and activated Ataxia-telangiectasia mutated kinase/AMP-activated protein kinase/UNC-51-like kinase-1 (ATM/AMPK/ULK1) pathway. The ROS and ATM/AMPK/ULK1 pathway were upstream modulators of the aescin-induced autophagy, as N-acetyl-L-cysteine (NAC) or ATM kinase inhibitor (KU-55933) remarkably suppressed aescin-induced autophagy and consequently promoted aescin-induced apoptosis, whereas overexpression of ATG5 partly attenuated NAC-induced enhancement in aescin-induced apoptosis. In conclusion, this study provides new insights into the roles of aescin-mediated oxidative stress and autophagy in cancer cell survival. Our results suggest that combined administration of the antioxidants or autophagic inhibitors with aescin might be a potential strategy to enhance the anticancer effect of aescin.	[Li, Bin; Wu, Guo-liang; Dai, Wei; Wang, Gang; Su, Hao-yuan; Shen, Xue-ping; Zhan, Rui; Gao, Quan-gen; Shen, Gen-hai] First Peoples Hosp Wu Jiang, Dept Gen Surg, Suzhou 215200, Peoples R China; [Xie, Jia-ming; Wang, Zhong] Soochow Univ, Dept Gen Surg, Affiliated Hosp 2, Suzhou 215004, Peoples R China; [Qin, Zheng-hong] Soochow Univ, Dept Pharmacol, Suzhou 215123, Peoples R China; [Qin, Zheng-hong] Soochow Univ, Jiangsu Key Lab Translat Res & Therapy Neuropsyco, Jiangsu Key Lab Prevent & Translat Med Geriatr Di, Lab Aging & Nervous Dis,Coll Pharmaceut Sci, Suzhou 215123, Peoples R China		Gao, QG; Shen, GH (corresponding author), First Peoples Hosp Wu Jiang, Dept Gen Surg, Suzhou 215200, Peoples R China.; Qin, ZH (corresponding author), Soochow Univ, Dept Pharmacol, Suzhou 215123, Peoples R China.; Qin, ZH (corresponding author), Soochow Univ, Jiangsu Key Lab Translat Res & Therapy Neuropsyco, Jiangsu Key Lab Prevent & Translat Med Geriatr Di, Lab Aging & Nervous Dis,Coll Pharmaceut Sci, Suzhou 215123, Peoples R China.	qinzhenhong@suda.edu.cn; wjyygqg@sohu.com; wjsgh3026@sina.com			Jiangsu Provincial Commission of Health and Family Planning [YG201402, YG201503]; Jiangsu Provincial Medical Youth Talent [QNRC2016249]; Suzhou Science and Technology Bureau [SYSD2013041, SYSD2016044, SYSD2017041, SYS201788]; Wujiang District Science and Technology Bureau [WS201301]; Wujiang District Commission of Health and Family Planning [WWK201607, WWK201609]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81602613]	This work was supported by grants from the Jiangsu Provincial Commission of Health and Family Planning (No. YG201402, YG201503), Jiangsu Provincial Medical Youth Talent, (No. QNRC2016249), Suzhou Science and Technology Bureau (No. SYSD2013041, SYSD2016044, SYSD2017041 and SYS201788), Wujiang District Science and Technology Bureau (No. WS201301), Wujiang District Commission of Health and Family Planning (No. WWK201607 and WWK201609) and National Natural Science Foundation of China (No. 81602613).	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Sin.	DEC	2018	39	12					1874	1884		10.1038/s41401-018-0047-1			11	Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	HG2DU	WOS:000454773800007	29921885	Bronze, Green Published			2022-04-25	
J	Cao, ZX; Yang, YT; Yu, S; Li, YZ; Wang, WW; Huang, J; Xie, XF; Xiong, L; Lei, S; Peng, C				Cao, Zhi-Xing; Yang, Yu-Ting; Yu, Si; Li, Yu-Zhi; Wang, Wen-Wen; Huang, Jing; Xie, Xiao-Fang; Xiong, Liang; Lei, Song; Peng, Cheng			Pogostone induces autophagy and apoptosis involving PI3K/Akt/mTOR axis in human colorectal carcinoma HCT116 cells	JOURNAL OF ETHNOPHARMACOLOGY			English	Article						Pogostone; Autophagy; Apoptosis; Akt; mTOR	IN-VITRO; POGOSTEMONIS HERBA; MAMMALIAN TARGET; CANCER; ANTICANCER; PATHWAY; PROLIFERATION; INHIBITION; MEDICINE; PROTEIN	Ethnophamacological relevance: Pogostemon cablin is a medicinal herb widely used to treat gastrointestinal diseases in many Asian countries. Pogostone is an important constituent of Pogostemon cablin, and possesses various bioactivitys. In this study, we performed to investigate the anti-colorectal tumor property of Pogostone by inducing aurophagy and apoptosis in human colorectal cancer cells, and to define the potential molecular mechanisms. Materials and methods: In vitro, The anti-tumor activity of pogostone was assessed using MIT assay. Autophagy was monitored by transmission electron microscopy observation and mRFP-GFP-LC3 fluorescence analysis in colorectal tumor cell line. Apoptosis was measured by flow cytometry and annexinV-FITC/PI staining. The protein expressions or activition of LC3-II, AKT, mTOR, caspase-3 and caspase-7 were detected through western blotting. In vivo, the anti-tumor effect of pogostone was tested with HCT116 colorectal tumor cells transplantation tumor model. The expression of Ki-67 was determined by Immunohistochemistry staining and the apoptosis was evaluated using TUNEL assay. Results: In vitro, pogostone exhibits significant anti-tumor activity against human cancer cell lines, especially for HCT116 (18.7 +/- 1.93 g/ml). Transmission electron microscopy observation, mRFP-GFP-LC3 fluorescence analysis, flow cytometry and assay and western blotting detection revealed that the anti-colorectal tumor activity of pogostone was dependent on inducing autophagy and apoptosis through up-regulating the expression of LC3-II, cleaved caspase-7 and caspase-3, and decreasing the phosphorylation of AKT/mTOR. In vivo, 150 mg/kg pogostone inhibited the HCT116 tumor growth in immunodeficient mice with an inhibitory rate of 43.3%, decreased the expression of Ki67, and induced apoptosis in three days. Conclusion: Pogostone showed anti-colorectal tumor effects by inducing autophagy and apoptosis involving PI3K/Akt/mTOR axis. Thus, pogostone may be a promising lead compound to be further developed for cancer therapy.	[Cao, Zhi-Xing; Yang, Yu-Ting; Yu, Si; Li, Yu-Zhi; Wang, Wen-Wen; Huang, Jing; Xie, Xiao-Fang; Xiong, Liang; Peng, Cheng] Chengdu Univ Tradit Chinese Med, Key Lab Standardizat Chinese Herbal Med,Minist Ed, Key Lab Breeding Base Cofounded Sichuan Prov,Phar, Key Lab Systemat Res Dev & Utilizat Chinese Med R, Chengdu, Peoples R China; [Cao, Zhi-Xing; Yang, Yu-Ting; Yu, Si; Li, Yu-Zhi; Wang, Wen-Wen; Huang, Jing; Xie, Xiao-Fang; Xiong, Liang; Peng, Cheng] MOST, Beijing, Peoples R China; [Lei, Song] West China Hosp, Dept Pathol, Chengdu, Peoples R China; [Wang, Wen-Wen; Huang, Jing] Chengdu Univ Tradit Chinese Med, Sch Med Technol, Chengdu, Peoples R China		Peng, C (corresponding author), Chengdu Univ Tradit Chinese Med, Key Lab Standardizat Chinese Herbal Med,Minist Ed, Key Lab Breeding Base Cofounded Sichuan Prov,Phar, Key Lab Systemat Res Dev & Utilizat Chinese Med R, Chengdu, Peoples R China.; Peng, C (corresponding author), MOST, Beijing, Peoples R China.	pengchengchengdu@l26.com		Xiong, Liang/0000-0001-6222-8340	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81300437, 81403149]; Youth Scientific Research Fund of CDUTCM [ZRQN1450, CGPY1402]; Sichuan Province Youth Science and Technology Innovation Research Team project [2014TD0007, 2016TD0006]	This study was supported by the National Natural Science Foundation of China (81300437, 81403149), Youth Scientific Research Fund of CDUTCM (ZRQN1450, CGPY1402), Sichuan Province Youth Science and Technology Innovation Research Team project (2014TD0007, 2016TD0006).	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Ethnopharmacol.	APR 18	2017	202						20	27		10.1016/j.jep.2016.07.028			8	Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine	ET3YN	WOS:000400216000003	27416805				2022-04-25	
J	Mbaveng, AT; Noulala, CGT; Samba, ARM; Tankeo, SB; Abdelfatah, S; Fotso, GW; Happi, EN; Ngadjui, BT; Beng, VP; Kuete, V; Efferth, T				Mbaveng, Armelle T.; Noulala, Cedric G. T.; Samba, Anne R. M.; Tankeo, Simplice B.; Abdelfatah, Sara; Fotso, Ghislain W.; Happi, Emmanuel N.; Ngadjui, Bonaventure T.; Beng, Veronique P.; Kuete, Victor; Efferth, Thomas			The alkaloid, soyauxinium chloride, displays remarkable cytotoxic effects towards a panel of cancer cells, inducing apoptosis, ferroptosis and necroptosis	CHEMICO-BIOLOGICAL INTERACTIONS			English	Article						Cancer; Cell death; Indoloquinazoline; Multidrug resistance; Natural product	GROWTH-FACTOR RECEPTOR; BREAST-CANCER; MULTIDRUG-RESISTANCE; MEDICINAL-PLANTS; DRUG-RESISTANCE; MODES; TRANSPORTER; MODULATION; EXPRESSION; FLAVONOIDS	The cytotoxic potential of a naturally occurring indoloquinazoline alkaloid, soyauxinium chloride (SCHL), was determined on a broad panel of animal and human cancer cell lines, including various sensitive and drug-resistant phenotypes. The cytotoxicity, SCHL-induced autophagic, ferroptotic, and necmptotic cell death were evaluated by the resazurin reduction assay (RRA). Caspase-Glo assay was used to detect the activity of caspases using spectrophotometric analysis. Flow cytometry was applied for cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). SCHL and doxorubicin (reference molecule) exhibited cytotoxic effects towards the 18 cancer cell lines tested. The IC50 values obtained ranged from 3.64 mu M (towards CCRF-CEM leukemia cells) to 16.86 mu M (against the BRAF-wildtype SKMe1-505 melanoma cells for SCHL). Collateral sensitivity of the resistant HCT116 p53(-/-) colon adenocarcinoma cells to SCHL was observed as well as the normal sensitivity of CEM/ADR5000 leukemia cells, MDA-MB-231-BCRP breast adenocarcinoma cells and U87. MG Delta EGFR glioblastoma cells. SCHL induced apoptosis in CCRF-CEM cells via caspases 3/7-, 8- and 9-activation, MMP alteration and increased ROS production, and otherwise ferroptosis and necroptosis. SCHL is a prominent cytotoxic alkaloid that should be further studied to develop a novel drug to combat cancers including refractory phenotypes.	[Mbaveng, Armelle T.; Tankeo, Simplice B.; Abdelfatah, Sara; Kuete, Victor; Efferth, Thomas] Johannes Gutenberg Univ Mainz, Inst Pharmaceut & Biomed Sci, Dept Pharmaceut Biol, Staudinger Weg 5, D-55128 Mainz, Germany; [Mbaveng, Armelle T.; Samba, Anne R. M.; Tankeo, Simplice B.; Kuete, Victor] Univ Dschang, Fac Sci, Dept Biochem, Dschang, Cameroon; [Noulala, Cedric G. T.; Fotso, Ghislain W.; Ngadjui, Bonaventure T.] Univ Yaounde I, Fac Sci, Dept Organ Chem, POB 812, Yaounde, Cameroon; [Samba, Anne R. M.; Beng, Veronique P.] Univ Yaounde I, Fac Sci, Dept Biochem, Yaounde, Cameroon; [Happi, Emmanuel N.] Univ Douala, Fac Sci, Dept Chem, Douala, Cameroon		Efferth, T (corresponding author), Johannes Gutenberg Univ Mainz, Inst Pharmaceut & Biomed Sci, Dept Pharmaceut Biol, Staudinger Weg 5, D-55128 Mainz, Germany.; Kuete, V (corresponding author), POB 1499, Bafoussam, Cameroon.	armbatsa@yahoo.fr; cedric.noulala@hotmail.fr; annecesarine@gmail.com; simplicetankeo@yahoo.fr; saabdelf@uni-mainz.de; ghis152001@gmail.com; ngeufa@yahoo.fr; ngadjuibt@yahoo.fr; v.penlap@yahoo.fr; kuetevictor@yahoo.fr; efferth@uni-mainz.de			Alexander von Humboldt FoundationAlexander von Humboldt Foundation; Yaounde-Bielefeld Bilateral Graduate School Natural Products with Antiparasite and Antibacterial Activity (YaBiNaPA) [DAAD] [57316173]	ATM is thankful to Alexander von Humboldt Foundation for an 18 months fellowship in Prof. Dr. Thomas Efferth's laboratory in Mainz, Germany, through the ''Georg Foster Research Fellowship for Experienced Researchers'' program. VK is grateful to the Alexander von Humboldt Foundation for the 6-month further research stay fellowship in Mainz. CGTN is particularly grateful to the Yaounde-Bielefeld Bilateral Graduate School Natural Products with Antiparasite and Antibacterial Activity (YaBiNaPA) [DAAD, project ID 57316173] for providing research facilities in Cameroon. The authors acknowledge the Institute of Molecular Biology gGmbH (IMB) (Mainz, Germany) for MMP measurements by flow cytometry.	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Interact.	JAN 5	2021	333								109334	10.1016/j.cbi.2020.109334			9	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	PI1BB	WOS:000600832900008	33245930				2022-04-25	
J	Ding, JJ; Gou, Q; Jia, X; Liu, Q; Jin, JH; Shi, JJ; Hou, YZ				Ding, Jiajun; Gou, Qian; Jia, Xiao; Liu, Qian; Jin, Jianhua; Shi, Juanjuan; Hou, Yongzhong			AMPK phosphorylates PPAR delta to mediate its stabilization, inhibit glucose and glutamine uptake and colon tumor growth	JOURNAL OF BIOLOGICAL CHEMISTRY			English	Article							ACTIVATED-RECEPTOR-DELTA; ENDOPLASMIC-RETICULUM STRESS; PEROXISOME-PROLIFERATOR; ENDOTHELIAL DYSFUNCTION; LIGAND ACTIVATION; AUTOPHAGY; PROTEINS; PATHWAY; KINASE; IDENTIFICATION	Peroxisome proliferator-activated receptor delta (PPAR delta) is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase 5'AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy in coordination with PPAR delta. However, the molecular mechanism of the AMPK/PPAR delta pathway on cancer progression is still unclear. Here, we found that activated AMPK induced PPAR delta-S50 phosphorylation in cancer cells, whereas the PPAR delta/S50A (nonphosphorylation mimic) mutant reversed this event. Further analysis showed that the PPAR delta/S50E (phosphorylation mimic) but not the PPAR delta/S50A mutant increased PPAR delta protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPAR delta. Furthermore, PPAR delta-S50 phosphorylation decreased PPAR delta transcription activity and alleviated PPAR delta-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPAR delta/S50E mutant but not the PPAR delta/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPAR delta-S50 phosphorylation, accumulation of misfolded PPAR delta protein, and inhibition of PPAR delta transcription activity contributing to the suppression of colon tumor formation.	[Ding, Jiajun; Jia, Xiao; Shi, Juanjuan; Hou, Yongzhong] Jiangsu Univ, Sch Life Sci, Zhenjiang, Jiangsu, Peoples R China; [Gou, Qian] Jiangsu Univ, Sch Med, Zhenjiang, Jiangsu, Peoples R China; [Liu, Qian; Jin, Jianhua] Jiangsu Univ, Affiliated Wujin Peoples Hosp, Dept Oncol, Changzhou, Jiangsu, Peoples R China		Shi, JJ; Hou, YZ (corresponding author), Jiangsu Univ, Sch Life Sci, Zhenjiang, Jiangsu, Peoples R China.; Shi, JJ; Hou, YZ (corresponding author), Jiangsu Univ, Sch Med, Zhenjiang, Jiangsu, Peoples R China.	sjj@ujs.edu.cn; houyz@ujs.edu.cn		Hou, Yongzhong/0000-0003-2019-8686	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81972618, 81672711, 81872275]; Natural Science FoundationNational Natural Science Foundation of China (NSFC) [M2020002]; Changzhou Sci Tech Program [CJ20200004]; Jiangsu Commission of Health	This article contains supporting information. Acknowledgments-This work was supported by the National Natural Science Foundation of China (81972618, 81672711, 81872275) , Jiangsu Commission of Health, Natural Science Foundation (M2020002) , and Changzhou Sci & Tech Program (Grant No. CJ20200004) .	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Biol. Chem.	SEP	2021	297	3							100954	10.1016/j.jbc.2021.100954			11	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	WF5RS	WOS:000706361700004	34270958	gold, Green Published			2022-04-25	
J	Chen, L; Meng, Y; Guo, XQ; Sheng, XT; Tai, GH; Zhang, FL; Cheng, HR; Zhou, YF				Chen, Lei; Meng, Yue; Guo, Xiaoqing; Sheng, Xiaotong; Tai, Guihua; Zhang, Fenglei; Cheng, Hairong; Zhou, Yifa			Gefitinib enhances human colon cancer cells to TRAIL-induced apoptosis of via autophagy- and JNK-mediated death receptors upregulation	APOPTOSIS			English	Article						TRAIL; Gefitinib; DR4; DR5; Autophagy; JNK	TYROSINE KINASE INHIBITOR; PHASE-I SAFETY; ZD1839 IRESSA; RESISTANCE; EXPRESSION; LIGAND; COMBINATION; ANTITUMOR; ANTIBODY; FAMILY	Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. Here, we report that gefitinib and TRAIL in combination produce a potent synergistic effect on TRAIL-sensitive human colon cancer HCT116 cells and an additive effect on TRAIL-resistant HT-29 cells. Interestingly, gefitinib increases the expression of cell surface receptors DR4 and DR5, possibly explaining the synergistic effect. Knockdown of DR4 and DR5 by siRNA significantly decreases gefitinib- and TRAIL-mediated cell apoptosis, supporting this idea. Because the inhibition of gefitinib-induced autophagy by 3-MA significantly decreases DR4 and DR5 upregulation, as well as reduces gefitinib- and TRAIL-induced apoptosis, we conclude that death receptor upregulation is autophagy mediated. Furthermore, our results indicate that death receptor expression may also be regulated by JNK activation, because pre-treatment of cells with JNK inhibitor SP600125 significantly decreases gefitinib-induced death receptor upregulation. Interestingly, SP600125 also inhibits the expression CHOP, yet CHOP has no impact on death receptor expressions. We also find here that phosphorylation of Akt and ERK might also be required for TRAIL sensitization. In summary, our results indicate that gefitinib effectively enhances TRAIL-induced apoptosis, likely via autophagy and JNK- mediated death receptor expression and phosphorylation of Akt and ERK.	[Chen, Lei; Meng, Yue; Guo, Xiaoqing; Sheng, Xiaotong; Tai, Guihua; Cheng, Hairong; Zhou, Yifa] Northeast Normal Univ, Sch Life Sci, Jilin Prov Key Lab Chem & Biol Changbai Mt Nat Dr, Changchun 130024, Peoples R China; [Zhang, Fenglei] Jilin Univ, Hosp 1, Dept Radiol, Part 2, 3302 Jilin Rd, Changchun 130024, Peoples R China		Cheng, HR; Zhou, YF (corresponding author), Northeast Normal Univ, Sch Life Sci, Jilin Prov Key Lab Chem & Biol Changbai Mt Nat Dr, Changchun 130024, Peoples R China.	chenghr893@nenu.edu.cn; zhouyf383@nenu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81302172]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2013M530959, 2014T70270]	This work was supported by the National Natural Science Foundation of China (No. 81302172) and the China Postdoctoral Science Foundation (2013M530959 & 2014T70270). We would also like to thank Prof. KH Mayo for critical reading and editing of this manuscript.	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J	Li, Y; Cho, MH; Lee, SS; Lee, DE; Cheong, H; Choi, Y				Li, Yan; Cho, Mi Hyeon; Lee, Seon Sook; Lee, Dong-Eun; Cheong, Heesun; Choi, Yongdoo			Hydroxychloroquine-loaded hollow mesoporous silica nanoparticles for enhanced autophagy inhibition and radiation therapy	JOURNAL OF CONTROLLED RELEASE			English	Article						Radiation therapy; Autophagy; Hydroxychloroquine; Hollow mesoporous silica nanoparticle; Cancer	TRIAL; RADIORESISTANCE; TEMOZOLOMIDE; MECHANISMS; DELIVERY; CELLS	Radiotherapy (RT) is a major modality for cancer treatment, along with surgery and chemotherapy. Despite its therapeutic effect, the recurrence and metastasis of tumors due to the acquired resistance of cancer cells to RT remain significant clinical problems. Therefore, it is imperative to overcome radioresistance and improve radiosensitivity in cancer patients. Here, we synthesized hydroxychloroquine (HCQ)-loaded hollow mesoporous silica nanoparticles (HMSNs) to enable effective inhibition of radiation-induced cytoprotective autophagy and enhance the therapeutic efficacy of RT. HCQ-HMSN-treated HCT116 colon cancer cells showed a 200-fold higher intracellular uptake of HCQ than that of free HCQ-treated cells, thereby effectively inhibiting the radiation-induced autophagy of cancer cells. In vivo imaging and therapy studies of a tumor xenograft model showed preferential accumulation of HCQ-HMSNs in tumor tissues and significant enhancement of RT by inhibiting autophagy in the tumor sites. Histopathology analyses of major organs, blood chemistry profiles, and changes in body weights of mice confirmed the good biocompatibility of HCQ-HMSNs.	[Li, Yan; Cho, Mi Hyeon; Lee, Seon Sook; Choi, Yongdoo] Natl Canc Ctr, Res Inst, Div Translat Sci, 323 Ilsan Ro, Goyang 10408, Gyeonggi, South Korea; [Lee, Dong-Eun; Cheong, Heesun] Natl Canc Ctr, Res Inst, Div Canc Biol, 323 Ilsan Ro, Goyang 10408, Gyeonggi, South Korea		Choi, Y (corresponding author), Natl Canc Ctr, Res Inst, Div Translat Sci, 323 Ilsan Ro, Goyang 10408, Gyeonggi, South Korea.; Cheong, H (corresponding author), Natl Canc Ctr, Res Inst, Div Canc Biol, 323 Ilsan Ro, Goyang 10408, Gyeonggi, South Korea.	heesunch@ncc.re.kr; ydchoi@ncc.re.kr		Cho, mi hyeon/0000-0001-9429-4692; Cheong, Heesun/0000-0003-1946-107X	National Cancer Center grant [1910070, 2010960, 2011440]; Ministry of Oceans and Fisheries, Korea	This work was supported by the National Cancer Center grant (1910070, 2010960, and 2011440) and by the Ministry of Oceans and Fisheries, Korea (the project title: Development of marine material based near infrared fluorophore complex and diagnostic imaging instruments).	Arriagada FJ, 1999, J COLLOID INTERF SCI, V211, P210, DOI 10.1006/jcis.1998.5985; Barker HE, 2015, NAT REV CANCER, V15, P409, DOI 10.1038/nrc3958; Bristol ML, 2012, AUTOPHAGY, V8, P739, DOI 10.4161/auto.19313; Chaiswing Luksana, 2018, Critical Reviews in Oncogenesis, V23, P39, DOI 10.1615/CritRevOncog.2018025946; Chang L, 2014, CANCER METAST REV, V33, P469, DOI 10.1007/s10555-014-9493-5; Chen F, 2014, SCI REP-UK, V4, DOI 10.1038/srep05080; Fang XL, 2011, NANOSCALE, V3, P1632, DOI 10.1039/c0nr00893a; Gao Y, 2011, ACS NANO, V5, P9788, DOI 10.1021/nn2033105; Gewirtz DA, 2014, RADIAT RES, V182, P363, DOI 10.1667/RR13774.1; Hong Suk Ho, 2018, Journal of Pharmaceutical Investigation, V48, P3, DOI 10.1007/s40005-017-0356-2; Hong SH, 2017, CHEM-ASIAN J, V12, P1700, DOI 10.1002/asia.201700371; Hong SH, 2017, NANOTECHNOLOGY, V28, DOI 10.1088/1361-6528/aa66b0; Kimura S, 2007, AUTOPHAGY, V3, P452, DOI 10.4161/auto.4451; Klionsky DJ, 2008, AUTOPHAGY, V4, P151, DOI 10.4161/auto.5338; Park Jungyoul, 2018, Journal of Biomedical and Translational Research, V19, P130; Pellegrini P, 2014, AUTOPHAGY, V10, P562, DOI 10.4161/auto.27901; Rangwala R, 2014, AUTOPHAGY, V10, P1369, DOI 10.4161/auto.29118; Rosenfeld MR, 2014, AUTOPHAGY, V10, P1359, DOI 10.4161/auto.28984; Rouschop KMA, 2010, J CLIN INVEST, V120, P127, DOI 10.1172/JCI40027; Shi SX, 2013, NANOMEDICINE-UK, V8, P2027, DOI 10.2217/nnm.13.177; Tam SY, 2017, RADIAT ONCOL, V12, DOI 10.1186/s13014-017-0795-y; Vogl DT, 2014, AUTOPHAGY, V10, P1380, DOI 10.4161/auto.29264; Wang XH, 2018, INT J PHARMACEUT, V536, P1, DOI 10.1016/j.ijpharm.2017.09.007; Wang Y, 2016, AUTOPHAGY, V12, P949, DOI 10.1080/15548627.2016.1162930; Yin S, 2018, J CONTROL RELEASE, V288, P148, DOI 10.1016/j.jconrel.2018.08.015	25	17	17	6	65	ELSEVIER	AMSTERDAM	RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS	0168-3659	1873-4995		J CONTROL RELEASE	J. Control. Release	SEP 10	2020	325						100	110		10.1016/j.jconrel.2020.06.025			11	Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	NA9PK	WOS:000560148400008	32621826				2022-04-25	
J	Liu, EY; Ryan, KM				Liu, Emma Y.; Ryan, Kevin M.			Autophagy and cancer - issues we need to digest	JOURNAL OF CELL SCIENCE			English	Article						Autophagy; Cancer; Therapy	RAPAMYCIN-INDUCED AUTOPHAGY; MALIGNANT GLIOMA-CELLS; TUMOR-SUPPRESSOR GENE; COLON-CANCER; REGULATES AUTOPHAGY; TARGETING AUTOPHAGY; METABOLIC STRESS; MAMMALIAN TARGET; UP-REGULATION; BECLIN 1	Autophagy is an evolutionarily conserved catabolic pathway that has multiple roles in carcinogenesis and cancer therapy. It can inhibit the initiation of tumorigenesis through limiting cytoplasmic damage, genomic instability and inflammation, and the loss of certain autophagy genes can lead to cancer. Conversely, autophagy can also assist cells in dealing with stressful metabolic environments, thereby promoting cancer cell survival. In fact, some cancers rely on autophagy to survive and progress. Furthermore, tumour cells can exploit autophagy to cope with the cytotoxicity of certain anticancer drugs. By contrast, it appears that certain therapeutics require autophagy for the effective killing of cancer cells. Despite these dichotomies, it is clear that autophagy has an important, if complex, role in cancer. This is further exemplified by the fact that autophagy is connected with major cancer networks, including those driven by p53, mammalian target of rapamycin (mTOR), RAS and glutamine metabolism. In this Commentary, we highlight recent advances in our understanding of the role that autophagy has in cancer and discuss current strategies for targeting autophagy for therapeutic gain. This article is part of a Minifocus on Autophagy. For further reading, please see related articles: 'Ubiquitin-like proteins and autophagy at a glance' by Tomer Shpilka et al. (J. Cell Sci. 125, 2343-2348) and 'Autophagy and cell growth - the yin and yang of nutrient responses' by Thomas Neufeld (J. Cell Sci. 125, 2359-2368).	[Liu, Emma Y.; Ryan, Kevin M.] Beatson Inst Canc Res, Tumour Cell Death Lab, Glasgow G61 1BD, Lanark, Scotland		Ryan, KM (corresponding author), Beatson Inst Canc Res, Tumour Cell Death Lab, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Lanark, Scotland.	k.ryan@beatson.gla.ac.uk		Ryan, Kevin M./0000-0002-1059-9681	Cancer Research UKCancer Research UK; Association for International Cancer Research; Cancer Research UKCancer Research UK [15816] Funding Source: researchfish	Work in the Tumour Cell Death Laboratory is supported by Cancer Research UK and the Association for International Cancer Research.	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Cell Sci.	MAY 15	2012	125	10					2349	2358		10.1242/jcs.093708			10	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	970CZ	WOS:000306107000002	22641689	Bronze, Green Accepted			2022-04-25	
J	Wang, XX; Shen, C; Liu, ZD; Peng, F; Chen, X; Yang, G; Zhang, DM; Yin, ZQ; Ma, JC; Zheng, ZX; Zhao, BX; Liu, HL; Wang, LG; Wu, JN; Han, DY; Wang, KK; Zhong, C; Hou, X; Zhao, WY; Shu, MT; Wang, XZ; Zhao, SG				Wang, Xiaoxiong; Shen, Chen; Liu, Zhendong; Peng, Fei; Chen, Xin; Yang, Guang; Zhang, Daming; Yin, Zhiqin; Ma, Jichao; Zheng, Zhixing; Zhao, Boxian; Liu, Huailei; Wang, Ligang; Wu, Jianing; Han, Dayong; Wang, Kaikai; Zhong, Chen; Hou, Xu; Zhao, Wenyang; Shu, Mengting; Wang, Xinzhuang; Zhao, Shiguang			Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma	CELL DEATH & DISEASE			English	Article							HISTONE DEACETYLASE INHIBITORS; COLORECTAL-CANCER; MALIGNANT GLIOMA; TEMOZOLOMIDE; AGENT; DEATH; MECHANISMS; CANDIDATE; PATHWAYS; TARGET	Glioblastoma is the most common and aggressive primary brain tumor in adults. New drug design and development is still a major challenge for glioma treatment. Increasing evidence has shown that nitazoxanide, an antiprotozoal drug, has a novel antitumor role in various tumors and exhibits multiple molecular functions, especially autophagic regulation. However, whether nitazoxanide-associated autophagy has an antineoplastic effect in glioma remains unclear. Here, we aimed to explore the underlying molecular mechanism of nitazoxanide in glioblastoma. Our results showed that nitazoxanide suppressed cell growth and induced cell cycle arrest in glioblastoma by upregulating ING1 expression with a favorable toxicity profile. Nitazoxanide inhibited autophagy through blockage of late-stage lysosome acidification, resulting in decreased cleavage of ING1. A combination with chloroquine or Torin1 enhanced or impaired the chemotherapeutic effect of nitazoxanide in glioblastoma cells. Taken together, these findings indicate that nitazoxanide as an autophagy inhibitor induces cell cycle arrest in glioblastoma via upregulated ING1 due to increased transcription and decreased post-translational degradation by late-stage autophagic inhibition.	[Wang, Xiaoxiong; Shen, Chen; Liu, Zhendong; Peng, Fei; Chen, Xin; Yang, Guang; Zhang, Daming; Yin, Zhiqin; Zheng, Zhixing; Zhao, Boxian; Liu, Huailei; Wang, Ligang; Wu, Jianing; Han, Dayong; Wang, Kaikai; Zhong, Chen; Hou, Xu; Zhao, Wenyang; Shu, Mengting; Wang, Xinzhuang; Zhao, Shiguang] Harbin Med Univ, Affiliated Hosp 1, Dept Neurosurg, 23 Youzheng St, Harbin 150001, Heilongjiang, Peoples R China; [Wang, Xiaoxiong; Shen, Chen; Liu, Zhendong; Peng, Fei; Chen, Xin; Yang, Guang; Zhang, Daming; Yin, Zhiqin; Zheng, Zhixing; Zhao, Boxian; Liu, Huailei; Wang, Ligang; Wu, Jianing; Han, Dayong; Wang, Kaikai; Zhong, Chen; Hou, Xu; Zhao, Wenyang; Shu, Mengting; Wang, Xinzhuang; Zhao, Shiguang] Harbin Med Univ, Inst Brain Sci, 23 Youzheng St, Harbin 150001, Heilongjiang, Peoples R China; [Wang, Xiaoxiong; Shen, Chen; Liu, Zhendong; Peng, Fei; Chen, Xin; Yang, Guang; Zhang, Daming; Yin, Zhiqin; Zheng, Zhixing; Zhao, Boxian; Liu, Huailei; Wang, Ligang; Wu, Jianing; Han, Dayong; Wang, Kaikai; Zhong, Chen; Hou, Xu; Zhao, Wenyang; Shu, Mengting; Wang, Xinzhuang; Zhao, Shiguang] Harbin Med Univ, Inst Neurosci, Sinorussian Med Res Ctr, 23 Youzheng St, Harbin 150001, Heilongjiang, Peoples R China; [Ma, Jichao] Harbin Med Univ, Dept Pharmacol, Coll Pharm, State Prov Key Labs Biomed Pharmaceut China, 157 Baojian St, Harbin 150001, Heilongjiang, Peoples R China		Zhao, SG (corresponding author), Harbin Med Univ, Affiliated Hosp 1, Dept Neurosurg, 23 Youzheng St, Harbin 150001, Heilongjiang, Peoples R China.; Zhao, SG (corresponding author), Harbin Med Univ, Inst Brain Sci, 23 Youzheng St, Harbin 150001, Heilongjiang, Peoples R China.; Zhao, SG (corresponding author), Harbin Med Univ, Inst Neurosci, Sinorussian Med Res Ctr, 23 Youzheng St, Harbin 150001, Heilongjiang, Peoples R China.	guangsz@hotmail.com	Zhang, Daming/AAD-3489-2019	Zhang, Daming/0000-0003-0280-2093; Wang, Xiaoxiong/0000-0002-8949-8970	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81572482, 81672486, 81402062]; Postgraduate Innovation Research Project (Sino-Russia Special Fund) of Harbin Medical University [YJSCX2017-57HYD]; Special Fund for Translational Research of Sino-Russia Medical Research Center in Harbin Medical University [CR201410]	This work was surpported by the National Natural Science Foundation of China (grant numbers 81572482, 81672486, and 81402062), Postgraduate Innovation Research Project (Sino-Russia Special Fund) of Harbin Medical University (YJSCX2017-57HYD to X.X.W.) and the Special Fund for Translational Research of Sino-Russia Medical Research Center in Harbin Medical University (grant number CR201410 to S.G.Z.).	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OCT 9	2018	9								1032	10.1038/s41419-018-1058-z			15	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	GW1VA	WOS:000446668100006	30302016	gold, Green Published			2022-04-25	
J	Zhong, S; Ji, DF; Li, YG; Lin, TB; Lv, ZQ; Chen, HP				Zhong, Shi; Ji, Dong-Feng; Li, You-Gui; Lin, Tian-Bao; Lv, Zhi-Qiang; Chen, Hua-Ping			Activation of P27kip1-cyclin D1/E-CDK2 pathway by polysaccharide from Phellinus linteus leads to S-phase arrest in HT-29 cells	CHEMICO-BIOLOGICAL INTERACTIONS			English	Article						Polysaccharide; S-phase arrest; P27kip1; Cyclins/CDK complexes	DEPENDENT KINASE INHIBITOR; COLON-CANCER CELLS; CYCLE ARREST; P27(KIP1); APOPTOSIS; DEATH; INDUCTION; ANTITUMOR; G(1)	Our previous study showed that polysaccharide (P1) from Phellinus linteus exhibits a significant inhibitive activity on human colorectal carcinoma cells (HT-29). However its novel molecular mechanism remains unknown. To obtain insights into P1's mechanism of action, we examined its effects on cell proliferation in vitro and in vivo, cell cycle distribution, apoptosis, autophagy, and expression of several cell cycle interrelated proteins in HT-29 cells. Interestingly, we found that volume and weight of the solid tumor significantly decreased in P1(200 mg/kg)-treated mice compared with the control. However, slightly increased the body weight of the P1 treated tumor-bearing mice, with no significant increased ALT, AST levels in serum and LPO concentration in liver and kidney indicated that P1 has no toxicity to mammals at a dose of 200 mg/kg. Furthermore, P1 caused a significantly dose-dependent increase in the S-phase cell cycle, but no apoptosis and autophagy in HT-29 cells. RT-PCR and Western blot results showed significantly down-regulated expressions of cyclin D1, cyclin E, and CDK2, as well as increased expressions of P27kip1 in P1(100 mu g/mL)-treated HT-29 cells. These results suggested that the activation of P27kip1-cyclin D1/E-CDK2 pathway is involved in P1-induced S-phase cell cycle arrest in HT-29 cells. (C) 2013 Elsevier Ireland Ltd. All rights reserved.	[Zhong, Shi; Ji, Dong-Feng; Li, You-Gui; Lin, Tian-Bao; Lv, Zhi-Qiang] Zhejiang Acad Agr Sci, Sericultural Res Inst, Hangzhou 310021, Zhejiang, Peoples R China; [Chen, Hua-Ping] Hangzhou Qing Zheng Biol Sci Technol Co, Hangzhou 311700, Zhejiang, Peoples R China		Ji, DF (corresponding author), 198 Shigiao Rd, Hangzhou 310021, Zhejiang, Peoples R China.	dong_fengji@126.com			earmarked fund for Modern Agro-Industry Technology Research System of China [CARS-22-ZJ0105]; Zhejiang Sericultural Sci-Tech Innovation Team [2011R50028]; Zhejiang Academy of Agricultural Science [2012R06Y01E01]	We are grateful to Hangzhou Biosci Biotech Co., Ltd. for their technical assistance. This study was supported by the earmarked fund for Modern Agro-Industry Technology Research System of China (CARS-22-ZJ0105), by the Zhejiang Sericultural Sci-Tech Innovation Team (2011R50028), and by the Zhejiang Academy of Agricultural Science (2012R06Y01E01).	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Interact.	NOV 25	2013	206	2					222	229		10.1016/j.cbi.2013.09.008			8	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology	273GK	WOS:000328523100013	24060681				2022-04-25	
J	Zheng, Z; Xu, LT; Zhang, SF; Li, WP; Tou, FF; He, QS; Rao, J; Shen, Q				Zheng, Zhi; Xu, Liting; Zhang, Shuofeng; Li, Wuping; Tou, Fangfang; He, Qinsi; Rao, Jun; Shen, Qiang			Peiminine inhibits colorectal cancer cell proliferation by inducing apoptosis and autophagy and modulating key metabolic pathways	ONCOTARGET			English	Article						colorectal cancer; peiminine; natural product; metabolomics; cancer therapy	POLYUNSATURATED FATTY-ACIDS; BIOMARKERS; DISEASE; DEATH; ADENOSYLHOMOCYSTEINE; SIGNATURES; DIAGNOSIS; GLUTAMINE; SURVIVAL; IDENTIFY	Peiminine, a compound extracted from the bulbs of Fritillaria thunbergii and traditionally used as a medication in China and other Asian countries, was reported to inhibit colorectal cancer cell proliferation and tumor growth by inducing autophagic cell death. However, its mechanism of anticancer action is not well understood, especially at the metabolic level, which was thought to primarily account for peiminine's efficacy against cancer. Using an established metabolomic profiling platform combining ultra-performance liquid chromatography/tandem mass spectrometry with gas chromatography/mass spectrometry, we identified metabolic alterations in colorectal cancer cell line HCT-116 after peiminine treatment. Among the identified 236 metabolites, the levels of 57 of them were significantly (p < 0.05) different between peiminine-treated and - untreated cells in which 45 metabolites were increased and the other 12 metabolites were decreased. Several of the affected metabolites, including glucose, glutamine, oleate (18: 1n9), and lignocerate (24: 0), may be involved in regulation of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway and in the oxidative stress response upon peiminine exposure. Peiminine predominantly modulated the pathways responsible for metabolism of amino acids, carbohydrates, and lipids. Collectively, these results provide new insights into the mechanisms by which peiminine modulates metabolic pathways to inhibit colorectal cancer cell growth, supporting further exploration of peiminine as a potential new strategy for treating colorectal cancer.	[Zheng, Zhi; Xu, Liting; Li, Wuping; Tou, Fangfang; He, Qinsi; Rao, Jun] Jiangxi Canc Hosp, Jiangxi Canc Ctr, Dept Internal Med, Jiangxi Prov Key Lab Translat Med & Oncol,Div 5, Nanchang 330029, Jiangxi, Peoples R China; [Zheng, Zhi; Xu, Liting; Tou, Fangfang; He, Qinsi; Rao, Jun] Nanchang Univ, Sch Grad Study, Med Coll, Nanchang 330029, Jiangxi, Peoples R China; [Zheng, Zhi; Shen, Qiang] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA; [Zhang, Shuofeng] Beijing Univ Chinese Med, Dept Pharmacol, Beijing 100102, Peoples R China		Rao, J (corresponding author), Jiangxi Canc Hosp, Jiangxi Canc Ctr, Dept Internal Med, Jiangxi Prov Key Lab Translat Med & Oncol,Div 5, Nanchang 330029, Jiangxi, Peoples R China.; Rao, J (corresponding author), Nanchang Univ, Sch Grad Study, Med Coll, Nanchang 330029, Jiangxi, Peoples R China.; Shen, Q (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA.	raojun1986@126.com; qshen@mdanderson.org		Shen, Qiang/0000-0002-1491-5434	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81260592, 81303119]; Cancer Center Support Grant from the NIH/NCI (MDACC) [CA016672]; Startup fund from MDACC; Duncan Family Institute Seed Funding Research Program; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016672] Funding Source: NIH RePORTER	This work was supported by grant No. 81260592 and No. 81303119 from the National Natural Science Foundation of China (ZZ); in part by a Cancer Center Support Grant CA016672 from the NIH/NCI (MDACC); Startup fund from MDACC (QS); and Duncan Family Institute Seed Funding Research Program (QS). The authors thank Amy Ninetto, PhD, ELS, Department of Scientific Publications, The University of Texas MD Anderson Cancer Center for her editing of the manuscript.	Alonso-Aperte E, 2008, EUR J CLIN NUTR, V62, P295, DOI 10.1038/sj.ejcn.1602722; Altman BJ, 2016, NAT REV CANCER, V16, P619, DOI 10.1038/nrc.2016.71; Andres Ibarra R, 2011, HPB SURG, V2011; Aran V, 2016, CLIN COLORECTAL CANC, V15, P195, DOI 10.1016/j.clcc.2016.02.008; Bertini I, 2012, CANCER RES, V72, P356, DOI 10.1158/0008-5472.CAN-11-1543; Brosnan JT, 2013, AMINO ACIDS, V45, P413, DOI 10.1007/s00726-012-1280-4; Calder PC, 2009, BIOCHIMIE, V91, P791, DOI 10.1016/j.biochi.2009.01.008; Chan ECY, 2009, J PROTEOME RES, V8, P352, DOI 10.1021/pr8006232; Coghlin C, 2015, PROTEOM CLIN APPL, V9, P64, DOI 10.1002/prca.201400082; Currie E, 2013, CELL METAB, V18, P153, DOI 10.1016/j.cmet.2013.05.017; da Silva T, 2015, ANN ONCOL, V26, DOI 10.1093/annonc/mdv233.190; Dang CV, 2012, GENE DEV, V26, P877, DOI 10.1101/gad.189365.112; Daye D, 2012, SEMIN CELL DEV BIOL, V23, P362, DOI 10.1016/j.semcdb.2012.02.002; de Wit M, 2014, J PROTEOMICS, V99, P26, DOI 10.1016/j.jprot.2014.01.001; DeBerardinis RJ, 2008, CELL METAB, V7, P11, DOI 10.1016/j.cmet.2007.10.002; Gao D, 2016, J CHROMATOGR B, V1014, P17, DOI 10.1016/j.jchromb.2016.01.003; Gao R, 2015, SCI REP-UK, V5, DOI 10.1038/srep18175; Gilroy DW, 2004, FASEB J, V18, P489, DOI 10.1096/fj.03-0837com; Guo H, 2013, MOL MED REP, V7, P1103, DOI 10.3892/mmr.2013.1312; Halama A, 2015, J TRANSL MED, V13, DOI 10.1186/s12967-015-0576-z; Huang Q, 2013, CANCER RES, V73, P4992, DOI 10.1158/0008-5472.CAN-13-0308; Ingrosso D, 2003, LANCET, V361, P1693, DOI 10.1016/S0140-6736(03)13372-7; Jemal A, 2011, CA-CANCER J CLIN, V61, P69, DOI [10.3322/caac.20107, 10.3322/caac.20115]; Jin X, 2014, ONCOTARGET, V5, P1635, DOI 10.18632/oncotarget.1744; Ko H, 2011, J CELL BIOCHEM, V112, P2471, DOI 10.1002/jcb.23171; Li QG, 2016, INT J CANCER, V139, P2502, DOI 10.1002/ijc.30388; Lu SC, 2000, INT J BIOCHEM CELL B, V32, P391, DOI 10.1016/S1357-2725(99)00139-9; Ludwig C, 2009, MAGN RESON CHEM, V47, pS68, DOI 10.1002/mrc.2519; Lyu Q, 2015, BIOCHEM BIOPH RES CO, V462, P38, DOI 10.1016/j.bbrc.2015.04.102; McDunn JE, 2013, PROSTATE, V73, P1547, DOI 10.1002/pros.22704; Mondul A, 2015, P 106 ANN M AM ASS C, P75; O'Donovan TR, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0134676; O'Neill LAJ, 2016, NAT REV IMMUNOL, V16, P553, DOI 10.1038/nri.2016.70; Raina K, 2013, AUTOPHAGY, V9, P697, DOI 10.4161/auto.23960; Rao J, 2014, METABOLOMICS, V10, P775, DOI 10.1007/s11306-014-0624-3; Santos CR, 2012, FEBS J, V279, P2610, DOI 10.1111/j.1742-4658.2012.08644.x; Shimizu S, 2014, INT J MOL SCI, V15, P3145, DOI 10.3390/ijms15023145; Sullivan LB, 2016, NAT REV CANCER, V16, P680, DOI 10.1038/nrc.2016.85; Tan SZ, 2016, EYE, V30, P773, DOI 10.1038/eye.2016.37; Toiyama Y, 2013, JNCI-J NATL CANCER I, V105, P849, DOI 10.1093/jnci/djt101; Tolstikov V, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0114019; Trincheri NF, 2007, CARCINOGENESIS, V28, P922, DOI 10.1093/carcin/bgl223; Tsujimoto Y, 2003, J CELL PHYSIOL, V195, P158, DOI 10.1002/jcp.10254; Uchiyama K, 2017, J GASTROENTEROL, V52, P677, DOI 10.1007/s00535-016-1261-6; Valli A, 2008, CLIN CHIM ACTA, V395, P106, DOI 10.1016/j.cca.2008.05.018; Wang H, 2016, ONCOGENE, V35, P2011, DOI 10.1038/onc.2015.304; WARBURG O, 1956, SCIENCE, V123, P309, DOI 10.1126/science.123.3191.309; White E, 2015, CLIN CANCER RES, V21, P5037, DOI 10.1158/1078-0432.CCR-15-0490; Woodle ES, 1998, TRANSPLANTATION, V66, P681, DOI 10.1097/00007890-199809270-00001; Wu XD, 2014, MED ONCOL, V31, DOI 10.1007/s12032-014-0894-7; Xue Y, 2015, MUTAGENESIS, V30, P303, DOI 10.1093/mutage/geu076; Zhao GX, 2005, BIOCHEM BIOPH RES CO, V336, P909, DOI 10.1016/j.bbrc.2005.08.204; Zheng Z, 2016, OPEN LIFE SCI, V11, P358, DOI 10.1515/biol-2016-0047	53	27	29	4	28	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	JUL 18	2017	8	29					47619	47631		10.18632/oncotarget.17411			13	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	FA8KD	WOS:000405694000076	28496003	gold, Green Published, Green Submitted			2022-04-25	
J	Wang, JG; Zhang, JB; Zhang, CJ; Wong, YK; Lim, TK; Hua, ZC; Liu, B; Tannenbaum, SR; Shen, HM; Lin, QS				Wang, Jigang; Zhang, Jianbin; Zhang, Chong-Jing; Wong, Yin Kwan; Lim, Teck Kwang; Hua, Zi-Chun; Liu, Bin; Tannenbaum, Steven R.; Shen, Han-Ming; Lin, Qingsong			In situ Proteomic Profiling of Curcumin Targets in HCT116 Colon Cancer Cell Line	SCIENTIFIC REPORTS			English	Article							MAMMALIAN TARGET; AUTOPHAGY; RAPAMYCIN; MTOR; DERIVATIVES; MECHANISM; SURVIVAL; PATHWAY; PROBE	To date, the exact targets and mechanism of action of curcumin, a natural product with anti-inflammatory and anti-cancer properties, remain elusive. Here we synthesized a cell permeable curcumin probe (Cur-P) with an alkyne moiety, which can be tagged with biotin for affinity enrichment, or with a fluorescent dye for visualization of the direct-binding protein targets of curcumin in situ. iTRAQ (TM) quantitative proteomics approach was applied to distinguish the specific binding targets from the non-specific ones. In total, 197 proteins were confidently identified as curcumin binding targets from HCT116 colon cancer cell line. Gene Ontology analysis showed that the targets are broadly distributed and enriched in the nucleus, mitochondria and plasma membrane, and they are involved in various biological functions including metabolic process, regulation, response to stimulus and cellular process. Ingenuity Pathway Analysis (TM) (IPA) suggested that curcumin may exert its anticancer effects over multiple critical biological pathways including the EIF2, eIF4/p70S6K, mTOR signaling and mitochondrial dysfunction pathways. Functional validations confirmed that curcumin downregulates cellular protein synthesis, and induces autophagy, lysosomal activation and increased ROS production, thus leading to cell death.	[Wang, Jigang; Tannenbaum, Steven R.] Singapore MIT Alliance Res & Technol SMART, Interdisciplinary Res Grp Infect Dis, Singapore 138602, Singapore; [Wang, Jigang; Wong, Yin Kwan; Lim, Teck Kwang; Lin, Qingsong] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore; [Wang, Jigang; Hua, Zi-Chun] Nanjing Univ, Coll Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China; [Zhang, Jianbin; Shen, Han-Ming] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore; [Zhang, Chong-Jing; Liu, Bin] Natl Univ Singapore, Dept Chem & Biomol Engn, Singapore 117585, Singapore; [Tannenbaum, Steven R.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA; [Tannenbaum, Steven R.] MIT, Dept Chem, Cambridge, MA 02139 USA		Wang, JG (corresponding author), Singapore MIT Alliance Res & Technol SMART, Interdisciplinary Res Grp Infect Dis, Singapore 138602, Singapore.; Wang, JG; Lin, QS (corresponding author), Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore.; Wang, JG (corresponding author), Nanjing Univ, Coll Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China.; Shen, HM (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore.	jigang@smart.mit.edu; han-ming_shen@nuhs.edu.sg; dbslinqs@nus.edu.sg	Liu, Bin/K-6445-2012; SHEN, Han-Ming/B-5942-2011; Zhang, Chong-Jing/AAO-5782-2021	Liu, Bin/0000-0002-0956-2777; SHEN, Han-Ming/0000-0001-7369-5227; Zhang, Chong-Jing/0000-0002-3396-9999	NUS research scholarshipNational University of Singapore	J.Z. is supported by NUS research scholarship. We thank Dr. Liqian Gao and Dr. Siewli Lai for critical review of this manuscript.	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J	Tavera-Mendoza, L; Wang, TT; Lallemant, B; Zhang, R; Nagai, Y; Bourdeau, R; Calderon, MR; Desbarats, J; Mader, S; White, JH				Tavera-Mendoza, L; Wang, TT; Lallemant, B; Zhang, R; Nagai, Y; Bourdeau, R; Calderon, MR; Desbarats, J; Mader, S; White, JH			Convergence of vitamin D and retinoic acid signalling at a common hormone response element	EMBO REPORTS			English	Article						vitamin D; retinoic acid; nuclear receptors; autophagy; cross-talk; cyclin-dependent kinase inhibitors	SQUAMOUS CARCINOMA-CELLS; COLON-CANCER CELLS; INDUCED DIFFERENTIATION; ANALOG EB1089; DEPENDENT KINASES; GENE-EXPRESSION; IMMUNE-SYSTEM; PROLIFERATION; PROTEIN; CHEMOPREVENTION	Although 1,25-dihydroxyvitamin D-3 (1,25D(3)) and retinoic acid ( RA) have distinct developmental and physiological roles, both regulate the cell cycle. We provide molecular and genomic evidence that their cognate nuclear receptors regulate common genes through everted repeat TGA(C/T) TPyN8PuG(G/T) TCA (ER8) response elements. ER8 motifs were found in the promoters of several target genes of 1,25D3 and/or RA. Notably, an element was characterized in the cyclin-dependent kinase (CDK) inhibitor p19(ink4d) gene, and 1,25D(3)- or RA-induced p19(INK4D) expression. P19(ink4d) knockdown together with depletion of p27(kip1), another CDK inhibitor regulated by 1,25D3 and RA, rendered cells resistant to ligand-induced growth arrest. Remarkably, p19(INK4D)-deficient cells showed increased autophagic cell death, which was markedly enhanced by 1,25D3, but not RA, and attenuated by loss of p27(KIP1). These results show a limited crosstalk between 1,25D3 and RA signalling by means of overlapping nuclear receptor DNA binding specificities, and uncover a role for p19(INK4D) in control of cell survival.	McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada; McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada; McGill Univ, McGill Univ & Genome Quebec Innovat Ctr, Montreal, PQ, Canada; Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada		White, JH (corresponding author), McGill Univ, Dept Med, 3655 Drummond St, Montreal, PQ H3G 1Y6, Canada.	john.white@mcgill.ca	white, john h/N-9782-2013	white, john h/0000-0002-4785-2687; Desbarats, Julie/0000-0002-2495-7152; Calderon, Mario R/0000-0001-6618-1789			Adachi M, 1997, BLOOD, V90, P126; Akutsu N, 2001, MOL ENDOCRINOL, V15, P1127, DOI 10.1210/me.15.7.1127; Bond J, 2004, EXP CELL RES, V292, P151, DOI 10.1016/j.yexcr.2003.09.021; Bourdeau V, 2004, MOL ENDOCRINOL, V18, P1411, DOI 10.1210/me.2003-0441; Ceruti JM, 2005, ONCOGENE, V24, P4065, DOI 10.1038/sj.onc.1208570; Chambon P, 1996, FASEB J, V10, P940, DOI 10.1096/fasebj.10.9.8801176; Chawla A, 2001, SCIENCE, V294, P1866, DOI 10.1126/science.294.5548.1866; Cobbold SP, 2003, IMMUNOL REV, V196, P109, DOI 10.1046/j.1600-065X.2003.00078.x; Colonna M, 2003, NAT REV IMMUNOL, V3, P445, DOI 10.1038/nri1106; Cunningham JJ, 2002, MOL CELL NEUROSCI, V19, P359, DOI 10.1006/mcne.2001.1090; DIMRI GP, 1995, P NATL ACAD SCI USA, V92, P9363, DOI 10.1073/pnas.92.20.9363; Dow R, 2001, J BIOL CHEM, V276, P45945, DOI 10.1074/jbc.M103593200; Florentin E, 1996, EUR J BIOCHEM, V240, P699, DOI 10.1111/j.1432-1033.1996.0699h.x; Freemantle SJ, 2003, ONCOGENE, V22, P7305, DOI 10.1038/sj.onc.1206936; Gellon G, 1998, BIOESSAYS, V20, P116, DOI 10.1002/(SICI)1521-1878(199802)20:2<116::AID-BIES4>3.3.CO;2-N; HIRAI H, 1995, MOL CELL BIOL, V15, P2762; Hong WK, 1997, SCIENCE, V278, P1073, DOI 10.1126/science.278.5340.1073; Hoyer-Hansen M, 2005, CELL DEATH DIFFER, V12, P1297, DOI 10.1038/sj.cdd.4401651; Kim DG, 2002, J BIOL CHEM, V277, P38930, DOI 10.1074/jbc.M205941200; Lin R, 2004, BIOESSAYS, V26, P21, DOI 10.1002/bies.10368; Lin R, 2003, ENDOCRINOLOGY, V144, P749, DOI 10.1210/en.2002-0026; Lin R, 2002, MOL ENDOCRINOL, V16, P1243, DOI 10.1210/me.16.6.1243; Liu TX, 2000, BLOOD, V96, P1496, DOI 10.1182/blood.V96.4.1496.h8001496_1496_1504; Oyadomari S, 2004, CELL DEATH DIFFER, V11, P381, DOI 10.1038/sj.cdd.4401373; Palmer HG, 2003, CANCER RES, V63, P7799; Stephensen CB, 2001, ANNU REV NUTR, V21, P167, DOI 10.1146/annurev.nutr.21.1.167; TANAKA K, 1995, BIOCHEM BIOPH RES CO, V211, P1023, DOI 10.1006/bbrc.1995.1913; Thompson PD, 2002, BIOCHEM BIOPH RES CO, V299, P730, DOI 10.1016/S0006-291X(02)02742-0; TINI M, 1993, GENE DEV, V7, P295, DOI 10.1101/gad.7.2.295; van Rossum MM, 2000, ARCH DERMATOL RES, V292, P16, DOI 10.1007/PL00007455; Zindy F, 1999, P NATL ACAD SCI USA, V96, P13462, DOI 10.1073/pnas.96.23.13462	31	72	77	0	5	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	1469-221X			EMBO REP	EMBO Rep.	FEB	2006	7	2					180	185		10.1038/sj.embor.7400594			6	Biochemistry & Molecular Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Cell Biology	023QX	WOS:000236142400013	16322758	Green Published			2022-04-25	
J	Vallecillo-Hernandez, J; Barrachina, MD; Ortiz-Masia, D; Coll, S; Esplugues, JV; Calatayud, S; Hernandez, C				Vallecillo-Hernandez, Jorge; Dolores Barrachina, Maria; Ortiz-Masia, Dolores; Coll, Sandra; Vicente Esplugues, Juan; Calatayud, Sara; Hernandez, Carlos			Indomethacin Disrupts Autophagic Flux by Inducing Lysosomal Dysfunction in Gastric Cancer Cells and Increases Their Sensitivity to Cytotoxic Drugs	SCIENTIFIC REPORTS			English	Article							NONSTEROIDAL ANTIINFLAMMATORY DRUGS; DOWN-REGULATION; COLORECTAL-CANCER; INDUCED APOPTOSIS; INHIBITION; DEATH; SUPPRESSION; METASTASIS; MECHANISM; SURVIVIN	NSAIDs inhibit tumorigenesis in gastrointestinal tissues and have been proposed as coadjuvant agents to chemotherapy. The ability of cancer epithelial cells to adapt to the tumour environment and to resist cytotoxic agents seems to depend on rescue mechanisms such as autophagy. In the present study we aimed to determine whether an NSAID with sensitizing properties such as indomethacin modulates autophagy in gastric cancer epithelial cells. We observed that indomethacin causes lysosomal dysfunction in AGS cells and promotes the accumulation of autophagy substrates without altering mTOR activity. Indomethacin enhanced the inhibitory effects of the lysosomotropic agent chloroquine on lysosome activity and autophagy, but lacked any effect when both functions were maximally reduced with another lysosome inhibitor (bafilomycin B1). Indomethacin, alone and in combination with chloroquine, also hindered the autophagic flux stimulated by the antineoplastic drug oxaliplatin and enhanced its toxic effect, increasing the rate of apoptosis/necrosis and undermining cell viability. In summary, our results indicate that indomethacin disrupts autophagic flux by disturbing the normal functioning of lysosomes and, by doing so, increases the sensitivity of gastric cancer cells to cytotoxic agents, an effect that could be used to overcome cancer cell resistance to antineoplastic regimes.	[Vallecillo-Hernandez, Jorge; Dolores Barrachina, Maria; Coll, Sandra; Vicente Esplugues, Juan; Calatayud, Sara; Hernandez, Carlos] Univ Valencia, Fac Med, Dept Farmacol, Ave Blasco Ibanez 15, Valencia 46010, Spain; [Vallecillo-Hernandez, Jorge; Dolores Barrachina, Maria; Ortiz-Masia, Dolores; Coll, Sandra; Vicente Esplugues, Juan; Calatayud, Sara; Hernandez, Carlos] Univ Valencia, Fac Med, CIBERehd, Ave Blasco Ibanez 15, Valencia 46010, Spain; [Ortiz-Masia, Dolores] Univ Valencia, Fac Med, Dept Med, Ave Blasco Ibanez 15, Valencia 46010, Spain; [Vicente Esplugues, Juan; Hernandez, Carlos] Hosp Dr Peset, FISABIO, Ave Cataluna 21, Valencia 46020, Spain		Calatayud, S (corresponding author), Univ Valencia, Fac Med, Dept Farmacol, Ave Blasco Ibanez 15, Valencia 46010, Spain.; Calatayud, S (corresponding author), Univ Valencia, Fac Med, CIBERehd, Ave Blasco Ibanez 15, Valencia 46010, Spain.	sara.calatayud@uv.es	SAEZ, CARLOS HERNANDEZ/M-3029-2014; ORTIZ-MASIA, MARIA DOLORES/M-1413-2017; Esplugues, Juan/ABC-1488-2021; Barrachina, Maria/ABB-9683-2021; Calatayud, Sara/ABB-9665-2021	SAEZ, CARLOS HERNANDEZ/0000-0001-8536-429X; ORTIZ-MASIA, MARIA DOLORES/0000-0002-7924-9962; Calatayud, Sara/0000-0001-9675-2423; Barrachina, Maria Dolores/0000-0002-4332-2929; Esplugues Mota, Juan Vicente/0000-0001-8205-021X	Ministerio de Economia y CompetitividadSpanish Government [SAF2013-43441-P]; European Regional Development Fund of the European Union (ERDF) [SAF2013-43441-P]; Ministerio de Economia, Industria y CompetitividadSpanish Government [SAF2016-80072P]; ERDFEuropean Commission [SAF2016-80072P]; CIBERehd [CB06/04/0071, ACCESS EHD16PI02]; Generalitat ValencianaGeneralitat ValencianaEuropean CommissionGeneral Electric [PROMETEOII/2014/035]; FISABIO [UGP-14-164]; Ministerio de Economia y Competitividad of SpainSpanish Government [RYC-2011-09571]	We thank Brian Normanly for his English language editing. This work was supported by Ministerio de Economia y Competitividad and the European Regional Development Fund of the European Union (ERDF) [SAF2013-43441-P], Ministerio de Economia, Industria y Competitividad and ERDF [SAF2016-80072P], CIBERehd [CB06/04/0071 and ACCESS EHD16PI02], Generalitat Valenciana [PROMETEOII/2014/035] and FISABIO (UGP-14-164). Carlos Hernandez acknowledges support from the 'Ramon y Cajal' program from Ministerio de Economia y Competitividad of Spain (RYC-2011-09571).	Brouxhon S, 2007, CANCER RES, V67, P7654, DOI 10.1158/0008-5472.CAN-06-4415; Chiou SK, 2011, BIOCHEM PHARMACOL, V81, P1317, DOI 10.1016/j.bcp.2011.03.019; Davidson SM, 2017, ANNU REV PHARMACOL, V57, P481, DOI 10.1146/annurev-pharmtox-010715-103101; Deharo E, 2003, BIOCHEM PHARMACOL, V66, P809, DOI 10.1016/S0006-2952(03)00396-4; Florey O, 2015, AUTOPHAGY, V11, P88, DOI 10.4161/15548627.2014.984277; Gewirtz DA, 2016, CANCER RES, V76, P5610, DOI 10.1158/0008-5472.CAN-16-0722; Gowrishankar S, 2016, J CELL BIOL, V212, P617, DOI 10.1083/jcb.201602082; Gurpinar E, 2014, CLIN CANCER RES, V20, P1104, DOI 10.1158/1078-0432.CCR-13-1573; Gyparaki MT, 2014, TRENDS MOL MED, V20, P239, DOI 10.1016/j.molmed.2014.01.009; Harada S, 2015, J PHARMACOL EXP THER, V355, P353, DOI 10.1124/jpet.115.226431; Hernandez C, 2016, J GASTROENTEROL, V51, P691, DOI 10.1007/s00535-015-1137-1; Huang SB, 2010, AUTOPHAGY, V6, P256, DOI 10.4161/auto.6.2.11124; Huang Z, 2016, INT J CANCER, V139, P23, DOI 10.1002/ijc.29990; Jamshidi F, 2008, CELL CYCLE, V7, P917, DOI 10.4161/cc.7.7.5620; Kenific CM, 2015, TRENDS CELL BIOL, V25, P37, DOI 10.1016/j.tcb.2014.09.001; Klionsky DJ, 2016, AUTOPHAGY, V12, P1, DOI 10.1080/15548627.2015.1100356; Kroemer G, 2015, J CLIN INVEST, V125, P1, DOI 10.1172/JCI78652; LALA PK, 1988, CANCER RES, V48, P1072; Lee HJ, 2017, J CLIN BIOCHEM NUTR, V60, P55, DOI 10.3164/jcbn.16-69; Leibowitz B, 2014, P NATL ACAD SCI USA, V111, P16520, DOI 10.1073/pnas.1415178111; Li M, 2013, J BIOL CHEM, V288, P35769, DOI 10.1074/jbc.M113.511212; Lonnroth C, 2014, INT J ONCOL, V45, P2208, DOI 10.3892/ijo.2014.2686; Ock CY, 2017, J MOL MED, V95, P405, DOI 10.1007/s00109-016-1491-3; Pu J, 2016, J CELL SCI, V129, P4329, DOI 10.1242/jcs.196287; Rebecca VW, 2016, ONCOGENE, V35, P1, DOI 10.1038/onc.2015.99; Restivo A, 2015, BRIT J CANCER, V113, P1133, DOI 10.1038/bjc.2015.336; Ricchi P, 2003, BRIT J CANCER, V88, P803, DOI 10.1038/sj.bjc.6600829; Sahin IH, 2014, CANCER LETT, V345, P249, DOI 10.1016/j.canlet.2013.09.001; Soon SS, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0107866; Sun WY, 2016, ONCOL LETT, V11, P4193, DOI 10.3892/ol.2016.4493; Tse AKW, 2014, J INVEST DERMATOL, V134, P1397, DOI 10.1038/jid.2013.471; Wu WKK, 2009, BIOCHEM BIOPH RES CO, V382, P79, DOI 10.1016/j.bbrc.2009.02.140; Yu L, 2009, MOL PHARMACOL, V75, P1364, DOI 10.1124/mol.108.053546	33	22	22	0	12	NATURE PUBLISHING GROUP	LONDON	MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND	2045-2322			SCI REP-UK	Sci Rep	FEB 26	2018	8								3593	10.1038/s41598-018-21455-1			10	Multidisciplinary Sciences	Science Citation Index Expanded (SCI-EXPANDED)	Science & Technology - Other Topics	FX4KW	WOS:000426045700014	29483523	Green Published, gold			2022-04-25	
J	Behrouj, H; Seghatoleslam, A; Mokarram, P; Ghavami, S				Behrouj, Hamid; Seghatoleslam, Atefeh; Mokarram, Pooneh; Ghavami, Saeid			Effect of casein kinase 1 alpha inhibition on autophagy flux and the AKT/phospho-beta-catenin (S552) axis in HCT116, a RAS-mutated colorectal cancer cell line	CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY			English	Article						RAS oncogene; casein kinase 1 alpha; autophagy; AKT pathway; phospho-beta-catenin (S552)	UNFOLDED PROTEIN RESPONSE; WNT/BETA-CATENIN; COLON-CANCER; MTOR; PHOSPHORYLATION; SUPPRESSES; APOPTOSIS; PATHWAY; DEATH; AKT	The Wnt/beta-catenin pathway, which interferes with cell proliferation, differentiation, and autophagy, is commonly dysregulated in colorectal cancer (CRC). Mutation of the RAS oncogene is the most prevalent genetic alteration in CRC and has been linked to activation of protein kinase B (AKT) signaling. Phosphorylation of beta-catenin at Ser 552 by AKT contributes to beta-catenin stability, transcriptional activity, and increase of cell proliferation. Casein kinase 1 alpha (CK1 alpha) is an enzyme that simultaneously regulates Wnt/beta-catenin and AKT. The link of the AKT and Wnt pathway to autophagy in RAS-mutated CRC cells has not well identified. Therefore, we investigated how pharmacological CK1 alpha inhibition (D4476) is involved in regulation of autophagy, Wnt/beta-catenin, and An pathways in RAS-mutated CRC cell lines. qRT-PCR and immunoblotting experiments revealed that phospho-AKT (S473) and phospho-beta-catenin (S552) are constitutively increased in RAS-mutated CRC cell lines, in parallel with augmented CK1 alpha expression. The results also showed that D4476 significantly reduced the AKT/phospho-beta-catenin (S552) axis concomitantly with autophagy flux inhibition in RAS-mutated CRC cells. Furthermore, D4476 significantly induced apoptosis in RAS-mutated CRC cells. In conclusion, our results indicate that CK1 alpha inhibition reduces autophagy flux and promotes apoptosis by interfering with the AKT/phospho-beta-catenin (S552) axis in RAS-mutated CRC cells.	[Behrouj, Hamid; Seghatoleslam, Atefeh; Mokarram, Pooneh] Shiraz Univ Med Sci, Sch Med, Dept Biochem, Shiraz, Iran; [Mokarram, Pooneh; Ghavami, Saeid] Shiraz Univ Med Sci, Autophagy Res Ctr, Shiraz, Iran; [Ghavami, Saeid] Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada; [Ghavami, Saeid] Univ Manitoba, Res Inst Oncol & Hematol, Canc Care Manitoba, Winnipeg, MB, Canada; [Ghavami, Saeid] Katowice Sch Technol, Fac Med, Katowice, Poland		Mokarram, P (corresponding author), Shiraz Univ Med Sci, Sch Med, Dept Biochem, Shiraz, Iran.; Mokarram, P; Ghavami, S (corresponding author), Shiraz Univ Med Sci, Autophagy Res Ctr, Shiraz, Iran.; Ghavami, S (corresponding author), Univ Manitoba, Max Rady Coll Med, Rady Fac Hlth Sci, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada.; Ghavami, S (corresponding author), Univ Manitoba, Res Inst Oncol & Hematol, Canc Care Manitoba, Winnipeg, MB, Canada.; Ghavami, S (corresponding author), Katowice Sch Technol, Fac Med, Katowice, Poland.	mokaram2@gmail.com; saeid.ghavami@umanitoba.ca	Behrouj, Hamid/AAC-1604-2022	Ghavami, Saeid/0000-0001-5948-508X	Shiraz University of Medical Sciences [96-15414]; office of the President and Vice President for Science and Technology, Iran National Science Foundation (INSF) [96015616]	This article was adapted from the thesis written by Hamid Behrouj and was financially supported by Shiraz University of Medical Sciences Grant No. 96-15414. P. Mokarram and S. Ghavami conceived and designed the analysis, verified the analytical methods, monitored the data of this study, and drafted the manuscript. H. Behrouj contributed in data collection, analysis, and interpretation and in the literature search. A. Seghatoleslam verified the analytical methods. All authors critically evaluated the data and approved the final manuscript. This project was also supported by the office of the President and Vice President for Science and Technology, Iran National Science Foundation (INSF; Grant No. 96015616). The authors would like to thank Science Impact (Winnipeg, Canada) for (post-)editing themanuscript.	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J. Physiol. Pharmacol.	MAR	2021	99	3					284	293		10.1139/cjpp-2020-0449			10	Pharmacology & Pharmacy; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Physiology	QX2OM	WOS:000629187400004	33635146				2022-04-25	
J	Martisova, A; Sommerova, L; Kuricova, K; Podhorec, J; Vojtesek, B; Kankova, K; Hrstka, R				Martisova, Andrea; Sommerova, Lucia; Kuricova, Katarina; Podhorec, Jan; Vojtesek, Borivoj; Kankova, Katerina; Hrstka, Roman			AGR2 silencing contributes to metformin-dependent sensitization of colorectal cancer cells to chemotherapy	ONCOLOGY LETTERS			English	Article						AGR2; diabetes mellitus; colorectal cancer; AMPK; autophagy; ROS	PROTEIN DISULFIDE-ISOMERASE; DIABETES-MELLITUS; ANTERIOR GRADIENT-2; PANCREATIC-CANCER; STEM-CELLS; PROMOTES; SURVIVAL; RISK; 5-FLUOROURACIL; PROLIFERATION	There is growing epidemiological evidence indicating an association between diabetes mellitus and the increased incidence of colorectal cancer (CRC). The preferred initial and most widely used pharmacological agent for the treatment of type 2 diabetes is metformin, which in parallel reduces the risk of CRC and improves patient prognosis. AMP-activated protein kinase (AMPK) appears to be tightly associated with the beneficial metabolic effects of metformin, serving as a cellular energy sensor activated in response to a variety of conditions that deplete cellular energy levels. Such conditions include nutrient starvation (particularly glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. The aim of the present study was to determine the effect of metformin on CRC cell lines, with different levels of anterior gradient 2 (AGR2) expression, exposed to 5-fluorouracil (5-FU) and oxaliplatin, alone or in combination with metformin. AGR2 has recently emerged as a factor involved in colon carcinogenesis. In AGR2-knockout cells, markedly higher levels of phosphorylated-AMPK were observed in comparison with control cells transfected with GFP-scrambled guide RNA, which indicated that the presence of AGR2 may interfere with the metformin-dependent activation of AMPK. In addition, metformin in combination with 5-FU and oxaliplatin induced ROS production and attenuated autophagy. This effect was enhanced in AGR2-knockout cells.	[Martisova, Andrea; Sommerova, Lucia; Podhorec, Jan; Vojtesek, Borivoj; Kankova, Katerina; Hrstka, Roman] Masaryk Mem Canc Inst, Reg Ctr Appl Mol Oncol, Zluty Kopec 7, Brno 65653, Czech Republic; [Kuricova, Katarina; Kankova, Katerina] Masaryk Univ, Fac Med, Dept Pathophysiol, Brno 62500, Czech Republic		Hrstka, R (corresponding author), Masaryk Mem Canc Inst, Reg Ctr Appl Mol Oncol, Zluty Kopec 7, Brno 65653, Czech Republic.	hrstka@mou.cz	Chalásová, Katarína/ABA-6857-2021; Hrstka, Roman/AAM-4430-2020	Chalásová, Katarína/0000-0003-4796-5152; Hrstka, Roman/0000-0002-6139-2664; Kankova, Katerina/0000-0001-9548-0630; Kankova, Katerina/0000-0002-5574-1768; Martisova, Andrea/0000-0002-0081-0498	Ministry of Health, Czech Republic-Conceptual Development of Research Organization (Masaryk Memorial Cancer Institute) [00209805]; MEYS-NPS I [LO1413]; GACRGrant Agency of the Czech Republic [16-14829S, 19-02014S]	The present study was supported by the Ministry of Health, Czech Republic-Conceptual Development of Research Organization (Masaryk Memorial Cancer Institute; grant no. 00209805), by the project MEYS-NPS I-LO1413 and GACR 16-14829S and 19-02014S.	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Lett.	NOV	2019	18	5					4964	4973		10.3892/ol.2019.10800			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JW7HS	WOS:000503219600064	31612008	Green Published, gold			2022-04-25	
J	Pouyafar, A; Rezabakhsh, A; Rahbarghazi, R; Heydarabad, MZ; Shokrollahi, E; Sokullu, E; Khaksar, M; Nourazarian, A; Avci, CB				Pouyafar, Ayda; Rezabakhsh, Aysa; Rahbarghazi, Reza; Heydarabad, Milad Zadi; Shokrollahi, Elhameh; Sokullu, Emel; Khaksar, Majid; Nourazarian, Alireza; Avci, Cigir Biray			Treatment of cancer stem cells from human colon adenocarcinoma cell line HT-29 with resveratrol and sulindac induced mesenchymal-endothelial transition rate	CELL AND TISSUE RESEARCH			English	Article						Human cancer stem cells; Sulindac; Resveratrol; Endothelial differentiation; Autophagy	RESISTANCE	In the current experiment, the combined regime of resveratrol and a Wnt-3a inhibitor, sulindac, were examined on the angiogenic potential of cancer stem cells from human colon adenocarcinoma cell line HT-29 during 7days. Cancer stem cells were enriched via a magnetic-activated cell sorter technique and cultured in endothelial induction medium containing sulindac and resveratrol. Expression of endothelial markers such as the von Willebrand factor (vWF) and vascular endothelial cadherin (VE-cadherin) and genes participating in mesenchymal-to-epithelial transition was studied by real-time PCR assay. Protein levels of Wnt-3a and angiogenic factor YKL-40 were examined by western blotting. ELISA was used to determine the level of N-acetylgalactosaminyltransferase 11 (GALNT11) during mesenchymal-endothelial transition. Autophagy status was monitored by PCR array under treatment with the resveratrol plus sulindac. Results showed that resveratrol and sulindac had the potential to decrease the cell survival of HT-29 cancer cells and the clonogenic capacity of cancer stem cells compared with the control (p<0.05). The expression of VE-cadherin and vWF was induced in cancer stem cells incubated with endothelial differentiation medium enriched with resveratrol (p<0.05). Interestingly, the Wnt-3a level was increased in the presence of resveratrol and sulindac (p<0.05). YKL-40 was reduced after cell exposure to sulindac and resveratrol. The intracellular content of resistance factor GALNT11 was diminished after treatment with resveratrol (p<0.05). Resveratrol had the potential to induce the transcription of autophagy signaling genes in cancer stem cells during endothelial differentiation (p<0.05). These data show that resveratrol could increase cancer stem cell trans-differentiation toward endothelial lineage while decrease cell resistance by modulation of autophagy signaling and GALNT11 synthesis.	[Pouyafar, Ayda; Rahbarghazi, Reza; Shokrollahi, Elhameh; Khaksar, Majid] Tabriz Univ Med Sci, Stem Cell Res Ctr, Imam Reza St,Golgasht St, Tabriz 5166614756, Iran; [Rezabakhsh, Aysa] Tabriz Univ Med Sci, Aging Res Inst, Tabriz, Iran; [Rahbarghazi, Reza] Tabriz Univ Med Sci, Fac Adv Med Sci, Dept Appl Cell Sci, Tabriz, Iran; [Heydarabad, Milad Zadi] Yasuj Univ Med Sci, Med Plants Res Ctr, Yasuj, Iran; [Sokullu, Emel] Izmir Katip Celebi Univ, Bioengn Dept, Izmir, Turkey; [Sokullu, Emel] Harvard Med Sch, Harvard MIT Hlth Sci & Technol, Div Biomed Engn, Brigham & Womens Hosp, Cambridge, MA USA; [Nourazarian, Alireza] Tabriz Univ Med Sci, Fac Med, Dept Biochem & Clin Labs, Golgasht St, Tabriz 5166616471, Iran; [Avci, Cigir Biray] Ege Univ, Fac Med, Dept Med Biol, Izmir, Turkey		Rahbarghazi, R (corresponding author), Tabriz Univ Med Sci, Stem Cell Res Ctr, Imam Reza St,Golgasht St, Tabriz 5166614756, Iran.; Rahbarghazi, R (corresponding author), Tabriz Univ Med Sci, Fac Adv Med Sci, Dept Appl Cell Sci, Tabriz, Iran.; Nourazarian, A (corresponding author), Tabriz Univ Med Sci, Fac Med, Dept Biochem & Clin Labs, Golgasht St, Tabriz 5166616471, Iran.; Avci, CB (corresponding author), Ege Univ, Fac Med, Dept Med Biol, Izmir, Turkey.	rezarahbardvm@gmail.com; Nourazariana@tbzmed.ac.ir; cbavci@gmail.com	Rahbarghazi, Reza/L-7238-2017; Avci, Cigir Biray/AAH-2300-2019; Rezabakhsh, Aysa/AAZ-1312-2020; Nourazarian, Alireza/G-3873-2015	Rahbarghazi, Reza/0000-0003-3864-9166; Avci, Cigir Biray/0000-0001-8251-4520; Rezabakhsh, Aysa/0000-0003-3942-7848; Sokullu, Emel/0000-0003-1302-1997; Nourazarian, Alireza/0000-0003-2082-1335	Tabriz University of Medical Sciences	This study was supported by a grant from the Tabriz University of Medical Sciences.	Akbarzadeh M, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-16940-y; Bomken S, 2010, BRIT J CANCER, V103, P439, DOI 10.1038/sj.bjc.6605821; Buhrmann C, 2018, NUTRIENTS, V10, DOI 10.3390/nu10070888; Campagnolo P, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0125122; Cilibrasi C, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0169854; Della Corte CM, 2014, BIOMEDICINES, V2, P345, DOI 10.3390/biomedicines2040345; Desiderio V, 2015, ONCOTARGET, V6, P71, DOI 10.18632/oncotarget.2698; Druzhkova I, 2019, CLIN COLORECTAL CANC, V18, pE74, DOI 10.1016/j.clcc.2018.10.003; Du BW, 2016, MOLECULES, V21, DOI 10.3390/molecules21070965; Evans C, 2006, BRIT J CANCER, V94, P1412, DOI 10.1038/sj.bjc.6603104; Fan F, 2012, CANCER MED-US, V1, P5, DOI 10.1002/cam4.4; Fu YJ, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0102535; HARRISON DE, 1991, BLOOD, V78, P1237; Hope C, 2008, MOL NUTR FOOD RES, V52, pS52, DOI 10.1002/mnfr.200700448; Huang F, 2014, EXP THER MED, V7, P1611, DOI 10.3892/etm.2014.1662; Jia ZF, 2010, J NEURO-ONCOL, V98, P329, DOI 10.1007/s11060-009-0092-1; Krushkal J, 2017, CANCER INFORM, V16, DOI 10.1177/1176935117747259; Pandey PR, 2011, BREAST CANCER RES TR, V130, P387, DOI 10.1007/s10549-010-1300-6; Reddivari L, 2016, BMC COMPLEM ALTERN M, V16, DOI 10.1186/s12906-016-1254-2; Rezabakhsh A, 2017, J CELL BIOCHEM, V118, P1518, DOI 10.1002/jcb.25814; Rosello S, 2018, CANCER TREAT REV, V63, P156, DOI 10.1016/j.ctrv.2018.01.001; Seino M, 2015, ANTICANCER RES, V35, P85; Signorelli P, 2005, J NUTR BIOCHEM, V16, P449, DOI 10.1016/j.jnutbio.2005.01.017; Wang S, 2012, HUMAN GENET EMBRYOL, VS2, P2161; Yamamoto Y, 1999, J BIOL CHEM, V274, P27307, DOI 10.1074/jbc.274.38.27307; Yao DB, 2011, MOL CANCER RES, V9, P1608, DOI 10.1158/1541-7786.MCR-10-0568; Zhang RR, 2015, STEM CELL RES THER, V6, DOI 10.1186/s13287-015-0249-0; Zhang W, 2010, BMC CANCER, V10, DOI 10.1186/1471-2407-10-593; Zhou S, 2001, NAT MED, V7, P1028, DOI 10.1038/nm0901-1028	29	20	21	1	9	SPRINGER	NEW YORK	233 SPRING ST, NEW YORK, NY 10013 USA	0302-766X	1432-0878		CELL TISSUE RES	Cell Tissue Res.	JUN	2019	376	3					377	388		10.1007/s00441-019-02998-9			12	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	HZ6AP	WOS:000468934500006	30758710				2022-04-25	
J	Liu, Q; Sun, Y; Lv, YF; Le, ZY; Xin, YH; Zhang, P; Liu, Y				Liu, Qi; Sun, Yong; Lv, Yuefeng; Le, Ziyu; Xin, Yuhu; Zhang, Ping; Liu, Yong			TERT alleviates irradiation-induced late rectal injury by reducing hypoxia-induced ROS levels through the activation of NF-kappa B and autophagy	INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE			English	Article						radiation; late rectal injury; hypoxia; telomerase reverse transcriptase; autophagy	ENDOTHELIAL GROWTH-FACTOR; CROSS-TALK; OXIDATIVE STRESS; UP-REGULATION; CANCER CELLS; RADIATION; TELOMERASE; MITOCHONDRIA; RESISTANCE; RESPONSES	The hypoxic microenvironment which is present following irradiation has been proven to promote radiation-induced injury to normal tissues. Previous studies have demonstrated that telomerase reverse transcriptase (TERT) is regulated by hypoxia, and that it plays a protective role in the process of wound repair. However, its effects on radiation-induced injury remain unclear. In this study, we examined the effects of human TERT on irradiation-induced late rectal injury in fibroblasts under hypoxic conditions. We also performed in vivo experiments. The rectums of 5-week-old female C57BL/6N mice were irradiated locally with a single dose of 25 Gy. We then examined the fibrotic changes using hematoxylin and eosin staining, and Masson's staining. The expression of hypoxia inducible factor-1 alpha (HIF-1 alpha) and TERT was analyzed by immunohistochemistry. In in vitro experiments, apoptosis, reactive oxygen species (ROS) production and the autophagy level induced by exposure to hypoxia were assayed in fibroblasts. The association between TERT, nuclear factor-kappa B (NF-kappa B) and the autophagy level was examined by western blot analysis. The antioxidant effects of TERT were examined on the basis of the ratio of glutathione to glutathione disulfide (GSH/GSSG) and mitochondrial membrane potential. Rectal fibrosis was induced significantly at 12 weeks following irradiation. The HIF-1 alpha and TERT expression levels increased in the fibrotic region. The TERT-overexpressing fibroblasts (transfected with an hTERT-expressing lentiviral vector) exhibited reduced apoptosis, reduced ROS production, a higher autophagy level, a higher GSH/GSSG ratio and stable mitochondrial membrane potential compared with the fibroblasts in which TERT had been silenced by siRNA. NF-kappa B was activated by TERT, and the inhibition of TERT reduced the autophagy level in the fibroblasts. These results demonstrate that TERT decreases cellular ROS production, while maintaining mitochondrial function and protecting the cells from hypoxia-induced apoptosis, which may thus attenuate the effects of irradiation-induced hypoxia on rectal injury following irradiation.	[Liu, Qi; Sun, Yong; Xin, Yuhu; Zhang, Ping; Liu, Yong] Fudan Univ, Shanghai Canc Ctr, Canc Res Inst, 270 Dong An Rd, Shanghai 200032, Peoples R China; [Le, Ziyu; Liu, Yong] Fudan Univ, Shanghai Canc Ctr, Dept Radiat Oncol, Shanghai 200032, Peoples R China; [Liu, Qi; Sun, Yong; Le, Ziyu; Xin, Yuhu; Zhang, Ping; Liu, Yong] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China; [Lv, Yuefeng] Hubei Univ Med, Shiyan Taihe Hosp, Dept Obstet, Shiyan 442000, Hubei, Peoples R China		Liu, Y (corresponding author), Fudan Univ, Shanghai Canc Ctr, Canc Res Inst, 270 Dong An Rd, Shanghai 200032, Peoples R China.	drliuyong@hotmail.com			Scientific Research Foundation for the Returned Overseas Chinese Scholars from the 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]; Shanghai Pujiang ProgramShanghai Pujiang Program [13P1401600]; 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 the China State Education Ministry, the National Natural Science Foundation of China (nos. 81202148 and 31370838), the Shanghai Pujiang Program (no. 13P1401600), and the Foundation of Shanghai Committee of Science and Technology of China (no. 12DZ2260100).	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J. Mol. Med.	SEP	2016	38	3					785	793		10.3892/ijmm.2016.2673			9	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	DU8EA	WOS:000382444900012	27431814	Green Submitted, hybrid, Green Published			2022-04-25	
J	Ge, CC; Wang, YX; Feng, YL; Wang, SZ; Zhang, KM; Xu, XJ; Zhang, ZY; Zhao, Y; Wang, YM; Gao, L; Dai, FJ; Xie, SQ; Wang, CJ				Ge, Chaochao; Wang, Yuxia; Feng, Yongli; Wang, Senzhen; Zhang, Kemeng; Xu, Xiaojuan; Zhang, Zhiyang; Zhao, Yuan; Wang, Yanming; Gao, Lei; Dai, Fujun; Xie, Songqiang; Wang, Chaojie			Suppression of oxidative phosphorylation and IDH2 sensitizes colorectal cancer to a naphthalimide derivative and mitoxantrone	CANCER LETTERS			English	Article						Mitochondria; Reactive oxygen species; Autophagy; Senescence; Tricarboxylic acid cycle	MITOCHONDRIAL COMPLEX-III; INDUCED ROS PRODUCTION; CELL-DEATH; METABOLISM; INHIBITORS	Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Oxidative phosphorylation (OXPHOS) has attracted a considerable attention in CRC. It is of great interest to explore novel therapies that inhibit OXPHOS for CRC treatment. Compound 6c is a novel naphthalimide derivative. However, the effects of 6c on CRC and the underlying mechanism are unclear. In this study, 6c suppressed CRC tumor growth and metastasis. RNA-seq data showed that 6c triggered the inhibition of OXPHOS and tricarboxylic acid cycle. 6c specifically inhibited mitochondrial complex III activity and the expression of isocitrate dehydrogenase 2 (IDH2), resulting in oxidative stress. Antioxidants reversed 6c-induced cell death, senescence, and autophagosomes formation. 6c inhibited autophagy flux; however, pretreatment with autophagy inhibitors resulted in the reduction of 6cinduced cytoplasmic vacuolization and proliferation inhibition. Moreover, combinatory treatment of 6c and mitoxantrone (MIT) showed stronger inhibitory effects on CRC compared with the single agent. Downregulation of IDH2 induced reactive oxygen species production, leading to MIT accumulation and autophagic cell death after co-treatment with 6c and MIT. In summary, our findings indicated 6c as a promising candidate for CRC treatment.	[Ge, Chaochao; Feng, Yongli; Wang, Senzhen; Zhang, Zhiyang; Zhao, Yuan; Gao, Lei; Dai, Fujun; Wang, Chaojie] Henan Univ, Key Lab Nat Med & Immunoengn, Kaifeng 475004, Henan, Peoples R China; [Wang, Yuxia] Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China; [Wang, Senzhen; Zhang, Kemeng; Wang, Yanming; Gao, Lei; Dai, Fujun] Henan Univ, Sch Life Sci, Kaifeng 475004, Henan, Peoples R China; [Xu, Xiaojuan; Xie, Songqiang] Henan Univ, Sch Pharm, Kaifeng 475004, Henan, Peoples R China		Dai, FJ; Wang, CJ (corresponding author), Henan Univ, Key Lab Nat Med & Immunoengn, Kaifeng 475004, Henan, Peoples R China.; Xie, SQ (corresponding author), Henan Univ, Sch Pharm, Kaifeng 475004, Henan, Peoples R China.	fjdwl@hotmail.com; xiesq@henu.edu.cn; wcjsxq@henu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81703004, U1904151, 81772832, 32000271, 22073023]; Young Backbone Teacher in Colleges and Universities of Henan Province [2020GGJS033]; Postdoctoral Research Foundation of ChinaChina Postdoctoral Science Foundation [2019M652527, 2020M672214]; Start-up Fund of Postdoctoral Research Program of Henan Province [1901009]; Postgraduate Education Reform Project of Henan Province [2019SJGLX081Y]; Innovative Research Team (in Science and Technology) in University of Henan Province [19IRTSTHN004]; Guangdong Provincial Key Laboratory of Drug Non-clinical Evaluation and Research [2018B030323024]	This work was supported by National Natural Science Foundation of China (81703004, U1904151, 81772832, 32000271and 22073023) , The Young Backbone Teacher in Colleges and Universities of Henan Province (2020GGJS033) , Postdoctoral Research Foundation of China (2019M652527and 2020M672214) , Start-up Fund of Postdoctoral Research Program of Henan Province (1901009) , Postgraduate Education Reform Project of Henan Province (2019SJGLX081Y) , Innovative Research Team (in Science and Technology) in University of Henan Province (19IRTSTHN004) , and Guangdong Provincial Key Laboratory of Drug Non-clinical Evaluation and Research (2018B030323024) .	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OCT 28	2021	519						30	45		10.1016/j.canlet.2021.06.015		JUN 2021	16	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	UH0VH	WOS:000689658000001	34166768				2022-04-25	
J	Ding, L; Wang, LY; Sui, LM; Zhao, HY; Xu, XX; Li, TY; Wang, XN; Li, WJ; Zhou, P; Kong, L				Ding, Lei; Wang, Liyong; Sui, Leiming; Zhao, Huanying; Xu, Xiaoxue; Li, Tengyan; Wang, Xiaonan; Li, Wenjing; Zhou, Ping; Kong, Lu			Claudin-7 indirectly regulates the integrin/FAK signaling pathway in human colon cancer tissue	JOURNAL OF HUMAN GENETICS			English	Article							CELLS; CARCINOMA; CARCINOGENESIS; AUTOPHAGY; MIGRATION; NETWORKS; PROTEINS; GELSOLIN; DATABASE	The claudin family of proteins is integral to the structure and function of tight junctions. The role of claudin-7 (Cldn-7, CLDN7) in regulating the integrin/focal adhesion kinase (FAK)/ERK signaling pathway remains poorly understood. Therefore, we investigated differences in gene expression, primarily focusing on CLDN7 and integrin/FAK/ERK signaling pathway genes, between colon cancer and adjacent normal tissues. Quantitative real-time reverse transcription-PCR and immunohistochemistry were utilized to verify the results of mRNA and protein expression, respectively. In silico analysis was used to predict co-regulation between Cldn-7 and integrin/FAK/ERK signaling pathway components, and the STRING database was used to analyze protein-protein interaction pairs among these proteins. Meta-analysis of expression microarrays in The Cancer Genome Atlas (TCGA) database was used to identify significant correlations between Cldn-7 and components of predicted genes in the integrin/FAK/ERK signaling pathway. Our results showed marked cancer stage-specific decreases in the protein expression of Cldn-7, Gelsolin, MAPK1 and MAPK3 in colon cancer samples, and the observed changes for all proteins except Cldn-7 were in agreement with changes in the corresponding mRNA levels. Cldn-7 might indirectly regulate MAPK3 via KRT8 due to KRT8 co-expression with MAPK3 or CLDN7. Our bioinformatics methods supported the hypothesis that Cldn-7 does not directly regulate any genes in the integrin/FAK/ERK signaling pathway. These factors may participate in a common network that regulates cancer progression in which the MAPK pathway serves as the central node.	[Ding, Lei; Li, Tengyan; Wang, Xiaonan; Li, Wenjing] Capital Med Univ, Beijing Shijitan Hosp, Dept Oncol, Beijing 100038, Peoples R China; [Wang, Liyong; Sui, Leiming; Zhao, Huanying; Xu, Xiaoxue; Kong, Lu] Capital Med Univ, Dept Biochem & Mol Biol, Beijing, Peoples R China; [Zhou, Ping] Capital Med Univ, Inst Biomed Engn, Dept Bioinformat, Beijing, Peoples R China		Ding, L (corresponding author), Capital Med Univ, Beijing Shijitan Hosp, Dept Oncol, Beijing 100038, Peoples R China.; Kong, L (corresponding author), Capital Med Univ, Inst Canc, Dept Biochem & Mol Biol, 10 Xitoutiao, Beijing 100069, Peoples R China.	dinglei1005@126.com; konglu@ccmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81372585, 81272406]; Scientific Research Program of Beijing Municipal Commission of Education [KM201410025026, KM201510025009, KZ201410025020]	This work was supported by the National Natural Science Foundation of China (grant no. 81372585 and 81272406) and the Scientific Research Program of Beijing Municipal Commission of Education (grant no. KM201410025026, KM201510025009 and KZ201410025020).	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Hum. Genet.	AUG	2016	61	8					711	720		10.1038/jhg.2016.35			10	Genetics & Heredity	Science Citation Index Expanded (SCI-EXPANDED)	Genetics & Heredity	DU7ZE	WOS:000382432300007	27121327				2022-04-25	
J	Choi, J; Jo, M; Lee, E; Choi, D				Choi, JongYeob; Jo, MinWha; Lee, EunYoung; Choi, DooSeok			ERK1/2 is involved in luteal cell autophagy regulation during corpus luteum regression via an mTOR-independent pathway	MOLECULAR HUMAN REPRODUCTION			English	Article						autophagy; luteal cell; mTOR; AKT; ERK1/2	ALPHA-INTERACTING PROTEIN; RIBOSOMAL S6 KINASE; COLON-CANCER CELLS; TUBEROUS SCLEROSIS; HORMONE ANTAGONIST; SIGNALING PATHWAY; IN-VIVO; APOPTOSIS; DEATH; AKT	Autophagy is known to be regulated by the phosphoinositide-3 kinase (PI3K)-protein kinase B (AKT) and/or mitogen-activated protein kinase 1/2 (MEK1/2)-extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, leading to activation of mammalian target of rapamycin (mTOR), a major negative regulator of autophagy. However, some reports have also suggested that autophagic regulation by the PI3K-AKT and/or MEK1/2-ERK1/2 pathways may not be mediated by mTOR activity, and there is no direct evidence of the involvement of these pathways in luteal cell autophagy regulation. To elucidate the luteal cell-specific regulatory mechanisms of autophagy induction during corpus luteum (CL) regression, we evaluated whether luteal cell autophagy is regulated by the PI3K-AKT pathway and/or MEK1/2-ERK1/2 pathway and if this regulation is mediated by mTOR. We found that autophagy induction increased despite mTOR activation in luteal cells cultured with prostaglandin F2 alpha (PGF2 alpha), an important mediator of CL regression, suggesting that PGF2 alpha-induced autophagy is independent of mTOR regulation. We also found that PGF2 alpha-induced autophagy was not mediated by AKT activity, because AKT inhibition using a PI3K inhibitor (wortmannin) did not change autophagy induction or mTOR activity. In contrast, ERK1/2 activity increased in PGF2 alpha-treated luteal cells, as did the levels of autophagy induction despite increased mTOR activity. Furthermore, PGF2 alpha-mediated up-regulation of luteal cell autophagy was reversed by addition of ERK1/2 inhibitors, despite a decrease in mTOR activity. These in vitro results suggest that luteal cell autophagy is induced by increased ERK1/2 activity during CL regression, and is independent of mTOR activity. This finding was further supported by in vivo experiments in a pseudo-pregnant rat model, which showed that induction of luteal cell autophagy increased during luteal stage progression and that this was accompanied by increased ERK1/2 and mTOR activity. Taken together, our findings indicate that activation of ERK1/2 is a key event in the induction of luteal cell autophagy during CL regression which is not associated with mTOR regulation.	[Choi, JongYeob; Lee, EunYoung; Choi, DooSeok] Sungkyunkwan Univ, Dept Obstet & Gynecol, Samsung Med Ctr, Infertil Clin,Sch Med, Seoul 135710, South Korea; [Jo, MinWha] Samsung Biochem Res Inst, Clin Res Ctr, Seoul, South Korea		Choi, D (corresponding author), Sungkyunkwan Univ, Dept Obstet & Gynecol, Samsung Med Ctr, Infertil Clin,Sch Med, 50 Irwon Dong, Seoul 135710, South Korea.	dooseok.choi@samsung.com			Samsung Biomedical Research InstituteSamsung [SBRI GLI-B2-341-2]	This study was supported by a grant from the Samsung Biomedical Research Institute [grant number SBRI GLI-B2-341-2].	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Hum. Reprod.	OCT	2014	20	10					972	980		10.1093/molehr/gau061			9	Developmental Biology; Obstetrics & Gynecology; Reproductive Biology	Science Citation Index Expanded (SCI-EXPANDED)	Developmental Biology; Obstetrics & Gynecology; Reproductive Biology	AT0HT	WOS:000344618300005	25107837	Bronze			2022-04-25	
J	Schroll, MM; Liu, X; Herzog, SK; Skube, SB; Hummon, AB				Schroll, Monica M.; Liu, Xin; Herzog, Sarah K.; Skube, Susan B.; Hummon, Amanda B.			Nutrient restriction of glucose or serum results in similar proteomic expression changes in 3D colon cancer cell cultures	NUTRITION RESEARCH			English	Article						Nutrient restriction; Three dimensional cell culture; Autophagy; Apoptosis; Quantitative proteomics; Colorectal cancer	CALORIE RESTRICTION; PROTEIN; AUTOPHAGY; PREVENTION; GENE	Nutrient restriction, also known as caloric restriction, has been extensively examined for its positive impact on lifespan, immune system boost, and aging. In addition, nutrient restriction is implicated in decreasing cancer initiation and progression. Given the phenotypic changes associated with nutrient restriction, we hypothesized significant protein expression alterations must be associated with caloric restriction. To compare the molecular and phenotypic changes caused by glucose restriction and fetal bovine serum restriction there is need for an efficient model system. We establish 3-dimensional cell culture models, known as spheroids, in the HCT 116 colorectal cancer cell line as a high throughput model for studying the proteomic changes associated with nutrient restriction. Flow cytometry was used to assess apoptosis and autophagy levels in the spheroids under nutrient restriction. Isobaric tags for relative and absolute quantification and liquid chromatography tandem mass spectrometry were used to determine differential protein abundances between the nutrient restriction conditions. We identified specific proteins that have implications in cancer progression and metastasis that are differentially regulated by restriction of either glucose or serum. These proteins include the up regulation of sirtuin 1 and protein inhibitor of activated STAT 1 and down-regulation of multi-drug resistance protein and Zinc finger and BTB domain-containing protein 7A. The results indicate nutrient restriction causes lower apoptotic and higher autophagy rates in HCT 116 spheroids. In addition, proteins shown to be differentially regulated by both glucose and serum restriction were similarly regulated. (C) 2016 Elsevier Inc. All rights reserved.	[Schroll, Monica M.; Liu, Xin; Herzog, Sarah K.; Skube, Susan B.; Hummon, Amanda B.] Univ Notre Dame, Harper Canc Res Inst, Dept Chem & Biochem, Notre Dame, IN 46556 USA		Hummon, AB (corresponding author), 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA.	ahummon@nd.edu		Hummon, Amanda/0000-0002-1969-9013; Herzog, Sarah/0000-0003-3782-7389	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01GM110406]; National Science Foundation (CAREER Award)National Science Foundation (NSF) [CHE-1351595]; Walther Cancer Foundation; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM110406, T32GM075762] Funding Source: NIH RePORTER	We thank the Notre Dame Mass Spectrometry and Proteomics Facility for their assistance. In addition, we thank Katelyn Ludwig for her helpfulness in procedures and data analysis and William Andrews for artwork assistance. This work was funded by the National Institutes of Health (R01GM110406), and the National Science Foundation (CAREER Award, CHE-1351595). The Walther Cancer Foundation provided salary support for ABH.	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Res.	OCT	2016	36	10					1068	1080		10.1016/j.nutres.2016.08.002			13	Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED)	Nutrition & Dietetics	EE0SG	WOS:000389288600003	27865348	Green Accepted			2022-04-25	
J	Zou, Y; Yan, C; Zhang, HB; Xu, JY; Zhang, DY; Huang, ZJ; Zhang, YH				Zou, Yu; Yan, Chang; Zhang, Huibin; Xu, Jinyi; Zhang, Dayong; Huang, Zhangjian; Zhang, Yihua			Synthesis and evaluation of N-heteroaromatic ring-based analogs of piperlongumine as potent anticancer agents	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY			English	Article						Piperlongumine; N-heteroaromatic ring; Solubility; Anticancer activity; ROS	DRUG DISCOVERY; DERIVATIVES; SOLUBILITY; DESIGN; CELLS	Piperlongumine (PL) selectively targets a wide spectrum of cancer cells and induces their death by triggering various pathways, including apoptosis, necrosis and autophagy. However, the poor solubility is a serious concern for intensive study and clinical application. We synthesized its analogs 1-9 by replacement of the trimethoxyphenyl of PL with an N-heteroaromatic ring and/or not introduction of 2-Cl. These compounds improved aqueous solubility and displayed potent anticancer activity. The most active compound 9 selectively enhanced ROS levels in colon cancer cells and inhibited the cell proliferation but sparing non-tumor colon cells. Importantly, 9 significantly repressed tumor growth in an HCT-116 xenograft mouse model, suggesting that these N-heteroaromatic ring-based analogs of PL warrant further investigation. (C) 2017 Elsevier Masson SAS. All rights reserved.	[Zou, Yu; Yan, Chang; Zhang, Huibin; Xu, Jinyi; Zhang, Dayong; Huang, Zhangjian; Zhang, Yihua] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China; [Zou, Yu; Yan, Chang; Zhang, Huibin; Zhang, Dayong; Huang, Zhangjian; Zhang, Yihua] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Jiangsu, Peoples R China		Huang, ZJ; Zhang, YH (corresponding author), China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China.				National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21372261, 81673305]; Jiangsu Province Funds for Distinguished Young Scientists [BK20160033]; Program for New Century Excellent Talents in UniversityProgram for New Century Excellent Talents in University (NCET) [NCET-13-1033]; Jiangsu Shuang Chuang team	This study was supported by grants from the National Natural Science Foundation of China (No. 21372261 and No. 81673305) and Jiangsu Province Funds for Distinguished Young Scientists (BK20160033). Part of the work was supported by the Program for New Century Excellent Talents in University (NCET-13-1033) and the Jiangsu Shuang Chuang team.	Adams DJ, 2012, P NATL ACAD SCI USA, V109, P15115, DOI 10.1073/pnas.1212802109; Alelyunas YW, 2010, BIOORG MED CHEM LETT, V20, P7312, DOI 10.1016/j.bmcl.2010.10.068; Alhassan A., 2016, PLOS ONE, V11; Fofaria NM, 2016, INT J PHARMACEUT, V498, P12, DOI 10.1016/j.ijpharm.2015.11.045; Gross G, 2012, INT J PHARMACEUT, V437, P103, DOI 10.1016/j.ijpharm.2012.07.071; Kong EH, 2008, ONCOL REP, V20, P785, DOI 10.3892/or_00000075; Ku SK, 2014, INFLAMM RES, V63, P369, DOI 10.1007/s00011-014-0708-6; Liao Y, 2016, J MED CHEM, V59, P7974, DOI 10.1021/acs.jmedchem.6b00772; Lipinski CA, 2001, ADV DRUG DELIVER REV, V46, P3, DOI 10.1016/S0169-409X(00)00129-0; Palucki M, 2010, J MED CHEM, V53, P5897, DOI 10.1021/jm1002638; Park BS, 2008, PHYTOTHER RES, V22, P1195, DOI 10.1002/ptr.2432; Punganuru SR, 2016, EUR J MED CHEM, V107, P233, DOI 10.1016/j.ejmech.2015.10.052; Raj L, 2011, NATURE, V475, P231, DOI 10.1038/nature10167; Seo YH, 2014, BIOORG MED CHEM LETT, V24, P5727, DOI 10.1016/j.bmcl.2014.10.054; Wu YL, 2014, EUR J MED CHEM, V82, P545, DOI 10.1016/j.ejmech.2014.05.070; Xie WH, 1997, MAR ENVIRON RES, V44, P429, DOI 10.1016/S0141-1136(97)00017-2; Xiong XX, 2015, ACTA PHARMACOL SIN, V36, P362, DOI 10.1038/aps.2014.141; Yan WJ, 2016, FREE RADICAL BIO MED, V97, P109, DOI 10.1016/j.freeradbiomed.2016.05.021; Yang B, 2016, ENVIRON SCI POLLUT R, V23, P3399, DOI 10.1007/s11356-015-5544-x; Zhang YJ, 2017, BIOORG MED CHEM LETT, V27, P2308, DOI 10.1016/j.bmcl.2017.04.035	20	19	20	2	21	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER	ISSY-LES-MOULINEAUX	65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE	0223-5234	1768-3254		EUR J MED CHEM	Eur. J. Med. Chem.	SEP 29	2017	138						313	319		10.1016/j.ejmech.2017.06.046			7	Chemistry, Medicinal	Science Citation Index Expanded (SCI-EXPANDED); Index Chemicus (IC)	Pharmacology & Pharmacy	FH6OQ	WOS:000411297000025	28686911				2022-04-25	
J	Liu, YQ; Wang, GY; Li, Y; Zhao, Q; Fan, LQ; Tan, BB; Li, BK; Yu, B; Xi, JC				Liu, Youqiang; Wang, Guiying; Li, Yong; Zhao, Qun; Fan, Liqiao; Tan, Bibo; Li, Baokun; Yu, Bin; Xi, Jinchuan			miR-424-5p reduces 5-fluorouracil resistance possibly by inhibiting Src/focal adhesion kinase signalling-mediated epithelial-mesenchymal transition in colon cancer cells	JOURNAL OF PHARMACY AND PHARMACOLOGY			English	Article						miR-424-5p; epithelial; mesenchymal transition; 5-fluorouracil resistance; colon cancer; Src; focal adhesion kinase	EMT; INVASION; PROLIFERATION; AUTOPHAGY; MIGRATION; MARKERS; SRC	Objectives miR-424-5p negatively regulates various malignant biological behaviours in tumour cells. We explored the relationship between miR-424-5p and 5-fluorouracil resistance in colon cancer cells. Methods We developed 5-fluorouracil-resistant HT-29 cells and detected miR-424-5p expression using real-time fluorescence quantitative PCR. Cell viability was assessed using Cell Counting Kit-8 (CCK-8) assay. Immunofluorescence and western blotting were performed to determine protein levels. Apoptosis was detected by Annexin V-FITC/PI staining. Key findings miR-424-5p was downregulated in 5-fluorouracil-resistant HT-29 cells. A miR-424-5p mimic enhanced the sensitivity of the resistant cells to 5-fluorouracil, whereas a miR-424-5p inhibitor promoted 5-fluorouracil resistance in HT-29 cells. Furthermore, the miR-424-5p mimic downregulated vimentin and upregulated E-cadherin in 5-fluorouracil-resistant HT-29 cells, whereas the miR-424-5p inhibitor exhibited opposite effects. The miR-424-5p inhibitor significantly inhibited 5-fluorouracil-induced HT-29 cell apoptosis and Src and focal adhesion kinase phosphorylation, whereas the miR-424-5p mimic showed opposite effects. Pretreatment with Src inhibitor 1 or focal adhesion kinase inhibitor 2 blocked the increase in Src and focal adhesion kinase phosphorylation and vimentin expression level and the decrease in E-cadherin expression level in miR-424-5p inhibitor-exposed HT-29 cells. Conclusions miR-424-5p suppressed epithelial-mesenchymal transition by inhibiting the Src/focal adhesion kinase signalling pathway to reduce 5-fluorouracil resistance in colon cancer cells.	[Liu, Youqiang; Wang, Guiying; Li, Yong; Zhao, Qun; Fan, Liqiao; Tan, Bibo; Li, Baokun; Yu, Bin; Xi, Jinchuan] Hebei Med Univ, Hosp 4, Shijiazhuang 050051, Hebei, Peoples R China; [Wang, Guiying] Hebei Med Univ, Hosp 3, Shijiazhuang, Hebei, Peoples R China		Li, Y (corresponding author), Hebei Med Univ, Hosp 4, Shijiazhuang 050051, Hebei, Peoples R China.	liyonghhm@aliyun.com			2018 Hebei Province Key RD Plan [182777186]	This study was supported by 2018 Hebei Province Key R&D Plan (grant number 182777186).	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Pharm. Pharmacol.	AUG	2021	73	8					1062	1070		10.1093/jpp/rgab031		MAR 2021	9	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	TZ0ND	WOS:000684172200007	33793771				2022-04-25	
J	Chen, H; Huang, JT; Chen, CY; Jiang, YM; Feng, XZ; Liao, Y; Yang, ZL				Chen, Hao; Huang, Jintuan; Chen, Chunyu; Jiang, Yingming; Feng, Xingzhi; Liao, Yi; Yang, Zuli			NGFR Increases the Chemosensitivity of Colorectal Cancer Cells by Enhancing the Apoptotic and Autophagic Effects of 5-fluorouracil via the Activation of S100A9	FRONTIERS IN ONCOLOGY			English	Article						colorectal cancer; NGFR; apoptosis; autophagy; chemosensitivity	DEATH	Colorectal cancer (CRC) is currently the third leading cause of cancer-related deaths worldwide, and 5-fluorouracil (5-FU)-based chemotherapies serve as important adjuvant therapies before and after surgery for CRC. However, the efficacy of CRC chemotherapy is limited by chemoresistance, and therefore the discovery of novel markers to indicate chemosensitivity is essential. Nerve growth factor receptor (NGFR), a cell surface receptor, is involved in cell death and survival. Our previous study indicated that NGFR acts as a tumor suppressor, and high expression is associated with better outcomes in patients receiving 5-FU-based adjuvant chemotherapy after surgery. The aim of this study was to investigate the effect of NGFR on the chemotherapeutic response in CRC. Chemosensitivity was investigated using DLD1 and HCT8 cells after NGFR transfection. Apoptosis was investigated by flow cytometry. Autophagy was assessed using GFP-LC3B transient transfection. Gene expression was measured using an mRNA microarray. Beclin-1 and Bcl-2 protein expressions were assessed by western blot. NGFR and S100 calcium-binding protein A9 (S100A9) expressions in CRC patients were investigated by immunohistochemistry. The results showed that the half maximal inhibitory concentration of NGFR-transfected cells was lower than that of controls in DLD1 and HCT8 cells after 5-FU treatment, and cell viability was lower than in empty-vector cells. Tumor sizes were also smaller than in empty-vector cells in vivo. The percentages of apoptotic and autophagic cells were higher in NGFR-transfected cells. NGFR elevated the expression of S100A9 after 5-FU treatment. The combination of Bcl-2 and Beclin-1 was significantly suppressed by overexpressed NGFR. Five-year overall and disease-free survival in NGFR+/S100A9+ patients was better than in NGFR-/S100A9- patients. This study's findings suggest that NGFR may serve as a marker predicting CRC patients' chemosensitivity.	[Chen, Hao; Huang, Jintuan; Chen, Chunyu; Jiang, Yingming; Liao, Yi; Yang, Zuli] Sun Yat Sen Univ, Dept Gastrointestinal Surg, Affiliated Hosp 6, Guangzhou, Peoples R China; [Feng, Xingzhi] Sun Yat Sen Univ, Guangdong Inst Gastroenterol, Affiliated Hosp 6, Guangzhou, Peoples R China		Yang, ZL (corresponding author), Sun Yat Sen Univ, Dept Gastrointestinal Surg, Affiliated Hosp 6, Guangzhou, Peoples R China.	yangzuli@mail.sysu.edu.cn			National Key Clinical Discipline; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81802322, 81772594, 81902949]; Science and Technology Program of Guangzhou [201803010095]; Natural Science Foundation of Guangdong Province, ChinaNational Natural Science Foundation of Guangdong Province [2019A1515011723]; Medical Scientific Research Foundation of Guangdong Province, China [A2019483]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [19ykpy09]	This work was supported by grants from the National Key Clinical Discipline, the National Natural Science Foundation of China (Grant no. 81802322 & Grant no. 81772594 & Grant no. 81902949), the Science and Technology Program of Guangzhou (Grant no. 201803010095), Natural Science Foundation of Guangdong Province, China (Grant No. 2019A1515011723), Medical Scientific Research Foundation of Guangdong Province, China (Grant No. A2019483) and also supported by the Fundamental Research Funds for the Central Universities (Grant no. 19ykpy09).	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Oncol.	APR 30	2021	11								652081	10.3389/fonc.2021.652081			14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	SB5OJ	WOS:000650043000001	33996571	gold, Green Published			2022-04-25	
J	Chang, SH; Minai-Tehrani, A; Shin, JY; Park, S; Kim, JE; Yu, KN; Hong, SH; Hong, CM; Lee, KH; Beck, GR; Cho, MH				Chang, Seung-Hee; Minai-Tehrani, Arash; Shin, Ji-Young; Park, Sungjin; Kim, Ji-Eun; Yu, Kyeong-Nam; Hong, Seong-Ho; Hong, Choong-Man; Lee, Kee-Ho; Beck, George R., Jr.; Cho, Myung-Haing			Beclin1-induced Autophagy Abrogates Radioresistance of Lung Cancer Cells by Suppressing Osteopontin	JOURNAL OF RADIATION RESEARCH			English	Article						Osteopontin(OPN); Beclin-1(BECN1); Gamma-irradiation; p53; Angiogenesis	ENDOTHELIAL GROWTH-FACTOR; TUMOR-GROWTH; BREAST-CANCER; IN-VIVO; GENE; METASTASIS; EXPRESSION; APOPTOSIS; PROMOTER; COLON	Osteopontin (OPN) serves as an indicator of resistance to radiotherapy. However, the role of OPN in the development of acquired radioresistance in human lung cancer cells has not yet been fully elucidated. Therefore, the potential importance of OPN as a marker of lung cancer with a potential significant role in the development of radioresistance against repeated radiotherapy has prompted us to define the pathways by which OPN regulates lung cancer cell growth. In addition, autophagy has been reported to play a key role in the radiosensitization of cancer cells. Here, we report that increased OPN expression through induction of nuclear p53 following irradiation was inhibited by exogenous beclin-1 (BECN1). Our results clearly show that BECN1 gene expression led to induction of autophagy and inhibition of cancer cell growth and angiogenesis. Our results suggest that the induction of autophagy abrogated the radioresistance of the cancer cells. Interestingly, we showed that knockdown of OPN by lentivirus-mediated shRNA induced the autophagy of human lung cancer cell. Taken together, these results suggest that OPN and BECN1 can be molecular targets for overcoming radioresistance by controlling autophagy.	[Chang, Seung-Hee; Minai-Tehrani, Arash; Shin, Ji-Young; Park, Sungjin; Kim, Ji-Eun; Yu, Kyeong-Nam; Hong, Seong-Ho; Cho, Myung-Haing] Seoul Natl Univ, Coll Vet Med, Toxicol Lab, Seoul 151742, South Korea; [Kim, Ji-Eun; Cho, Myung-Haing] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Nanofus Technol, Seoul 151742, South Korea; [Hong, Choong-Man] Osong Hlth Technol Adm Complex, Div Med Device Management, Cheongwon 363700, South Korea; [Lee, Kee-Ho] Korea Inst Radiol & Med Sci, Lab Radiat Mol Oncol, Seoul 139709, South Korea; [Beck, George R., Jr.] Emory Univ, Sch Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30322 USA; [Cho, Myung-Haing] Seoul Natl Univ, Grad Grp Tumor Biol, Seoul 151742, South Korea; [Cho, Myung-Haing] Seoul Natl Univ, Natl Inst Food & Drug Safety, Ctr Food Safety & Toxicol, Seoul 151742, South Korea; [Cho, Myung-Haing] Seoul Natl Univ, Adv Inst Convergence Technol, Suwon 443270, South Korea		Cho, MH (corresponding author), Seoul Natl Univ, Coll Vet Med, Toxicol Lab, Seoul 151742, South Korea.	mchotox@snu.ac.kr	Cho, Myung-Haing/B-7362-2014; Beck, George/AAO-2117-2020	Cho, Myung-Haing/0000-0002-3993-2011; Park, Sungjin/0000-0001-5801-5537	National Research Foundation of the Ministry of Education, Science and Technology (MEST) in Korea [NRF-2012-0000102]; Research Institute for Veterinary Science, Seoul National University; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R03CA136059, R01CA136716] Funding Source: NIH RePORTER	This work was supported by the National Research Foundation (NRF-2012-0000102) of the Ministry of Education, Science and Technology (MEST) in Korea. M.H. CHO was also partially supported by the Research Institute for Veterinary Science, Seoul National University.	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Radiat. Res.	MAY	2012	53	3					422	432		10.1269/jrr.11148			11	Biology; Oncology; Radiology, Nuclear Medicine & Medical Imaging	Science Citation Index Expanded (SCI-EXPANDED)	Life Sciences & Biomedicine - Other Topics; Oncology; Radiology, Nuclear Medicine & Medical Imaging	984NH	WOS:000307196500010	22481206	gold, Green Published			2022-04-25	
J	Wang, CD; Ma, YP; Hu, QW; Xie, TT; Wu, JY; Zeng, F; Song, FZ				Wang, Changdong; Ma, Yongping; Hu, Qiongwen; Xie, Tingting; Wu, Jiayan; Zeng, Fan; Song, Fangzhou			Bifidobacterial recombinant thymidine kinase-ganciclovir gene therapy system induces FasL and TNFR2 mediated antitumor apoptosis in solid tumors	BMC CANCER			English	Article						Tumor gene therapy; Bifidobacterium; Apoptosis; Thymidine kinase; Ganciclovir	COLON-CANCER CELLS; BINDING PROTEIN-6; DELIVERY-SYSTEM; BLADDER-CANCER; OVARIAN-CANCER; ACTIVATION; ADENOVIRUS; DEATH; NECROPTOSIS; EXPRESSION	Background: Directly targeting therapeutic suicide gene to a solid tumor is a hopeful approach for cancer gene therapy. Treatment of a solid tumor by an effective vector for a suicide gene remains a challenge. Given the lack of effective treatments, we constructed a bifidobacterial recombinant thymidine kinase (BF-rTK) -ganciclovir (GCV) targeting system (BKV) to meet this requirement and to explore antitumor mechanisms. Methods: Bifidobacterium (BF) or BF-rTK was injected intratumorally with or without ganciclovir in a human colo320 intestinal xenograft tumor model. The tumor tissues were analyzed using apoptosis antibody arrays, real time PCR and western blot. The colo320 cell was analyzed by the gene silencing method. Autophagy and necroptosis were also detected in colo320 cell. Meanwhile, three human digestive system xenograft tumor models (colorectal cancer colo320, gastric cancer MKN-45 and liver cancer SSMC-7721) and a breast cancer (MDA-MB-231) model were employed to validate the universality of BF-rTK + GCV in solid tumor gene therapy. The survival rate was evaluated in three human cancer models after the BF-rTK + GCV intratumor treatment. The analysis of inflammatory markers (TNF-alpha) in tumor indicated that BF-rTK + GCV significantly inhibited TNF-alpha expression. Results: The results suggested that BF-rTK + GCV induced tumor apoptosis without autophagy and necroptosis occurrence. The apoptosis was transduced by multiple signaling pathways mediated by FasL and TNFR2 and mainly activated the mitochondrial control of apoptosis via Bid and Bim, which was rescued by silencing Bid or/and Bim. However, BF + GCV only induced apoptosis via Fas/FasL signal pathway accompanied with increased P53 expression. We further found that BF-rTK + GCV inhibited the expression of the inflammatory maker of TNF-alpha. However, BF-rTK + GCV did not result in necroptosis and autophagy. Conclusions: BF-rTK + GCV induced tumor apoptosis mediated by FasL and TNFR2 through the mitochondrial control of apoptosis via Bid and Bim without inducing necroptosis and autophagy. Furthermore, BF-rTK + GCV showed to repress the inflammation of tumor through downregulating TNF-alpha expression. Survival analysis results of multiple cancer models confirmed that BF-rTK + GCV system has a wide field of application in solid tumor gene therapy.	[Wang, Changdong; Ma, Yongping; Hu, Qiongwen; Xie, Tingting; Wu, Jiayan; Zeng, Fan; Song, Fangzhou] Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Biochem & Mol Biol, Yi XueYuan Rd 1, Chongqing 400016, Peoples R China		Ma, YP (corresponding author), Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Biochem & Mol Biol, Yi XueYuan Rd 1, Chongqing 400016, Peoples R China.	yongpingm@yahoo.com			Chongqing Science & Technology Commission (CSTC)Natural Science Foundation Project of CQ CSTC [2011BB5125]; National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [30972585]	This work was supported by grants from Chongqing Science & Technology Commission (CSTC no. 2011BB5125); The construction of pBEX plasmid was supported by grants from the National Natural Science Foundation of China (NSFC no. 30972585).	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J	Garofalo, M; Iovine, B; Kuryk, L; Capasso, C; Hirvinen, M; Vitale, A; Yliperttula, M; Bevilacqua, MA; Cerullo, V				Garofalo, Mariangela; Iovine, Barbara; Kuryk, Lukasz; Capasso, Cristian; Hirvinen, Mari; Vitale, Andrea; Yliperttula, Marjo; Bevilacqua, Maria Assunta; Cerullo, Vincenzo			Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity	MOLECULAR CANCER THERAPEUTICS			English	Article							LUNG-CANCER CELLS; IN-VIVO; MODEL; PROLIFERATION; AUTOPHAGY; INHIBITION; ENDOSTATIN; GROWTH; MICE	Oncolytic viruses are able to specifically replicate, infect, and kill only cancer cells. Their combination with chemotherapeutic drugs has shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In this study, we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction, and used this strategy to deliver an active antitumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant antiproliferative activity. An ad hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus-carnosine complex. This complex showed enhanced antitumor efficacy in vitro and in vivo in different tumor models. In HCT-116 colorectal and A549 lung cancer cell lines, the complex showed higher transduction ratio and infectious titer compared with an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cell lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs. (C) 2016 AACR.	[Garofalo, Mariangela; Kuryk, Lukasz; Capasso, Cristian; Hirvinen, Mari; Cerullo, Vincenzo] Univ Helsinki, Lab ImmunoViroTherapy, Div Pharmaceut Biosci, CDR,Fac Pharm, Helsinki 00790, Finland; [Garofalo, Mariangela; Iovine, Barbara; Bevilacqua, Maria Assunta] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy; [Kuryk, Lukasz] Oncos Therapeut Ltd, Helsinki, Finland; [Kuryk, Lukasz] Natl Inst Hyg, Dept Virol, Natl Inst Publ Hlth, PL-00791 Warsaw, Poland; [Vitale, Andrea] Univ Naples Parthenope, Dept Movement Sci & Wellness DiSMEB, Naples, Italy; [Vitale, Andrea] CEINGE Biotecnol Avanzate, Naples, Italy; [Yliperttula, Marjo] Univ Helsinki, Div Pharmaceut Biosci, Helsinki 00790, Finland; [Yliperttula, Marjo] Univ Helsinki, Ctr Drug Res, Helsinki 00790, Finland		Cerullo, V (corresponding author), Univ Helsinki, POB 56, Helsinki 00790, Finland.	vincenzo.cerullo@helsinki.fi	Kuryk, Lukasz/D-9596-2018; Garofalo, Mariangela/Q-9469-2018; Cerullo, Vincenzo/B-9075-2015	Kuryk, Lukasz/0000-0003-1887-6361; Garofalo, Mariangela/0000-0002-5001-7826; Cerullo, Vincenzo/0000-0003-4901-3796	University of Helsinki; K. Albin Johansson Foundation; Foundation for the Finnish Cancer Institute; CDR; Division of Pharmaceutical Biosciences (University of Helsinki); Doctoral School BCMB University of Naples Federico II; CREME grant [CUP B25B09000050007]; Marie Curie Innovative Training Network (ITN) grant, ADVance [FP7-290002]	V. Cerullo was supported by the three-year research grant (University of Helsinki), K. Albin Johansson Foundation, Foundation for the Finnish Cancer Institute, CDR, and Division of Pharmaceutical Biosciences (University of Helsinki). M. Garofalo was supported by Doctoral School BCMB University of Naples Federico II. A. Vitale was supported by CREME grant, CUP B25B09000050007. L. Kuryk was supported by Marie Curie Innovative Training Network (ITN) grant, ADVance (FP7-290002).	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Cancer Ther.	APR	2016	15	4					651	660		10.1158/1535-7163.MCT-15-0559			10	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	DI6GD	WOS:000373596300011	26861248				2022-04-25	
J	Fang, LM; Li, B; Guan, JJ; Xu, HD; Shen, GH; Gao, QG; Qin, ZH				Fang, Li-mei; Li, Bin; Guan, Jun-jie; Xu, Hai-dong; Shen, Gen-hai; Gao, Quan-gen; Qin, Zheng-hong			Transcription factor EB is involved in autophagy-mediated chemoresistance to doxorubicin in human cancer cells	ACTA PHARMACOLOGICA SINICA			English	Article						transcription factor EB (TFEB); LoVo cells; HeLa cells; doxorubicin; autophagy; apoptosis; chemotherapy resistance; 3-methyladenine	LYSOSOMAL BIOGENESIS; DRUG-RESISTANCE; ATG PROTEINS; TUMORIGENESIS; APOPTOSIS; BECLIN-1; GENE; INHIBITION; METABOLISM; MECHANISMS	Transcription factor EB (TFEB) is a master regulator of autophagy activity and lysosomal biogenesis, but its role in autophagy-mediated cell survival and chemotherapy resistance is not completely understood. In this study, we explored whether TFEB played an important role in autophagy-mediated chemotherapy resistance in human cancer LoVo and HeLa cells in vitro. Treatment of human colon cancer LoVo cells with doxorubicin (0.5 mu mol/L) induced autophagy activation and nuclear translocation of TFEB, which resulted from inactivation of the mTOR pathway. In both LoVo and HeLa cells, overexpression of TFEB enhanced doxorubicin-induced autophagy activation and significantly decreased doxorubicin-induced cell death, whereas knockdown of TFEB with small interfering RNA blocked doxorubicin-induced autophagy and significantly enhanced the cytotoxicity of doxorubicin. In LoVo cells, autophagy inhibition by 3-methyladenine (3-MA) or knockdown of autophagy-related gene Atg5 increased cell death in response to doxorubicin, and abolished TFEB overexpression-induced chemotherapy resistance, suggesting that the inhibition of autophagy made cancer cells more sensitive to doxorubicin. The results demonstrate that TFEB-mediated autophagy activation decreases the sensitivity of cancer cells to doxorubicin.	[Fang, Li-mei; Guan, Jun-jie; Xu, Hai-dong; Qin, Zheng-hong] Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou 215123, Peoples R China; [Fang, Li-mei; Guan, Jun-jie; Xu, Hai-dong; Qin, Zheng-hong] Soochow Univ, Jiangsu Key Lab Prevent & Translat Med Geriatr Di, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Coll Pharmaceut Sci,Lab Aging & Nervous Dis, Suzhou 215123, Peoples R China; [Li, Bin; Shen, Gen-hai; Gao, Quan-gen] First Peoples Hosp Wu Jiang, Dept Gen Surg, Suzhou 215200, Peoples R China		Qin, ZH (corresponding author), Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou 215123, Peoples R China.; Qin, ZH (corresponding author), Soochow Univ, Jiangsu Key Lab Prevent & Translat Med Geriatr Di, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Coll Pharmaceut Sci,Lab Aging & Nervous Dis, Suzhou 215123, Peoples R China.; Gao, QG (corresponding author), First Peoples Hosp Wu Jiang, Dept Gen Surg, Suzhou 215200, Peoples R China.	wjyygqg@sohu.com; qinzhenhong@suda.edu.cn	Xu, Haidong/Q-1095-2019		Jiangsu Provincial Commission of Health and Family Planning [YG201402, YG201503]; Suzhou Wujiang District Science and Technology Bureau [WS201301]	This work was supported by the Jiangsu Provincial Commission of Health and Family Planning 2014 (No YG201402) and 2015 (No YG201503) as well as by Suzhou Wujiang District Science and Technology Bureau 2013 (No WS201301).	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Sin.	SEP	2017	38	9					1305	1316		10.1038/aps.2017.25			12	Chemistry, Multidisciplinary; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Pharmacology & Pharmacy	FG7EJ	WOS:000410575900008	28603284	Green Published, Bronze			2022-04-25	
J	Fan, XJ; Wan, XB; Huang, Y; Cai, HM; Fu, XH; Yang, ZL; Chen, DK; Song, SX; Wu, PH; Liu, Q; Wang, L; Wang, JP				Fan, X-J; Wan, X-B; Huang, Y.; Cai, H-M; Fu, X-H; Yang, Z-L; Chen, D-K; Song, S-X; Wu, P-H; Liu, Q.; Wang, L.; Wang, J-P			Epithelial-mesenchymal transition biomarkers and support vector machine guided model in preoperatively predicting regional lymph node metastasis for rectal cancer	BRITISH JOURNAL OF CANCER			English	Article						SVM; EMT; regional lymph node metastasis; colorectal cancer	COLORECTAL-CANCER; TUMOR PROGRESSION; POOR-PROGNOSIS; EXPRESSION PROFILE; CARCINOMA; OVEREXPRESSION; TUMORIGENESIS; AUTOPHAGY; INVASION; BECLIN-1	BACKGROUND: Current imaging modalities are inadequate in preoperatively predicting regional lymph node metastasis (RLNM) status in rectal cancer (RC). Here, we designed support vector machine (SVM) model to address this issue by integrating epithelial-mesenchymal-transition (EMT)-related biomarkers along with clinicopathological variables. METHODS: Using tissue microarrays and immunohistochemistry, the EMT-related biomarkers expression was measured in 193 RC patients. Of which, 74 patients were assigned to the training set to select the robust variables for designing SVM model. The SVM model predictive value was validated in the testing set (119 patients). RESULTS: In training set, eight variables, including six EMT-related biomarkers and two clinicopathological variables, were selected to devise SVM model. In testing set, we identified 63 patients with high risk to RLNM and 56 patients with low risk. The sensitivity, specificity and overall accuracy of SVM in predicting RLNM were 68.3%, 81.1% and 72.3%, respectively. Importantly, multivariate logistic regression analysis showed that SVM model was indeed an independent predictor of RLNM status (odds ratio, 11.536; 95% confidence interval, 4.113-32.361; P < 0.0001). CONCLUSION: Our SVM-based model displayed moderately strong predictive power in defining the RLNM status in RC patients, providing an important approach to select RLNM high-risk subgroup for neoadjuvant chemoradiotherapy. British Journal of Cancer (2012) 106, 1735-1741. doi:10.1038/bjc.2012.82 www.bjcancer.com Published online 26 April 2012 (C) 2012 Cancer Research UK	[Fan, X-J; Huang, Y.; Fu, X-H; Yang, Z-L; Chen, D-K; Song, S-X; Wu, P-H; Wang, L.; Wang, J-P] Sun Yat Sen Univ, Affiliated Hosp 6, Gastrointestinal Inst, Guangzhou 510655, Guangdong, Peoples R China; [Wan, X-B] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Med Oncol, Guangzhou 510630, Guangdong, Peoples R China; [Cai, H-M] Sun Yat Sen Univ, Sch Informat Sci & Technol, Guangzhou 510000, Guangdong, Peoples R China; [Liu, Q.] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol So China, Guangzhou 510060, Guangdong, Peoples R China		Wang, JP (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 6, Gastrointestinal Inst, Guangzhou 510655, Guangdong, Peoples R China.	leiwangyinghu@yahoo.com.cn; wangjpgz@yahoo.com.cn	Chen, Dianke/E-2248-2011; Cai, Hongmin/M-8240-2019	Cai, Hongmin/0000-0002-2747-7234	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30872488, 81072042, 81001086, 81000934]	This work was supported by National Natural Science Foundation of China ( No. 30872488 and 81072042 to L Wang, No. 81001086 to XJ Fan and No. 81000934 to XB Wan).	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J. Cancer	MAY 22	2012	106	11					1735	1741		10.1038/bjc.2012.82			7	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	946LQ	WOS:000304353500005	22538975	Green Published, hybrid			2022-04-25	
J	Banerjee, A; Banerjee, V; Czinn, S; Blanchard, T				Banerjee, Aditi; Banerjee, Vivekjyoti; Czinn, Steven; Blanchard, Thomas			Increased reactive oxygen species levels cause ER stress and cytotoxicity in andrographolide treated colon cancer cells	ONCOTARGET			English	Article						andrographolide; chemotherapy; reactive oxygen species; endoplasmic reticulum stress; unfolded protein response	UNFOLDED PROTEIN RESPONSE; AIRWAY EPITHELIAL-CELLS; MEDIATED APOPTOSIS; DOWN-REGULATION; BREAST-TUMOR; G2/M PHASE; V-SRC; DEATH; AUTOPHAGY; SUPPRESSION	Chemotherapy continues to play an essential role in the management of many cancers including colon cancer, the third leading cause of death due to cancer in the United States. Many naturally occurring plant compounds have been demonstrated to possess anti-cancer cell activity and have the potential to supplement existing chemotherapy strategies. The plant metabolite andrographolide induces cell death in cancer cells and apoptosis is dependent upon the induction of endoplasmic reticulum stress (ER stress) leading to the unfolded protein response (UPR). The goal of the present study was to determine the mechanism by which andrographolide induces ER stress and to further evaluate its role in promoting cell death pathways. The T84 and COLO 205 cancer cell lines were used to demonstrate that andrographolide induces increased ROS levels, corresponding anti-oxidant response molecules, and reduced mitochondrial membrane potential. No increases in ROS levels were detected in control colon fibroblast cells. Andrographolide-induced cell death, UPR signaling, and CHOP, Bax, and caspase 3 apoptosis elements were all inhibited in the presence of the ROS scavenger NAC. Additionally, andrographolide-induced suppression of cyclins B1 and D1 were also reversed in the presence of NAC. Finally, Akt phosphorylation and phospho-mTOR levels that are normally suppressed by andrographolide were also expressed at normal levels in the absence of ROS. These data demonstrate that andrographolide induces ER stress leading to apoptosis through the induction of ROS and that elevated ROS also play an important role in down-regulating cell cycle progression and cell survival pathways as well.	[Banerjee, Aditi; Banerjee, Vivekjyoti; Czinn, Steven; Blanchard, Thomas] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA		Banerjee, A (corresponding author), Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA.	abanerjee@peds.umaryland.edu			Department of Pediatrics at the University of Maryland School of Medicine	We wish to thank the Department of Pediatrics at the University of Maryland School of Medicine for supporting this research.	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J	Hu, CX; Cao, YB; Li, P; Tang, XR; Yang, MH; Gu, SL; Xiong, K; Li, T; Xiao, TB				Hu, Changxiao; Cao, Yibo; Li, Ping; Tang, Xiaorong; Yang, Minhui; Gu, Shengliang; Xiong, Kai; Li, Tian; Xiao, Tianbao			Oleanolic Acid Induces Autophagy and Apoptosis via the AMPK-mTOR Signaling Pathway in Colon Cancer	JOURNAL OF ONCOLOGY			English	Article							GROWTH; PHOSPHORYLATION; CELLS	Aims. The purpose of this study was to explore the biological functions of the mTOR and AMPK signaling pathways in colon cancer (CC). The potential molecular mechanisms by which oleanolic acid (OA) induces autophagy and apoptosis were also investigated. Methods. The biological functions of mTOR were analyzed by GeneCards, the Search Tool for the Retrieval of Interacting Genes (STRING), and the Database for Annotation, Visualization and Integrated Discovery (DAVID). Least absolute shrinkage and selection operator (LASSO) regression analysis was used to obtain prognostic and survival data of CC patients from the Gene Expression Omnibus (GEO) database. The effects of OA on the CC cell lines HCT-116 and SW-480 were analyzed by CCK-8, colony formation assay, and high-content system (HCS) array scan. The apoptosis rate of SW-480 and HCT-116 cells was detected by flow cytometry. The mRNA and protein expression levels in HCT-116 and SW-480 cells and NCM-460 normal colonic epithelial cells were detected by RT-PCR and Western blotting. Results. mTOR was highly expressed in CC patients and acted as an oncogene. The AMPK signaling pathway mediated by mTOR predicted the poor prognosis of CC patients. OA effectively inhibited the proliferation and viability of CC cells. Furthermore, the apoptosis rate of CC cells was clearly increased following OA administration. Regarding the molecular mechanism of OA, the results indicated that mTOR and the antiapoptosis gene Bcl-2 were downregulated by OA. In addition, regulator genes of autophagy and apoptosis, including BAX, caspase-9, caspase-8, and caspase-3, were significantly upregulated by OA. Moreover, OA upregulated AMPK and its downstream proteins, including TSC2, BAX, Beclin 1, LC3B-II, and ULK1, to induce autophagy and apoptosis in CC cells. Conclusion. The findings from this study demonstrate that OA could effectively inhibit the proliferation and viability of CC cells. The anti-CC activity of OA is closely related to the activation of the AMPK-mTOR signaling pathway. Activation of AMPK and inhibition of mTOR are involved in the induction of autophagy and apoptosis by OA. OA induced autophagy and apoptosis mainly in an AMPK activation-dependent manner in CC cells.	[Hu, Changxiao; Yang, Minhui; Gu, Shengliang; Xiong, Kai] Guizhou Univ Tradit Chinese Med, Coll Clin Med, 71 Baoshan North Rd, Guiyang 550001, Peoples R China; [Cao, Yibo; Li, Ping; Tang, Xiaorong; Xiao, Tianbao] Guizhou Univ Tradit Chinese Med, Affiliated Hosp 1, Colorectal & Anal Surg, 71 Baoshan North Rd, Guiyang 550001, Peoples R China; [Li, Tian] Fourth Mil Med Univ, 169 Changle West Rd, Xian 710032, Peoples R China		Xiao, TB (corresponding author), Guizhou Univ Tradit Chinese Med, Affiliated Hosp 1, Colorectal & Anal Surg, 71 Baoshan North Rd, Guiyang 550001, Peoples R China.; Li, T (corresponding author), Fourth Mil Med Univ, 169 Changle West Rd, Xian 710032, Peoples R China.	doc_huchangxiao@163.com; 47030959@qq.com; 418835868@qq.com; 406817855@qq.com; 2726030816@qq.com; 850712786@qq.com; 1255354266@qq.com; fmmult@foxmail.com; prof_xiaotianbao@163.com		Li, Tian/0000-0002-8281-4459	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81860854, 8186150460]; Science and Technology Projects of Guizhou Province [7788, 7153]	This research was financially supported by the National Natural Science Foundation of China (nos. 81860854 and 8186150460) and Science and Technology Projects of Guizhou Province (nos. 7788, Qiankehe LH[2015] and 7153, Qiankehe LH[2017]).	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Oncol.	JUL 17	2021	2021								8281718	10.1155/2021/8281718			17	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	TR5IU	WOS:000678998600001	34326874	Green Published, gold			2022-04-25	
J	Banfi, S; Caruso, E; Zaza, S; Mancini, M; Gariboldi, MB; Monti, E				Banfi, Stefano; Caruso, Enrico; Zaza, Stefano; Mancini, Monica; Gariboldi, Marzia B.; Monti, Elena			Synthesis and photodynamic activity of a panel of BODIPY dyes	JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY			English	Article						BODIPY; Photodynamic activity; Singlet oxygen; HCT 116; Apoptosis; Heavy atom effect	RESONANCE ENERGY-TRANSFER; HIGHLY EFFICIENT; SINGLET OXYGEN; IN-VITRO; THERAPY; EMISSION; CANCER; CELLS; PHOTOSENSITIZERS; DERIVATIVES	Eight BODIPY dyes were synthesized and used as photosensitizers (PSs) on the human colon carcinoma cell line HCT116. In this panel of molecules, the structure varies in the substituents on pyrrole 2, 6 positions and on the phenyl ring at the indacene 8 position. For these compounds relevant physico-chemical parameters, such as singlet oxygen production, fluorescent quantum yield, absorbance profile and a relative rank of lipophilicity were determined. Our results indicate that some of these novel PSs are very effective in reducing the growth/viability of HCT116 cells when irradiated with a green LED source, whereas they are practically devoid of activity in the dark, up to 5 mu M. To evaluate whether cell death is induced under these conditions, flow cytometric analysis of the percentage of apoptotic and autophagic cells was performed on four molecules, chosen for their efficacy/structural characteristics. Our data indicate that phototoxicity likely occurs mainly through apoptotic cell death, whereas autophagy seems to play a minor role in determining cell fate. Furthermore, the relationship between singlet oxygen generation and the PS efficacy is confirmed, thus underscoring the importance of the heavy-atom effect and of the presence of an aryl substituent at dipyrromethene 8 (meso) position. Among the PSs here described, the most efficient BODIPY was successfully tested on three other human cancer cell lines of different tissue origin, MCF7 (breast), A2780 and A2780/CP8 (ovary, sensitive and resistant to cisplatin, respectively), yielding IC50 values comparable to those obtained on HCT116. (c) 2012 Elsevier B.V. All rights reserved.	[Banfi, Stefano; Caruso, Enrico; Zaza, Stefano; Mancini, Monica; Gariboldi, Marzia B.; Monti, Elena] Univ Insubria, Dept Theoret & Appl Sci DiSTA, I-21100 Varese, VA, Italy		Banfi, S (corresponding author), Univ Insubria, Dept Theoret & Appl Sci DiSTA, Via H Dunant 3, I-21100 Varese, VA, Italy.	stefano.banfi@uninsubria.it	Gariboldi, Marzia Bruna/U-1331-2019	gariboldi, marzia bruna/0000-0002-5683-0885; Mancini, Monica/0000-0003-4128-9018			Atilgan S, 2006, CHEM COMMUN, P4398, DOI 10.1039/b612347c; Banfi S, 2004, BIOORGAN MED CHEM, V12, P4853, DOI 10.1016/j.bmc.2004.07.011; Banfi S, 2006, J MED CHEM, V49, P3293, DOI 10.1021/jm050997m; BEHRENS BC, 1987, CANCER RES, V47, P414; Berg K., PHOTOSENSITIZERS MED; Buytaert E, 2007, BBA-REV CANCER, V1776, P86, DOI 10.1016/j.bbcan.2007.07.001; Colella G, 2001, BRIT J CANCER, V84, P1387, DOI 10.1054/bjoc.2001.1751; Coskun A, 2005, ORG LETT, V7, P5187, DOI 10.1021/ol052020h; Coskun A, 2005, J AM CHEM SOC, V127, P10464, DOI 10.1021/ja052574f; Coskun A, 2006, J AM CHEM SOC, V128, P14474, DOI 10.1021/ja066144g; Dost Z, 2006, TETRAHEDRON, V62, P8484, DOI 10.1016/j.tet.2006.06.082; Dougherty TJ, 1998, JNCI-J NATL CANCER I, V90, P889, DOI 10.1093/jnci/90.12.889; Erten-Ela S, 2008, ORG LETT, V10, P3299, DOI 10.1021/ol8010612; Gorman A, 2004, J AM CHEM SOC, V126, P10619, DOI 10.1021/ja047649e; Grosjean P, 1998, BRIT J CANCER, V77, P1989, DOI 10.1038/bjc.1998.330; JOHNSON S, 1999, REV CONT PHARMACOTHE; KAROLIN J, 1994, J AM CHEM SOC, V116, P7801, DOI 10.1021/ja00096a042; Klionsky DJ, 2008, AUTOPHAGY, V4, P151, DOI 10.4161/auto.5338; Kochevar IE, 2000, METHOD ENZYMOL, V319, P20; Lim SH, 2010, J MED CHEM, V53, P2865, DOI 10.1021/jm901823u; LISSI EA, 1993, CHEM REV, V93, P699, DOI 10.1021/cr00018a004; Liu JY, 2008, ORG LETT, V10, P5421, DOI 10.1021/ol8023677; Loudet A, 2008, TETRAHEDRON, V64, P3642, DOI 10.1016/j.tet.2008.01.117; MacDonald IJ, 2001, J PORPHYR PHTHALOCYA, V5, P105, DOI 10.1002/jpp.328; Osterloh J, 2002, J PORPHYR PHTHALOCYA, V6, P305, DOI 10.1142/S1088424602000373; Pandey RK, 2000, J PORPHYR PHTHALOCYA, V4, P368, DOI 10.1002/(SICI)1099-1409(200006/07)4:4<368::AID-JPP244>3.0.CO;2-6; Reiners JJ, 2010, AUTOPHAGY, V6, P7, DOI 10.4161/auto.6.1.10220; Saki N, 2006, TETRAHEDRON, V62, P2721, DOI 10.1016/j.tet.2005.12.021; Scalise I, 2004, J PHOTOCH PHOTOBIO A, V162, P105, DOI 10.1016/S1010-6030(03)00317-4; Singh-Rachford TN, 2008, J AM CHEM SOC, V130, P16164, DOI 10.1021/ja807056a; TRONCONI M, 1995, CANCER LETT, V88, P41, DOI 10.1016/0304-3835(94)03612-M; Umezawa K, 2008, J AM CHEM SOC, V130, P1550, DOI 10.1021/ja077756j; Wittmershaus BP, 2001, J FLUORESC, V11, P119, DOI 10.1023/A:1016629518660; Yano S, 2011, J PHOTOCH PHOTOBIO C, V12, P46, DOI 10.1016/j.jphotochemrev.2011.06.001; Yogo T, 2005, J AM CHEM SOC, V127, P12162, DOI 10.1021/ja0528533; Zeng L, 2006, J AM CHEM SOC, V128, P10, DOI 10.1021/ja055064u	36	42	42	1	57	ELSEVIER SCIENCE SA	LAUSANNE	PO BOX 564, 1001 LAUSANNE, SWITZERLAND	1011-1344			J PHOTOCH PHOTOBIO B	J. Photochem. Photobiol. B-Biol.	SEP 3	2012	114						52	60		10.1016/j.jphotobiol.2012.05.010			9	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	987KJ	WOS:000307415500006	22705078				2022-04-25	
J	Deitersen, J; El-Kashef, DH; Proksch, P; Stork, B				Deitersen, Jana; El-Kashef, Dina H.; Proksch, Peter; Stork, Bjoern			Anthraquinones and autophagy - Three rings to rule them all?	BIOORGANIC & MEDICINAL CHEMISTRY			English	Review						Anthraquinones; Autophagy; AKT pathway; Emodin; Chemotherapy-resistance	EMODIN INDUCES APOPTOSIS; NF-KAPPA-B; FUNGUS STEMPHYLIUM-GLOBULIFERUM; ACTIVATED PROTEIN-KINASE; COLON-CANCER CELLS; ALOE-EMODIN; IN-VITRO; BIOACTIVE METABOLITES; ARSENIC CYTOTOXICITY; ANTIOXIDANT ACTIVITY	In order to overcome therapy resistance in cancer, scientists search in nature for novel lead structures for the development of improved chemotherapeutics. Anthraquinones belong to a class of tricyclic organic natural compounds with promising anti-cancer effects. Anthraquinone derivatives are rich in structural diversity, and exhibit pleiotropic properties, among which the modulation of autophagy seems promising in the context of overcoming cancer-therapy resistance. Among the most promising derivatives in this regard are emodin, aloe emodin, rhein, physcion, chrysophanol and altersolanol A. On the molecular level, these compounds target autophagy via different upstream pathways including the AKT/mTOR-axis and transcription of autophagy-related proteins. The role of autophagy is pro-survival as well as cell death-promoting, depending on derivatives and their cell type specificity. This review summarizes observed effects of anthraquinone derivatives on autophagy and discusses targeted pathways and crosstalks. A cumulative knowledge about this topic paves the way for further research on modes of action, and aids to find a therapeutic window of anthraquinones in cancer-therapy.	[Deitersen, Jana; Stork, Bjoern] Heinrich Heine Univ, Inst Mol Med 1, Med Fac, Univ Str 1, D-40225 Dusseldorf, Germany; [El-Kashef, Dina H.; Proksch, Peter] Heinrich Heine Univ, Fac Math & Nat Sci, Inst Pharmaceut Biol & Biotechnol, Univ Str 1, D-40225 Dusseldorf, Germany		Deitersen, J; Stork, B (corresponding author), Heinrich Heine Univ, Inst Mol Med 1, Med Fac, Univ Str 1, D-40225 Dusseldorf, Germany.	jana.deitersen@hhu.de; bjoern.stork@hhu.de	Proksch, Peter/AAR-4593-2020; Stork, Björn/C-2160-2011	Stork, Björn/0000-0002-4167-7806	Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)German Research Foundation (DFG) [315775584/STO 864/5-1, 270650915/GRK 2158]	We thank Michelle Klein for the technical support in the analysis of cell death mediated by altersolanol A. We thank the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) for financial support of the projects 315775584/STO 864/5-1 (to BS) and 270650915/GRK 2158 (subproject 1c to PP and subproject 3b to BS).	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Med. Chem.	OCT 15	2019	27	20							115042	10.1016/j.bmc.2019.115042			11	Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry	IY4SO	WOS:000486383500004	31420258	hybrid			2022-04-25	
J	Fattahi, Y; Heidari, HR; Khosroushahi, AY				Fattahi, Yasin; Heidari, Hamid Reza; Khosroushahi, Ahmad Yari			Review of short-chain fatty acids effects on the immune system and cancer	FOOD BIOSCIENCE			English	Review						Acetate; Butyrate; Capric acid; Caprylic acid; Caproic acid; Propionate	HISTONE DEACETYLASE INHIBITORS; PROTEIN-COUPLED RECEPTOR; NF-KAPPA-B; SUPPRESSES COLONIC INFLAMMATION; CYTOKINE-INDUCED VCAM-1; SODIUM-BUTYRATE; GUT MICROBIOTA; MEDIATED APOPTOSIS; GENE-EXPRESSION; METABOLITE BUTYRATE	Short-chain fatty acids (SCFA), as end products of indigestible-fiber-fermentation by gut-bacteria, affect inflammatory disease and cancer. SCFA are quickly absorbed in the colon through their transporters categorized as SMCT1/SLC5a8, MCT1/SLAC16a, and SCFA-HCO3 exchangers. These compounds have anti-inflammatory and anticancer properties by activating FFR2/GPR43, FFR3/GPR41, GPR109, olfactory receptor 78, and inhibiting histone deacetylases (HDAC). SCFA suppresses inflammation by influencing chemotaxis, immune cells' differentiation, and the production of cytokines from different cell types. In addition to autophagy induction ability of SCFA in cancer cells, they can also induce apoptosis in tumoral cells. SCFA has not shown significant effects on normal cells' propagation. On the other hand, previous reports showed their preventive impacts on cancer cell proliferation, which has been named the "Butyrate paradox" and discussed in terms of the "Warburg effect."	[Fattahi, Yasin] Tabriz Univ Med Sci, Fac Pharm, Biotechnol Res Ctr, Student Res Comm, Tabriz, Iran; [Heidari, Hamid Reza; Khosroushahi, Ahmad Yari] Tabriz Univ Med Sci, Drug Appl Res Ctr, Tabriz, Iran; [Heidari, Hamid Reza] Tabriz Univ Med Sci, Fac Pharm, Dept Pharmaceut Biotechnol, Tabriz, Iran; [Khosroushahi, Ahmad Yari] Tabriz Univ Med Sci, Fac Adv Med Sci, Dept Med Nanotechnol, Tabriz, Iran		Khosroushahi, AY (corresponding author), Tabriz Univ Med Sci, Fac Adv Med Sci, Daneshgah St,POB 51548-53431, Tabriz, Iran.	yarikhosroushahia@tbzmed.ac.ir	Heidari, Hamid Reza/M-4362-2017	Heidari, Hamid Reza/0000-0001-7371-4977	Drug Applied Research Center, Tabriz University of Medical Science [59585]	This study was supported financially by the Drug Applied Research Center, Tabriz University of Medical Science, with the grant number of 59585.	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DEC	2020	38								100793	10.1016/j.fbio.2020.100793			10	Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology	PC6SU	WOS:000597129200012					2022-04-25	
J	Arslan, FD; Kocak, A; Aydin, C; Pala, EE; Oncel, D; Diniz, G; Kaya, T; Ugurlu, L; Degirmenci, M; Ozkan, B; Soysal, Y; Said, HM				Arslan, Fatma Demet; Kocak, Ayse; Aydin, Cengiz; Pala, Emel Ebru; Oncel, Dilek; Diniz, Gulden; Kaya, Tayfun; Ugurlu, Levent; Degirmenci, Mustafa; Ozkan, Bulent; Soysal, Yasemin; Said, Harun Muayad			Evaluation of potential tumor markers that may predict neoadjuvant treatment efficiency in rectal cancer	TURKISH JOURNAL OF BIOCHEMISTRY-TURK BIYOKIMYA DERGISI			English	Article						Beclin 1; carbonic anhydrase-9; hypoxia-inducible factor-1 alpha; neoadjuvant treatment; rectal cancer; Survivin	CARBONIC-ANHYDRASE; COLORECTAL-CANCER; CHEMORADIATION THERAPY; BECLIN 1; EXPRESSION; HYPOXIA; AUTOPHAGY; SURVIVIN; CHEMORADIOTHERAPY; CELLS	Objectives: The recurrence of rectal cancer or its resistance to neoadjuvant treatment develops due to the adaptation to hypoxia, apoptosis or autophagy. Survivin, one of the inhibitors of apoptosis; Beclin 1, which is a positive regulator in the autophagy pathway; and hypoxia-inducible factor-1 alpha (HIF-1 alpha) and carbonic anhydrase-9 (CA9), which are associated with tumor tissue hypoxia, may be related to resistance to treatment. Our aim was to evaluate the potential tumor markers that may help to monitor the response to neoadjuvant treatment in locally advanced rectal cancer (RC). Methods: Twenty-five patients with locally advanced RC were included in the study. Gene expression and protein levels of Beclin 1, Survivin, HIF-1 alpha, and CA9 were analyzed in fresh tissue specimens and blood samples. The relationships of these markers to tumor staging and regression grade were evaluated. Results: Higher blood CA9 gene expression levels and lower blood HIF-1 alpha protein levels were found in the response group according to tumor regression grade. After neoadjuvant treatment, tissue Beclin 1 and blood Survivin gene expressions and tissue CA9, blood Beclin 1 and blood HIF-1 alpha protein levels decreased significantly. Conclusion: Beclin 1, Survivin, HIF-1 alpha ve CA9 may help to predict the effects of the applied treatment approach.	[Arslan, Fatma Demet] Univ Hlth Sci, Tepecik Training & Res Hosp, Dept Med Biochem, Gaziler St,468, TR-35180 Izmir, Turkey; [Kocak, Ayse; Soysal, Yasemin; Said, Harun Muayad] Dokuz Eylul Univ, Inst Hlth Sci, Dept Mol Med, Izmir, Turkey; [Aydin, Cengiz] Univ Hlth Sci, Tepecik Training & Res Hosp, Gen Surg Clin, Izmir, Turkey; [Pala, Emel Ebru; Diniz, Gulden; Kaya, Tayfun; Ugurlu, Levent] Univ Hlth Sci, Tepecik Training & Res Hosp, Med Pathol Clin, Izmir, Turkey; [Oncel, Dilek] Univ Hlth Sci, Tepecik Training & Res Hosp, Radiol Clin, Izmir, Turkey; [Degirmenci, Mustafa] Univ Hlth Sci, Tepecik Training & Res Hosp, Oncol Clin, Izmir, Turkey; [Ozkan, Bulent] Katip Celebi Univ, Fac Med, Dept Biostat, Izmir, Turkey		Arslan, FD (corresponding author), Univ Hlth Sci, Tepecik Training & Res Hosp, Dept Med Biochem, Gaziler St,468, TR-35180 Izmir, Turkey.	fatmademet.arslan@gmail.com	Arslan, Fatma Demet/ABG-6885-2021; Said, Harun Muayad/AAZ-7299-2021; Arslan İnce, Fatma Demet/AAZ-5735-2021; Kocak, Ayse/W-3229-2017	Arslan, Fatma Demet/0000-0003-0766-0303; Diniz, Gulden/0000-0003-1512-7584; Kocak, Ayse/0000-0002-1510-2937	Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [116S225]	The present study was funded by a grant from the Scientific and Technological Research Council of Turkey with the number 116S225.	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J. Biochem.	AUG	2021	46	4					445	454		10.1515/tjb-2020-0507			10	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	UM8XD	WOS:000693607700014		gold			2022-04-25	
J	Enayat, S; Ceyhan, MS; Taskoparan, B; Stefek, M; Banerjee, S				Enayat, Shabnam; Ceyhan, M. Seyma; Taskoparan, Betul; Stefek, Milan; Banerjee, Sreeparna			CHNQ, a novel 2-Chloro-1,4-naphthoquinone derivative of quercetin, induces oxidative stress and autophagy both in vitro and in vivo	ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS			English	Article						CHNQ; Quercetin; Colon cancer; Oxidative stress; Autophagy	CANCER CELL-LINES; ALDOSE REDUCTASE; TARGET; INHIBITION; 1,4-NAPHTHOQUINONES; PHOSPHORYLATION; BIOAVAILABILITY; CYTOTOXICITY; CROSSTALK; MECHANISM	Quercetin (Qc) shows strong antitumor effects but has limited clinical application due to poor water solubility and bioavailability. In a screening of novel semi-synthetic derivatives of Qc, 3,7-dihydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxyphenyl]-5-hydroxychromen-4-one (CHNQ) could ameliorate acetic acid induced acute colitis in vivo more efficiently than Qc. Since inflammation contributes to colorectal cancer (CRC), we have hypothesized that CHNQ may have anti-cancer effects. Using CRC cell lines HCT-116 and HT-29, we report that CHNQ was three-fold more cytotoxic than Qc along with a robust induction of apoptosis. As expected from naphthoquinones such as CHNQ, a strong induction of oxidative stress was observed. This was accompanied by reactive oxygen species (ROS) induced autophagy marked by a dramatic increase in the lipidation of LC3, decreased activation of Akt/PKB, acidic vesicle accumulation and puncta formation in HCT-116 cells treated with CHNQ. Interestingly, an incomplete autophagy was observed in HT-29 cells where CHNQ treatment led to LC3 lipidation, but not the formation of acidic vacuoles. CHNQ-induced cytotoxicity, ROS formation and autophagy were also detected in vivo in Saccharomyces cerevisiae strain RDKY3615 (WinstonS288C background). Overall, we propose that CHNQ can induce cancer cell death through the induction of oxidative stress, and may be examined further as a potential chemotherapeutic drug. (C) 2016 Elsevier Inc. All rights reserved.	[Enayat, Shabnam; Ceyhan, M. Seyma; Taskoparan, Betul; Banerjee, Sreeparna] Middle E Tech Univ, Dept Biol Sci, TR-06800 Ankara, Turkey; [Stefek, Milan] Slovak Acad Sci, Inst Expt Pharmacol & Toxicol, Dubravska Cesta 9, Bratislava 84104, Slovakia		Banerjee, S (corresponding author), Middle E Tech Univ, Dept Biol Sci, TR-06800 Ankara, Turkey.	banerjee@metu.edu.tr	enayat, shabnam/AGD-9425-2022; Banerjee, Sreeparna/AAZ-6742-2020	Banerjee, Sreeparna/0000-0003-4596-6768; Stefek, Milan/0000-0002-2707-8030; Taskoparan Yaglikci, Betul/0000-0003-1890-1547	TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK); Slovak Academy of SciencesSlovak Academy of Sciences [113S006]	The authors would like to gratefully acknowledge Dr Cagdas Devrim Son at METU for his help with microscopy. This work was supported by the TUBITAK 2513 Bilateral Cooperation Program between TUBITAK and the Slovak Academy of Sciences (Project no: 113S006 to MS and SB).	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Biochem. Biophys.	APR 15	2016	596						84	98		10.1016/j.abb.2016.03.004			15	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	DK0UE	WOS:000374626900008	26946942				2022-04-25	
J	Yan, C; Luo, L; Goto, S; Urata, Y; Guo, CY; Doi, H; Kitazato, K; Li, TS				Yan, Chen; Luo, Lan; Goto, Shinji; Urata, Yoshishige; Guo, Chang-Ying; Doi, Hanako; Kitazato, Kaio; Li, Tao-Sheng			Enhanced autophagy in colorectal cancer stem cells does not contribute to radio-resistance	ONCOTARGET			English	Article						cancer stem cells; autophagy; radio-resistance	TUMOR MICROENVIRONMENT; RADIORESISTANCE FACTOR; OXIDATIVE STRESS; RECTAL-CANCER; RADIATION; THERAPY; RADIOTHERAPY; INHIBITION; RADIOSENSITIVITY; 5-FLUOROURACIL	Autophagy, an essential catabolic pathway of degrading cellular components within the lysosome, has been found to benefit the growth and therapeutic resistance of cancer cells. In this study, we investigated the role of autophagy in the radiosensitivity of cancer stem cells. By separating CD44(+)/CD133(+) cancer stem cells from parental HCT8 human colorectal cancer cells, we found a significantly higher level of autophagy in the CD44(+)/CD133(+) cells than in the parental cells. Exposure to 5 Gy of eta-ray significantly damaged both CD44(+)/CD133(+) cells and parental cells, but the radiation-induced damage did not differ between the groups. Unexpectedly, autophagy was not significantly induced by radiation exposure in the CD44(+)/CD133(+) cells and parental cells. The inhibition of autophagy by the silencing of ATG7, a factor required for autophagy at the stage of autophagosome precursor synthesis, did not significantly change the growth and radiation-induced damage in both CD44(+)/CD133(+) cells and parental cells. Although an enhanced basic level of autophagy was found in the CD44(+)/CD133(+) cancer stem cells, our data suggest that the canonical autophagy in cancer cells plays few roles, if any, in radio-sensitivity.	[Yan, Chen; Luo, Lan; Goto, Shinji; Urata, Yoshishige; Guo, Chang-Ying; Doi, Hanako; Li, Tao-Sheng] Nagasaki Univ, Dept Stem Cell Biol, Grad Sch Biomed Sci, Nagasaki, Japan; [Guo, Chang-Ying] Jiangxi Canc Hosp, Dept Thorac Surg, Nanchang, Peoples R China; [Kitazato, Kaio] Nagasaki Univ, Div Mol Pharmacol Infect Agents, Dept Mol Microbiol & Immunol, Grad Sch Biomed Sci, Nagasaki, Japan		Li, TS (corresponding author), Nagasaki Univ, Dept Stem Cell Biol, Grad Sch Biomed Sci, Nagasaki, Japan.; Kitazato, K (corresponding author), Nagasaki Univ, Div Mol Pharmacol Infect Agents, Dept Mol Microbiol & Immunol, Grad Sch Biomed Sci, Nagasaki, Japan.	kkholi@nagasaki-u.ac.jp; litaoshe@nagasaki-u.ac.jp	chang-ying, guo/F-2770-2018	Luo, Lan/0000-0001-7549-9852; Li, Tao-Sheng/0000-0002-7653-8873	Ministry of Education, Science, Sports, Culture and Technology, JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); collaborative Research program of Atomic-bomb Disease Institute of Nagasaki University; 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) [25462061] Funding Source: KAKEN	This study was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology, Japan, and collaborative Research program of the Atomic-bomb Disease Institute of Nagasaki University. The funder played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.	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J	Gil, J; Pesz, KA; Sasiadek, MM				Gil, Justyna; Pesz, Karolina A.; Sasiadek, Maria M.			May autophagy be a novel biomarker and antitumor target in colorectal cancer?	BIOMARKERS IN MEDICINE			English	Review						ATG; autophagy; autophagosome; BECN1; colorectal cancer; gene expression; immunohistochemistry; LC3; protein expression	INFLAMMATORY-BOWEL-DISEASE; COLON-CANCER; MICROSATELLITE INSTABILITY; FAVORABLE PROGNOSIS; DOWN-REGULATION; CROHNS-DISEASE; CELL-DEATH; BECLIN 1; EXPRESSION; APOPTOSIS	Autophagy is a catabolic process associated with intracellular self-digestion of damaged organelles or redundant proteins enabling maintenance of cell homeostasis. It is accepted that impaired autophagy is closely linked to cancer development and has been extensively studied in a variety of malignancies including colorectal cancer (CRC) to elucidate its influence on carcinogenesis, metastasis and antitumor therapy response. CRC remains a great epidemiological problem because of poor 5-year survival and treatment resistance. Many studies concerning autophagy in CRC gave inconsistent and contradictory results, illustrating a multifaceted nature of this process. In this review, we focus on current knowledge of autophagy in CRC development to determinate its role as a potential prognostic and predictive biomarker as well as target in antitumor therapy.	[Gil, Justyna; Pesz, Karolina A.; Sasiadek, Maria M.] Wroclaw Med Univ, Dept Genet, Wroclaw, Poland		Gil, J (corresponding author), Wroclaw Med Univ, Dept Genet, Wroclaw, Poland.	justyna.gil@umed.wroc.pl	/L-5618-2019	/0000-0003-0991-7686; Pesz, Karolina/0000-0003-1482-1021; Sasiadek, Maria/0000-0002-7599-7074	National Science Centre (Poland) [DEC-2012/07/D/NZ5/04305]	This work was financed from the funds of the National Science Centre (Poland) decision number DEC-2012/07/D/NZ5/04305. 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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Wei MF, 2014, AUTOPHAGY, V10, P1179, DOI 10.4161/auto.28679; White E, 2015, CLIN CANCER RES, V21, P5037, DOI 10.1158/1078-0432.CCR-15-0490; White EJ, 2011, AM J CANCER RES, V1, P362; Wojciechowska U., ZACHOROWANIA ZGONY N; Wong PM, 2013, AUTOPHAGY, V9, P124, DOI 10.4161/auto.23323; Wu SH, 2015, INT J CLIN EXP PATHO, V8, P3882; Xu YH, 2013, ONCOL LETT, V5, P411, DOI 10.3892/ol.2012.1015; Yamazaki K, 2007, J HUM GENET, V52, P575, DOI 10.1007/s10038-007-0156-z; Yang ZF, 2010, CURR OPIN CELL BIOL, V22, P124, DOI 10.1016/j.ceb.2009.11.014; Yang ZL, 2015, CLIN RES HEPATOL GAS, V39, P98, DOI 10.1016/j.clinre.2014.06.014; Zhang HY, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0096418; Zhang MY, 2014, INT J MOL SCI, V15, P14372, DOI 10.3390/ijms150814372	87	15	18	0	10	FUTURE MEDICINE LTD	LONDON	UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND	1752-0363	1752-0371		BIOMARK MED	Biomark. Med.	OCT	2016	10	10					1081	1094		10.2217/bmm-2016-0083			14	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	DZ8PM	WOS:000386133200008	27626110				2022-04-25	
J	Lin, FF; Song, ZF				Lin, Fangfang; Song, Zhangfa			LNCRNA UCA1 REGULATING CELL AUTOPHAGY THROUGH AKT/MTOR SIGNAL PATHWAY FOR INHIBITING COLON CANCER CELL PROLIFERATION, PROMOTING CELL APOPTOSIS, AND INCREASING CELL CYCLE ARREST	ACTA MEDICA MEDITERRANEA			English	Article						lncRNA UCA1; AMPK/mTOR signaling pathway; cell autophagy; colon cancer; cell proliferation; apoptosis; cell cycle		Objective: To analyze long-chain non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) regulating cell autophagy through the protein kinase B/rapamycin target protein (AKT/mTOR) signaling pathway, which inhibits colon cancer cell proliferation and promotes apoptosis and cell cycle arrest. Methods: Caco-2 cells were cultured at the same concentration and transfected into si-NC, si-UCA1, and si-UCA1 + 100nmol LRAPA (autophagy inhibitor) groups. Each group was set up with four replicate wells. After 6 h, it was replaced with dual antibodies and the medium of serum to be cultured for 24 h. Cell proliferation was measured using the CCK-8 method in each group. The cell apoptosis and cell cycle changes in each group were detected using flow cytometry, away from light. The expression of microtubule-associated protein light chain 3 (LC3), p62, AKT, and mTOR of cells in each group were determined using Western blotting and PCR. Results: The cell proliferation of each group was the same after 24 h. After longer periods of time, the differences in cell proliferation of each group were more obvious. At 72 h, compared with the Si-nc group, the proliferation ability of the si-uca1 and si-uca1 + Rapa group decreased significantly (P < 0.05), and the proliferation ability of the si-uca1 + Rapa group increased significantly (P < 0.05). Compared with the Si-nc group, the apoptosis ability of the si-uca1 and si-uca1 + Rapa group was significantly higher (P < 0.05), and the apoptosis ability of the si-uca1 + Rapa group was significantly lower than that of the si-uca1 group (P< 0.05). In comparison to the Si-nc group, the G1 phase cells in the si-uca1 group were significantly reduced, and the S phase and G phase cells were significantly increased (P < 0.05); compared with the si-uca1 group, the G1 phase cells of the si-uca1 + Rapa group were significantly increased, and the S phase and G phase cells were significantly reduced (P< 0.05). In comparison to the Si-nc group, the expression level of LC3 and p62 in the Si UCA1 group was significantly lower, and the expression levels of Akt and mTOR were significantly higher (P < 0.05) Conclusion: lncRNA UCA1 may regulate cell autophagy through the AKT/mTOR signaling pathway, thereby inhibiting colon cancer cell proliferation, promoting apoptosis, and blocking the G2 phase of the cell cycle.	[Lin, Fangfang] Zhejiang Univ, Med Coll, Hangzhou 310011, Peoples R China; [Lin, Fangfang] Jiangshan Peoples Hosp, Dept Pathol, Jiangshan 324100, Peoples R China; [Song, Zhangfa] Zhejiang Univ, Med Coll, Shao Yifu Hosp, Dept Anorectal Surg, Hangzhou 310016, Peoples R China		Song, ZF (corresponding author), Zhejiang Univ, Med Coll, Shao Yifu Hosp, Dept Anorectal Surg, Hangzhou 310016, Peoples R China.	zpty71@163.com					Ananthanarayanan M, 2016, HEPATOLOGY, V64, P16, DOI 10.1002/hep.28525; Cui NI, 2019, J CELL BIOCHEM, V120, P376; Dai ZB, 2018, ONCOL REP, V40, P867, DOI 10.3892/or.2018.6512; Hamraz M, 2020, FASEB J, V34, P222, DOI 10.1096/fj.201900706RR; He K, 2016, ONCOGENE, V35, P148, DOI 10.1038/onc.2015.79; Jahanafrooz Z, 2020, J CELL PHYSIOL, V235, P4153, DOI 10.1002/jcp.29337; Lee KH, 2017, MOL MED REP, V15, P2163, DOI 10.3892/mmr.2017.6254; Nakayama H, 2019, INT J ONCOL, V55, P211, DOI 10.3892/ijo.2019.4812; Schmuck R, 2020, LANGENBECK ARCH SURG, V405, P71, DOI 10.1007/s00423-019-01850-6; Song GH, 2016, J EXP CLIN CANC RES, V35, DOI 10.1186/s13046-016-0427-7; Wang Bishi, 2015, Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, V31, P898; Wang WenXia, 2017, World Forestry Research, V30, P1; Wang Y, 2018, J CELL BIOCHEM, V119, P1841, DOI 10.1002/jcb.26345; Xiao C, 2016, EUR REV MED PHARMACO, V20, P2819; Xu JS, 2019, ARTIF CELL NANOMED B, V47, P2634, DOI 10.1080/21691401.2019.1614594; Zhuang B, 2019, J MOD ONCOL, V27, P924	16	0	0	0	1	CARBONE EDITORE	PALERMO	VIA QUINTINO SELLA, 68, PALERMO, 90139, ITALY	0393-6384	2283-9720		ACTA MEDICA MEDITERR	Acta Medica Mediterr.		2021	37	1					139	143		10.19193/0393-6384_2021_1_20			5	Medicine, General & Internal	Science Citation Index Expanded (SCI-EXPANDED)	General & Internal Medicine	QM4UO	WOS:000621776000020					2022-04-25	
J	Jin, HR; Du, CH; Wang, CZ; Yuan, CS; Du, W				Jin, Hong Ri; Du, Charles H.; Wang, Chong-Zhi; Yuan, Chun-Su; Du, Wei			Ginseng metabolite protopanaxadiol interferes with lipid metabolism and induces endoplasmic reticulum stress and p53 activation to promote cancer cell death	PHYTOTHERAPY RESEARCH			English	Article						BH3-only protein Puma and Noxa; ER stress; fatty acid synthase (FASN); ginseng; p53; Protopanaxadiol (PPD)	UNFOLDED PROTEIN RESPONSE; COLON-CANCER; COMPOUND K; INHIBITION; APOPTOSIS; PATHWAY; FAMILY; BCL-2	Protopanaxadiol (PPD), a ginseng metabolite generated by the gut bacteria, was shown to induce colorectal cancer cell death and enhance the anticancer effect of chemotherapeutic agent 5-FU. However, the mechanism by which PPD promotes cancer cell death is not clear. In this manuscript, we showed that PPD activated p53 and endoplasmic reticulum (ER) stress and induced expression of BH3-only proteins Puma and Noxa to promote cell death. Induction of Puma by PPD was p53-dependent, whereas induction of Noxa was p53-independent. On the other hand, PPD also induced prosurvival mechanisms including autophagy and expression of Bcl2 family apoptosis regulator Mcl-1. Inhibition of autophagy or knockdown of Mcl-1 significantly enhanced PPD-induced cell death. Interestingly, PPD inhibited expression of genes involved in fatty acid and cholesterol biosynthesis and induced synergistic cancer cell death with fatty acid synthase inhibitor cerulenin. As PPD-induced ER stress was not significantly affected by inhibition of new protein synthesis, we suggest PPD may induce ER stress directly through causing lipid disequilibrium.	[Jin, Hong Ri; Du, Wei] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA; [Du, Charles H.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA; [Wang, Chong-Zhi; Yuan, Chun-Su] Univ Chicago, Tang Ctr Herbal Med Res, Chicago, IL 60637 USA; [Wang, Chong-Zhi; Yuan, Chun-Su] Univ Chicago, Dept Anesthesia & Crit Care, Box 428, Chicago, IL 60637 USA; [Jin, Hong Ri] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA		Du, W (corresponding author), Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA.	wei@uchicago.edu	Wang, Chong-Zhi/B-8337-2014	Wang, Chong-Zhi/0000-0002-0950-2109; Du, Wei/0000-0003-3962-370X	National Institute of Health, USAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIH R01 GM120046]; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM120046] Funding Source: NIH RePORTER	National Institute of Health, Grant/Award Number: NIH R01 GM120046, USA	Bae EA, 2000, BIOL PHARM BULL, V23, P1481, DOI 10.1248/bpb.23.1481; Bunz F, 1999, J CLIN INVEST, V104, P263, DOI 10.1172/JCI6863; Cory S, 2002, NAT REV CANCER, V2, P647, DOI 10.1038/nrc883; da Rocha Adriana B., 2001, Current Opinion in Pharmacology, V1, P364; Hasegawa H, 1996, PLANTA MED, V62, P453, DOI 10.1055/s-2006-957938; Hou NS, 2014, P NATL ACAD SCI USA, V111, pE2271, DOI 10.1073/pnas.1318262111; Jin HR, 2014, CELL DEATH DIS, V5, DOI 10.1038/cddis.2014.169; Jin HR, 2012, CELL DEATH DIS, V3, DOI 10.1038/cddis.2012.122; Li BH, 2011, CANCER LETT, V301, P185, DOI 10.1016/j.canlet.2010.11.015; Li BH, 2010, CANCER CELL, V17, P469, DOI 10.1016/j.ccr.2010.03.019; Little JL, 2007, CANCER RES, V67, P1262, DOI 10.1158/0008-5472.CAN-06-1794; Mann J, 2002, NAT REV CANCER, V2, P143, DOI 10.1038/nrc723; Nakano K, 2001, MOL CELL, V7, P683, DOI 10.1016/S1097-2765(01)00214-3; Oda E, 2000, SCIENCE, V288, P1053, DOI 10.1126/science.288.5468.1053; Puthalakath H, 2002, CELL DEATH DIFFER, V9, P505, DOI 10.1038/sj/cdd/4400998; Puthalakath H, 2007, CELL, V129, P1337, DOI 10.1016/j.cell.2007.04.027; Tabas I, 2011, NAT CELL BIOL, V13, P184, DOI 10.1038/ncb0311-184; Thomenius MJ, 2003, J CELL SCI, V116, P4493, DOI 10.1242/jcs.00829; Volmer R, 2015, CURR OPIN CELL BIOL, V33, P67, DOI 10.1016/j.ceb.2014.12.002; Walter P, 2011, SCIENCE, V334, P1081, DOI 10.1126/science.1209038; Wang CZ, 2015, NUTRIENTS, V7, P799, DOI 10.3390/nu7020799; Wang CZ, 2012, INT J ONCOL, V40, P1970, DOI 10.3892/ijo.2012.1399; Zhang L, 2011, CELL DEATH DIFFER, V18, P864, DOI 10.1038/cdd.2010.152; Zhang ZY, 2015, J PHARMACOL SCI, V127, P83, DOI 10.1016/j.jphs.2014.11.003; Zhang ZY, 2013, INT J MOL SCI, V14, P2980, DOI 10.3390/ijms14022980	25	7	7	1	12	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0951-418X	1099-1573		PHYTOTHER RES	Phytother. Res.	MAR	2019	33	3					610	617		10.1002/ptr.6249			8	Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	HO6UH	WOS:000461067400012	30537241	Green Accepted, Green Submitted			2022-04-25	
J	Wang, F; Wu, DL; Chen, JX; Chen, SL; He, FR; Fu, HS; Wu, QH; Liu, S; Li, XG; Wang, WF				Wang, Fei; Wu, Dinglan; Chen, Jianxiang; Chen, Shiliang; He, Fengrong; Fu, Housheng; Wu, Qinghui; Liu, Shuan; Li, Xionggen; Wang, Weifu			Long non-coding RNA HOXA-AS2 promotes the migration, invasion and stemness of bladder cancer via regulating miR-125b/Smad2 axis	EXPERIMENTAL CELL RESEARCH			English	Article						Bladder cancer; HOXA-AS2; miR-125b; Samd2; Migration and invasion; Stemness	ANTISENSE LINCRNA HOXA-AS2; COLON-CANCER; MESENCHYMAL TRANSITION; APOPTOSIS; PROLIFERATION; RESISTANCE; DIHYDROTANSHINONE; CRYPTOTANSHINONE; STATISTICS; AUTOPHAGY	Long non-coding RNA HOXA-AS2 (HOXA cluster antisense RNA 2) has been reported to function as an oncogene in different types of cancers including breast cancer, liver cancer, gastric cancer and colorectal cancer, etc. However, its role in the development and progression of bladder cancer remains unknown. This study aimed to examine the expression of HOXA-AS2 in bladder cancer, to explore its role in the migration, invasion and stemness of bladder cancer cells and to further identify the potential downstream target miRNAs of HOXA-AS2 in this type of cancer. Our results firstly demonstrated the upregulation of HOXA-AS2 in both bladder cancer cells and clinical bladder tumors. Such upregulation was also positively correlated with the advanced stage, invasion and lymph node metastasis of bladder cancer as well as the expression of cancer stem cell marker OCT4 in patients. After knockdown of HOXA-AS2 in bladder cancer 5637 and T24 cells, the migration, invasion and sternness of cancer cells were significantly inhibited, indicating the capability of HOXA-AS2 to promote the migration, invasion and sternness of bladder cancer cells. Knockdown of HOXA-AS2 also suppressed in vivo tumor growth in the nude mice. Furthermore, this study also identified miR-125b as a downstream target of HOXA-AS2 and revealed the downregulation of miR-125b by HOXA-AS2 as well as the involvement of HOXA-AS2/miR-125b/Smad2 interactions in the functional role of HOXA-AS2 in mediating the migration, invasion and sternness of bladder cancer cells. Together, our findings suggest that HOXA-AS2 might be a potential biomarker and target for the diagnosis, monitoring and treatment of bladder cancer.	[Wang, Fei; He, Fengrong; Fu, Housheng; Wu, Qinghui; Liu, Shuan; Wang, Weifu] Peoples Hosp Hainan Prov, Dept Urol, Haikou, Hainan, Peoples R China; [Wu, Dinglan] Southern Med Univ, Shenzhen Hosp, Clin Innovat & Res Ctr, Shenzhen, Peoples R China; [Chen, Jianxiang] Xiangnan Coll, Affiliated Hosp, Dept Urol, Cenzhou, Peoples R China; [Chen, Shiliang] Peoples Hosp Hainan Prov, Dept Pathol, Haikou, Hainan, Peoples R China; [Li, Xionggen] Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Gen Practice, Shenzhen, Peoples R China		Wang, WF (corresponding author), Peoples Hosp Hainan Prov, Dept Urol, Haikou, Hainan, Peoples R China.; Li, XG (corresponding author), Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Gen Practice, Shenzhen, Peoples R China.	shengshengzhu@yeah.net; szs_lxg@sina.com		Wu, Dinglan/0000-0002-5057-9626	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81760461]; Major Scientific and Technological Hainan Province [ZDZX20130036]; Hainan Province Scientific and Technological Cooperation Special Foundation [KJHZ2015-25]	This study was supported by National Natural Science Foundation of China (Grant no. 81760461), Major Scientific and Technological Hainan Province (Grant no. ZDZX20130036) and Hainan Province Scientific and Technological Cooperation Special Foundation (Grant no. KJHZ2015-25).	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Cell Res.	FEB 1	2019	375	1					1	10		10.1016/j.yexcr.2018.11.005			10	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	HI7KX	WOS:000456636200001	30412716				2022-04-25	
J	Crighton, D; Wilkinson, S; Ryan, KM				Crighton, Diane; Wilkinson, Simon; Ryan, Kevin M.			DRAM links autophagy to p53 and programmed cell death	AUTOPHAGY			English	Article						DRAM; p53; autophagy; apoptosis; cancer	TUMOR-SUPPRESSOR; COLON-CANCER; BECLIN-1; PROTEIN; GENE; TUMORIGENESIS; APOPTOSIS; UVRAG	It is clear that changes in autophagy and autophagy regulators occur during tumor development and that this can have profound effects in certain tumor settings. The fact that p53, a key tumor suppressor mutated in approximately 50% of human cancers, has now also been shown to induce autophagy, has placed autophagy center stage in the minds of those interested in the development and treatment of malignant disease. p53 is a transcription factor that responds to cellular stress and prevents the propagation of cells which may otherwise form a tumor. The recent discovery, therefore, of DRAM (damage-regulated autophagy modulator) as a new p53 target which modulates autophagy is a major step forward in understanding how p53 controls autophagy and how this relates to tumor suppression. DRAM is a lysosomal protein that is not only critical for the ability of p53 to induce autophagy, but also for p53's ability to induce programmed cell death - a facet of p53 considered central to its tumor suppressive effects. The fact that DRAM is also inactivated in certain cancers underscores its importance and highlights the possibility that autophagy may have a more profound role in cancer than was first believed.	Beatson Inst Canc Res, Canc Res UK Beatson Labs, Tumour Cell Death Lab, Glasgow G61 1BD, Lanark, Scotland		Ryan, KM (corresponding author), Beatson Inst Canc Res, Canc Res UK Beatson Labs, Tumour Cell Death Lab, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Lanark, Scotland.	k.ryan@beatson.gla.ac.uk		Wilkinson, Simon/0000-0003-1082-8218; Ryan, Kevin M./0000-0002-1059-9681			Arico S, 2001, J BIOL CHEM, V276, P35243, DOI 10.1074/jbc.C100319200; Baehrecke EH, 2005, NAT REV MOL CELL BIO, V6, P505, DOI 10.1038/nrm1666; Botti J, 2006, AUTOPHAGY, V2, P67, DOI 10.4161/auto.2.2.2458; Crighton D, 2004, BBA-REV CANCER, V1705, P3, DOI 10.1016/j.bbcan.2004.09.001; Crighton D, 2006, CELL, V126, P121, DOI 10.1016/j.cell.2006.05.034; Eskelinen EL, 2005, AUTOPHAGY, V1, P1, DOI 10.4161/auto.1.1.1270; Feng ZH, 2005, P NATL ACAD SCI USA, V102, P8204, DOI 10.1073/pnas.0502857102; Furuta S, 2004, ONCOGENE, V23, P3898, DOI 10.1038/sj.onc.1207539; Goi T, 2003, SURG TODAY, V33, P702, DOI 10.1007/s00595-002-2567-y; Ionov Y, 2004, ONCOGENE, V23, P639, DOI 10.1038/sj.onc.1207178; Irwin MS, 2003, CANCER CELL, V3, P403, DOI 10.1016/S1535-6108(03)00078-3; Liang C, 2006, NAT CELL BIOL, V8, P688, DOI 10.1038/ncb1426; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; Lum JJ, 2005, NAT REV MOL CELL BIO, V6, P439, DOI 10.1038/nrm1660; Mizushima N, 2001, J CELL BIOL, V152, P657, DOI 10.1083/jcb.152.4.657; Mizushima N, 2005, CELL DEATH DIFFER, V12, P1535, DOI 10.1038/sj.cdd.4401728; 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; Ramadan S, 2005, BIOCHEM BIOPH RES CO, V331, P713, DOI 10.1016/j.bbrc.2005.03.156; Ryan KM, 2001, CURR OPIN CELL BIOL, V13, P332, DOI 10.1016/S0955-0674(00)00216-7; Shimizu S, 2004, NAT CELL BIOL, V6, P1221, DOI 10.1038/ncb1192; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	22	153	162	1	8	LANDES BIOSCIENCE	GEORGETOWN	810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA	1554-8627			AUTOPHAGY	Autophagy	JAN-FEB	2007	3	1					72	74		10.4161/auto.3438			3	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	126FY	WOS:000243499200022	17102582	Bronze			2022-04-25	
J	Jing, YM; Liang, WQ; Liu, J; Zhang, L; Wei, JG; Yang, JH; Zhang, Y; Huang, ZL				Jing, Yuanming; Liang, Wenqing; Liu, Jian; Zhang, Lin; Wei, Jianguo; Yang, Jianhui; Zhang, Yu; Huang, Zongliang			Autophagy-mediating microRNAs in cancer chemoresistance	CELL BIOLOGY AND TOXICOLOGY			English	Review						Autophagy; Cancer; Chemoresistance; Hypoxia; MicroRNA	CELL LUNG-CANCER; CISPLATIN-INDUCED APOPTOSIS; DRUG-RESISTANCE; HEPATOCELLULAR-CARCINOMA; MULTIDRUG-RESISTANCE; MOLECULAR-MECHANISMS; INHIBITING AUTOPHAGY; COLORECTAL-CANCER; MYELOID-LEUKEMIA; DOWN-REGULATION	Chemoresistance is a complex phenomenon responsible for failure in response to chemotherapy agents and more than 90% of deaths in cancer patients. MicroRNAs (miRNAs), as a subgroup of non-coding RNAs with lengths between 21 and 25 nucleotides, are involved in various cancer processes like chemoresistance via interacting with their target mRNAs and suppressing their expression. Autophagy is a greatly conserved procedure involving the lysosomal degradation of cytoplasmic contents and organelles to deal with environmental stresses like hypoxia and starvation. Autophagy contributes to response to chemotherapy agents: autophagy can act as a protective mechanism for mediating the resistance in response to chemotherapy or can induce autophagic cell death and mediate the sensitivity to chemotherapy. On the other hand, one of the processes targeted by microRNAs in the regulation of chemoresistance is autophagy. Hence, we studied the literatures on chemoresistance mechanisms, the miRNAs' role in cancer, and the miRNAs' role in chemoresistance by modulating autophagy.	[Jing, Yuanming; Zhang, Lin; Wei, Jianguo; Yang, Jianhui; Zhang, Yu] Zhejiang Univ, Sch Med, Shaoxing Hosp, Dept Gastrointestinal Surg,Shaoxing Peoples Hosp, Shaoxing 312000, Zhejiang, Peoples R China; [Liang, Wenqing] Zhejiang Univ, Sch Med, Shaoxing Hosp, Dept Orthopaed,Shaoxing Peoples Hosp, Shaoxing 312000, Zhejiang, Peoples R China; [Liu, Jian] Shanghai Oriental Hepatobiliary Hosp, Dept Hepatobiliary Surg, Shanghai 200438, Peoples R China; [Huang, Zongliang] Tongji Univ, Sch Med, Tongji Hosp, Dept Radiol, 389 Xincun Rd, Shanghai 200065, Peoples R China		Huang, ZL (corresponding author), Tongji Univ, Sch Med, Tongji Hosp, Dept Radiol, 389 Xincun Rd, Shanghai 200065, Peoples R China.	5224471@qq.com; 13587342011@163.com; jianliu926@163.com; zhangl@usx.edu.cn; mickmouse88@163.com; yjheart@126.com; 25216838@qq.com; zonglianghuang@tongji.edu.cn		Zhang, Lin/0000-0002-3767-0249	Nature Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province [LY18H060013]; Public Welfare Application Plan Project of Shaoxing [2018C30109]	The current work was funded by Nature Science Foundation of Zhejiang Province (#LY18H060013 to WQL) and Public Welfare Application Plan Project of Shaoxing (#2018C30109 to YMJ).	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Toxicol.	DEC	2020	36	6					517	536		10.1007/s10565-020-09553-1		SEP 2020	20	Cell Biology; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Toxicology	OQ9IO	WOS:000565177200001	32875398				2022-04-25	
J	Zhu, FX; Wang, XT; Zeng, HQ; Yin, ZH; Ye, ZZ				Zhu, Fang-Xiao; Wang, Xiao-Tao; Zeng, Hui-Qiong; Yin, Zhi-Hua; Ye, Zhi-Zhong			A predicted risk score based on the expression of 16 autophagy-related genes for multiple myeloma survival	ONCOLOGY LETTERS			English	Article						multiple myeloma; autophagy; autophagy-related genes; survival	SET ENRICHMENT ANALYSIS; BREAST-CANCER; COLON-CANCER; CELLS; HYPOXIA; MACROAUTOPHAGY; RESISTANCE; INHIBITION; PATHWAY	\ Autophagy has an important role in the pathogenesis of plasma cell development and multiple myeloma (MM); however, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined. In the present study, the expression profiles of 234 ARGs were obtained from a Gene Expression Omnibus dataset (accession GSE24080), which contains 559 samples of patients with MM analyzed with 54,675 probes. Univariate Cox regression analysis identified 55 ARGs that were significantly associated with event-free survival of MM. Furthermore, a risk score with 16 survival-associated ARGs was developed using multivariate Cox regression analysis, including ATIC, BNIP3L, CALCOCO2, DNAJB1, DNAJB9, EIF4EBP1, EVA1A, FKBP1B, FOXO1, FOXO3, GABARAP, HIF1A, NCKAP1, PRKAR1A and SUPT20H, was constructed. Using this prognostic signature, patients with MM could be separated into high- and low-risk groups with distinct clinical outcomes. The area under the curve values for the receiver operating characteristic curves were 0.740, 0.741 and 0.712 for 3, 5 and 10 years prognosis predictions, respectively. Notably, the prognostic role of this risk score could be validated with another four independent cohorts (accessions: GSE57317, GSE4581, GSE4452 and GSE4204). In conclusion, ARGs may serve vital roles in the progression of MM, and the ARGs-based prognostic model may provide novel ideas for clinical applications in MM.	[Zhu, Fang-Xiao; Zeng, Hui-Qiong; Yin, Zhi-Hua; Ye, Zhi-Zhong] Shenzhen Futian Hosp Rheumat Dis, Dept Rheumatol, 22 Nonglin Rd, Shenzhen 518040, Guangdong, Peoples R China; [Wang, Xiao-Tao] Guilin Med Coll, Affiliated Hosp 2, Dept Hematol, Guilin 541001, Guangxi, Peoples R China		Ye, ZZ (corresponding author), Shenzhen Futian Hosp Rheumat Dis, Dept Rheumatol, 22 Nonglin Rd, Shenzhen 518040, Guangdong, Peoples R China.	yezhizhong2000@163.com			Program of Scientific and Technology Project (Guilin Science Research and Technology Development) [2016012706-2]; Sanming Project of Medicine in Shenzhen [SZSM201602087]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81460038]; Guangxi Natural Science Foundation of China [2017GXNSFAA198178]; Shenzhen Futian Public Welfare Scientific Research Project [FTWS2017020, FTWS2018005]	The present study was supported by the Program of Scientific and Technology Project (Guilin Science Research and Technology Development; grant no. 2016012706-2), Sanming Project of Medicine in Shenzhen (grant no. SZSM201602087), National Natural Science Foundation of China (grant no. 81460038), Guangxi Natural Science Foundation of China (grant no. 2017GXNSFAA198178) and Shenzhen Futian Public Welfare Scientific Research Project (grant nos. FTWS2017020 and FTWS2018005).	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Lett.	NOV	2019	18	5					5310	5324		10.3892/ol.2019.10881			15	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	JW7HS	WOS:000503219600099	31612041	gold, Green Published			2022-04-25	
J	Wawszczyk, J; Jesse, K; Szewerniak, A; Kapral, M; Weglarz, L				Wawszczyk, Joanna; Jesse, Katarzyna; Szewerniak, Aleksandra; Kapral, Malgorzata; Weglarz, Ludmila			THE INDUCTION OF CYTOTOXICITY BY PTEROSTILBENE IN VARIOUS HUMAN CANCER CELL LINES	ACTA POLONIAE PHARMACEUTICA			English	Article						pterostilbene; cytotoxic activity; SRB assay; cancer cell lines	CYCLE ARREST; APOPTOSIS; RESVERATROL; ANTIOXIDANT; ANTICANCER; AUTOPHAGY	Pterostilbene is a naturally occurring compound found primarily in blueberries and grapes. It has been found to possess several biological activities such as antioxidative and anti-inflammatory. The study evaluated the cytotoxic activity of pterostilbene in various human cancer cell lines, i.e., melanoma (A2058, C32), colon carcinoma (HT-29, SW1116), breast adenocarcinoma (MCF-7, SKBR3) and ovary adenocarcinoma (SKOV3). The cells were treated with pterostilbene concentrations ranging from 5 to 75 mu M for 72 h. The cytotoxicity of pterostilbene was evaluated using the Sulforhodamine B assay and expressed as a percentage of that of untreated control cells. The concentration of pterostilbene required for 50% reduction of cell viability (IC50) was calculated from log dose-response curves. The results of this study showed that pterostilbene exerted dosedependent cytotoxic effect on cancer cells. Among the all cell lines tested, the C32 melanoma cells were the most sensitive to the cytotoxic effect of pterostilbene (IC50 similar to 10 mu M) and SW1116 colon cancer cells showed the lowest sensitivity (IC50 similar to 70 mu M).	[Wawszczyk, Joanna] Dept Biochem, Jednosci 8, PL-41200 Sosnowiec, Poland; Med Univ Silesia, Sch Pharm, Div Lab Med Sosnowiec, Katowice, Poland		Wawszczyk, J (corresponding author), Dept Biochem, Jednosci 8, PL-41200 Sosnowiec, Poland.	jwawszczyk@sum.edu.pl		Wawszczyk, Joanna/0000-0001-8739-3342; Kapral, Malgorzata/0000-0001-5189-1171	Medical University of Silesia (Katowice, Poland) [KNW-2-013/N/5/K, KNW-2-I18/D/6/N]	This work was supported by grants no. KNW-2-013/N/5/K and KNW-2-I18/D/6/N from the Medical University of Silesia (Katowice, Poland).	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PHARM.	SEP-OCT	2018	75	5					1161	1166		10.32383/appdr/83592			6	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	HX3UR	WOS:000467319200011		Bronze			2022-04-25	
J	Al-Bari, MAA; Ito, Y; Ahmed, S; Radwan, N; Ahmed, HS; Eid, N				Al-Bari, Md Abdul Alim; Ito, Yuko; Ahmed, Samrein; Radwan, Nada; Ahmed, Hend S.; Eid, Nabil			Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Review						autophagy; natural products; anticancer drugs; mTOR signaling; autophagy modulators; resveratrol; omega-3 PUFAs	CELL-CYCLE ARREST; DEACETYLASE INHIBITOR TRICHOSTATIN; ENDOPLASMIC-RETICULUM STRESS; STARVATION-INDUCED AUTOPHAGY; ROTTLERIN INDUCES AUTOPHAGY; UBIQUITIN-PROTEASOME SYSTEM; EXERTS ANTITUMOR-ACTIVITY; ACTIVATED PROTEIN-KINASE; COLON-CANCER; CYTOPROTECTIVE AUTOPHAGY	Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic interventions in various diseases, including cancers. According to the framework of autophagy, the suppression or induction of autophagy can exert therapeutic properties through the promotion of cell death or cell survival, which are the two main events targeted by cancer therapies. Remarkably, natural products have attracted attention in the anticancer drug discovery field, because they are biologically friendly and have potential therapeutic effects. In this review, we summarize the up-to-date knowledge regarding natural products that can modulate autophagy in various cancers. These findings will provide a new position to exploit more natural compounds as potential novel anticancer drugs and will lead to a better understanding of molecular pathways by targeting the various autophagy stages of upcoming cancer therapeutics.	[Al-Bari, Md Abdul Alim] Univ Rajshahi, Dept Pharm, Rajshahi 6205, Bangladesh; [Ito, Yuko] Osaka Med & Pharmaceut Univ, Dept Gen & Gastroenterol Surg, 27 Daigaku Machi, Takatsuki 5698686, Japan; [Ahmed, Samrein] Sheffield Hallam Univ, Coll Hlth & Wellbeing & Life Sci, Dept Biosci & Chem, City Campus,Howard St, Sheffield S1 1WB, S Yorkshire, England; [Radwan, Nada; Eid, Nabil] United Arab Emirates Univ, Coll Med & Hlth Sci, Dept Anat, Al Ain 17666, U Arab Emirates; [Ahmed, Hend S.] Omdurman Ahlia Univ, Fac Med, Dept Hematol & Blood Transfus, Lab Sci, Khartoum 786, Sudan		Eid, N (corresponding author), United Arab Emirates Univ, Coll Med & Hlth Sci, Dept Anat, Al Ain 17666, U Arab Emirates.	alimalbari347@ru.ac.bd; yuko.ito@ompu.ac.jp; Samrein.Ahmed@shu.ac.uk; NadaA.Radwan@outlook.com; hind.salaheldien@gmail.com; nabileidm@uaeu.ac.ae	Al-Bari, Md. Abdul Alim/C-2946-2018	Al-Bari, Md. 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J. Mol. Sci.	SEP	2021	22	18							9807	10.3390/ijms22189807			66	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	UV8TR	WOS:000699744000001	34575981	Green Published, gold, Green Accepted			2022-04-25	
J	Necchi, V; Sommi, P; Vanoli, A; Manca, R; Ricci, V; Solcia, E				Necchi, Vittorio; Sommi, Patrizia; Vanoli, Alessandro; Manca, Rachele; Ricci, Vittorio; Solcia, Enrico			Proteasome Particle-Rich Structures Are Widely Present in Human Epithelial Neoplasms: Correlative Light, Confocal and Electron Microscopy Study	PLOS ONE			English	Article							ACTIVATED PROTEIN-KINASE; GROWTH-FACTOR RECEPTOR; HELICOBACTER-PYLORI; REGULATED KINASES; RAS MUTATIONS; CAGA PROTEIN; CANCER; CARCINOMA; AUTOPHAGY; BRAF	A novel cytoplasmic structure has been recently characterized by confocal and electron microscopy in H. pylori-infected human gastric epithelium, as an accumulation of barrel-like proteasome reactive particles colocalized with polyubiquitinated proteins, H. pylori toxins and the NOD1 receptor. This proteasome particle-rich cytoplasmic structure (PaCS), a sort of focal proteasome hyperplasia, was also detected in dysplastic cells and was found to be enriched in SHP2 and ERK proteins, known to play a role in H. pylori-mediated gastric carcinogenesis. However, no information is available on its occurrence in neoplastic growths. In this study, surgical specimens of gastric cancer and various other human epithelial neoplasms have been investigated for PaCSs by light, confocal and electron microscopy including correlative confocal and electron microscopy (CCEM). PaCSs were detected in gastric cohesive, pulmonary large cell and bronchioloalveolar, thyroid papillary, parotid gland, hepatocellular, ovarian serous papillary, uterine cervix and colon adenocarcinomas, as well as in pancreatic serous microcystic adenoma. H. pylori bodies, their virulence factors (VacA, CagA, urease, and outer membrane proteins) and the NOD1 bacterial proteoglycan receptor were selectively concentrated inside gastric cancer PaCSs, but not in PaCSs from other neoplasms which did, however, retain proteasome and polyubiquitinated proteins reactivity. No evidence of actual microbial infection was obtained in most PaCS-positive neoplasms, except for H. pylori in gastric cancer and capsulated bacteria in a colon cancer case. Particle lysis and loss of proteasome distinctive immunoreactivities were seen in some tumour cell PaCSs, possibly ending in sequestosomes or autophagic bodies. It is concluded that PaCSs are widely represented in human neoplasms and that both non-infectious and infectious factors activating the ubiquitin-proteasome system are likely to be involved in their origin. PaCS detection might help clarify the role of the ubiquitin-proteasome system in carcinogenesis.	[Necchi, Vittorio; Vanoli, Alessandro; Solcia, Enrico] Univ Pavia, Dept Human Pathol & Genet, I-27100 Pavia, Italy; [Necchi, Vittorio] Univ Pavia, Ctr Grandi Strumenti, I-27100 Pavia, Italy; [Sommi, Patrizia; Manca, Rachele; Solcia, Enrico] Fdn IRCCS Policlin San Matteo, Serv Anat Pathol, Pavia, Italy; [Sommi, Patrizia; Ricci, Vittorio] Univ Pavia, Dept Physiol, I-27100 Pavia, Italy		Necchi, V (corresponding author), Univ Pavia, Dept Human Pathol & Genet, Via Palestro 3, I-27100 Pavia, Italy.	vricci@unipv.it; solciae@smatteo.pv.it	Vanoli, Alessandro/J-4469-2016	Vanoli, Alessandro/0000-0002-2976-7032	Italian Ministry of HealthMinistry of Health, Italy; University of Pavia	This work was supported by grants from the Italian Ministry of Health to Fondazione IRCCS Policlinico San Matteo (to ES) and from the University of Pavia (to VR). 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	Hussain, A; Qazi, AK; Mupparapu, N; Kumar, A; Mintoo, MJ; Mahajan, G; Sharma, PR; Singh, SK; Bharate, SB; Zargar, MA; Ahmed, QN; Mondhe, DM; Vishwakarma, RA; Hamid, A				Hussain, Aashiq; Qazi, Asif Khurshid; Mupparapu, Nagaraju; Kumar, Ashok; Mintoo, Mubashir Javeed; Mahajan, Girish; Sharma, Parduman Raj; Singh, Shashank Kumar; Bharate, Sandip B.; Zargar, Mohmmad Afzal; Ahmed, Qazi Naveed; Mondhe, Dilip Manikrao; Vishwakarma, Ram A.; Hamid, Abid			A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis	MOLECULAR CARCINOGENESIS			English	Article						PI3K; signaling; inhibitor; therapeutics; colorectal cancer	KRAS P.G13D MUTATION; PLUS IRINOTECAN; CANCER; PATHWAY; LEUCOVORIN; FLUOROURACIL; CHEMOTHERAPY; IDELALISIB; APOPTOSIS; AUTOPHAGY	Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is responsible for initiation, chemo-resistance, and poor prognosis of colorectal cancer (CRC). Therefore, PI3K pathway inhibition can provide a plausible way of attaining CRC treatment. We report PI3K target specific synthesis and selection of a potent molecule, that is, 2,3-dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) from quinazolinone series based on the structural activity relationship after evaluation in diverse cancers. This molecule inhibited the PI3K enzyme activity and transcriptional as well as translational expression levels in colorectal cancer (CRC) models. This was associated with subsequent decrease in phosphorylation of its downstream effector proteins, that is, p-Akt((Ser-473)) and p-mTORC1((Ser-2448)) and decreased ERK signaling. Furthermore, DHNQ decreased expression of cyclins that caused G(1) arrest and decreased Bcl-2/Bax ratio after mitochondrial membrane potential loss, reactive oxygen species generation, and an increase in cytosolic Ca2+ loads that is responsible for the decreased CRC cell proliferation and survival. These biochemical changes triggered apoptotic cell death with altered autophagic Beclin-1 and LC3 expression. It seemed that the PI3K-Akt signaling regulated apoptosis and autophagy through different mechanisms but mTORC1 mediated autophagy appeared not to be involved in the cell death induction by DHNQ. The molecule also showed significant anticancer efficacy in in vivo tumor models without any mortality indicating its non-toxic nature with possible clinical significance. Overall, the selective elucidation of DHNQ molecular mechanism will provide the possible strategies for the clinical development in CRC that may respond to this specific, potent and novel P13K inhibitor. (c) 2016 Wiley Periodicals, Inc.	[Hussain, Aashiq; Qazi, Asif Khurshid; Kumar, Ashok; Mintoo, Mubashir Javeed; Mahajan, Girish; Sharma, Parduman Raj; Singh, Shashank Kumar; Mondhe, Dilip Manikrao; Hamid, Abid] Indian Inst Integrat Med, CSIR, Canc Pharmacol Div, Canal Rd, Jammu 180001, India; [Mupparapu, Nagaraju; Bharate, Sandip B.; Ahmed, Qazi Naveed; Vishwakarma, Ram A.] Indian Inst Integrat Med, CSIR, Div Med Chem, Jammu, India; [Singh, Shashank Kumar; Bharate, Sandip B.; Ahmed, Qazi Naveed; Mondhe, Dilip Manikrao; Vishwakarma, Ram A.; Hamid, Abid] Govt India, Acad Sci & Innovat Res, CSIR, New Delhi, India; [Zargar, Mohmmad Afzal] Univ Kashmir, Dept Biochem, Srinagar, Jammu & Kashmir, India		Hamid, A (corresponding author), Indian Inst Integrat Med, CSIR, Canc Pharmacol Div, Canal Rd, Jammu 180001, India.; Hamid, A (corresponding author), Govt India, Acad Sci & Innovat Res, CSIR, New Delhi, India.	ahdar@iiim.ac.in	Jani, Arpit/B-5376-2017; Zargar, Mohammad/G-7393-2018; Bharate, Sandip B/B-7104-2018	Zargar, Mohammad/0000-0002-2844-7141; singh, shashank/0000-0001-8532-7421; Mupparapu, Nagaraju/0000-0003-2900-7479; Ahmed, Qazi Naveed/0000-0002-6890-7587	CSIRCouncil of Scientific & Industrial Research (CSIR) - India [BSC-0205]	Grant sponsor: CSIR grant; Grant number: BSC-0205	Bharate SB, 2012, ARKIVOC, P308, DOI 10.3998/ark.5550190.0013.826; Chandarlapaty S, 2011, CANCER CELL, V19, P58, DOI 10.1016/j.ccr.2010.10.031; Chang F, 2003, LEUKEMIA, V17, P590, DOI 10.1038/sj.leu.2402824; Cunningham D, 2004, NEW ENGL J MED, V351, P337, DOI 10.1056/NEJMoa033025; Danielsen SA, 2015, BBA-REV CANCER, V1855, P104, DOI 10.1016/j.bbcan.2014.09.008; De Roock W, 2010, JAMA-J AM MED ASSOC, V304, P1812, DOI 10.1001/jama.2010.1535; Delbridge ARD, 2015, CELL DEATH DIFFER, V22, P1071, DOI 10.1038/cdd.2015.50; Deng T, 2013, MED ONCOL, V30, DOI 10.1007/s12032-013-0752-z; Diehl JA, 1998, GENE DEV, V12, P3499, DOI 10.1101/gad.12.22.3499; Ebi H, 2013, P NATL ACAD SCI USA, V110, P21124, DOI 10.1073/pnas.1314124110; Engelman JA, 2009, NAT REV CANCER, V9, P550, DOI 10.1038/nrc2664; Furman RR, 2014, NEW ENGL J MED, V370, P997, DOI 10.1056/NEJMoa1315226; Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013; Hong YS, 2014, LANCET ONCOL, V15, P1245, DOI 10.1016/S1470-2045(14)70377-8; IARC, 2012, GLOBOCAN 2012; Jung CH, 2010, FEBS LETT, V584, P1287, DOI 10.1016/j.febslet.2010.01.017; Liang JY, 2003, CELL CYCLE, V2, P339, DOI 10.4161/cc.2.4.433; Lindqvist LM, 2014, P NATL ACAD SCI USA, V111, P8512, DOI 10.1073/pnas.1406425111; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Majeed R, 2016, MOL CARCINOGEN, V55, P964, DOI 10.1002/mc.22339; Mao C, 2013, CANCER-AM CANCER SOC, V119, P714, DOI 10.1002/cncr.27804; Miller BW, 2015, CLIN CANCER RES, V21, P1525, DOI 10.1158/1078-0432.CCR-14-2522; OLTVAI ZN, 1993, CELL, V74, P609, DOI 10.1016/0092-8674(93)90509-O; Qazi AK, 2015, CANCER LETT, V359, P47, DOI 10.1016/j.canlet.2014.12.034; Qazi AK, 2014, BMC CELL BIOL, V15, DOI 10.1186/1471-2121-15-36; Qazi AK, 2013, ANTI-CANCER AGENT ME, V13, P1552, DOI 10.2174/1871520613666131125123241; Shrotriya S, 2015, MOL CARCINOGEN, V54, P1734, DOI 10.1002/mc.22246; Shugg RPP, 2013, J BIOL CHEM, V288, P35346, DOI 10.1074/jbc.M113.507525; 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]; Stark AK, 2015, CURR OPIN PHARMACOL, V23, P82, DOI 10.1016/j.coph.2015.05.017; Van Cutsem E, 2011, J CLIN ONCOL, V29, P2011, DOI 10.1200/JCO.2010.33.5091; Yuan TL, 2008, ONCOGENE, V27, P5497, DOI 10.1038/onc.2008.245; Zhang J, 2011, GASTROENTEROLOGY, V141, P50, DOI 10.1053/j.gastro.2011.05.010	33	7	7	0	15	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0899-1987	1098-2744		MOL CARCINOGEN	Mol. Carcinog.	DEC	2016	55	12					2135	2155		10.1002/mc.22457			21	Biochemistry & Molecular Biology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Oncology	EC1GY	WOS:000387854100021	26764221				2022-04-25	
J	Guo, C; Liu, P; Deng, GL; Han, Y; Chen, YH; Cai, CJ; Shen, H; Deng, GP; Zeng, S				Guo, Cao; Liu, Ping; Deng, Ganlu; Han, Ying; Chen, Yihong; Cai, Changjing; Shen, Hong; Deng, Gongping; Zeng, Shan			Honokiol induces ferroptosis in colon cancer cells by regulating GPX4 activity	AMERICAN JOURNAL OF CANCER RESEARCH			English	Article						Honokiol (HNK); ferroptosis; reactive oxygen species (ROS); colon cancer (CC); GPX4	CYCLE ARREST; IN-VITRO; DEATH; IRON; APOPTOSIS; AUTOPHAGY; PROGRESSION; INHIBITION; MECHANISMS; RESISTANCE	Colon cancer (CC) is a prevalent malignancy worldwide. Approaches to specifically induce tumor cell death have historically been a popular research topic. Honokiol (HNK), which exhibits highly efficient and specific anticancer effects, is a biphenolic compound found in Magnolia grandiflora. In the present study, we aim to study the effect of HNK on CC cells and elucidate the potential underlying mechanisms. Seven CC cell lines (RKO, HCT116, SW48, HT29, LS174T, HCT8, and SW480) were used. Cells were exposed to HNK and subjected to a series of assays to evaluate characteristics such as cellular activity, reactive oxygen species (ROS) levels and ferroptosis-related protein expression levels. Lentiviral transduction was also used to verify molecular mechanisms in vivo and in vitro. We here observed that HNK reduced the viability of CC cell lines by increasing ROS and Fe2+ levels. Transmission electron microscopy revealed HNK-induced changes in mitochondrial morphology. HNK decreased the activity of Glutathione Peroxidase 4 (GPX4) but did not affect system Xc-. Thus, our datas indicated that HNK can induce ferroptosis in CC cells by reducing the activity of GPX4. As a potential therapeutic drug, HNK showed good anticancer effects through diverse signal transduction mechanisms and multiple pathways.	[Guo, Cao; Liu, Ping; Han, Ying; Chen, Yihong; Cai, Changjing; Shen, Hong; Zeng, Shan] Cent South Univ, Xiangya Hosp, Dept Oncol, Changsha 410008, Hunan, Peoples R China; [Guo, Cao; Shen, Hong] Cent South Univ, Xiangya Hosp, Key Lab Mol Radiat Oncol Hunan Prov, Changsha 410008, Peoples R China; [Guo, Cao; Liu, Ping; Han, Ying; Chen, Yihong; Cai, Changjing; Shen, Hong; Zeng, Shan] Cent South Univ, Natl Clin Res Ctr Geriatr Disorders, Xiangya Hosp, Changsha 410008, Peoples R China; [Deng, Ganlu] Guangxi Med Univ, Affiliated Hosp 1, Dept Oncol, Shuangyong Rd, Nanning 530021, Guangxi Zhuang, Peoples R China; [Deng, Gongping] Hainan Med Univ, Dept Emergency, Hainan Gen Hosp, Hainan Affiliated Hosp, 19 Xiuhua Rd, Haikou 570311, Hainan, Peoples R China		Zeng, S (corresponding author), Cent South Univ, Xiangya Hosp, Dept Oncol, Changsha 410008, Hunan, Peoples R China.; Deng, GP (corresponding author), Hainan Med Univ, Dept Emergency, Hainan Gen Hosp, Hainan Affiliated Hosp, 19 Xiuhua Rd, Haikou 570311, Hainan, Peoples R China.	denggong-ping@hainmc.edu.cn; zengshan2000@csu.edu.cn	Cai, Changjing/ABA-4542-2021; Shen, Hong/N-9734-2019	Shen, Hong/0000-0002-6456-8231	National Key R&D Program of China [2018YFC1313300]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81070362, 81172470, 81372629, 81772627, 81874073, 81974384, 81902500]; Nature Science Foundation of Hunan ProvinceNatural Science Foundation of Hunan Province [2015JC3021, 2016JC2037]; CSCO Cancer Research Foundation [Y-HR2019-0182, Y-2019Genecast-043]	This study was supported by grants from National Key R&D Program of China (No. 2018YFC1313300), National Natural Science Foundation of China (No.: 81070362, 81172470, 81372629, 81772627, 81874073, 81974384 & 81902500), key projects from the Nature Science Foundation of Hunan Province (No. 2015JC3021 & 2016JC2037), two projects from CSCO Cancer Research Foundation (No. Y-HR2019-0182 & Y-2019Genecast-043). All animal experiments and procedures were directed and approved by the Experimental Animal Ethics Committee of Central South University.	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J. Cancer Res.		2021	11	6					3039	3054					16	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	TA4KS	WOS:000667218200012	34249443				2022-04-25	
J	Yu, CH; Chu, SC; Yang, SF; Hsieh, YS; Lee, CY; Chen, PN				Yu, Ching-Han; Chu, Shu-Chen; Yang, Shun-Fa; Hsieh, Yih-Shou; Lee, Chih-Yi; Chen, Pei-Ni			Induction of apoptotic but not autophagic cell death by Cinnamomum cassia extracts on human oral cancer cells	JOURNAL OF CELLULAR PHYSIOLOGY			English	Article						apoptosis; autophagy; Cinnamomum cassia; oral cancer	EPITHELIAL-MESENCHYMAL TRANSITION; CARCINOMA-CELLS; CYCLE ARREST; PROTEASE ACTIVITIES; IN-VITRO; INVASION; INHIBITION; GROWTH; FAK; EXPRESSION	Cinnamomum cassia has been widely studied in different fields to reveal its antidiabetic, antidepressive, antiviral, anti-inflammatory, antiosteoporotic, and anticancer effects. Its antimalignant activities have been explored in lung cancer, breast cancer, colorectal cancer, and even oral cancer, but the detailed signaling mechanism and effects of this plant on animal models needto be clarified. In the current study, C. cassia extract (CCE) was used to investigate the antitumorigenesis mechanism in vitro and in vivo. The major constituents of CCE used in this study were coumarin, cinnamic acid, and cinnamic aldehyde. CCE reduced the viability, number, and colony formation of human oral cancer cells, and induced their apoptosis. Caspase-3 activation, Bcl-2 reduction, and phosphatidylserine inversion were involved in CCE-stimulated apoptosis. CCE also enhanced the expression of autophagic markers, including acidic vesicular organelle, microtubule-associated protein 1 light chain 3-I, autophagy-related protein 14, rubicon, and p62. The combined treatment of CCE and caspase inhibitor significantly restored mitochondrial membrane potential ((m)) and cell viability. However, the combined treatment of CCE and autophagy inhibitor further reduced the cell viability indicating that autophagy might be a survival pathway of CCE-treated SASVO3 cells. In contrast, CCE treatment for 12 days did not adversely affect SASVO3 tumor-bearing nude mice. CCE also elicited dose-dependent effects on the decrease in tumor volume, tumor weight, and Ki-67 expression. These results suggested that CCE showed the potential for the complementary treatment of oral caner.	[Yu, Ching-Han] Chung Shan Med Univ, Sch Med, Dept Physiol, Taichung, Taiwan; [Yu, Ching-Han; Yang, Shun-Fa] Chung Shan Med Univ Hosp, Dept Med Res, Taichung, Taiwan; [Chu, Shu-Chen] Cent Taiwan Univ Sci & Technol, Inst & Dept Food Sci, Taichung, Taiwan; [Yang, Shun-Fa] Chung Shan Med Univ, Med, Taichung, Taiwan; [Hsieh, Yih-Shou; Lee, Chih-Yi; Chen, Pei-Ni] Chung Shang Med Univ, Inst Biochem Microbiol & Immunol, 110,Sect 1,Chien Kuo N Rd, Taichung 402, Taiwan; [Hsieh, Yih-Shou; Chen, Pei-Ni] Chung Shan Med Univ Hosp, Clin Lab, Taichung, Taiwan		Chen, PN (corresponding author), Chung Shang Med Univ, Inst Biochem Microbiol & Immunol, 110,Sect 1,Chien Kuo N Rd, Taichung 402, Taiwan.	peini@csmu.edu.tw	Yang, Shun-Fa/AAN-1519-2020	Yang, Shun-Fa/0000-0002-0365-7927	Ministry of Science and Technology TaiwanMinistry of Science and Technology, Taiwan [MOST 106-2320-B-040 -016, MOST 106-2320-B-040-020-MY3]	Ministry of Science and Technology Taiwan, Grant/Award Numbers: MOST 106-2320-B-040 -016, MOST 106-2320-B-040-020-MY3	Anantharaju PG, 2017, PLOS ONE, V12, DOI 10.1371/journal.pone.0186208; BOXENBAUM H, 1995, J CLIN PHARMACOL, V35, P957, DOI 10.1002/j.1552-4604.1995.tb04011.x; Chang WL, 2017, ENVIRON TOXICOL, V32, P456, DOI 10.1002/tox.22250; Chen CY, 2009, J BIOMED SCI, V16, DOI 10.1186/1423-0127-16-100; 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; Chen PN, 2006, J DENT RES, V85, P220, DOI 10.1177/154405910608500303; Chen SF, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0031864; Chu SC, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0101579; Fatima M, 2016, J MICROBIOL BIOTECHN, V26, P151, DOI 10.4014/jmb.1508.08024; Goswami SK, 2014, J SEX MED, V11, P1475, DOI 10.1111/jsm.12535; Ho YS, 2001, INT J CANCER, V91, P393, DOI 10.1002/1097-0215(200002)9999:9999&lt;::AID-IJC1070&gt;3.0.CO;2-#; Hsieh YS, 2013, FOOD CHEM TOXICOL, V62, P908, DOI 10.1016/j.fct.2013.10.021; 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 SF, 2016, FOOD CHEM TOXICOL, V94, P1, DOI 10.1016/j.fct.2016.05.009; Huh JE, 2015, PHYTOTHER RES, V29, P30, DOI 10.1002/ptr.5218; INGS RMJ, 1990, XENOBIOTICA, V20, P1201, DOI 10.3109/00498259009046839; Jacobson JJ, 2012, HEAD NECK ONCOL, DOI 10.1186/1758-3284-4-15; Kim EC, 2015, BIOSCI BIOTECH BIOCH, V79, P617, DOI 10.1080/09168451.2014.993917; Kim SH, 2017, ONCOTARGET, V8; Kumar M., 2017, ANTICANCER AGENTS ME, V18; Lee MA, 2013, J NAT PROD, V76, P1278, DOI 10.1021/np400216m; Liao JC, 2012, EVID-BASED COMPL ALT, V2012, DOI 10.1155/2012/429320; Lin CY, 2017, ENVIRON TOXICOL, V32, P1878, DOI 10.1002/tox.22410; Lu KH, 2016, FOOD CHEM TOXICOL, V97, P177, DOI 10.1016/j.fct.2016.09.006; 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 CH, 2018, ENDOCRINOL METAB, V33, P121, DOI 10.3803/EnM.2018.33.1.121; Park GH, 2018, BMC COMPLEM ALTERN M, V18, DOI 10.1186/s12906-018-2096-x; Park SH, 2012, TOXICOL LETT, V212, P252, DOI 10.1016/j.toxlet.2012.06.007; Rad SK, 2015, PLOS ONE, V10, DOI 10.1371/journal.pone.0145216; Ranasinghe P, 2017, TRIALS, V18, DOI 10.1186/s13063-017-2192-0; Shen ZP, 2017, MED SCI MONITOR, V23, P2096, DOI 10.12659/MSM.901183; Shin WY, 2017, J ETHNOPHARMACOL, V205, P173, DOI 10.1016/j.jep.2017.03.043; Siegel RL, 2018, CA-CANCER J CLIN, V68, P7, DOI 10.3322/caac.21442; Song MY, 2017, AM J CHINESE MED, V45, P1017, DOI [10.1142/S0192415X17500549, 10.1142/s0192415x17500549]; Tian F, 2017, BIOCHEM BIOPH RES CO, V493, P1260, DOI 10.1016/j.bbrc.2017.09.136; WONG DYK, 1990, J ORAL MAXIL SURG, V48, P385, DOI 10.1016/0278-2391(90)90436-6; Wu CN, 2017, INT J BIOCHEM CELL B, V84, P58, DOI 10.1016/j.biocel.2017.01.005; Wu HC, 2018, INT J MED SCI, V15, P115, DOI 10.7150/ijms.22293; Zada W, 2016, NAT PROD RES, V30, P1212, DOI 10.1080/14786419.2015.1047776; Zhou Z, 2017, MED SCI MONITOR, V23, P462, DOI 10.12659/MSM.903170	43	13	13	2	55	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0021-9541	1097-4652		J CELL PHYSIOL	J. Cell. Physiol.	APR	2019	234	4					5289	5303		10.1002/jcp.27338			15	Cell Biology; Physiology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Physiology	HK0TE	WOS:000457613700178	30317581				2022-04-25	
J	Wang, N; Feng, YB				Wang, Ning; Feng, Yibin			Elaborating the Role of Natural Products-Induced Autophagy in Cancer Treatment: Achievements and Artifacts in the State of the Art	BIOMED RESEARCH INTERNATIONAL			English	Review							CELL LUNG-CANCER; ENDOPLASMIC-RETICULUM STRESS; HEPATOCELLULAR-CARCINOMA CELLS; GASTRIC ADENOCARCINOMA CELLS; IN-VITRO; PROTECTIVE AUTOPHAGY; COLON-CANCER; CYTOPROTECTIVE AUTOPHAGY; APOPTOTIC MECHANISMS; MITOTIC CATASTROPHE	Autophagy is a homeostatic process that is highly conserved across different types of mammalian cells. Autophagy is able to relieve tumor cell from nutrient and oxidative stress during the rapid expansion of cancer. Excessive and sustained autophagy may lead to cell death and tumor shrinkage. It was shown in literature that many anticancer natural compounds and extracts could initiate autophagy in tumor cells. As summarized in this review, the tumor suppressive action of natural products-induced autophagy may lead to cell senescence, provoke apoptosis-independent cell death, and complement apoptotic cell death by robust or target-specific mechanisms. In some cases, natural products-induced autophagy could protect tumor cells from apoptotic death. Technical variations in detecting autophagy affect data quality, and study focus should be made on elaborating the role of autophagy in deciding cell fate. In vivo study monitoring of autophagy in cancer treatment is expected to be the future direction. The clinical-relevant action of autophagy-inducing natural products should be highlighted in future study. As natural products are an important resource in discovery of lead compound of anticancer drug, study on the role of autophagy in tumor suppressive effect of natural products continues to be necessary and emerging.	[Wang, Ning; Feng, Yibin] Univ Hong Kong, Sch Chinese Med, Hong Kong, Hong Kong, Peoples R China; [Wang, Ning; Feng, Yibin] Univ Hong Kong, Shenzhen Inst Res & Innovat HKU SIRI, Shenzhen 518057, Peoples R China		Feng, YB (corresponding author), Univ Hong Kong, Sch Chinese Med, 10 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China.	yfeng@hku.hk			Research Council of the University of Hong KongUniversity of Hong Kong [10401764, 104002889, 104002587]; Research Grant Committee (RGC) of Hong Kong SAR of China (RGC General Research Fund) [10500362]; Wong's Donation for Modern Oncology of Chinese Medicine [20006276]; Gala Family Trust for Immunology and Stem Cell Research of Natural Products [200007008]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81302808]	The study was financially supported by grants from the Research Council of the University of Hong Kong (Project codes 10401764, 104002889, and 104002587), the Research Grant Committee (RGC) of Hong Kong SAR of China (RGC General Research Fund, Project code 10500362), Wong's Donation for Modern Oncology of Chinese Medicine (Project code 20006276), Gala Family Trust for Immunology and Stem Cell Research of Natural Products (Project code 200007008), and Natural Science Foundation of China (Project code 81302808).	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Int.		2015	2015								934207	10.1155/2015/934207			14	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	CD9BF	WOS:000351390100001	25821829	Green Published, Green Submitted, gold			2022-04-25	
J	Wang, JW; Wang, XH; Liu, K; Gu, L; Yu, L; Han, L; Meng, ZJ				Wang, Jianwen; Wang, Xuehai; Liu, Kai; Gu, Li; Yu, Lei; Han, Li; Meng, Zhaojin			Suppressing UVRAG Induces Radiosensitivity by Triggering Lysosomal Membrane Permeabilization in Hypopharyngeal Squamous Cell Carcinoma	ONCOTARGETS AND THERAPY			English	Article						UVRAG; autophagy; radiosensitivity; hypopharyngeal squamous cell carcinoma; lysosomal membrane permeabilization	COLORECTAL-CANCER; AUTOPHAGY; ACTIVATION; CISPLATIN; APOPTOSIS; INDUCTION	Introduction: Radiotherapy is one of the most important methods in the treatment of patients with hypopharyngeal squamous cell carcinoma (HSCC). However, radioresistance will be developed after repeated irradiation. Among many key factors contributing to radioresistance, enhanced autophagy is recognized as one of the most important. The ultraviolent irradiation resistance-associated gene (UVRAG) is reported to be a crucial gene involved in the process of autophagy. Here, we test whether UVRAG has effect on the radioresistance of HSCC. Methods: HSCC cell line Fadu cells were treated with irradiation to test levels of autophagy. Tumor tissues from primary and recurrent HSCC patients were tested by immunohistochemistry. Then, we knocked down UVRAG to test its role in cell growth and the malignant behaviors. Response of cells to treatment was examined using LDH release assay, immunofluorescence, Western blot analysis and colony formation. Results: We found that irradiation induced autophagy in Fadu cells. Immunohistochemistry of primary and irradiated HSCC tumor tissues showed that UVRAG was upregulated after irradiation treatment. Inhibiting UVRAG with siRNA interfered cell growth, cell cycle, malignant behaviors and autophagic flux in Fadu cells. Knocking down UVRAG increased DNA damage and cell death induced by irradiation. Finally, we found that inhibiting UVRAG induced lysosomal membrane permeabilization, which contributed to radiosensitization of Fadu cells. Conclusion: Our findings supported the oncogenic properties of UVRAG in HSCC and inhibiting UVRAG increased radiosensitivity in HSCC by triggering lysosomal membrane permeabilization. Therefore, UVRAG might be a promising target in the treatment of HSCC.	[Wang, Jianwen; Wang, Xuehai; Liu, Kai; Gu, Li; Yu, Lei; Han, Li; Meng, Zhaojin] Shandong Univ, Weihai Municipal Hosp, Cheeloo Coll Med, Dept Otolaryngol, Weihai 264200, Shandong, Peoples R China		Wang, XH (corresponding author), Shandong Univ, Weihai Municipal Hosp, Cheeloo Coll Med, Dept Otolaryngol, Weihai 264200, Shandong, Peoples R China.	xuehai581@163.com			Medical Science Technology Development Program of Shandong Province [2018WS103]	This work was supported by the Medical Science Technology Development Program of Shandong Province (2018WS103).	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J	Ramirez, JAZ; Romagnoli, GG; Falasco, BF; Gorgulho, CM; Fogolin, CS; dos Santos, DC; Junior, JPA; Lotze, MT; Ureshino, RP; Kaneno, R				Zamame Ramirez, Jofer Andree; Romagnoli, Graziela Gorete; Falasco, Bianca Francisco; Gorgulho, Carolina Mendonca; Fogolin, Carla Sanzochi; dos Santos, Daniela Carvalho; Araujo Junior, Joao Pessoa; Lotze, Michael Thomas; Ureshino, Rodrigo Portes; Kaneno, Ramon			Blocking drug-induced autophagy with chloroquine in HCT-116 colon cancer cells enhances DC maturation and T cell responses induced by tumor cell lysate	INTERNATIONAL IMMUNOPHARMACOLOGY			English	Article						Autophagy; Cancer; Colorectal; Chemotherapy; Dendritic cells; Cytotoxic T cells	ANTIGEN PRESENTATION; INDUCED APOPTOSIS; 5-FLUOROURACIL; INHIBITION; DEGRADATION; EXPRESSION; INDUCTION; CD4(+); DEATH; ASSAY	Autophagy is an important mechanism for tumor escape, allowing tumor cells to recover from the damage induced by chemotherapy, radiation therapy, and immunotherapy and contributing to the development of resistance. The pharmacological inhibition of autophagy contributes to increase the efficacy of antineoplastic agents. Exposing tumor cells to low concentrations of select autophagy-inducing antineoplastic agents increases their immunogenicity and enhances their ability to stimulate dendritic cell (DC) maturation. We tested whether the application of an autophagy-inhibiting agent, chloroquine (CQ), in combination with low concentrations of 5-fluorouracil (5-FU) increases the ability of tumor cells to induce DC maturation. DCs sensitized with the lysate of HCT-116 cells previously exposed to such a combination enhanced the DC maturation/activation ability. These matured DCs also increased the allogeneic responsiveness of both CD4+ and CD8 + T cells, which showed a greater proliferative response than those from DCs sensitized with control lysates. The T cells expanded in such cocultures were CD69+ and PD-1- and produced higher levels of IFN-gamma and lower levels of IL-10, consistent with the preferential activation of Th1 cells. Cocultures of autologous DCs and lymphocytes improved the generation of cytotoxic T lymphocytes, as assessed by the expression of CD107a, perforin, and granzyme B. The drug combination increased the expression of genes related to the CEACAM family (BECN1, ATGs, MAPLC3B, ULK1, SQSTM1) and tumor suppressors (PCBP1). Furthermore, the decreased expression of genes related to metastasis and tumor progression (BNIP3, BNIP3L, FOSL2, HES1, LAMB3, LOXL2, NDRG1, P4HA1, PIK3R2) was noted. The combination of 5-FU and CQ increases the ability of tumor cells to drive DC maturation and enhances the ability of DCs to stimulate T cell responses.	[Zamame Ramirez, Jofer Andree; Romagnoli, Graziela Gorete; Falasco, Bianca Francisco; Gorgulho, Carolina Mendonca; Fogolin, Carla Sanzochi; Araujo Junior, Joao Pessoa; Kaneno, Ramon] Sao Paulo State Univ, Inst Biosci Botucatu, Dept Chem & Biol Sci, UNESP, Campus Rubiao Jr,Rua Prof Dr Plinio Pinto e Silva, BR-18618691 Botucatu, SP, Brazil; [Zamame Ramirez, Jofer Andree; Romagnoli, Graziela Gorete; Gorgulho, Carolina Mendonca] Sao Paulo State Univ, Sch Med Botucatu, Dept Pathol, UNESP, Botucatu, SP, Brazil; [dos Santos, Daniela Carvalho] Sao Paulo State Univ, Ctr Electron Microscopy, Inst Biosci Botucatu, UNESP, Botucatu, SP, Brazil; [Lotze, Michael Thomas] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA; [Ureshino, Rodrigo Portes] Univ Fed Sao Paulo, Dept Biol Sci, UNIFESP, Sao Paulo, SP, Brazil		Kaneno, R (corresponding author), Sao Paulo State Univ, Inst Biosci Botucatu, Dept Chem & Biol Sci, UNESP, Campus Rubiao Jr,Rua Prof Dr Plinio Pinto e Silva, BR-18618691 Botucatu, SP, Brazil.	rskaneno@yahoo.com.br	Araujo Jr, Joao Pessoa/Q-3043-2019; Ureshino, Rodrigo P/C-4095-2014; Ureshino, Rodrigo/ABC-5150-2020; Carvalho dos Santos, Daniela/E-3102-2012; Mendonca Gorgulho, Carolina/L-9511-2017; Zamame Ramirez, Jofer Andree/P-5163-2015	Araujo Jr, Joao Pessoa/0000-0002-9153-1485; Ureshino, Rodrigo P/0000-0003-3371-3376; Ureshino, Rodrigo/0000-0003-3371-3376; Carvalho dos Santos, Daniela/0000-0001-8062-104X; Mendonca Gorgulho, Carolina/0000-0001-6569-8647; Zamame Ramirez, Jofer Andree/0000-0002-1196-6893	CAPESCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Brazilian Council for Research CNPq, Brazil; Sao Paulo Research Foundation (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)	This research did not receive any specific grant from funding agencies in the public, commercial, or not for profit sectors. JAZR and CMG were recipients of doctorate scholarships from CAPES and the Brazilian Council for Research CNPq, Brazil. GGR was the recipient of a postdoctoral fellowship from CAPES. BFF and CSF were the recipients of scientific initiation scholarships from the Sao Paulo Research Foundation (FAPESP).	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Immunopharmacol.	JUL	2020	84								106495	10.1016/j.intimp.2020.106495			10	Immunology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Immunology; Pharmacology & Pharmacy	LY3SB	WOS:000540446500070	32298965	Green Published, Bronze			2022-04-25	
J	Liang, CY; Feng, PH; Ku, BS; Oh, BH; Jung, JU				Liang, Chengyu; Feng, Pinghui; Ku, Bonsu; Oh, Byung-Ha; Jung, Jae U.			UVRAG - A new player in autophagy and tumor cell growth	AUTOPHAGY			English	Article						UVRAG; autophagy; tumor suppression; Beclin 1; Bcl-2	COLON-CANCER; GENE; INHIBITION; BECLIN-1; PROTEIN; CLONING	Autophagy has a well-documented role in the maintenance of homeostasis and the response to stressful environments and it is often deregulated in various human diseases including cancer. The regulation of the Beclin 1-PI3KC3 complex lipid kinase activity is a critical element in the autophagy signaling pathway. Previous studies(1) have demonstrated that Beclin 1-PI3KC3-mediated autophagy is negatively regulated by a proto-oncogene Bcl-2. We have recently identified a novel coiled-coil UVRAG tumor suppressor candidate, which positively engages in Beclin 1-dependent autophagy. UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis. This finding adds a new player to the emerging picture of the autophagy network, underscoring the importance of the coordinated activity between Bcl-2 and UVRAG in the regulation of Beclin 1-PI3KC3-mediated autophagy and tumor cell control.	Harvard Univ, Sch Med, Tumor Virol Div, New England Primat Res Ctr, Southborough, MA 01772 USA; Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, New England Primat Res Ctr, Southborough, MA 01772 USA; Pohang Univ Sci & Technol, Ctr Biomol Recognit, Dept Life Sci, Pohang, South Korea		Jung, JU (corresponding author), Harvard Univ, Sch Med, Tumor Virol Div, New England Primat Res Ctr, POB 9102,1 Pine Hill Dr, Southborough, MA 01772 USA.	jae_jung@hms.harvard.edu	Oh, Byung-Ha/C-2061-2011	Ku, Bonsu/0000-0003-1784-8975			Aita VM, 1999, GENOMICS, V59, P59, DOI 10.1006/geno.1999.5851; Bekri S, 1997, CYTOGENET CELL GENET, V79, P125, DOI 10.1159/000134699; Goi T, 2003, SURG TODAY, V33, P702, DOI 10.1007/s00595-002-2567-y; Ionov Y, 2004, ONCOGENE, V23, P639, DOI 10.1038/sj.onc.1207178; Ito H, 2005, INT J ONCOL, V26, P1401; Klionsky DJ, 2005, J CELL SCI, V118, P7, DOI 10.1242/jcs.01620; Kondo Y, 2005, NAT REV CANCER, V5, P726, DOI 10.1038/nrc1692; 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 PFC, 2006, UVRAG NATURE CELL BI, V8, P688; Liang XH, 1999, NATURE, V402, P672, DOI 10.1038/45257; 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; Proikas-Cezanne T, 2004, ONCOGENE, V23, P9314, DOI 10.1038/sj.onc.1208331; Susan PP, 2001, J CELL PHYSIOL, V187, P48, DOI 10.1002/1097-4652(2001)9999:9999<00::AID-JCP1050>3.3.CO;2-9; Yorimitsu T, 2005, CELL DEATH DIFFER, V12, P1542, DOI 10.1038/sj.cdd.4401765; Yue ZY, 2003, P NATL ACAD SCI USA, V100, P15077, DOI 10.1073/pnas.2436255100	17	55	57	0	7	TAYLOR & FRANCIS INC	PHILADELPHIA	530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA	1554-8627	1554-8635		AUTOPHAGY	Autophagy	JAN-FEB	2007	3	1					69	71		10.4161/auto.3437			3	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	126FY	WOS:000243499200021	17106237	Bronze			2022-04-25	
J	Zhang, SH; Zhang, YY; Cheng, Q; Ma, ZQ; Gong, GW; Deng, ZM; Xu, K; Wang, GY; Wei, YS; Zou, XP				Zhang, Shihu; Zhang, Yiyang; Cheng, Qing; Ma, Zhaoqun; Gong, Guanwen; Deng, Zhengming; Xu, Kun; Wang, Gaoyuan; Wei, Yousong; Zou, Xiaoping			Silencing protein kinase C zeta by microRNA-25-5p activates AMPK signaling and inhibits colorectal cancer cell proliferation	ONCOTARGET			English	Article						colorectal cancer (CRC); protein kinase C zeta (PKC zeta); AMP-activated protein kinase (AMPK); microRNA-25-5p; cell proliferation	INDUCED APOPTOSIS; REGULATES APOPTOSIS; EPITHELIAL-CELLS; ENERGY STRESS; AUTOPHAGY; GROWTH; EXPRESSION; PATHWAY; PHOSPHORYLATION; SURVIVAL	Developing novel strategies against human colorectal cancer (CRC) cells is needed. Activation of AMP-activated protein kinase (AMPK) could possibly inhibit CRC cells. Protein kinase C zeta (PKC zeta) is an AMPK negative regulator. Here we found that PKC zeta expression was significantly elevated in human colon cancer tissues and CRC cells. PKC zeta upregulation was correlated with AMPK in-activation and mTOR complex 1 (mTORC1) over-activation. Reversely, PKC zeta shRNA knockdown activated AMPK signaling and inhibited HT-29 cell proliferation. Significantly, downregulation of microRNA-25-5p (miR-25-5p), a PKC zeta-targeting miRNA, could be the cause of PKC zeta upregulation. Exogenous expression of miR-25-5p silenced PKC zeta to activate AMPK signaling, which inhibited HT-29 cell proliferation. In vivo studies showed that HT-29 xenograft growth in mice was inhibited after expressing PKC zeta shRNA or miR-25-5p. Collectively, PKC zeta could be a novel oncogenic protein of human CRC. PKC zeta silence, by targeted-shRNA or miR-25-5p expression, activates AMPK and inhibits HT-29 cell proliferation.	[Zhang, Shihu; Ma, Zhaoqun; Gong, Guanwen; Deng, Zhengming; Xu, Kun; Wang, Gaoyuan; Wei, Yousong] Nanjing Univ Chinese Med, Dept Gen Surg, Affiliated Hosp, Nanjing, Jiangsu, Peoples R China; [Zhang, Yiyang; Zou, Xiaoping] Nanjing Med Univ, Digest Dept, Affiliated Drum Tower Clin Med Sch, Nanjing, Jiangsu, Peoples R China; [Cheng, Qing] Nanjing Med Univ, Dept Obstet & Gynaecol, Obstet & Gynecol Hosp, Nanjing, Jiangsu, Peoples R China		Wei, YS (corresponding author), Nanjing Univ Chinese Med, Dept Gen Surg, Affiliated Hosp, Nanjing, Jiangsu, Peoples R China.; Zou, XP (corresponding author), Nanjing Med Univ, Digest Dept, Affiliated Drum Tower Clin Med Sch, Nanjing, Jiangsu, Peoples R China.	weiyousongnanjlw@yeah.net; zouxiaopingmunj@163.com			National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC)	This work is partly supported by the National Science Foundation of China.	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J	Kim, WK; Pyee, Y; Chung, HJ; Park, HJ; Hong, JY; Son, KH; Lee, SK				Kim, Won Kyung; Pyee, Yuna; Chung, Hwa-Jin; Park, Hyen Joo; Hong, Ji-Young; Son, Kun Ho; Lee, Sang Kook			Antitumor Activity of Spicatoside A by Modulation of Autophagy and Apoptosis in Human Colorectal Cancer Cells	JOURNAL OF NATURAL PRODUCTS			English	Article							STEROIDAL SAPONIN; LIRIOPE-PLATYPHYLLA; ANTICANCER AGENTS; GROWTH-FACTOR; PATHWAY; INHIBITION; CLEAVAGE; THERAPY; P53; MITOCHONDRIA	The antitumor activity of spicatoside A (1), a steroidal saponin isolated from the tuber of Liriope platyphylla, and its underlying mechanisms were investigated in HCT116 human colorectal cancer cells. Compound 1 induced autophagy and apoptotic cell death and inhibited tumor growth in a nude mouse xenograft model implanted with HCT116 cells. Treatment with 1 for 24 h enhanced the formation of acidic vesicular organelles in the cytoplasm, indicating the induction of the onset of autophagy. This event was associated with the regulation of autophagic markers including microtubule-associated protein 1 light chain 3 (LC3)-II, p62, beclin 1, lysosomal-associated membrane protein 1 (LAMP 1), and cathepsin D by inhibiting the PI3K/Akt/mTOR signaling pathway, regulating mitogen-activated protein kinase (MAPK) signaling, and increasing p53 levels. However, a prolonged exposure to 1 resulted in apoptosis characterized by the accumulation of a sub-G1 cell population and an annexin V/propidium iodide (PI)-positive cell population. Apoptosis induced by 1 was associated with the regulation of apoptotic proteins including Bcl-2, Bax, and Bid, the release of cytochrome c into the cytosol, and the accumulation of cleaved poly-ADP-ribose polymerase (PAR?). Further study revealed that cleavage of beclin 1 by caspases plays a critical role in the 1-mediated switch from autophagy to apoptosis. Taken together, these findings highlight the significance of 1 in the modulation of crosstalk between autophagy and apoptosis, as well as the potential use of 1 as a novel candidate in the treatment of human colorectal cancer cells.	[Kim, Won Kyung; Pyee, Yuna; Chung, Hwa-Jin; Park, Hyen Joo; Hong, Ji-Young; Lee, Sang Kook] Seoul Natl Univ, Coll Pharm, Inst Nat Prod Res, Seoul 151742, South Korea; [Son, Kun Ho] Andong Natl Univ, Dept Food Sci & Nutr, Andong 760749, South Korea		Lee, SK (corresponding author), Seoul Natl Univ, Coll Pharm, Inst Nat Prod Res, Seoul 151742, South Korea.	sklee61@snu.ac.kr		Lee, Sang Kook/0000-0002-4306-7024	National Research Foundation of Korea (NRF) - Korean government (MEST)Ministry of Education, Science and Technology, Republic of KoreaNational Research Foundation of KoreaKorean Government [20120004939, 2009-0083533]; Ministry of Food and Drug SafetyMinistry of Food & Drug Safety (MFDS) [12172MFDS989]	This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (No. 20120004939 and 2009-0083533) and a grant (12172MFDS989) from the Ministry of Food and Drug Safety in 2012.	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Nat. Prod.	APR	2016	79	4					1097	1104		10.1021/acs.jnatprod.6b00006			8	Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Plant Sciences; Pharmacology & Pharmacy	DK4UM	WOS:000374915800053	27064730				2022-04-25	
J	Man, SL; Lv, PP; Cui, JX; Liu, FR; Peng, L; Ma, L; Liu, CX; Gao, WY				Man, Shuli; Lv, Panpan; Cui, Jingxia; Liu, Furui; Peng, Lei; Ma, Long; Liu, Changxiao; Gao, Wenyuan			Paris saponin II-induced paraptosis-associated cell death increased the sensitivity of cisplatin	TOXICOLOGY AND APPLIED PHARMACOLOGY			English	Article						Paris Saponin II; Paraptosis; Endoplasmic Reticulum Stress; Cytoplasmic Vacuolation; Mitochondrial Swelling	COLON-CANCER CELLS; RHIZOMA PARIDIS; FORMOSANIN C; LUNG-CANCER; ACTIVATION; RESISTANCE; APOPTOSIS; AUTOPHAGY	Paris Saponin II (PSII) has been regarded as an effective and imperative component isolated from Rhizoma Paridis saponins (RPS) and exhibited strong anti-tumor effects on a variety of cancer. Our results revealed that human non-small lung cancer cell lines NCI-H460 and NCI-H520 were exposed to 1 mu M of PSII, which inhibited the proliferation of lung cancer cells and activated apoptosis, autophagy and paraptosis. PSII induced paraptosis-associated cell death prior to apoptosis and autophagy. It induced paraptosis based on ER stress through activation of the JNK pathway. Meanwhile, PSII increased the cytotoxicity of cisplatin through paraptosis-associated pathway. All in all, PSII induced paraptosis based on induction of non-apoptotic cell death, which would be a possible approach to suppress the multi-drug resistant to apoptosis.	[Man, Shuli; Lv, Panpan; Cui, Jingxia; Liu, Furui; Peng, Lei; Ma, Long] Tianjin Univ Sci & Technol, Natl & Local United Engn Lab Metab Control Fermen, Tianjin Key Lab Ind Microbiol,China Int Sci & Tec, State Key Lab Food Nutr & Safety,Key Lab Ind Micr, Tianjin 300457, Peoples R China; [Gao, Wenyuan] Tianjin Univ, Sch Pharmaceut Sci & Technol, Tianjin Key Lab Modern Drug Delivery & High Effic, Tianjin 300072, Peoples R China; [Liu, Changxiao] State Key Labs Pharmacodynam & Pharmacokinet, Tianjin 300193, Peoples R China		Man, SL (corresponding author), Tianjin Univ Sci & Technol, Natl & Local United Engn Lab Metab Control Fermen, Tianjin Key Lab Ind Microbiol,China Int Sci & Tec, State Key Lab Food Nutr & Safety,Key Lab Ind Micr, Tianjin 300457, Peoples R China.; Gao, WY (corresponding author), Tianjin Univ, Sch Pharmaceut Sci & Technol, Tianjin Key Lab Modern Drug Delivery & High Effic, Tianjin 300072, Peoples R China.	msl@tust.edu.cn; biochemgao@163.com			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81673647, 81673535, 81503086];  [18PTSYJC00140];  [19JCYBJC27800]	This work was supported by grants 81673647, 81673535 and 81503086 from National Natural Science Foundation of China and Tianjin Municipal Science and Technology Committee (18PTSYJC00140 and 19JCYBJC27800).	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Appl. Pharmacol.	NOV 1	2020	406								115206	10.1016/j.taap.2020.115206			9	Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Toxicology	OE4SM	WOS:000580522200004	32835762				2022-04-25	
J	Nerome, K; Ito-Kureha, T; Paganini, T; Fukuda, T; Igarashi, Y; Ashitomi, H; Ikematsu, S; Yamamoto, T				Nerome, Kuniaki; Ito-Kureha, Taku; Paganini, Tiziana; Fukuda, Takao; Igarashi, Yasuhiro; Ashitomi, Hiroto; Ikematsu, Shinya; Yamamoto, Tadashi			Potent and broad anticancer activities of leaf extracts from Melia azedarach L. of the subtropical Okinawa islands	AMERICAN JOURNAL OF CANCER RESEARCH			English	Article						Cancer; anticancer therapeutics; plant extracts; Melia azedarach; autophagy inhibitors	DRUG DISCOVERY; CELL-DEATH; CYTOTOXIC LIMONOIDS; CANCER-CELLS; IN-VITRO; AUTOPHAGY; INHIBITION; MTOR; HYDROXYCHLOROQUINE; MACROAUTOPHAGY	Plant extracts have been traditionally used for various therapeutic applications. By conducting an initial screening of several subtropical plants, in this study, we evaluated the anticancer activities of Melia azedarach L. The extract from Melia azedarach L. leaves (MLE) show high cytotoxic effects on cancer cells and in vivo mouse and dog tumor models. During the initial screening, MLE showed strong antiproliferative activity against HT-29 colon, A549 lung, and MKN1 gastric cancer cells. In subsequent tests, using 39 human tumor cell lines, we confirmed the potent anticancer activities of MLE. The anticancer activity of MLE was also confirmed in vivo. MLE markedly inhibited the growth of transplanted gastric MKN1 cancer xenografts in mice. To elucidate the mechanism underlying the anticancer effects of MLE, MLE-treated MKN1 cells were observed using an electron microscope; MLE treatment induced autophagy. Furthermore, western blot analysis of proteins in lysates of MLE-treated cells revealed induction of light chain 3 (LC3)-II autophagosomal proteins. Thus, MLE appeared to suppress MKN1 cell proliferation by inducing autophagy. In addition, in the mouse macrophage cell line J774A.1, MLE treatment induced TNF-alpha production, which might play a role in tumor growth suppression in vivo. We also performed a preclinical evaluation of MLE treatment on dogs with various cancers in veterinary hospitals. Dogs with various types of cancers showed a mean recovery of 76% when treated with MLE. Finally, we tried to identify the active substances present in MLE. All the active fractions obtained by reverse-phase chromatography contained azedarachin B-related moieties, such as 3-deacetyl-12-hydroxy-amoorastatin, 12-hydroxy-amoorastatin, and 12-hydroxyamoorastaton. In conclusion, MLE contains substances with promising anticancer effects, suggesting their future use as safe and effective anticancer agents.	[Nerome, Kuniaki] Inst Biol Resources, 893-2 Nakayama, Nago, Okinawa 9050004, Japan; [Ito-Kureha, Taku; Paganini, Tiziana; Yamamoto, Tadashi] Okinawa Inst Sci & Technol Grad Univ, Cell Signal Unit, Onna, Okinawa 9040495, Japan; [Fukuda, Takao; Igarashi, Yasuhiro] Toyama Prefectural Univ, Fac Engn, Biotechnol Res Ctr, 5180 Kurokawa, Imizu, Toyama 9390398, Japan; [Fukuda, Takao; Igarashi, Yasuhiro] Toyama Prefectural Univ, Fac Engn, Dept Biotechnol, 5180 Kurokawa, Imizu, Toyama 9390398, Japan; [Ashitomi, Hiroto; Ikematsu, Shinya] Okinawa Coll, Natl Inst Technol, Henoko 905, Nago, Okinawa 9052192, Japan		Nerome, K (corresponding author), Inst Biol Resources, 893-2 Nakayama, Nago City, Okinawa 9050004, Japan.	rnerome_ibr@train.ocn.ne.jp			Okinawa Institute of Science and Technology Graduate SchoolOkinawa Institute of Science & Technology Graduate University; Institute of Biological Resources, Okinawa, Japan	We thank Dr. T. Yoshikawa and Mr. S. Mukai (Institute of Biological Resources, Okinawa, Japan) for their skillful technical help and general support. We thank Ms. N. Ohmine (Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan: OIST) and Dr. O. Elisseeva (Institute of Physical and Chemical Research, Kanagawa, Japan: RIKEN) for their technical support. We also thank Dr. K. Kuroda (Nihon University School of Medicine, Tokyo, Japan) for useful comments on the manuscript. We are grateful to the Kyoritsu Seiyaku Corporation (Tokyo, Japan) for their cooperation in the preclinical evaluation of MLE in veterinary hospitals. We also appreciate the Okinawa Institute of Science and Technology Graduate School for providing partial funding for this work. Authors appreciate Dr. R. Nerome (Institute of Biological Resources, Okinawa, Japan) for her generous supports for preparing the manuscript and figures.	AHN JW, 1994, PHYTOCHEMISTRY, V36, P1493, DOI 10.1016/S0031-9422(00)89749-6; Balunas MJ, 2005, LIFE SCI, V78, P431, DOI 10.1016/j.lfs.2005.09.012; Benjamin D, 2011, NAT REV DRUG DISCOV, V10, P868, DOI 10.1038/nrd3531; Bursch W, 1996, CARCINOGENESIS, V17, P1595, DOI 10.1093/carcin/17.8.1595; Cragg GM, 1998, MED RES REV, V18, P315, DOI 10.1002/(SICI)1098-1128(199809)18:5<315::AID-MED3>3.3.CO;2-0; Crisan TO, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0018666; Djavaheri-Mergny M, 2006, J BIOL CHEM, V281, P30373, DOI 10.1074/jbc.M602097200; Dumontet C, 2010, NAT REV DRUG DISCOV, V9, P790, DOI 10.1038/nrd3253; Gonzalez-Malerva L, 2011, P NATL ACAD SCI USA, V108, P2058, DOI 10.1073/pnas.1018157108; Harris J, 2011, CYTOKINE, V56, P140, DOI 10.1016/j.cyto.2011.08.022; Harris J, 2011, J BIOL CHEM, V286, P9587, DOI 10.1074/jbc.M110.202911; ITOKAWA H, 1995, CHEM PHARM BULL, V43, P1171, DOI 10.1248/cpb.43.1171; Janku F, 2011, NAT REV CLIN ONCOL, V8, P528, DOI 10.1038/nrclinonc.2011.71; Jia GH, 2006, IMMUNOL CELL BIOL, V84, P448, DOI 10.1111/j.1440-1711.2006.01454.x; JOHNSON IS, 1963, CANCER RES, V23, P1390; Katanoda K, 2015, JPN J CLIN ONCOL, V45, P390, DOI 10.1093/jjco/hyv002; Keller CW, 2011, J BIOL CHEM, V286, P3970, DOI 10.1074/jbc.M110.159392; Ko A, 2014, CELL DEATH DIFFER, V21, P92, DOI 10.1038/cdd.2013.124; Kohli L, 2013, CANCER RES, V73, P4395, DOI 10.1158/0008-5472.CAN-12-3765; Levy JMM, 2017, NAT REV CANCER, V17, P528, DOI 10.1038/nrc.2017.53; Ma XH, 2011, CLIN CANCER RES, V17, P3478, DOI 10.1158/1078-0432.CCR-10-2372; Maeda M., 1990, MED PLANTS FOLK REME; Martino E, 2017, BIOORG MED CHEM LETT, V27, P701, DOI 10.1016/j.bmcl.2016.12.085; Maycotte P, 2012, AUTOPHAGY, V8, P200, DOI 10.4161/auto.8.2.18554; MONKS A, 1991, J NATL CANCER I, V83, P757, DOI 10.1093/jnci/83.11.757; Nakahira K, 2011, NAT IMMUNOL, V12, P222, DOI 10.1038/ni.1980; Newman DJ, 2007, J NAT PROD, V70, P461, DOI 10.1021/np068054v; OCHI M, 1978, CHEM LETT, P99, DOI 10.1246/cl.1978.99; Rangwala R, 2014, AUTOPHAGY, V10, P1391, DOI 10.4161/auto.29119; Rosenfeld MR, 2014, AUTOPHAGY, V10, P1359, DOI 10.4161/auto.28984; Saitoh T, 2008, NATURE, V456, P264, DOI 10.1038/nature07383; Samaddar JS, 2008, MOL CANCER THER, V7, P2977, DOI 10.1158/1535-7163.MCT-08-0447; Scott AM, 2012, NAT REV CANCER, V12, P278, DOI 10.1038/nrc3236; Sivaprasad U, 2008, J CELL MOL MED, V12, P1265, DOI 10.1111/j.1582-4934.2008.00282.x; SKEHAN P, 1990, J NATL CANCER I, V82, P1107, DOI 10.1093/jnci/82.13.1107; Sliwkowski MX, 2013, SCIENCE, V341, P1192, DOI 10.1126/science.1241145; Surh YJ, 2003, NAT REV CANCER, V3, P768, DOI 10.1038/nrc1189; Tada K, 1999, PHYTOCHEMISTRY, V51, P787, DOI 10.1016/S0031-9422(99)00115-6; Takeya K, 1996, BIOORGAN MED CHEM, V4, P1355, DOI 10.1016/0968-0896(96)00128-9; Tan QG, 2011, CHEM REV, V111, P7437, DOI 10.1021/cr9004023; Thorburn A, 2014, MOL PHARMACOL, V85, P830, DOI 10.1124/mol.114.091850; Wander SA, 2011, J CLIN INVEST, V121, P1231, DOI 10.1172/JCI44145; Wei YJ, 2008, MOL CELL, V30, P678, DOI 10.1016/j.molcel.2008.06.001; Wu TT, 2016, INT J BIOL SCI, V12, P884, DOI 10.7150/ijbs.15194; Yamori T, 1997, JPN J CANCER RES, V88, P1205, DOI 10.1111/j.1349-7006.1997.tb00350.x; Yamori T, 2003, CANCER CHEMOTH PHARM, V52, pS74, DOI 10.1007/s00280-003-0649-1; Yamori T, 1999, CANCER RES, V59, P4042; Zhang B, 2005, INVEST NEW DRUG, V23, P547, DOI 10.1007/s10637-005-0909-5	48	1	1	0	1	E-CENTURY PUBLISHING CORP	MADISON	40 WHITE OAKS LN, MADISON, WI 53711 USA	2156-6976			AM J CANCER RES	Am. J. Cancer Res.		2020	10	2					581	594					14	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	KS0YF	WOS:000518037100016	32195029				2022-04-25	
J	Zhou, L; Gao, W; Wang, K; Huang, Z; Zhang, L; Zhang, Z; Zhou, J; Nice, EC; Huang, CH				Zhou, Li; Gao, Wei; Wang, Kui; Huang, Zhao; Zhang, Lu; Zhang, Zhe; Zhou, Jing; Nice, Edouard C.; Huang, Canhua			Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy	FASEB JOURNAL			English	Article						cancer therapy; ER stress; autophagic flux	ER STRESS; CELL-DEATH; APOPTOSIS; MITOCHONDRIAL; STATISTICS; RESISTANCE	Colorectal cancer (CRC) is one of the most prevalent neoplastic diseases worldwide, and effective treatment remains a challenge. Here, we found that the macrolide antibiotic brefeldin A (BFA) exhibits considerable antitumor activity both in vitro and in vivo. Induction of complete autophagic flux is characterized as a key event in BFA-induced CRC suppression. Mechanistically, BFA provokes endoplasmic reticulum stress-mediated binding immunoglobulin protein (Bip) expression, leading to increased Bip/Akt interaction and resultant decreased Akt phosphorylation, thereby activating autophagy. Autophagy inhibition or Bip suppression relieves BFA-induced cell death, suggesting a key role for Bip-regulated autophagy in the antitumor properties of BFA. Moreover, BFA acts synergistically with paclitaxel or 5-fluorouracil in CRC suppression. Collectively, our study provides an important molecular basis for BFA-induced autophagy and suggests that the antibiotic BFA could be repositioned as a potential anticancer drug for CRC treatment.	[Zhou, Li; Gao, Wei; Wang, Kui; Huang, Zhao; Zhang, Lu; Zhang, Zhe; Zhou, Jing; Huang, Canhua] Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Deans Off 17,Sect 3,South Renmin Rd, Chengdu 610041, Sichuan, Peoples R China; [Zhou, Li; Gao, Wei; Wang, Kui; Huang, Canhua] Sichuan Univ, West China Sch Basic Sci & Forens Med, Chengdu, Sichuan, Peoples R China; [Zhou, Li; Gao, Wei; Huang, Canhua] Hainan Med Univ, Affiliated Hosp 2, Dept Oncol, Haikou, Hainan, Peoples R China; [Nice, Edouard C.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia		Huang, CH (corresponding author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Deans Off 17,Sect 3,South Renmin Rd, Chengdu 610041, Sichuan, Peoples R China.	hcanhua@scu.edu.cn	Kang, Jeong-Han/J-3541-2019	Kang, Jeong-Han/0000-0002-9693-0696; Huang, Zhao/0000-0001-9994-2070	Chinese National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [81430071, 81790251, 81672381, 81602194]; National Key Research and Development Program of China [2016YFC1200203]	This work was supported by grants from the Chinese National Natural Science Foundation of China (NSFC; 81430071, 81790251, 81672381, 81602194) and the National Key Research and Development Program of China (2016YFC1200203). The authors declare no conflicts of interest.	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APR	2019	33	4					5520	5534		10.1096/fj.201801983R			15	Biochemistry & Molecular Biology; Biology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology	HR1JP	WOS:000462888500071	30668917	Bronze			2022-04-25	
J	Shintani, M; Sangawa, A; Yamao, N; Miyake, T; Kamoshida, S				Shintani, Michiko; Sangawa, Akiko; Yamao, Naoki; Miyake, Toshihiko; Kamoshida, Shingo			Immunohistochemical analysis of cell death pathways in gastrointestinal adenocarcinoma	BIOMEDICAL RESEARCH-TOKYO			English	Article							APOPTOSIS-INDUCING FACTOR; CASPASES 3; GASTRIC-CARCINOMA; PROTEINS BCL-2; FACTOR AIF; CANCER; EXPRESSION; AUTOPHAGY; 5-FLUOROURACIL; MECHANISMS	Caspase-8 and caspase-9 play crucial roles in the extrinsic and intrinsic apoptotic pathways, respectively. The nuclear translocation of apoptosis-inducing factor (AI F) is involved in caspase-independent apoptosis. Microtubule-associated protein 1 light chain 3 (LC3) plays a pivotal role in autophagy. In the present study, we analyzed the expression of cleaved caspase-8 (CC8), cleaved caspase-9 (CC9), AIF, and LC3 in 160 gastrointestinal adenocarcinomas. The nuclear expression of AIF was rare. The expression of CC8 in gastric and colorectal adenocarcinomas did not differ, whereas the percentage of CC9-positive tumors in gastric adenocarcinomas was significantly higher than in colorectal adenocarcinomas. In contrast, the percentage of LC3-positive tumors in gastric adenocarcinomas was significantly lower than in colorectal adenocarcinomas. CC8 and CC9 occasionally co-existed in the same tumor cells in gastric adenocarcinoma. However, LC3-positive tumor cells in colorectal adenocarcinomas were constantly negative for CC8. No correlation was identified between the expression of any markers and clinicopathological parameters. These results suggest that different cell death pathways are activated in a manner that depends upon the primary site and cell type. The extrinsic and intrinsic apoptotic pathways may be mutually regulated in gastric adenocarcinomas. Also, autophagy may function as a cellular guardian to avoid apoptosis in colorectal adenocarcinomas.	[Shintani, Michiko] Kobe Univ, Grad Sch Hlth Sci, Pathol Lab, Div Med Biophys,Suma Ku, Kobe, Hyogo 6540142, Japan; [Sangawa, Akiko] Osaka Red Cross Hosp, Dept Diagnost Pathol, Osaka, Japan; [Yamao, Naoki] Kobe Cent Hosp Social Insurance, Dept Clin Lab, Kobe, Hyogo, Japan; [Miyake, Toshihiko] Kobe Cent Hosp Social Insurance, Dept Diagnost Pathol, Kobe, Hyogo, Japan		Shintani, M (corresponding author), Kobe Univ, Grad Sch Hlth Sci, Pathol Lab, Div Med Biophys,Suma Ku, 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 [20590355]	We would like to thank Dr. Masayuki Shintaku for his kind support. This study was supported by a Grant-in-Aid for Scientific Research (No. 20590355) from the Japan Society for the Promotion of Science.	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Res.	DEC	2011	32	6					379	386		10.2220/biomedres.32.379			8	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	867KY	WOS:000298454500004	22199128	Bronze			2022-04-25	
J	Niture, S; Dong, XL; Arthur, E; Chimeh, U; Niture, SS; Zheng, WF; Kumar, D				Niture, Suryakant; Dong, Xialan; Arthur, Elena; Chimeh, Uchechukwu; Niture, Samiksha S.; Zheng, Weifan; Kumar, Deepak			Oncogenic Role of Tumor Necrosis Factor alpha-Induced Protein 8 (TNFAIP8)	CELLS			English	Review						tumor necrosis factor alpha (TNF alpha); tumor necrosis factor alpha-inducing protein 8 (TNFAIP8); oncogene; autophagy; cell survival	SQUAMOUS-CELL CARCINOMA; DEATH EFFECTOR DOMAIN; NEGATIVE REGULATOR; POOR-PROGNOSIS; CANCER; TIPE2; EXPRESSION; OVEREXPRESSION; METASTASIS; APOPTOSIS	Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8) is a founding member of the TIPE family, which also includes TNFAIP8-like 1 (TIPE1), TNFAIP8-like 2 (TIPE2), and TNFAIP8-like 3 (TIPE3) proteins. Expression of TNFAIP8 is strongly associated with the development of various cancers including cancer of the prostate, liver, lung, breast, colon, esophagus, ovary, cervix, pancreas, and others. In human cancers, TNFAIP8 promotes cell proliferation, invasion, metastasis, drug resistance, autophagy, and tumorigenesis by inhibition of cell apoptosis. In order to better understand the molecular aspects, biological functions, and potential roles of TNFAIP8 in carcinogenesis, in this review, we focused on the expression, regulation, structural aspects, modifications/interactions, and oncogenic role of TNFAIP8 proteins in human cancers.	[Niture, Suryakant; Arthur, Elena; Chimeh, Uchechukwu; Kumar, Deepak] North Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst BBRI, Durham, NC 27707 USA; [Dong, Xialan; Zheng, Weifan] North Carolina Cent Univ, Biomfg Res Inst & Technol Enterprise BRITE, Durham, NC 27707 USA; [Niture, Samiksha S.] Catonsville High Sch, Catonsville, MD 21228 USA; [Kumar, Deepak] North Carolina Cent Univ, Dept Pharmaceut Sci, Durham, NC 27707 USA		Kumar, D (corresponding author), North Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst BBRI, Durham, NC 27707 USA.; Kumar, D (corresponding author), North Carolina Cent Univ, Dept Pharmaceut Sci, Durham, NC 27707 USA.	sniture@nccu.edu; xdong@nccu.edu; earthur1@nccu.edu; uchimeh@nccu.edu; samniture@gmail.com; wzheng@nccu.edu; dkumar@nccu.edu		Niture, Suryakant/0000-0003-0613-9399; Chimeh, Uchechukwu/0000-0002-1346-4088; zheng, weifan/0000-0001-9025-7229	National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U01CA194730, U54MD012392, R01MD012767]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA194730] Funding Source: NIH RePORTER; National Institute on Minority Health and Health DisparitiesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Minority Health & Health Disparities (NIMHD) [R01MD012767, U54MD012392] Funding Source: NIH RePORTER	We gratefully acknowledge the grants U01CA194730, U54MD012392, and R01MD012767 from the National Institutes of Health to D.K.	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J	Greene, LM; O'Boyle, NM; Nolan, DP; Meegan, MJ; Zisterer, DM				Greene, Lisa M.; O'Boyle, Niamh M.; Nolan, Derek P.; Meegan, Mary J.; Zisterer, Daniela M.			The vascular targeting agent Combretastatin-A4 directly induces autophagy in adenocarcinoma-derived colon cancer cells	BIOCHEMICAL PHARMACOLOGY			English	Article						Combretastatin; Autophagy; Apoptosis; Tubulin and mitochondria	A4 PHOSPHATE; DEATH; APOPTOSIS; INDUCTION; MODULATION; CARCINOMA; ANALOGS; TUMOR	Recent clinical data demonstrated that the vascular targeting agent Combretastatin-A4 phosphate (CA-4P) prolonged survival of patients with advanced anaplastic thyroid cancer without any adverse side effects. However, as a single agent CA-4 failed to reduce tumour growth in the murine CT-26 adenocarcinoma colon cancer model. Furthermore, the molecular mechanism of the innate resistance of HT-29 human adenocarcinoma cells to CA-4 is largely unknown. In this report, we demonstrate for the first time that prolonged exposure to CA-4 and an azetidinone cis-restricted analogue, CA-432 (chemical name; 4-(3-Hydroxy-4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one) induced autophagy in adenocarcinoma-derived CT-26, Caco-2 and HT-29 cells but not in fibrosarcoma-derived HT-1080 cells. Autophagy is a fundamental self-catabolic process which can facilitate a prolonged cell survival in spite of adverse stress by generating energy via lysosomal degradation of cytoplasmic constituents. Autophagy was confirmed by acridine orange staining of vesicle formation, electron microscopy and increased expression of LC3-II. Combretastatin-induced autophagy was associated with a loss of mitochondrial membrane potential and elongation of the mitochondria. Furthermore, inhibition of autophagy by the vacuolar H(+)ATPase inhibitor Bafilomycin-A1 (BAF-A1) significantly enhanced CA-432 induced HT-29 cell death. Both CA-4 and its synthetic derivative. CA-432 induced the formation of large hyperdiploid cells in Caco-2 and CT-26 cells. The formation of these polyploid cells was significantly inhibited by autophagy inhibitor, BAF-A1. Results presented within demonstrate that autophagy is a novel response to combretastatin exposure and may be manipulated to enhance the therapeutic efficacy of this class of vascular targeting agents. (c) 2012 Elsevier Inc. All rights reserved.	[Greene, Lisa M.; Nolan, Derek P.; Zisterer, Daniela M.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin 2, Ireland; [O'Boyle, Niamh M.; Meegan, Mary J.] Trinity Coll Dublin, Sch Pharm & Pharmaceut Sci, Dublin 2, Ireland		Greene, LM (corresponding author), Trinity Coll Dublin, Sch Biochem & Immunol, Dublin 2, Ireland.	greeneli@tcd.ie		O'Boyle, Niamh/0000-0001-5660-4944; Nolan, Derek/0000-0002-3742-4304; Zisterer, Daniela/0000-0001-5005-1023	Health Research Board Ireland	We would like to thank Health Research Board Ireland for funding the project. Sincere thanks to the following: Dr. Gavin Mc Manus (confocal microscope), Barry Moran (Flow cytometry) and Neal Leddy (EM), School of Biochemistry and Immunology, TCD.	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Pharmacol.	SEP 1	2012	84	5					612	624		10.1016/j.bcp.2012.06.005			13	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	987RS	WOS:000307435700004	22705646				2022-04-25	
J	Dziedzic, K; Gorecka, D; Szwengiel, A; Olejnik, A; Rychlik, J; Kreft, I; Drozdzytnska, A; Walkowiak, J				Dziedzic, Krzysztof; Gorecka, Danuta; Szwengiel, Artur; Olejnik, Anna; Rychlik, Joanna; Kreft, Ivan; Drozdzytnska, Agnieszka; Walkowiak, Jaroslaw			The cytotoxic effect of artificially digested buckwheat products on HT-29 colon cancer cells	JOURNAL OF CEREAL SCIENCE			English	Article						Polyphenolic substances; Thiamine; Amino acids; Processing	ANTIOXIDANT ACTIVITY; IN-VIVO; QUERCETIN; GROWTH; FLAVONOIDS; APOPTOSIS; AUTOPHAGY; EXTRACTS; SURVIVAL; PATHWAY	Recently Europeans are showing a growing interest in healthy foods. In light of this fact, the aim of our study was to evaluate the effect of buckwheat products (groats, hull, and bran) after in vitro digestion in an artificial gastrointestinal tract on the inhibition of HT-29 cancer cell proliferation. We investigated the content of individual flavonoids, phenolic acids, amino acids, and thiamine in these buckwheat products. The MTT (thiazolyl blue tetrazolium bromide) assay was used to evaluate the viability and metabolic activity of the colon cancer cells. We found significant (p < 0.05) negative correlations between HT-29 cell growth and the levels of catechin, quercetin, serine, proline, glycine, histidine and arginine in buckwheat samples after digestion. Our results highlight that buckwheat by-products are a rich source of bioactive substances such as: quercetin, catechin, serine, proline, glycine, histidine, and arginine. Therefore, buckwheat can be used as an additive in pro health foods.	[Dziedzic, Krzysztof; Szwengiel, Artur] Poznan Univ Life Sci, Inst Food Technol & Plant Origin, Wojska Polskiego 31, PL-60624 Poznan, Poland; [Dziedzic, Krzysztof; Walkowiak, Jaroslaw] Poznan Univ Med Sci, Dept Pediat Gastroenterol & Metab Dis, Szpitalna 27-33, PL-60572 Poznan, Poland; [Gorecka, Danuta] Poznan Univ Life Sci, Dept Gastron Sci & Funct Foods, Wojska Polskiego 31, PL-60624 Poznan, Poland; [Olejnik, Anna; Rychlik, Joanna; Drozdzytnska, Agnieszka] Poznan Univ Life Sci, Dept Biotechnol & Food Microbiol, Wojska Polskiego 48, PL-60627 Poznan, Poland; [Kreft, Ivan] Slovenian Forestry Inst, Dept Forest Physiol & Genet, Vecna Pot 2, Ljubljana 1000, Slovenia		Dziedzic, K (corresponding author), Poznan Univ Life Sci, Inst Food Technol & Plant Origin, Wojska Polskiego 31, PL-60624 Poznan, Poland.	dziedzic@up.poznan.pl	Drożdżyńska, Agnieszka/AAD-4573-2019; Szwengiel, Artur/V-6832-2018	Drożdżyńska, Agnieszka/0000-0002-4580-354X; Gorecka, Danuta/0000-0001-8897-7438; Szwengiel, Artur/0000-0003-4570-7221; Olejnik, Anna/0000-0002-4385-0051; Dziedzic, Krzysztof/0000-0003-1282-7446	POIG grant "New bioactive food with designed functional properties" [POIG 01.01.02-00-061/09]	This research was supported by POIG grant "New bioactive food with designed functional properties" POIG 01.01.02-00-061/09.	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Cereal Sci.	SEP	2018	83						68	73		10.1016/j.jcs.2018.07.020			6	Food Science & Technology	Science Citation Index Expanded (SCI-EXPANDED)	Food Science & Technology	GY3ZB	WOS:000448494900010					2022-04-25	
J	Chen, L; Huang, S; Li, CY; Gao, F; Zhou, XL				Chen, Lin; Huang, Shuai; Li, Chun Ying; Gao, Feng; Zhou, Xian Li			Pyrrolizidine alkaloids from Liparis nervosa with antitumor activity by modulation of autophagy and apoptosis	PHYTOCHEMISTRY			English	Article						Liparis nervosa; Orchidaceae; Pyrrolizidine alkaloids; Cytotoxicity; Human colorectal cancer cell line; Autophagy; Apoptosis	NERVOGENIC ACID-DERIVATIVES; ATRACTYLODES-LANCEA	Seven pyrrolizidine alkaloids, nervosine X-XV and nervosine VII N-oxide, together with a reaction product, namely chloride-(N-chloromethyl nervosine VII), were isolated from Liparis nervosa. Their structures were elucidated by extensive spectroscopic analyses. Most of these compounds were investigated for their cytotoxicity in vitro against HCT116 human cancer cell line, and the results showed that chloride-(N-chloromethyl nervosine VII) induced tumor cell death in a dose-dependent mariner. Furthermore, the mechanisms underlying its cytotoxicity were investigated, including apoptosis and autophagy. Apoptosis in HCT116 cells was associated with up-regulation of caspase-3 and -9 expressions by activation of the mitochondrial pathway. The autophagy inducing effect was associated with the regulation of autophagic markers, including LC3-II, p62, and Beclin 1. Mechanistic studies showed that JNK, ERK1/2, and p38 MAPKs signaling cascades play an important role in chloride-(N-chloromethyl nervosine VII) induced autophagy and apoptosis.	[Chen, Lin; Huang, Shuai; Gao, Feng; Zhou, Xian Li] Southwest Jiaotong Univ, Sch Life Sci & Engn, Chengdu 610031, Sichuan, Peoples R China; [Chen, Lin] China West Normal Univ, Sch Chem & Chem Engn, Nanchong 637002, Sichuan, Peoples R China; [Huang, Shuai; Li, Chun Ying] Georgia State Univ, Inst Biomed Sci, Ctr Mol & Translat Med, 511 Res Sci Ctr,157 Decatur St SE, Atlanta, GA 30303 USA		Gao, F; Zhou, XL (corresponding author), Southwest Jiaotong Univ, Sch Life Sci & Engn, Nat Prod Lab, Chengdu 610031, Sichuan, Peoples R China.	gaof@swjtu.edu.cn; zhouxl@swjtu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81402803]; project of Science and Technology Bureau of Chengdu [2015-HM01-00041-SF]; United States of America National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HL128647]; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL128647] Funding Source: NIH RePORTER	This research was supported by grants from National Natural Science Foundation of China (81402803), the project of Science and Technology Bureau of Chengdu (2015-HM01-00041-SF) and the United States of America National Institutes of Health (R01 HL128647 to Chunying Li). We thank Xiaoqing Gan, Yuning Hou, Xiaonan Sun and Yu Zhou for technical assistance.	Arnone A, 2009, TETRAHEDRON, V65, P786, DOI 10.1016/j.tet.2008.11.058; Beniddir MA, 2013, TETRAHEDRON LETT, V54, P2115, DOI 10.1016/j.tetlet.2013.01.052; BOWMAN WR, 1994, TETRAHEDRON, V50, P1295, DOI 10.1016/S0040-4020(01)80838-3; BUSH LP, 1993, AGR ECOSYST ENVIRON, V44, P81, DOI 10.1016/0167-8809(93)90040-V; Castells E, 2014, PHYTOCHEMISTRY, V108, P137, DOI 10.1016/j.phytochem.2014.09.006; Duan JA, 2008, ARCH PHARM RES, V31, P965, DOI 10.1007/s12272-001-1252-z; Editorial Committee of the Flora of China of Chinese Academy of Science, 1999, FLORA CHINA, V18, P71; Flores N, 2008, J NAT PROD, V71, P1538, DOI 10.1021/np800104p; Friedrich U, 2005, PHARMAZIE, V60, P455; Green DR, 2014, CELL, V157, P65, DOI 10.1016/j.cell.2014.02.049; Hartmann T, 1999, PLANTA, V207, P483, DOI 10.1007/s004250050508; Hua Y. 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J	Chen, MX; Zhao, ZY; Meng, QC; Liang, PP; Su, ZX; Wu, YX; Huang, JJ; Cui, J				Chen, Meixin; Zhao, Zhiyao; Meng, Qingcai; Liang, Puping; Su, Zexiong; Wu, Yaoxing; Huang, Junjiu; Cui, Jun			TRIM14 Promotes Noncanonical NF-kappa B Activation by Modulating p100/p52 Stability via Selective Autophagy	ADVANCED SCIENCE			English	Article						inflammation; noncanonical NF-kappa B signaling; p100; p52; selective autophagy; TRIM14	RIG-I; KINASE; DEGRADATION; PATHWAY; UBIQUITINATION; PROTEIN; MACROAUTOPHAGY; INFLAMMATION; COMPLEX; ALPHA	The noncanonical NF-kappa B signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-kappa B signaling largely relies on the abundance as well as the processing of the NF-kappa B family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-kappa B signaling pathway. TRIM14 promotes noncanonical NF-kappa B activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-kappa B-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-kappa B signaling and highlight the crosstalk between autophagy and innate immunity.	[Chen, Meixin; Zhao, Zhiyao; Meng, Qingcai; Liang, Puping; Su, Zexiong; Wu, Yaoxing; Huang, Junjiu; Cui, Jun] Sun Yat Sen Univ, Sch Life Sci, MOE Key Lab Gene Funct & Regulat, State Key Lab Oncol South China, Guangzhou 510006, Guangdong, Peoples R China; [Zhao, Zhiyao] Guangzhou Women & Childrens Med Ctr, Guangzhou Inst Pediat, Dept Internal Med, Guangzhou 510623, Guangdong, Peoples R China		Cui, J (corresponding author), Sun Yat Sen Univ, Sch Life Sci, MOE Key Lab Gene Funct & Regulat, State Key Lab Oncol South China, Guangzhou 510006, Guangdong, Peoples R China.	cuij5@mail.sysu.edu.cn	chen, meixin/AAT-4971-2020	CUI, JUN/0000-0002-8000-3708	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31870862, 91629101]; National Key Basic Research Program of ChinaNational Basic Research Program of China [2015CB859800, 2014CB910800]; Science and Technology Planning Project of Guangzhou, China [201804010385]	The authors thank Dr. Ryan G. Gaudet (Yale University) for polishing the article. This work was supported by National Natural Science Foundation of China (31870862, 91629101), National Key Basic Research Program of China (2015CB859800, 2014CB910800), and Science and Technology Planning Project of Guangzhou, China (201804010385).	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Sci.	JAN	2020	7	1							1901261	10.1002/advs.201901261		NOV 2019	11	Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Chemistry; Science & Technology - Other Topics; Materials Science	KB3PC	WOS:000495463400001	31921549	Green Published, gold			2022-04-25	
J	Zhou, PT; Li, YY; Li, B; Zhang, MC; Xu, C; Liu, FR; Bian, L; Liu, YH; Yao, Y; Li, D				Zhou, Pingting; Li, Yanyan; Li, Bo; Zhang, Meichao; Xu, Ci; Liu, Furao; Bian, Lei; Liu, Yuanhua; Yao, Yuan; Li, Dong			Autophagy inhibition enhances celecoxib-induced apoptosis in osteosarcoma	CELL CYCLE			English	Article						Celecoxib; apoptosis; autophagy; osteosarcoma	BREAST-CANCER CELLS; COLON-CANCER; PROSTATE-CANCER; CHEMOTHERAPY; DEATH; CARCINOMA; THERAPY; PATHWAY; PROTEIN; TARGET	Osteosarcoma (OS) is the most prevalent bone malignancy in childhood and adolescence, with highly aggressive and early systemic metastases. Here, we reported that celecoxib, a selective COX-2 inhibitor in the NSAID class, exhibits strong antitumor activity in dose dependent manner in two OS cell lines-143B and U2OS. We showed that celecoxib inhibits OS cell growth, causes G0/G1-phase arrest, modulates apoptosis and autophagy and reduces migration in OS cells. In addition, the results of fluorescent mitochondrial probe JC-1 test indicated that the mitochondrial pathway mediates celecoxib-induced apoptosis. Significantly, the autophagy inhibitor CQ combined with celecoxib causes greater cell proliferation inhibition and apoptosis. Pharmacologic inhibition of autophagy with another potent autophagy inhibitor SAR405 also enhances celecoxib-mediated suppression of cell viability. These results were confirmed with shRNAs targeting the autophagy-related gene Atg5. In OS tumor xenografts in vivo, celecoxib also presents antitumor activity. Taken together, our results shed light on the function and mechanism of antitumor action of celecoxib for treatment of OS patients.	[Zhou, Pingting; Li, Yanyan; Zhang, Meichao; Xu, Ci; Liu, Furao; Bian, Lei; Yao, Yuan; Li, Dong] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Dept Radiat Oncol, Shanghai, Peoples R China; [Li, Bo] Second Mil Med Univ, Changzheng Hosp, Dept Orthoped Oncol, Shanghai, Peoples R China; [Liu, Yuanhua] Nanjing Med Univ, Affiliated Canc Hosp, Canc Inst Jiangsu Prov, Dept Chemotherapy, Nanjing, Jiangsu, Peoples R China		Yao, Y; Li, D (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Dept Radiat Oncol, Shanghai, Peoples R China.	yaoyuan@shsmu.edu.cn; lidong@shsmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81370600]; Innovation Program for Ph.D. students in Shanghai Jiaotong University School of Medicine [BXJ201731]; Innovation Program of Shanghai Municipal Education CommissionInnovation Program of Shanghai Municipal Education Commission [15ZZ056]; Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2015022]; Shanghai Pujiang ProgramShanghai Pujiang Program [15PJ1404800]	This work was supported by the National Natural Science Foundation of China [81370600]; Innovation Program for Ph.D. students in Shanghai Jiaotong University School of Medicine [BXJ201731]; Innovation Program of Shanghai Municipal Education Commission [15ZZ056]; The Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2015022]; Shanghai Pujiang Program [15PJ1404800].	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J	Huang, Y; Li, S; Jia, ZH; Zhao, WW; Zhou, CF; Zhang, R; Ali, DW; Michalak, M; Chen, XZ; Tang, JF				Huang, Yuan; Li, Shi; Jia, Zhenhua; Zhao, Weiwei; Zhou, Cefan; Zhang, Rui; Ali, Declan William; Michalak, Marek; Chen, Xing-Zhen; Tang, Jingfeng			Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy	FRONTIERS IN ONCOLOGY			English	Article						autophagy; LC3B; transient receptor potential melastatin 8 (TRPM8); AMP-activated protein kinase(AMPK); cancer	CA2+; INVOLVEMENT; RESISTANCE	The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8-AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression.	[Huang, Yuan; Li, Shi; Jia, Zhenhua; Zhao, Weiwei; Zhou, Cefan; Zhang, Rui; Tang, Jingfeng] Hubei Univ Technol, Minist Educ, Key Lab Fermentat Engn, Natl Ctr Cellular Regulat & Mol Pharmaceut 111, Wuhan, Peoples R China; [Ali, Declan William; Chen, Xing-Zhen] Fac Med & Dent Alberta, Dept Physiol, Membrane Prot Dis Res Grp, Edmonton, AB, Canada; [Michalak, Marek] Univ Alberta, Dept Biochem, Edmonton, AB, Canada		Tang, JF (corresponding author), Hubei Univ Technol, Minist Educ, Key Lab Fermentat Engn, Natl Ctr Cellular Regulat & Mol Pharmaceut 111, Wuhan, Peoples R China.	Jingfeng_HUT@163.com		Zhou, Cefan/0000-0003-0680-3843; Tang, jingfeng/0000-0002-5524-4518	China National Science FoundationNational Natural Science Foundation of China (NSFC) [31871420, 31701228]; Hubei Province Science Foundation [2019CFB166]; Wuhan Science and Technology Project [2019020701011475]; Doctoral Scientific Research Foundation of Hubei University of Technology [BSQD2017032]	This study was supported by the China National Science Foundation (grants 31871420 to JT and 31701228 to CZ), the Hubei Province Science Foundation (grant 2019CFB166 to YH), the Wuhan Science and Technology Project (2019020701011475 to JT) and the Doctoral Scientific Research Foundation of Hubei University of Technology (grants BSQD2017032 to YH).	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Oncol.	DEC 4	2020	10								573127	10.3389/fonc.2020.573127			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	PG2NS	WOS:000599578000001	33344232	Green Published, gold			2022-04-25	
J	Huber, S; Valente, S; Chaimbault, P; Schohn, H				Huber, Sophie; Valente, Sergio; Chaimbault, Patrick; Schohn, Herve			Evaluation of Delta 2-pioglitazone, an analogue of pioglitazone, on colon cancer cell survival: Evidence of drug treatment association with autophagy and activation of the Nrf2/Keap1 pathway	INTERNATIONAL JOURNAL OF ONCOLOGY			English	Article						Delta 2-pioglitazone; pioglitazone; 15-deoxy-Delta(12,14)-prostaglandin J(2); oxidative stress; Nrf2/Keapl pathway; colon cancer	RECEPTOR-GAMMA; PPAR-GAMMA; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); HEME OXYGENASE-1; MITOCHONDRIAL-FUNCTION; LIQUID-CHROMATOGRAPHY; GLUTATHIONE; APOPTOSIS; INHIBITION; PROSTAGLANDIN	Thiazolidinediones have been shown to exhibit anti-proliferative effects against cancer cells derived from diverse tissue origins both in vivo and in vitro. We studied the anti-proliferative impact of 5-{4-(2-(5-ethyl-pyridin-2-yl)-ethoxy)benzylidene}-thiazolidine-2,4-dione (Delta 2-pioglitazone), an analogue of pioglitazone, which binds to the nuclear peroxisome proliferator activated receptor-gamma without activating it, on human adenocarcinoma-derived HT29 and HCT116 cells. In HTC116 cells, exposure to Delta 2-pioglitazone reduced cell growth, but HT29 cells reached the plateau phase of growth after three days. Delta 2-pioglitazone treatment did not trigger cells to enter apoptosis but enhanced the autophagy process. The effect of Delta 2-pioglitazone treatment was related to the increase of oxygen and nitric oxide-derived species production and decreased glutathione content. Moreover, pre-treatment with an antioxidant before addition of Delta 2-pioglitazone limited cell growth inhibition, reduced the production of reactive species and attenuated autophagy within the cells. The impact of the drug was associated with activation of the Nrf2/Keapl pathway as demonstrated by the increased protein content of several antioxidant enzymes, notably heme-oxygenase-1.	[Huber, Sophie; Valente, Sergio; Schohn, Herve] Univ Lorraine, CNRS, U7565, F-57070 Metz, France; [Chaimbault, Patrick] Univ Lorraine, Chem & Phys Lab, A2MC, EA 4632, F-57078 Metz 3, France		Schohn, H (corresponding author), Univ Lorraine, CNRS, U7565, SRSMC Campus Bridoux,Rue Gen Delestraint, F-57070 Metz, France.	herve.schohn@univ-lorraine.fr	Valente, Sergio/K-2198-2016	Valente, Sergio/0000-0002-2241-607X; CHAIMBAULT, Patrick/0000-0001-7588-8751	la Ligue Contre le CancerLigue nationale contre le cancer; Ministere de la Recherche et de la Technologie; Marie Curie Initial Training Network (ITN) in the FP7 People Programme - Natural Products and related Redox Catalysts: Basic Research and Applications in Medicine and Agriculture	We thank Dr Eric Battaglia and Professor Denyse Bagrel for discussion and reading of the manuscript and Professor S.N. Thornton for correcting the English. This study was supported by grants from la Ligue Contre le Cancer. Sophie Huber obtained financial support from Ministere de la Recherche et de la Technologie. Sergio Valente was granted from Marie Curie Initial Training Network (ITN) in the FP7 People Programme - Natural Products and related Redox Catalysts: Basic Research and Applications in Medicine and Agriculture.	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J. Oncol.	JUL	2014	45	1					426	438		10.3892/ijo.2014.2408			13	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	AI5BY	WOS:000336881600046	24788124	Bronze			2022-04-25	
J	Asp, ML; Tian, M; Wendel, AA; Belury, MA				Asp, Michelle L.; Tian, Min; Wendel, Angela A.; Belury, Martha A.			Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice	INTERNATIONAL JOURNAL OF CANCER			English	Article						colon-26 adenocarcinoma; rosiglitazone; muscle atrophy	EXPERIMENTAL CANCER CACHEXIA; WEIGHT-LOSS; MUSCLE; GLUCOSE; PROTEIN; METABOLISM; EXPRESSION; MORTALITY; ATROGIN-1; SURVIVAL	Cancer cachexia is a syndrome of unintentional weight loss that is characterized by wasting of both skeletal muscle and adipose tissue. Glucose intolerance and insulin resistance have been associated with cancer cachexia. However, it is unknown whether resistance to insulin has a role in the development of cachexia. In the present study, mate CD2F1 mice with colon-26 adenocarcinoma tumors underwent an insulin tolerance test before the onset of weight loss. Compared to mice without tumors, mice with tumors had a profoundly blunted blood glucose response to insulin. Corroborating these findings, mice with tumors had decreased phosphorylation of Akt in quadriceps muscle and epididymal adipose tissue at the end of the study. Expression of Akt-regulated genes Atrogin-1, MuRF-1, and Bnip3 was increased in muscle, suggesting a role for decreased insulin signaling in the induction of both proteasomal proteolysis and autophagy in cachectic muscle. Rosiglitazone treatment increased serum adiponectin, insulin sensitivity, and body weight, and decreased Atrogin-1 and MuRF-1 expression in the skeletal muscle of tumor-bearing mice. In conclusion, insulin resistance is an early event in mice with cachexia induced by colon-26 tumors. Rosiglitazone improves insulin sensitivity and decreases early markers of cachexia. These data provide evidence that insulin resistance is not only present in cachexia, but also has a role in cachexia pathogenesis. Correction of insulin resistance may be a novel therapeutic target for the treatment of cancer cachexia.	[Asp, Michelle L.; Tian, Min; Wendel, Angela A.; Belury, Martha A.] Ohio State Univ, Dept Human Nutr, Coll Educ & Human Ecol, Columbus, OH 43210 USA		Asp, ML (corresponding author), Ohio State Univ, Dept Human Nutr, Coll Educ & Human Ecol, Columbus, OH 43210 USA.						Acharyya S, 2005, CANCER CELL, V8, P421, DOI 10.1016/j.ccr.2005.10.004; Acharyya S, 2004, J CLIN INVEST, V114, P370, DOI 10.1172/jci200420174; Argiles JM, 2004, CURR DRUG TARGETS, V5, P265, DOI 10.2174/1389450043490505; BECK SA, 1989, BRIT J CANCER, V59, P677, DOI 10.1038/bjc.1989.140; CERSOSIMO E, 1991, SURGERY, V109, P459; DEWYS WD, 1980, AM J MED, V69, P491, DOI 10.1016/S0149-2918(05)80001-3; Dodesini AR, 2007, ACTA ONCOL, V46, P118, DOI 10.1080/02841860600791491; Fearon KC, 2006, AM J CLIN NUTR, V83, P1345, DOI 10.1093/ajcn/83.6.1345; Gomes MD, 2001, P NATL ACAD SCI USA, V98, P14440, DOI 10.1073/pnas.251541198; Goodwin PJ, 2002, J CLIN ONCOL, V20, P42, DOI 10.1200/JCO.20.1.42; Guerre-Millo M, 2008, DIABETES METAB, V34, P12, DOI 10.1016/j.diabet.2007.08.002; Kim KY, 2007, MOL PHARMACOL, V71, P1554, DOI 10.1124/mol.106.031948; Lazarus DD, 1996, CANCER LETT, V103, P71, DOI 10.1016/0304-3835(96)04197-3; Lehrke M, 2005, CELL, V123, P993, DOI 10.1016/j.cell.2005.11.026; Livak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262; Ma J, 2008, LANCET ONCOL, V9, P1039, DOI 10.1016/S1470-2045(08)70235-3; Mammucari C, 2007, CELL METAB, V6, P458, DOI 10.1016/j.cmet.2007.11.001; MOLEY JF, 1988, CANCER RES, V48, P2784; MOLEY JF, 1987, J SURG RES, V43, P21, DOI 10.1016/0022-4804(87)90042-4; MOLEY JF, 1985, CANCER RES, V45, P4925; Musi N, 2006, ENDOCRINE, V29, P73, DOI 10.1385/ENDO:29:1:73; Patel L, 2001, CURR BIOL, V11, P764, DOI 10.1016/S0960-9822(01)00225-1; PEACOCK JL, 1988, JPEN-PARENTER ENTER, V12, P260, DOI 10.1177/0148607188012003260; Proud CG, 2006, BIOCHEM SOC T, V34, P213, DOI 10.1042/BST0340213; Rohdenburg GL, 1919, J AMER MED ASSOC, V72, P1528, DOI 10.1001/jama.1919.02610210024007; Ryall JG, 2008, PHARMACOL THERAPEUT, V120, P219, DOI 10.1016/j.pharmthera.2008.06.003; Sandri M, 2004, CELL, V117, P399, DOI 10.1016/S0092-8674(04)00400-3; Stitt TN, 2004, MOL CELL, V14, P395, DOI 10.1016/S1097-2765(04)00211-4; TANAKA Y, 1990, CANCER RES, V50, P2290; TAYEK JA, 1992, J AM COLL NUTR, V11, P445; Vona-Davis L, 2007, OBES REV, V8, P395, DOI 10.1111/j.1467-789X.2007.00396.x; Warren S, 1932, AM J MED SCI, V184, P610, DOI 10.1097/00000441-193211000-00002; Wendel AA, 2008, J LIPID RES, V49, P98, DOI 10.1194/jlr.M700195-JLR200; WOLEVER TMS, 1991, AM J CLIN NUTR, V54, P846, DOI 10.1093/ajcn/54.5.846	34	110	113	2	10	WILEY	HOBOKEN	111 RIVER ST, HOBOKEN 07030-5774, NJ USA	0020-7136	1097-0215		INT J CANCER	Int. J. Cancer	FEB 1	2010	126	3					756	763		10.1002/ijc.24784			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	542SN	WOS:000273515500017	19634137				2022-04-25	
J	You, PT; Wu, HZ; Deng, M; Peng, JL; Li, FP; Yang, YF				You, Pengtao; Wu, Hezhen; Deng, Meng; Peng, Jingling; Li, Fangping; Yang, Yanfang			Brevilin A induces apoptosis and autophagy of colon adenocarcinoma cell CT26 via mitochondrial pathway and PI3K/AKT/mTOR inactivation	BIOMEDICINE & PHARMACOTHERAPY			English	Article						Brevilin A; Apoptosis; Autophagy; CT26; Mechanism	CENTIPEDA-MINIMA; MAMMALIAN AUTOPHAGY; MEDIATED CLEAVAGE; CANCER-CELLS; 6-O-ANGELOYLENOLIN; CONSTITUENTS; CROSSTALK	Brevilin A is a sesquiterpene lactone isolated from Centipeda minima and possesses inhibitory effects on proliferation of various tumor cells. In this study, Brevilin A inhibitory effect on proliferation and its molecular mechanism of action were investigated both in vivo and in vitro in colon adenocarcinoma CT26 cells. The results indicated that the inhibitory effect of Brevilin A in CT26 proliferation was dose-dependent and this effect was due to apoptosis. Furthermore, Brevilin A increased ROS levels, decreased mitochondrial membrane potential (MMP) and induced apoptosis of CT26 cell in a dose-dependent manner. Apoptosis induced by Brevilin A was higher than that induced by adriamycin under the same dose. Cleaved-caspase-8, cleaved-caspase-9 and cleaved-caspase-3 were up-regulated after Brevilin A treatment, together with an increase of Bax protein expression, while Bcl-2 was reduced. Further investigation revealed that Brevilin A inhibited the phosphorylation of PI3K, AKT and mTOR and promoted the expressions of autophagy-related proteins LC3-II, Beclin1 and Atg5 and consequent formation of autophagosomes, whereas 3-methyladenine (3-MA), a type III PI3K inhibitor, inhibited autophagosomes formation induced by Brevilin A. In vivo investigation suggested that Brevilin A significantly inhibited the growth of CT26 tumor compared to adriamycin and concurrently promoted the expressions of LC3-II and cleaved-caspase-3 in tumor tissues. Our results demonstrated that the anti-tumor activity of Brevilin A was mainly achieved by the induction of cell apoptosis and autophagy, suggesting a promising potential as antitumor drug against colon adenocarcinoma.	[You, Pengtao; Deng, Meng; Peng, Jingling; Li, Fangping; Yang, Yanfang] Hubei Univ Chinese Med, Key Lab Resources & Chem Chinese Med, 1 HuangJia Hu Rd West, Wuhan 430065, Hubei, Peoples R China; [Wu, Hezhen] Hubei Univ Chinese Med, Sch Pharm, Wuhan 430065, Hubei, Peoples R China; [Yang, Yanfang] Hubei Univ Chinese Med, Collaborat Innovat Ctr Tradit Chinese Med New Pro, Wuhan 430065, Hubei, Peoples R China		Yang, YF (corresponding author), Hubei Univ Chinese Med, Key Lab Resources & Chem Chinese Med, 1 HuangJia Hu Rd West, Wuhan 430065, Hubei, Peoples R China.	yyf0204@hbtcm.edu.cn		Wu, Hezhen/0000-0003-3284-8703	scientific research program of Hubei Provincial Department of Education, P.R. China [Q20162006]	This study was supported by the scientific research program of Hubei Provincial Department of Education (Q20162006), P.R. China.	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Pharmacother.	FEB	2018	98						619	625		10.1016/j.biopha.2017.12.057			7	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	FX5FR	WOS:000426104000076	29289836				2022-04-25	
J	Xue, Q; Wang, XB; Wang, P; Zhang, K; Liu, QH				Xue, Qin; Wang, Xiaobing; Wang, Pan; Zhang, Kun; Liu, Quanhong			Role of p38MAPK in apoptosis and autophagy responses to photodynamic therapy with Chlorin e6	PHOTODIAGNOSIS AND PHOTODYNAMIC THERAPY			English	Article						PDT; Ce6; p38MAPK; Autophagy; Apoptosis	CELL-DEATH; MAP KINASE; CANCER-THERAPY; CYTOCHROME-C; ACTIVATION; PATHWAY; TUMORIGENESIS; GENERATION; HYPERICIN; LINES	Background: Photodynamic therapy (PDT) has been undergoing clinical evaluation for the treatment of colorectal cancer. But the molecular mechanism of photodynamic injury in human colorectal cancer cells still remains unclear. Methods: Chlorin e6 (Ce6) was used to photosensitize SW620 cells. The inhibitory effect of PDT was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium bromide tetrazolium) assay and colony forming assay. Apoptosis was determined by nuclear DAPI (4'-6-diamidino-2-phenylindole) staining and Annexin V-PE/7-AAD assay. Monodansylcadaverine (MDC) staining was used to evaluate the abundance of autophagic vacuoles in PDT treated cells. The apoptosis and autophagy associated proteins were analyzed by western blotting. Moreover, we applied siRNA p38MAPK and p38MAPK inhibitor SB203580 to dissect its effect on cellular response to PDT in SW620 cells. Results: Ce6 mediated PDT (Ce6-PDT) induced apparent autophagy and apoptosis with dependent on ROS (reactive oxygen species) generation. When p38MAPK was inhibited by siRNA or inhibitor SB203580, a marked enhancement of apoptosis and autophagy in SW620 cells was detected after PDT. Moreover, autophagy inhibitor 3-methyladenine/Bafilomycin A1 greatly aggravated PDT induced photodamage in SW620 cells. Conclusion: Ce6-PDT induced ROS production to activate p38MAPK probably to prevent SW620 cells from photodamage. Inhibition of p38MAPK activation accelerated cell apoptosis, meanwhile enhanced autophagy may act as a cytoprotective process in SW620 cells. (C) 2014 Elsevier B.V. All rights reserved.	[Xue, Qin; Wang, Xiaobing; Wang, Pan; Zhang, Kun; Liu, Quanhong] Shaanxi Normal Univ, Key Lab Med Resources & Nat Pharmaceut Chem, Natl Engn Lab Resource Developing Endangered Chin, Minist Educ,Coll Life Sci, Xian 710062, Shaanxi, Peoples R China; [Xue, Qin] Fourth Mil Med Univ, Dept Urol, Xijing Hosp, Xian 710032, Peoples R China		Wang, XB (corresponding author), Shaanxi Normal Univ, Key Lab Med Resources & Nat Pharmaceut Chem, Natl Engn Lab Resource Developing Endangered Chin, Minist Educ,Coll Life Sci, Xian 710062, Shaanxi, Peoples R China.	wangxiaobing@snnu.edu.cn; lshaof@srmu.edu.cn			National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81472846]	This work was supported by National Natural Science Foundation of China (No. 81472846).	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Ther.	MAR	2015	12	1					84	91		10.1016/j.pdpdt.2014.12.001			8	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	CD6IR	WOS:000351193300011	25528442				2022-04-25	
J	Li, YY; Guo, F; Guan, YY; Chen, TG; Ma, KQ; Zhang, LW; Wang, ZH; Su, Q; Feng, LH; Liu, YM; Zhou, YZ				Li, Yuying; Guo, Fang; Guan, Yingying; Chen, Tinggui; Ma, Kaiqing; Zhang, Liwei; Wang, Zhuanhua; Su, Qiang; Feng, Liheng; Liu, Yaoming; Zhou, Yuzhi			Novel Anthraquinone Compounds Inhibit Colon Cancer Cell Proliferation via the Reactive Oxygen Species/JNK Pathway	MOLECULES			English	Article						anthraquinone derivatives; apoptosis; 3D-QSAR; ROS-JNK; HCT116	POTENTIAL ANTICANCER; IN-VITRO; APOPTOSIS; AUTOPHAGY; MITOXANTRONE; DYSFUNCTION; BORTEZOMIB; ARREST; DEATH; ACID	A series of amide anthraquinone derivatives, an important component of some traditional Chinese medicines, were structurally modified and the resulting antitumor activities were evaluated. The compounds showed potent anti-proliferative activities against eight human cancer cell lines, with no noticeable cytotoxicity towards normal cells. Among the candidate compounds, 1-nitro-2-acyl anthraquinone-leucine (8a) showed the greatest inhibition of HCT116 cell activity with an IC50 of 17.80 mu g/mL. In addition, a correlation model was established in a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using Comparative Molecular Field Analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). Moreover, compound 8a effectively killed tumor cells by reactive oxygen species (ROS)-JNK activation, causing an increase in ROS levels, JNK phosphorylation, and mitochondrial stress. Cytochrome c was then released into cytoplasm, which, in turn activated the cysteine protease pathway and ultimately induced tumor cell apoptosis, suggesting a potential use of this compound for colon cancer treatment.	[Li, Yuying; Guo, Fang; Guan, Yingying; Chen, Tinggui; Ma, Kaiqing; Zhang, Liwei; Wang, Zhuanhua; Su, Qiang; Feng, Liheng; Liu, Yaoming; Zhou, Yuzhi] Shanxi Univ, Inst Biotechnol, Key Lab Chem Biol & Mol Engn, Minist Educ, Taiyuan 030006, Peoples R China		Li, YY (corresponding author), Shanxi Univ, Inst Biotechnol, Key Lab Chem Biol & Mol Engn, Minist Educ, Taiyuan 030006, Peoples R China.	lyy9030@sxu.edu.cn; 201723002004@email.sxu.edu.cn; yanning654@126.com; Chentg@sxu.edu.cn; makaiqing@sxu.edu.cn; lwzhang@sxu.edu.cn; zhwang@sxu.edu.cn; suqchem1984@163.com; lhfeng@sxu.edu.cn; liuym1022@sxu.edu.cn; zhouyuzhi@sxu.edu.cn		Chen, Tinggui/0000-0001-8455-1317; Zhang, liwei/0000-0002-9247-6334	Transformation of Scientific and Technological Achievements Programs of Higher Education Institutions in Shanxi (TSTAP), Key projects of Shanxi Province [201903D321095]; Research on Key Technologies of Modernization of Traditional Chinese Medicine in Shanxi Province Zhendong Special Foundation [2016ZD0502]	This work was supported by Transformation of Scientific and Technological Achievements Programs of Higher Education Institutions in Shanxi (TSTAP), Key projects of Shanxi Province (No. 201903D321095), and Research on Key Technologies of Modernization of Traditional Chinese Medicine in Shanxi Province Zhendong Special Foundation (No. 2016ZD0502). We thank Prof. Daxiong Han from Medical College Xiamen University for software support.	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J	Onodera, R; Motoyama, K; Okamatsu, A; Higashi, T; Kariya, R; Okada, S; Arima, H				Onodera, Risako; Motoyama, Keiichi; Okamatsu, Ayaka; Higashi, Taishi; Kariya, Ryusho; Okada, Seiji; Arima, Hidetoshi			Involvement of cholesterol depletion from lipid rafts in apoptosis induced by methyl-beta-cyclodextrin	INTERNATIONAL JOURNAL OF PHARMACEUTICS			English	Article						Apoptosis; Methyl-beta-cyclodextrin; Cholesterol; Antitumor agent	RED-BLOOD-CELLS; CANCER-CELLS; DEATH; BAD; CASPASES; PROTEINS; CAVEOLAE; CHANNEL; BCL-2	Methyl-beta-cyclodextrin (M-beta-CyD), which is widely used as a lipid rafts disrupting agent, is known to induce cytotoxicity at high concentration. In the present study, we investigated the potential of M-beta-CyD as an antitumor drug. M-beta-CyD markedly caused apoptotic cell-death in KB cells, a human oral squamous carcinoma cell line, Ihara cells, a highly pigmented human melanoma cell line, and M213 cells, a human cholangiocarcinoma cell line, through cholesterol depletion in cell membranes. The DNA content and mitochondrial transmembrane potential in KB cells were significantly decreased after treatment with M-beta-CyD. Additionally, M-beta-CyD elevated the caspase-3/7 activity in KB cells. Meanwhile, M-beta-CyD did not induce the formation of autophagic vacuoles in KB cells. M-beta-CyD drastically inhibited the tumor growth after intratumoral injection to Colon-26 cells-bearing mice. These results strongly suggest that M-beta-CyD induced apoptosis in tumor cells and had the potential a novel antitumor agent and/or its lead compound. Copyright (C) 2013 Elsevier B.V. All rights reserved.	[Onodera, Risako; Motoyama, Keiichi; Okamatsu, Ayaka; Higashi, Taishi; Arima, Hidetoshi] Kumamoto Univ, Grad Sch Pharmaceut Sci, Chuo Ku, Kumamoto 8620973, Japan; [Kariya, Ryusho; Okada, Seiji] Kumamoto Univ, Div Hematopoiesis, Ctr AIDS Res, Chuo Ku, Kumamoto 8600811, Japan		Arima, H (corresponding author), Kumamoto Univ, Dept Phys Pharmaceut, Grad Sch Pharmaceut Sci, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan.	arimah@gpo.kumamoto-u.ac.jp	Okada, Seiji/F-5785-2013		Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [22790040]; Ministry of Health Labor and WelfareMinistry of Health, Labour and Welfare, Japan [24100701]; Japan Science Society	This work was partially supported by a Grant-in-Aid for Young Scientists (B) from Japan Society for the Promotion of Science (22790040) and by a Grant-in-Aid for Third Term Comprehensive Control Research for Cancer from Ministry of Health Labor and Welfare (24100701). This work was supported by the Sasakawa Scientific Research Grant from The Japan Science Society.	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J	Wilfinger, N; Austin, S; Scheiber-Mojdekhar, B; Berger, W; Reipert, S; Praschberger, M; Paur, J; Trondl, R; Keppler, BK; Zielinski, CC; Nowikovsky, K				Wilfinger, Nastasia; Austin, Shane; Scheiber-Mojdekhar, Barbara; Berger, Walter; Reipert, Siegfried; Praschberger, Monika; Paur, Jakob; Trondl, Robert; Keppler, Bernhard K.; Zielinski, Christoph C.; Nowikovsky, Karin			Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L-induced mitophagy	ONCOTARGET			English	Article						cancer; p53; BNIP3L; mitophagy; gallium complex	CELL-DEATH; PERMEABILITY TRANSITION; MITOCHONDRIA; P53; APOPTOSIS; AUTOPHAGY; INDUCTION; GALLIUM; METABOLISM; STABILITY	This study identifies BNIP3L as the key regulator of p53-dependent cell death mechanism in colon cancer cells targeted by the novel gallium based anticancer drug, KP46. KP46 specifically accumulated into mitochondria where it caused p53-dependent morphological and functional damage impairing mitochondrial dynamics and bioenergetics. Furthermore, competing with iron for cellular uptake, KP46 lowered the intracellular labile iron pools and intracellular heme. Accordingly, p53 accumulated in the nucleus where it activated its transcriptional target BNIP3L, a BH3 only domain protein with functions in apoptosis and mitophagy. Upregulated BNIP3L sensitized the mitochondrial permeability transition and strongly induced PARKIN-mediated mitochondrial clearance and cellular vacuolization. Downregulation of BNIP3L entirely rescued cell viability caused by exposure of KP46 for 24 hours, confirming that early induced cell death was regulated by BNIP3L. Altogether, targeting BNIP3L in wild-type p53 colon cancer cells is a novel anticancer strategy activating iron depletion signaling and the mitophagy-related cell death pathway.	[Wilfinger, Nastasia; Austin, Shane; Berger, Walter; Paur, Jakob; Zielinski, Christoph C.; Nowikovsky, Karin] Med Univ Vienna, Dept Internal Med 1, Vienna, Austria; [Wilfinger, Nastasia; Austin, Shane; Berger, Walter; Paur, Jakob; Zielinski, Christoph C.; Nowikovsky, Karin] Med Univ Vienna, Comprehens Canc Ctr, Vienna, Austria; [Scheiber-Mojdekhar, Barbara; Praschberger, Monika] Med Univ Vienna, Dept Med Chem, Vienna, Austria; [Reipert, Siegfried] Med Univ Vienna, Cell Imaging & Ultrastruct Res, Vienna, Austria; [Trondl, Robert; Keppler, Bernhard K.] Univ Vienna, Inst Inorgan Chem, Vienna, Austria		Nowikovsky, K (corresponding author), Med Univ Vienna, Dept Internal Med 1, Vienna, Austria.; Nowikovsky, K (corresponding author), Med Univ Vienna, Comprehens Canc Ctr, Vienna, Austria.	karin.nowikovsky@meduniwien.ac.at	Austin, Shane/AAI-4896-2021	Austin, Shane/0000-0002-8698-6055; Reipert, Siegfried/0000-0002-2043-3562; Keppler, Bernhard/0000-0003-0877-1822; Berger, Walter/0000-0003-0014-1658; Scheiber-Mojdehkar, Barbara/0000-0002-4114-9413; Nowikovsky, Karin/0000-0001-8435-8410	Jubilaumsfonds der Oesterreichischen Nationalbank [OeNB-15423]; Initiative Krebsforschungsprogramm [IK-04024]; ASHO (Austrian Society of Hematology & Medical Oncology) fellowship	The project was supported by the grants OeNB-15423 (Jubilaumsfonds der Oesterreichischen Nationalbank) and IK-04024 (Initiative Krebsforschungsprogramm) to K. Nowikovsky. N. Wilfinger is a recipient of an ASHO (Austrian Society of Hematology & Medical Oncology) fellowship and S. Austin is a DOC fellow of the Austrian Academy of Sciences.	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J	Shan, YL; Gao, Y; Jin, W; Fan, MM; Wang, Y; Gu, YH; Shan, CX; Sun, LJ; Li, X; Yu, B; Luo, Q; Xu, Q				Shan, Yunlong; Gao, Yuan; Jin, Wei; Fan, Minmin; Wang, Ying; Gu, Yanhong; Shan, Chenxiao; Sun, Lijun; Li, Xin; Yu, Biao; Luo, Qiong; Xu, Qiang			Targeting HIBCH to reprogram valine metabolism for the treatment of colorectal cancer	CELL DEATH & DISEASE			English	Article							III COLON-CANCER; PROMOTES CELL-PROLIFERATION; AMINO-ACID-METABOLISM; BCAT1 PROMOTES; BEVACIZUMAB; OXALIPLATIN; CETUXIMAB; PROTEIN; MTOR; FLUOROURACIL	Valine catabolism is known to be essential for cancer cells but the detailed mechanism remains unclear. This study is to explore the critical roles of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in colorectal cancers (CRC) and to develop a new therapy returning valine metabolism homeostasis. High HIBCH expression was first confirmed to correlate with poor survival in patients with CRC, which was then linked to the increased cell growth, resistant apoptosis, and decreased autophagy in CRC cells. The functions of HIBCH in CRC were dependent on its mitochondrial localization. High HIBCH level was further demonstrated to promote the metabolism of tricarboxylic acid cycle as well as oxidative phosphorylation in CRC cells. Based on above findings, we further discovered a novel valine catabolism inhibitor SBF-1. The pharmacological blockade of HIBCH mitochondrial localization with SBF-1 resulted in decreased cancer cell growth and increased autophagy, collectively contributing to the antitumor effect both in vitro and in vivo. Moreover, anti-VEGF therapy with bevacizumab increased HIBCH level in CRC cells, which in turn caused the resistance to the therapy. The interference with HIBCH function by SBF-1 significantly increased the antitumor efficacy of bevacizumab and led to a robust survival benefit. The present study identified HIBCH as a critical enzyme of valine catabolism in CRC progression and resistance to anti-VEGF therapy. We also provided a novel HIBCH inhibitor SBF-1, which highlighted the combined therapy using valine catabolic inhibitor along with anti-VEGF drugs, to control progression of CRC.	[Shan, Yunlong; Gao, Yuan; Jin, Wei; Fan, Minmin; Li, Xin; Luo, Qiong; Xu, Qiang] Nanjing Univ, Nanjing Drum Tower Hosp, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China; [Shan, Yunlong; Gao, Yuan; Jin, Wei; Fan, Minmin; Li, Xin; Luo, Qiong; Xu, Qiang] Nanjing Univ, Sch Life Sci, Nanjing 210023, Jiangsu, Peoples R China; [Wang, Ying; Gu, Yanhong] Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, Nanjing 210029, Jiangsu, Peoples R China; [Shan, Chenxiao] Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Jiangsu, Peoples R China; [Sun, Lijun; Yu, Biao] Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China		Luo, Q; Xu, Q (corresponding author), Nanjing Univ, Nanjing Drum Tower Hosp, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China.; Luo, Q; Xu, Q (corresponding author), Nanjing Univ, Sch Life Sci, Nanjing 210023, Jiangsu, Peoples R China.	qiongluo@nju.edu.cn; molpharm@163.com	Yu, Biao/G-9952-2017	Yu, Biao/0000-0002-3607-578X	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773743, 81730100]; National Key RAMP;D Program of China [2017YFA0506000]; National Science AMP; Technology Major Project "Key New Drug Creation and Manufacturing Program" [2018ZX09201002]; Natural Science Foundation of Jiangsu ProvinceNatural Science Foundation of Jiangsu Province [BK20150590]; Nanjing University Innovation and Creative Program for PhD candidate [CXCY17-25]	This study was supported by National Natural Science Foundation of China [Nos. 81773743, 81730100]; National Key R&D Program of China [2017YFA0506000]; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" [2018ZX09201002]; Natural Science Foundation of Jiangsu Province [BK20150590]; and Nanjing University Innovation and Creative Program for PhD candidate [CXCY17-25].	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AUG 13	2019	10								618	10.1038/s41419-019-1832-6			15	Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology	IS2DD	WOS:000481962300004	31409769	gold, Green Published			2022-04-25	
J	Shin, SY; Hyun, J; Yu, JR; Lim, Y; Lee, YH				Shin, Soon Young; Hyun, Jiye; Yu, Jae-Ran; Lim, Yoongho; Lee, Young Han			5-Methoxyflavanone induces cell cycle arrest at the G2/M phase, apoptosis and autophagy in HCT116 human colon cancer cells	TOXICOLOGY AND APPLIED PHARMACOLOGY			English	Article						5-methoxyflavanone; DNA damage checkpoint; Apoptosis; Caspase; Autophagy	MALIGNANT GLIOMA-CELLS; DOUBLE-STRAND BREAKS; NUCLEAR-DNA DAMAGE; DIETARY FLAVONOIDS; BIOAVAILABLE FLAVONOIDS; INTESTINAL-ABSORPTION; METABOLIC STABILITY; LIPID-PEROXIDATION; IN-VITRO; DEATH	Natural flavonoids have diverse pharmacological activities, including anti-oxidative, anti-inflammatory, and anti-cancer activities. In this study, we investigated the molecular mechanism underlying the action of 5-methoxyflavanone (5-MF) which has a strong bioavailability and metabolic stability. Our results show that 5-MF inhibited the growth and clonogenicity of HCT116 human colon cancer cells, and that it activated DNA damage responses, as revealed by the accumulation of p53 and the phosphorylation of DNA damage-sensitive proteins, including ataxia-telangiectasia mutated (ATM) at Ser1981, checkpoint kinase 2 (Chk2) at Thr68, and histone H2AX at Ser139. 5-MF-induced DNA damage was confirmed in a comet tail assay. We also found that 5-MF increased the cleavage of caspase-2 and -7, leading to the induction of apoptosis. Pretreatment with the ATM inhibitor KU55933 enhanced 5-MF-induced gamma-H2AX formation and caspase-7 cleavage. HCT116 cells lacking p53 (p53(-/-)) or p21 (p21(-/-)) exhibited increased sensitivity to 5-MF compared to wild-type cells. 5-MF further induced autophagy via an ERK signaling pathway. Blockage of autophagy with the MEK inhibitor U0126 potentiated 5-MF-induced gamma-H2AX formation and caspase-2 activation. These results suggest that a caspase-2 cascade mediates 5-MF-induced anti-tumor activity, while an ATM/Chk2/p53/p21 checkpoint pathway and ERK-mediated autophagy act as a survival program to block caspase-2-mediated apoptosis induced by 5-MF. (C) 2011 Elsevier Inc. All rights reserved.	[Shin, Soon Young; Lim, Yoongho; Lee, Young Han] Konkuk Univ, SMART Inst Adv Biomed Sci, Med Ctr, Seoul 143701, South Korea; [Shin, Soon Young; Lee, Young Han] Konkuk Univ, Res Ctr Transcript Control, Dept Biomed Sci & Technol, Seoul 143701, South Korea; [Hyun, Jiye; Lim, Yoongho] Konkuk Univ, Div Biosci & Biotechnol, BMIC, Seoul 143701, South Korea; [Yu, Jae-Ran] Konkuk Univ, Sch Med, Dept Environm & Trop Med, Seoul 143701, South Korea		Lim, Y (corresponding author), Konkuk Univ, SMART Inst Adv Biomed Sci, Med Ctr, 1 Hwayang Dong, Seoul 143701, South Korea.	yoongho@konkuk.ac.kr; yhlee58@konkuk.ac.kr			Korean Government MESTMinistry of Education, Science and Technology, Republic of KoreaKorean Government [NRF-2009-0084183, NRF-2010-0014208, NRF-2009-0093824]	This work was supported by the Disease Network Research Program (NRF-2009-0084183), the Basic Research Promotion Fund (NRF-2010-0014208), and the Priority Research Centers Program (NRF-2009-0093824), through a National Research Foundation of Korea grant funded by the Korean Government MEST.	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Appl. Pharmacol.	AUG 1	2011	254	3					288	298		10.1016/j.taap.2011.05.003			11	Pharmacology & Pharmacy; Toxicology	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy; Toxicology	795AO	WOS:000292944100008	21616090				2022-04-25	
J	Liu, GY; Bu, XX; Yan, H; Jia, WWG				Liu, Guo-Yu; Bu, Xuexian; Yan, Hang; Jia, William W. -G.			20S-protopanaxadiol-induced programmed cell death in glioma cells through caspase-dependent and -independent pathways	JOURNAL OF NATURAL PRODUCTS			English	Article							COLON-CANCER CELLS; REACTIVE OXYGEN; IN-VITRO; GINSENOSIDE RH-2; APOPTOSIS; MACROAUTOPHAGY; INHIBITION; MITOCHONDRIA; METABOLISM; ACTIVATION	20S-Protopanaxadiol (1) is an aglycon metabolic derivative of the protopanaxadiol-type ginseng saponins. In the present study, 1 was used to induce cytotoxicity for two human glioma cell lines, SF188 and U87MG. For the SF188 cells, 1 activated caspases-3, -8, -7, and -9 within 3 h and induced rapid apoptosis, which could be partially inhibited by a general caspase blocker and completely abolished when the caspase blocker was used in combination with an antioxidant. Compound 1 also induced cell death in U87MG cells but did not activate any caspases in these cells. Monodansylcadaverine staining showed that 1 induced dramatic autophagy in both cell lines. Elevated levels of superoxide anion in both cells and reduced levels of phosphorylated Akt in U87MG cells were also demonstrated. These results showed that 20S-protopanaxadiol (1) induces different forms of programmed cell death, including both typical apoptosis and autophagy through both caspase-dependent and -independent mechanisms.	Univ British Columbia, Dept Surg, Vancouver, BC V6T 2B5, Canada; Univ British Columbia, Brain Res Ctr, Vancouver, BC V6T 2B5, Canada		Jia, WWG (corresponding author), Univ British Columbia, Dept Surg, F233-2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada.	wjia@interchange.ubc.ca	JIA, WILLIAM/AAE-4322-2020				Arico S, 2001, J BIOL CHEM, V276, P35243, DOI 10.1074/jbc.C100319200; Ashkenazi A, 1998, SCIENCE, V281, P1305, DOI 10.1126/science.281.5381.1305; Bae EA, 2002, BIOL PHARM BULL, V25, P58, DOI 10.1248/bpb.25.58; BIEDERBICK A, 1995, EUR J CELL BIOL, V66, P3; Bras M, 2005, BIOCHEMISTRY-MOSCOW+, V70, P231, DOI 10.1007/s10541-005-0105-4; Castillo SS, 2004, CANCER RES, V64, P2782, DOI 10.1158/0008-5472.CAN-03-1530; Ellington AA, 2006, CARCINOGENESIS, V27, P298, DOI 10.1093/carcin/bgi214; Ellington AA, 2005, CARCINOGENESIS, V26, P159, DOI 10.1093/carcin/bgh297; Fei XF, 2002, ACTA PHARMACOL SIN, V23, P315; FISHER DE, 1994, CELL, V78, P539, DOI 10.1016/0092-8674(94)90518-5; Galindo MF, 2003, J NEUROCHEM, V84, P1066, DOI 10.1046/j.1471-4159.2003.01592.x; Gilaberte Y, 1997, PHOTODERMATOL PHOTO, V13, P43, DOI 10.1111/j.1600-0781.1997.tb00107.x; Goldshmit Y, 2001, J BIOL CHEM, V276, P46379, DOI 10.1074/jbc.M105637200; Gu YP, 2004, FEBS LETT, V577, P357, DOI 10.1016/j.febslet.2004.10.040; Hengartner MO, 2000, NATURE, V407, P770, DOI 10.1038/35037710; Herr I, 2001, BLOOD, V98, P2603, DOI 10.1182/blood.V98.9.2603; Jia WWG, 2004, CAN J PHYSIOL PHARM, V82, P431, DOI 10.1139/Y04-049; Kaufmann SH, 2001, TRENDS CELL BIOL, V11, P526, DOI 10.1016/S0962-8924(01)02173-0; Kim HE, 1999, LIFE SCI, V65, pPL33, DOI 10.1016/S0024-3205(99)00252-0; Leist M, 2001, NAT REV MOL CELL BIO, V2, P589, DOI 10.1038/35085008; Liu ZQ, 2003, J AGR FOOD CHEM, V51, P2555, DOI 10.1021/jf026228i; Luo HR, 2003, P NATL ACAD SCI USA, V100, P11712, DOI 10.1073/pnas.1634990100; Obara S, 2004, CANCER LETT, V208, P115, DOI 10.1016/j.canlet.2003.11.020; Oh M, 1999, INT J ONCOL, V14, P869; OTA T, 1991, J PHARM SCI, V80, P1141, DOI 10.1002/jps.2600801210; Park JA, 1997, CANCER LETT, V121, P73, DOI 10.1016/S0304-3835(97)00333-9; Popovich DG, 2002, ARCH BIOCHEM BIOPHYS, V406, P1, DOI 10.1016/S0003-9861(02)00398-3; Sanchez-Carbente MR, 2005, CELL DEATH DIFFER, V12, P279, DOI 10.1038/sj.cdd.4401560; Strasser A, 2000, ANNU REV BIOCHEM, V69, P217, DOI 10.1146/annurev.biochem.69.1.217; Takeuchi H, 2005, CANCER RES, V65, P3336, DOI 10.1158/0008-5472.CAN-04-3640; Tawab MA, 2003, DRUG METAB DISPOS, V31, P1065, DOI 10.1124/dmd.31.8.1065; Tsang WP, 2003, LIFE SCI, V73, P2047, DOI 10.1016/S0024-3205(03)00566-6; Zimmermann KC, 2001, PHARMACOL THERAPEUT, V92, P57, DOI 10.1016/S0163-7258(01)00159-0	33	48	52	0	11	AMER CHEMICAL SOC	WASHINGTON	1155 16TH ST, NW, WASHINGTON, DC 20036 USA	0163-3864			J NAT PROD	J. Nat. Prod.	FEB	2007	70	2					259	264		10.1021/np060313t			6	Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Plant Sciences; Pharmacology & Pharmacy	138VH	WOS:000244390900019	17261067				2022-04-25	
J	Ji, L; Zhong, B; Jiang, X; Mao, F; Liu, G; Song, B; Wang, CY; Jiao, Y; Wang, JP; Xu, ZB; Li, X; Zhan, B				Ji, Lu; Zhong, Bing; Jiang, Xi; Mao, Fei; Liu, Gang; Song, Bin; Wang, Cheng-Yuan; Jiao, Yong; Wang, Jiang-Ping; Xu, Zhi-Bin; Li, Xing; Zhan, Bo			Actein induces autophagy and apoptosis in human bladder cancer by potentiating ROS/JNK and inhibiting AKT pathways	ONCOTARGET			English	Article						human bladder cancer; Actein (ACT); autophagy and apoptosis; ROS and JNK; AKT	CELL-CYCLE ARREST; CASPASE ACTIVATION; BLACK COHOSH; COLON-CANCER; IN-VITRO; CIMICIFUGA-RACEMOSA; SIGNALING PATHWAY; INDUCTION; CDKS; EXPRESSION	Human bladder cancer is a common genitourinary malignant cancer worldwide. However, new therapeutic strategies are required to overcome its stagnated survival rate. Triterpene glycoside Actein (ACT), extracted from the herb black cohosh, suppresses the growth of human breast cancer cells. Our study attempted to explore the role of ACT in human bladder cancer cell growth and to reveal the underlying molecular mechanisms. We found that ACT significantly impeded the bladder cancer cell proliferation via induction of G2/M cycle arrest. Additionally, ACT administration triggered autophagy and apoptosis in bladder cancer cells, proved by the autophagosome formation, LC3B-II accumulation, improved cleavage of Caspases/poly (ADP-ribose) polymerase (PARP). Furthermore, reduction of reactive oxygen species (ROS) and p-c-Jun N-terminal kinase (JNK) could markedly reverse ACT-induced autophagy and apoptosis. In contrast, AKT and mammalian target of rapamycin (mTOR) were greatly de-phosphorylated by ACT, while suppressing AKT and mTOR activity could enhance the effects of ACT on apoptosis and autophagy induction. In vivo, ACT reduced the tumor growth with little toxicity. Taken together, our findings indicated that ACT suppressed cell proliferation, induced autophagy and apoptosis through promoting ROS/JNK activation, and blunting AKT pathway in human bladder cancer, which indicated that ACT might be an effective candidate against human bladder cancer in future.	[Ji, Lu; Zhong, Bing; Jiang, Xi; Mao, Fei] Nanjing Med Univ, Huaian Peoples Hosp 1, Dept Urol, Huaian 223300, Peoples R China; [Liu, Gang] Nanjing Med Univ, Huaian Peoples Hosp 1, Dept Orthopaed, Huaian 223300, Peoples R China; [Song, Bin; Wang, Cheng-Yuan; Jiao, Yong; Wang, Jiang-Ping; Xu, Zhi-Bin; Li, Xing; Zhan, Bo] Far East Biol Prod Co LTD, Branch Raw Mat & Nat Prod, Nanjing 210009, Jiangsu, Peoples R China		Liu, G (corresponding author), Nanjing Med Univ, Huaian Peoples Hosp 1, Dept Orthopaed, Huaian 223300, Peoples R China.	1345297715@qq.com					Biers S, 2017, CURR OPIN UROL, V27, P307, DOI 10.1097/MOU.0000000000000391; Cao QH, 2016, AM J TRANSL RES, V8, P3831; Chen CY, 2008, FOOD CHEM TOXICOL, V46, P2694, DOI 10.1016/j.fct.2008.04.024; Chen K, 2015, ACTA PHARMACOL SIN, V36, P1074, DOI 10.1038/aps.2015.44; Chen SN, 2002, J NAT PROD, V65, P601, DOI 10.1021/np010494t; Chowdhury IH, 2003, INT J CANCER, V107, P603, DOI 10.1002/ijc.11316; Duan FS, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0161886; 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Zhang SY, 2016, TUMOR BIOL, V37, P5165, DOI 10.1007/s13277-015-4375-1; Zhang X, 2015, SCI REP-UK, V5, DOI [10.1038/srep09803, 10.1038/srep09940]; Zhang YH, 2017, ONCOL REP, V37, P3509, DOI 10.3892/or.2017.5582; Zhao RL, 2015, J CANCER, V6, P623, DOI 10.7150/jca.11291; Zhu X, 2014, TOXICOL LETT, V227, P65, DOI 10.1016/j.toxlet.2014.03.015	72	20	21	1	9	IMPACT JOURNALS LLC	ORCHARD PARK	6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA		1949-2553		ONCOTARGET	Oncotarget	DEC 22	2017	8	68					112498	112515		10.18632/oncotarget.22274			18	Oncology; Cell Biology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Cell Biology	FS1WP	WOS:000419569800030	29348843	Green Submitted, Green Published, gold			2022-04-25	
J	Wang, J; Jiang, ZL; Lam, W; Gullen, EA; Yu, Z; Wei, Y; Wang, LH; Zeiss, C; Beck, A; Cheng, EC; Wu, CF; Cheng, YC; Zhang, YX				Wang, Jing; Jiang, Zaoli; Lam, Wing; Gullen, Elizabeth A.; Yu, Zhe; Wei, Ying; Wang, Lihui; Zeiss, Caroline; Beck, Amanda; Cheng, Ee-Chun; Wu, Chunfu; Cheng, Yung-Chi; Zhang, Yixuan			Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug	PLOS ONE			English	Article							DNA-DAMAGE; CELLS; TROXACITABINE; ACTIVATION; METABOLITE; EXPRESSION; CANCER; KINASE	Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.27 +/- 0.07 mu M and 0.18 +/- 0.023 mu M respectively. This inhibition was explicated by Malformin C's effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug.	[Wang, Jing; Jiang, Zaoli; Lam, Wing; Gullen, Elizabeth A.; Cheng, Ee-Chun; Cheng, Yung-Chi] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA; [Yu, Zhe; Wei, Ying; Wang, Lihui; Wu, Chunfu; Zhang, Yixuan] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang, Peoples R China; [Zeiss, Caroline; Beck, Amanda] Yale Univ, Sch Med, Comparat Med Sect, New Haven, CT 06510 USA; [Wang, Jing] Beijing Univ Chinese Med, Dept Hematol & Oncol, Dongzhimen Hosp, Beijing, Peoples R China		Cheng, YC (corresponding author), Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA.	yccheng@yale.edu; zhangyxzsh@163.com	Beck, Amanda P/H-9573-2017	Beck, Amanda P/0000-0003-1867-4110; Wang, Jing/0000-0002-2735-7283	NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA-154295]; Yung-Chi Cheng's lab at Yale University; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P01CA154295] Funding Source: NIH RePORTER	Yung-Chi Cheng is a Fellow of the National Foundation for Cancer Research, USA. Part of his salary is from the NCI grant from CA-154295. Most of the research support is funded by a trust fund to Yung-Chi Cheng's lab at Yale University. 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	Martinez-Reyes, I; Sanchez-Arago, M; Cuezva, JM				Martinez-Reyes, Inmaculada; Sanchez-Arago, Maria; Cuezva, Jose M.			AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells	BIOCHEMICAL JOURNAL			English	Article						ATP synthase; cancer; cellular stress; glycolysis; mitochondrion; translational control	ACTIVATED PROTEIN-KINASE; BETA-F1-ATPASE MESSENGER-RNA; BIOENERGETIC SIGNATURE; TRANSLATIONAL EFFICIENCY; MAMMALIAN TARGET; GENE-EXPRESSION; ATP SYNTHASE; ENERGY; BIOGENESIS; INHIBITION	Reprogramming of energetic metabolism is a phenotypic trait of cancer in which mitochondrial dysfunction represents a key event in tumour progression. In the present study, we show that the acquisition of the tumour-promoting phenotype in colon cancer HCT116 cells treated with oligomycin to inhibit ATP synthase is exerted by repression of the synthesis of nuclear-encoded mitochondrial proteins in a process that is regulated at the level of translation. Remarkably, the synthesis of glycolytic proteins is not affected in this situation. Changes in translational control of mitochondrial proteins are signalled by the activation of AMPK (AMP-activated protein kinase) and the GCN2 (general control non-derepressible 2) kinase, leading also to the activation of autophagy. Changes in the bioenergetic function of mitochondria are mimicked by the activation of AMPK and the silencing of ATF4 (activating transcription factor 4). These findings emphasize the relevance of translational control for normal mitochondria] function and for the progression of cancer. Moreover, they demonstrate that glycolysis and oxidative phosphorylation are controlled at different levels of gene expression, offering the cell a mechanistic safeguard strategy for metabolic adaptation under stressful conditions.	[Martinez-Reyes, Inmaculada; Sanchez-Arago, Maria; Cuezva, Jose M.] Univ Autonoma Madrid, Dept Biol Mol, Ctr Biol Mol Severo Ochoa,CSIC UAM,Inst Invest Ho, Ctr Invest Biomed Red Enfermedades Raras CIBERER, E-28049 Madrid, Spain		Cuezva, JM (corresponding author), Univ Autonoma Madrid, Dept Biol Mol, Ctr Biol Mol Severo Ochoa,CSIC UAM,Inst Invest Ho, Ctr Invest Biomed Red Enfermedades Raras CIBERER, E-28049 Madrid, Spain.	jmcuezva@cbm.uam.es	Cuezva, Jose M/F-8381-2011; Cuezva, Jose M/AAR-5392-2020; Martinez-Reyes, Inmaculada/P-9140-2018	Martinez-Reyes, Inmaculada/0000-0003-0479-1535; Cuezva Marcos, Jose Manuel/0000-0003-1118-248X	Ministerio de Educacion y CienciaSpanish GovernmentEuropean Commission [BFU2010-18903]; Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) del ISCIII; Comunidad de MadridComunidad de Madrid [S2010/BMD-2402]; Fundacion Ramon Areces; Junta para la Ampliacion de Estudios (JAE)-Consejo Superior de Investigaciones Cientificas (CSIC)	This work was supported by grants from the Ministerio de Educacion y Ciencia [grant number BFU2010-18903], the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) del ISCIII, and the Comunidad de Madrid [grant number S2010/BMD-2402]. The Centro de Biologia Molecular Severo Ochoa receives an institutional grant from Fundacion Ramon Areces. I.M.-R. is the recipient of a pre-doctoral fellowship from Junta para la Ampliacion de Estudios (JAE)-Consejo Superior de Investigaciones Cientificas (CSIC).	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J.	JUN 1	2012	444		2				249	259		10.1042/BJ20111829			11	Biochemistry & Molecular Biology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	950IQ	WOS:000304643200011	22435535	Green Accepted			2022-04-25	
J	Ma, D; Tremblay, P; Mahngar, K; Akbari-Asl, P; Collins, J; Hudlicky, T; McNulty, J; Pandey, S				Ma, Dennis; Tremblay, Phillip; Mahngar, Kevinjeet; Akbari-Asl, Pardis; Collins, Jonathan; Hudlicky, Tomas; McNulty, James; Pandey, Siyaram			A novel synthetic C-1 analogue of 7-deoxypancratistatin induces apoptosis in p53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement of activity by tamoxifen	INVESTIGATIONAL NEW DRUGS			English	Article						Colorectal cancer; Tamoxifen; Combination therapy; Apoptosis; Autophagy	BIOLOGICAL EVALUATION; 1ST-LINE TREATMENT; ENDOCRINE THERAPY; OXIDATIVE-STRESS; DNA MUTATIONS; BCL-2 FAMILY; COMPLEX-I; PANCRATISTATIN; LEUCOVORIN; ROS	The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies.	[Ma, Dennis; Tremblay, Phillip; Mahngar, Kevinjeet; Akbari-Asl, Pardis; Pandey, Siyaram] Univ Windsor, Dept Chem & Biochem, Windsor, ON N9B 3P4, Canada; [Collins, Jonathan; Hudlicky, Tomas] Brock Univ, Dept Chem, St Catharines, ON L2S 3A1, Canada; [Collins, Jonathan; Hudlicky, Tomas] Brock Univ, Ctr Biotechnol, St Catharines, ON L2S 3A1, Canada; [McNulty, James] McMaster Univ, Dept Chem, Hamilton, ON L8S 4M1, Canada		Pandey, S (corresponding author), Univ Windsor, Dept Chem & Biochem, 401 Sunset Ave, Windsor, ON N9B 3P4, Canada.	thudlicky@brocku.ca; jmcnult@mcmaster.ca; spandey@uwindsor.ca	Pandey, Siyaram/AAI-5491-2020; McNulty, James/E-7871-2011	Collins, Jonathan/0000-0002-5591-5772	Knights of Columbus Chapter 9671 (Windsor, Ontario); NSERCNatural Sciences and Engineering Research Council of Canada (NSERC); CIHRCanadian Institutes of Health Research (CIHR)	This work has been supported by the Knights of Columbus Chapter 9671 (Windsor, Ontario), NSERC, and a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship awarded to Dennis Ma. Thank you to Carly Griffin for providing the pancratistatin results presented in this manuscript. We would also like to thank Colleen Mailloux for the critical review of this manuscript.	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New Drugs	JUN	2012	30	3					1012	1027		10.1007/s10637-011-9668-7			16	Oncology; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Oncology; Pharmacology & Pharmacy	940GT	WOS:000303878700016	21494837				2022-04-25	
J	Li, XN; Wong, CC; Tang, Z; Wu, JL; Li, SF; Qian, Y; Xu, JY; Yang, ZY; Shen, Y; Yu, J; Cai, ZW				Li, Xiaona; Wong, Chi Chun; Tang, Zhi; Wu, Jianlin; Li, Shangfu; Qian, Yun; Xu, Jiaying; Yang, Zhiyi; Shen, Yang; Yu, Jun; Cai, Zongwei			Determination of amino acids in colon cancer cells by using UHPLC-MS/MS and [U-C-13(5)]-glutamine as the isotope tracer	TALANTA			English	Article						Amino acids; C-13(5)-glutamine isotope tracer; Glutaminolysis-inhibition; Hydrophilic interaction liquid chromatography; Mass spectrometry	TANDEM MASS-SPECTROMETRY; COLORECTAL-CANCER; UREA CYCLE; CHROMATOGRAPHY; METABOLISM; DERIVATIZATION; AUTOPHAGY; STANDARD; TISSUE; FLUIDS	Rapid and simple quantitative analysis of intracellular metabolites is a critical tool for monitoring the alteration of biologically significant metabolites in cell lines or in vivo. We established an ultra-high performance liquid chromatography (UHPLC) method, equipped with hydrophilic interaction liquid chromatography (HILIC) column coupled to tandem mass spectrometry (MS/MS) for the simultaneous determination of 19 amino acids and 2 related derivatives in human cell lines. Chromatographic separation was achieved within 20 min using a BEH amide column, with aqueous mobile phase containing 20 mM ammonium acetate and 20 mM ammonium hydroxide, and acetonitrile as the organic mobile'phase. Amino acids were analyzed in positive ion multiple reaction monitoring (MRM) mode without the need of derivatization. Intra- and inter-day precisions were less than 13.7%. The method was successfully applied to simultaneously detect the 21 compounds in a human colon cancer cell line DLD1. Moreover, metabolite fate of glutamine-derived carbons into amino acids in DLD1 cells was successfully traced by using [U-C-13(5)]glutamine as the isotope tracer. Metabolic consequences of glutaminolysis inhibition on amino acid metabolism were evaluated. Analysis of C-12- and U-C-13-labeled amino acids revealed the significantly decreased incorporation of [U-(13)C5]-glutamine derived carbons into aspartate, alanine and ornithine, indicating impaired metabolic flux via the tricarboxylic acid cycle and the urea cycle.	[Li, Xiaona; Tang, Zhi; Li, Shangfu; Yang, Zhiyi; Shen, Yang; Cai, Zongwei] Hong Kong Baptist Univ, Dept Chem, State Key Lab Environm & Biol Anal, Hong Kong, Hong Kong, Peoples R China; [Wong, Chi Chun; Xu, Jiaying; Yu, Jun] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China; [Wong, Chi Chun; Xu, Jiaying; Yu, Jun] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, State Key Lab Digest Dis, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China; [Wu, Jianlin] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau, Peoples R China; [Qian, Yun] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Gastroenterol, Hangzhou, Zhejiang, Peoples R China; [Qian, Yun] Zhejiang Univ, Inst Gastroenterol, Hangzhou, Zhejiang, Peoples R China		Cai, ZW (corresponding author), Hong Kong Baptist Univ, Dept Chem, State Key Lab Environm & Biol Anal, Hong Kong, Hong Kong, Peoples R China.	zwcai@hkbu.edu.hk	Wong, Chi Chun/C-4636-2016; Cai, Zongwei/ABD-4001-2020; Jun, Yu/D-8569-2015	Cai, Zongwei/0000-0002-8724-7684; Jun, Yu/0000-0001-5008-2153	Hong Kong Baptist University [IRMS/13-14/03]; Hong Kong Research Grants CouncilHong Kong Research Grants Council [GRF14114615, C2014-14E]; Hong Kong PhD Fellowship	This work was financially supported by Interdisciplinary Research Matching Scheme of Hong Kong Baptist University (IRMS/13-14/03) and Hong Kong Research Grants Council (GRF14114615 and C2014-14E). Xiaona Li would like to thank the Hong Kong PhD Fellowship Scheme.	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J	Breininger, SP; Malcomson, FC; Afshar, S; Turnbull, DM; Greaves, L; Mathers, JC				Breininger, S. P.; Malcomson, F. C.; Afshar, S.; Turnbull, D. M.; Greaves, L.; Mathers, J. C.			Effects of obesity and weight loss on mitochondrial structure and function and implications for colorectal cancer risk	PROCEEDINGS OF THE NUTRITION SOCIETY			English	Article; Proceedings Paper	Summer Meeting of the Nutrition-Society / Conference on Getting Energy Balance Right / Postgraduate Symposium	JUL 10-12, 2018	Univ Leeds, Leeds, ENGLAND	Nutr Soc	Univ Leeds	Obesity; Colorectal cancer; Mitochondria; Bariatric surgery	C-REACTIVE PROTEIN; ADIPOSE-TISSUE; SKELETAL-MUSCLE; DNA MUTATIONS; FECAL CALPROTECTIN; RESPIRATORY-CHAIN; OXIDATIVE STRESS; HUMAN BREAST; LIFE-SPAN; EXPRESSION	Colorectal cancer (CRC) is the third most common cancer globally. CRC risk is increased by obesity, and by its lifestyle determinants notably physical inactivity and poor nutrition. Obesity results in increased inflammation and oxidative stress which cause genomic damage and contribute to mitochondrial dysregulation and CRC risk. The mitochondrial dysfunction associated with obesity includes abnormal mitochondrial size, morphology and reduced autophagy, mitochondrial biogenesis and expression of key mitochondrial regulators. Although there is strong evidence that increased adiposity increases CRC risk, evidence for the effects of intentional weight loss on CRC risk is much more limited. In model systems, energy depletion leads to enhanced mitochondrial integrity, capacity, function and biogenesis but the effects of obesity and weight loss on mitochondria in the human colon are not known. We are using weight loss following bariatric surgery to investigate the effects of altered adiposity on mitochondrial structure and function in human colonocytes. In summary, there is strong and consistent evidence in model systems and more limited evidence in human subjects that over-feeding and/or obesity result in mitochondrial dysfunction and that weight loss might mitigate or reverse some of these effects.	[Breininger, S. P.; Malcomson, F. C.; Afshar, S.; Mathers, J. C.] Newcastle Univ, Human Nutr Res Ctr, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England; [Breininger, S. P.; Malcomson, F. C.; Mathers, J. C.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England; [Breininger, S. P.; Turnbull, D. M.; Greaves, L.; Mathers, J. C.] Newcastle Univ, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England; [Breininger, S. P.; Malcomson, F. C.; Turnbull, D. M.; Greaves, L.; Mathers, J. C.] Newcastle Univ, LLHW Ctr Ageing & Vital, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England; [Afshar, S.] North Cumbria Univ Hosp NHS Trust, Cumberland Infirm, Newtown Rd, Carlisle CA2 7HY, England		Breininger, SP (corresponding author), Newcastle Univ, Human Nutr Res Ctr, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.; Breininger, SP (corresponding author), Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.; Breininger, SP (corresponding author), Newcastle Univ, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.; Breininger, SP (corresponding author), Newcastle Univ, LLHW Ctr Ageing & Vital, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.	s.p.breininger@ncl.ac.uk		Greaves, Laura/0000-0002-8071-5916	Newcastle University Centre for Ageing and Vitality (Biotechnology and Biological Sciences Research Council)UK Research & Innovation (UKRI)Biotechnology and Biological Sciences Research Council (BBSRC); Newcastle University Centre for Ageing and Vitality (Medical Research Council)UK Research & Innovation (UKRI)Medical Research Council UK (MRC) [L016354]; Wellcome TrustWellcome TrustEuropean Commission [203105/Z/16/Z, 204709/Z/16/Z]; UK NIHR Biomedical Research Centre for Ageing and Age-related disease award; Northumbria Healthcare NHS Foundation Trust; MRCUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [MR/L016354/1, MR/K000608/1, G0800674] Funding Source: UKRI	This work was supported by the Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council L016354), The Wellcome Trust (203105/Z/16/Z and 204709/Z/16/Z), UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust and by Northumbria Healthcare NHS Foundation Trust.	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Nutr. Soc.	AUG	2019	78	3					426	437	PII S0029665119000533	10.1017/S0029665119000533			12	Nutrition & Dietetics	Science Citation Index Expanded (SCI-EXPANDED); Conference Proceedings Citation Index - Science (CPCI-S)	Nutrition & Dietetics	IO0OP	WOS:000479078500019	30898183	Bronze, Green Accepted			2022-04-25	
J	Bertin, S; Samson, M; Pons, C; Guigonis, JM; Gavelli, A; Baque, P; Brossette, N; Pagnotta, S; Ricci, JE; Pierrefite-Carle, V				Bertin, Samuel; Samson, Michel; Pons, Catherine; Guigonis, Jean-Marie; Gavelli, Adolfo; Baque, Patrick; Brossette, Nicole; Pagnotta, Sophie; Ricci, Jean-Ehrland; Pierrefite-Carle, Valerie			Comparative Proteomics Study Reveals That Bacterial CpG Motifs Induce Tumor Cell Autophagy in Vitro and in Vivo	MOLECULAR & CELLULAR PROTEOMICS			English	Article							TOLL-LIKE RECEPTORS; IMMUNOMODULATORY OLIGONUCLEOTIDE; EXPERIMENTAL-THERAPY; COLON-CANCER; LUNG-CANCER; DNA; DEGRADATION; SURVIVAL; PROTEIN; TOLL-LIKE-RECEPTOR-9	Unmethylated CpG dinucleotides, present in bacterial DNA, are recognized in vertebrates via the Toll-like receptor 9 (TLR9) and are known to act as an anticancer agent by stimulating immune cells to induce a proinflammatory response. Although the effects of CpG-oligodeoxynucleotides (CpG-ODNs) in immune cells have been widely studied, little is known regarding their molecular effects in TLR9-positive tumor cells. To better understand the role of these bacterial motifs in cancer cells, we analyzed proteome modifications induced in TLR9-positive tumor cells in vitro and in vivo after CpG-ODN treatment in a rat colon carcinoma model. Proteomics analysis of tumor cells by two-dimensional gel electrophoresis followed by mass spectrometry identified several proteins modulated by bacterial CpG motifs. Among them, several are related to autophagy including potential autophagic substrates. In addition, we observed an increased glyceraldehyde-3-phosphate dehydrogenase expression, which has been shown to be sufficient to trigger an autophagic process. Autophagy is a self-digestion pathway whereby cytoplasmic material is sequestered by a structure termed the autophagosome for subsequent degradation and recycling. As bacteria are known to trigger autophagy, we assessed whether bacterial CpG motifs might induce autophagy in TLR9-positive tumor cells. We showed that CpG-ODN can induce autophagy in rodent and human tumor cell lines and was TLR9-dependent. In addition, an increase in the number of autophagosomes can also be observed in vivo after CpG motif intratumoral injection. Our findings bring new insights on the effect of bacterial CpG motifs in tumor cells and may be relevant for cancer treatment and more generally for gene therapy approaches in TLR9-positive tissues. Molecular & Cellular Proteomics 7: 2311-2322, 2008.	[Pierrefite-Carle, Valerie] Fac Med, INSERM, U638, F-06107 Nice 2, France; [Bertin, Samuel; Samson, Michel; Pons, Catherine; Guigonis, Jean-Marie; Gavelli, Adolfo; Baque, Patrick; Brossette, Nicole; Pagnotta, Sophie; Ricci, Jean-Ehrland; Pierrefite-Carle, Valerie] Univ Nice Sophia Antipolis, Fac Med, F-06107 Nice, France; [Samson, Michel; Guigonis, Jean-Marie] IFR50, F-06107 Nice, France; [Gavelli, Adolfo] Ctr Hosp Princesse Grace, Serv Chirurg Gen & Digest, MC-98000 Monaco, Monaco; [Baque, Patrick] Hop St Roche, Serv Chirurg Urgence, F-06107 Nice, France; [Pagnotta, Sophie] Ctr Commun Microscopie Appl, F-06108 Nice, France; [Ricci, Jean-Ehrland] INSERM, U895, Ctr Mediterraneen Med Mol C3M, Cell Death & Survival AVENIR Team, F-06204 Nice 3, France		Pierrefite-Carle, V (corresponding author), Fac Med, INSERM, U638, Ave Valombrose, F-06107 Nice 2, France.	pierrefi@unice.fr	Pierrefite-Carle, Valerie/N-6329-2017; Ricci, Jean-Ehrland/I-7117-2016; RICCI, Jean Ehrland/AAS-4379-2020	Pierrefite-Carle, Valerie/0000-0003-3399-2934; Ricci, Jean-Ehrland/0000-0003-1585-8117; RICCI, Jean Ehrland/0000-0003-1585-8117	INSERM, Fondation de l'Avenir, France CancerInstitut National de la Sante et de la Recherche Medicale (Inserm); Association pour la Recherche sur le CancerFondation ARC pour la Recherche sur le CancerAustralian Research CouncilEuropean Commission	This work was supported by the INSERM, Fondation de l'Avenir, France Cancer, and Association pour la Recherche sur le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact.	Akhtar M, 2003, FASEB J, V17, P1319, DOI 10.1096/fj.02-0950fje; Andersen JM, 2006, BIOL REPROD, V74, P824, DOI 10.1095/biolreprod.105.048629; Bertin S, 2008, INT J MOL MED, V21, P309; Bohnhorst J, 2006, LEUKEMIA, V20, P1138, DOI 10.1038/sj.leu.2404225; Cayatte C, 2006, MOL CELL PROTEOMICS, V5, P2031, DOI 10.1074/mcp.M600165-MCP200; CHANDLER CS, 1983, BIOCHEM J, V210, P845, DOI 10.1042/bj2100845; Colell A, 2007, CELL, V129, P983, DOI 10.1016/j.cell.2007.03.045; Cuervo AM, 2000, J BIOL CHEM, V275, P33329, DOI 10.1074/jbc.M005655200; Cuervo AM, 1997, J BIOL CHEM, V272, P5606, DOI 10.1074/jbc.272.9.5606; Debnath J, 2005, AUTOPHAGY, V1, P66, DOI 10.4161/auto.1.2.1738; Delgado MA, 2008, EMBO J, V27, P1110, DOI 10.1038/emboj.2008.31; Deretic V, 2006, CURR OPIN IMMUNOL, V18, P375, DOI 10.1016/j.coi.2006.05.019; Droemann D, 2005, RESP RES, V6, DOI 10.1186/1465-9921-6-1; Duncan R, 2008, BRIT J CANCER, V98, P426, DOI 10.1038/sj.bjc.6604128; DUNN WA, 1990, J CELL BIOL, V110, P1923, DOI 10.1083/jcb.110.6.1923; El Andaloussi A, 2006, GLIA, V54, P526, DOI 10.1002/glia.20401; Hemmi H, 2000, NATURE, V408, P740, DOI 10.1038/35047123; Huang B, 2005, CANCER RES, V65, P5009, DOI 10.1158/0008-5472.CAN-05-0784; Jego G, 2006, LEUKEMIA, V20, P1130, DOI 10.1038/sj.leu.2404226; Krieg AM, 2002, ANNU REV IMMUNOL, V20, P709, DOI 10.1146/annurev.immunol.20.100301.064842; Krieg AM, 2006, NAT REV DRUG DISCOV, V5, P471, DOI 10.1038/nrd2059; Kuo CC, 2005, PROTEOMICS, V5, P894, DOI 10.1002/pmic.200401144; Lenaerts K, 2006, J PROTEOME RES, V5, P2113, DOI 10.1021/pr060183+; Li J, 2004, AM J PHYSIOL-LUNG C, V287, pL552, DOI 10.1152/ajplung.00436.2003; Lim LHK, 2007, FASEB J, V21, P968, DOI 10.1096/fj.06-7464rev; Lum JJ, 2005, NAT REV MOL CELL BIO, V6, P439, DOI 10.1038/nrm1660; MARTIN F, 1983, INT J CANCER, V32, P623, DOI 10.1002/ijc.2910320517; Massey A, 2004, INT J BIOCHEM CELL B, V36, P2420, DOI 10.1016/j.biocel.2004.04.010; Massey AC, 2006, AUTOPHAGY, V2, P325, DOI 10.4161/auto.3090; Merrell MA, 2006, MOL CANCER RES, V4, P437, DOI 10.1158/1541-7786.MCR-06-0007; Mizushima N, 2004, INT J BIOCHEM CELL B, V36, P2491, DOI 10.1016/j.biocel.2004.02.005; Noda T, 1998, J BIOL CHEM, V273, P3963, DOI 10.1074/jbc.273.7.3963; Pedersen G, 2005, CLIN EXP IMMUNOL, V141, P298, DOI 10.1111/j.1365-2249.2005.02848.x; Pierrefite-Carle V, 1999, J NATL CANCER I, V91, P2014, DOI 10.1093/jnci/91.23.2014; Platz J, 2004, J IMMUNOL, V173, P1219, DOI 10.4049/jimmunol.173.2.1219; Rayburn ER, 2007, INT J ONCOL, V30, P1511; Rayburn ER, 2006, PROSTATE, V66, P1653, DOI 10.1002/pros.20485; Scheule RK, 2000, ADV DRUG DELIVER REV, V44, P119, DOI 10.1016/S0169-409X(00)00090-9; Schmidt C, 2006, J NATL CANCER I, V98, P574, DOI 10.1093/jnci/djj198; SEGLEN PO, 1982, P NATL ACAD SCI-BIOL, V79, P1889, DOI 10.1073/pnas.79.6.1889; Song SW, 2007, NAT CELL BIOL, V9, P869, DOI 10.1038/ncb0807-869; Takeshita F, 2004, SEMIN IMMUNOL, V16, P17, DOI 10.1016/j.smim.2003.10.009; Wang H, 2006, MOL CANCER THER, V5, P2106, DOI 10.1158/1535-7163.MCT-06-0158; Wang H, 2006, MOL CANCER THER, V5, P1585, DOI 10.1158/1535-7163.MCT-06-0094; Watts JA, 2004, J MOL CELL CARDIOL, V36, P141, DOI 10.1016/j.yjmcc.2003.10.015; Xu Y, 2007, IMMUNITY, V27, P135, DOI 10.1016/j.immuni.2007.05.022	46	22	26	0	9	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC	BETHESDA	9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA	1535-9476	1535-9484		MOL CELL PROTEOMICS	Mol. Cell. Proteomics	DEC	2008	7	12					2311	2322		10.1074/mcp.M800100-MCP200			12	Biochemical Research Methods	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology	378NK	WOS:000261328200002	18632594	hybrid			2022-04-25	
J	Martinez-Useros, J; Garcia-Foncillas, J				Martinez-Useros, Javier; Garcia-Foncillas, Jesus			Obesity and colorectal cancer: molecular features of adipose tissue	JOURNAL OF TRANSLATIONAL MEDICINE			English	Review						Colorectal cancer; Obesity; Overweight; BMI; Adipose tissue; Cytokines; Inflammation; 4-HNE; MDA; MPE	BODY-MASS INDEX; GROWTH-FACTOR-I; MECHANISMS LINKING OBESITY; ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; COLON-CANCER; LIPID-PEROXIDATION; PHYSICAL-ACTIVITY; MISMATCH-REPAIR; UNITED-STATES	The huge part of population in developed countries is overweight or obese. Obesity is often determined by body mass index (BMI) but new accurate methods and ratios have recently appeared to measure body fat or fat located in the intestines. Early diagnosis of obesity is crucial since it is considered an increasing colorectal cancer risk factor. On the one hand, colorectal cancer has been strongly associated with lifestyle factors. A diet rich in red and processed meats may increase colorectal cancer risk; however, high-fiber diets (grains, cereals and fruits) have been associated with a decreased risk of colorectal cancer. Other life-style factors associated with obesity that also increase colorectal cancer risk are physical inactivity, smoking and high alcohol intake. Cutting-edge studies reported that high-risk transformation ability of adipose tissue is due to production of different pro-inflammatory cytokines like IL-8, IL-6 or IL-2 and other enzymes like lactate dehydrogenase (LDH) and tumour necrosis factor alpha (TNF alpha). Furthermore, oxidative stress produces fatty-acid peroxidation whose metabolites possess very high toxicities and mutagenic properties. 4-hydroxy-2-nonenal (4-HNE) is an active compounds that upregulates prostaglandin E2 which is directly associated with high proliferative colorectal cancer. Moreover, 4-HNE deregulates cell proliferation, cell survival, differentiation, autophagy, senescence, apoptosis and necrosis via mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PIK3CA)-AKT and protein kinase C pathways. Other product of lipid peroxidation is malondialdehyde (MDA) being able to regulate insulin through WNT-pathway as well as having demonstrated its mutagenic capability. Accumulation of point mutation enables genomic evolution of colorectal cancer described in the model of Fearon and Vogelstein. In this review, we will summarize different determination methods and techniques to assess a truthfully diagnosis and we will explain some of the capabilities that performs adipocytes as the largest endocrine organ.	[Martinez-Useros, Javier; Garcia-Foncillas, Jesus] FIIS Fdn Jimenez Diaz, Translat Oncol Div, Oncohlth Inst, Ave Reyes Catolicos 2, Madrid 28040, Spain		Martinez-Useros, J (corresponding author), FIIS Fdn Jimenez Diaz, Translat Oncol Div, Oncohlth Inst, Ave Reyes Catolicos 2, Madrid 28040, Spain.	javier.museros@oncohealth.eu		J, Garcia-Foncillas/0000-0002-7591-8006	RNA-Reg. CONSOLIDER-Consortium of the Spanish Ministry of Economy and Competitiveness [CSD2009-00080]	The authors wish to thank Ana Martin for valuable assistance during the preparation of this review. This work has been carried out with the support of the RNA-Reg. CONSOLIDER-Consortium (CSD2009-00080) of the Spanish Ministry of Economy and Competitiveness.	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Transl. Med.	JAN 22	2016	14								21	10.1186/s12967-016-0772-5			12	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	DB8JM	WOS:000368763000001	26801617	gold, Green Published			2022-04-25	
J	Gao, GY; Shi, XY; Shen, JF				Gao, Guangyu; Shi, Xinya; Shen, Jiaofeng			HS3ST2 and Its Related Molecules as Potential Biomarkers for Predicting Lymph Node Metastasis in Patients with Colorectal Cancer	ONCOTARGETS AND THERAPY			English	Article						microRNA; colorectal cancer; lymph node metastasis; prognostic signature	GENE-EXPRESSION; MIGRATION; PATHWAY; CELLS; COLON; HSA-MIR-125A-3P; DIFFERENTIATION; PROLIFERATION; INVASION; TARGET	Background: Lymph node metastasis is a major cause of cancer-related death in patients with colorectal cancer (CRC), but current strategies are limited to predicting this clinical behavior. Our study aims to establish a lymph node metastasis prediction model based on miRNA and mRNA to improve the accuracy of prediction. Methods: GSE56350, GSE70574, and GSE95109 were downloaded from the Gene Expression Omnibus (GEO) database and 569 colorectal cancer statistics were also downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed miRNAs were calculated by using R software. Besides, gene ontology and enriched pathway analysis of target mRNAs were analyzed by using FunRich. Furthermore, the mRNA-miRNA network was constructed using Cytoscape software. Gene expression level was also detected by performing qRT-PCR (quantitative real-time PCR) in colorectal cancer and lymph node tissues. Results: In total, 5 differentially expressed miRNAs were selected, and 34 mRNAs were identified after filtering. The research of KEGG indicated that mRNAs are enriched in many cancer pathways. Differentially expressed miRNAs were most enriched in the cytoplasm, nucleoside, transcription factor activity, and RNA binding. KEGG pathway analysis of these target genes was mainly enriched in 5 pathways including fatty acid elongation, MAPK signaling pathway, autophagy, signaling pathways regulating pluripotency of stem cells, and Th17 cell differentiation. The results of qRT-PCR indicated that hsa-miR-100 and hsa-miR-99a were differentially expressed in lymph node metastatic colorectal cancer tissues and lymph node non-metastasis tissues which all target HS3ST2. Besides, we also found they have a significant difference in colorectal cancer tissues compared with normal tissues. Conclusion: By using microarray and bioinformatics analyses, differentially expressed miRNAs were identified and a complete gene network was constructed. To our knowledge, HS3ST2 and related molecules including hsa-miR-100 and hsa-miR-99a were firstly identified as potential biomarkers in the development of lymph node metastatic colorectal cancer.	[Gao, Guangyu; Shi, Xinya; Shen, Jiaofeng] Soochow Univ, Dept Oncol, Affiliated Hosp 2, Suzhou 215004, Jiangsu, Peoples R China		Shen, JF (corresponding author), Soochow Univ, Dept Oncol, Affiliated Hosp 2, Suzhou 215004, Jiangsu, Peoples R China.	jfshenzz@163.com		Guang Yu Gao, Guang Yu Gao/0000-0002-1317-6764			Afratis N, 2012, FEBS J, V279, P1177, DOI 10.1111/j.1742-4658.2012.08529.x; Ahmadi A, 2017, GENE, V620, P15, DOI 10.1016/j.gene.2017.03.032; Amaravadi R, 2016, GENE DEV, V30, P1913, DOI 10.1101/gad.287524.116; Balch C, 2017, FRONT PHARMACOL, V8, DOI 10.3389/fphar.2017.00267; Chen Si-Xiang, 2018, Zhonghua Nan Ke Xue, V24, P442; Dankova Z, 2018, INT J MOL MED, V42, P3318, DOI 10.3892/ijmm.2018.3872; Dienstmann R, 2017, ANN ONCOL, V28, P1023, DOI 10.1093/annonc/mdx052; Djamgoz MBA, 2014, PHILOS T R SOC B, V369, DOI 10.1098/rstb.2013.0092; Eyvazi S, 2020, J GASTROINTEST CANC, V51, P579, DOI 10.1007/s12029-019-00290-1; Guinney J, 2015, NAT MED, V21, P1350, DOI 10.1038/nm.3967; Hellec C, 2018, PLOS ONE, V13, DOI 10.1371/journal.pone.0194676; Hwang JA, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0079634; Ikeda N, 2003, CLIN CANCER RES, V9, P1503; Jiang LL, 2013, CANCER INVEST, V31, P538, DOI 10.3109/07357907.2013.820314; Jin S, 2018, ONCOL LETT, V15, P9703, DOI 10.3892/ol.2018.8564; Kania EE, 2020, MOL PHARMACOL, V97, P159, DOI 10.1124/mol.119.118315; Kitahara O, 2001, CANCER RES, V61, P3544; Kumar AV, 2014, INT J CANCER, V135, P2579, DOI 10.1002/ijc.28921; Lechner S, 2003, GUT, V52, P1148, DOI 10.1136/gut.52.8.1148; Li B, 2017, J CLIN INVEST, V127, P3702, DOI 10.1172/JCI94012; Li L, 2017, EXP THER MED, V14, P1065, DOI 10.3892/etm.2017.4597; Ma X, 2019, J CANCER, V10, P6865, DOI 10.7150/jca.31952; Notterman DA, 2001, CANCER RES, V61, P3124; Okada R, 2019, CELLS-BASEL, V8, DOI 10.3390/cells8121535; Perez R, 2003, J GASTROINTEST SURG, V7, P884, DOI 10.1016/j.gassur.2003.08.001; Pollock BE, 2017, J NEUROSURG, V126, P852, DOI 10.3171/2015.11.JNS151300; Ren P, 2016, TUMOR BIOL, V37, P3215, DOI 10.1007/s13277-015-4150-3; Sin TK, 2016, INT J MOL SCI, V17, DOI 10.3390/ijms17020237; Steele SR, 2015, DIS COLON RECTUM, V58, P713, DOI 10.1097/DCR.0000000000000410; Sun Y, 2015, J RECEPT SIG TRANSD, V35, P600, DOI 10.3109/10799893.2015.1030412; Tominaga O, 1997, JPN J CANCER RES, V88, P855, DOI 10.1111/j.1349-7006.1997.tb00461.x; Veenman CJ, 2005, IEEE T PATTERN ANAL, V27, P1496, DOI 10.1109/TPAMI.2005.182; Vogel JD, 2017, DIS COLON RECTUM, V60, P999, DOI 10.1097/DCR.0000000000000926; Xu XL, 2019, EUR REV MED PHARMACO, V23, P7375, DOI 10.26355/eurrev_201909_18845; Xu X, 2016, BIOCHEM BIOPH RES CO, V479, P893, DOI 10.1016/j.bbrc.2016.09.087; Zuo QQ, 2014, INT J BIOL MARKER, V29, pE354, DOI 10.5301/jbm.5000107	36	1	1	0	1	DOVE MEDICAL PRESS LTD	ALBANY	PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND	1178-6930			ONCOTARGETS THER	OncoTargets Ther.		2021	14						3881	3894		10.2147/OTT.S311038			14	Biotechnology & Applied Microbiology; Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Oncology	SY3XP	WOS:000665824600001	34234457	Green Published, gold			2022-04-25	
J	Zhang, Z; Gao, W; Zhou, L; Chen, Y; Qin, SY; Zhang, L; Liu, JY; He, YJ; Lei, YL; Chen, HN; Han, JH; Zhou, ZG; Nice, EC; Li, CL; Huang, CH; Wei, XW				Zhang, Zhe; Gao, Wei; Zhou, Li; Chen, Yan; Qin, Siyuan; Zhang, Lu; Liu, Jiayang; He, Yujia; Lei, Yunlong; Chen, Hai-Ning; Han, Junhong; Zhou, Zong-Guang; Nice, Edouard C.; Li, Changlong; Huang, Canhua; Wei, Xiawei			Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy	THERANOSTICS			English	Article						Brigatinib; ALK independence; ER stress; ER-phagy; Colorectal cancer	UNFOLDED PROTEIN RESPONSE; SELECTIVE AUTOPHAGY; STRESS; APOPTOSIS; RESISTANCE	Rationale: The sustained and severe endoplasmic reticulum (ER) stress in cancer cells may contribute to apoptotic cell death, thus representing a potential target for cancer therapy. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small-cell lung cancer (NSCLC). However, it remains unclear if brigatinib has alternative model of action to exert antitumor effect in ALK-negative cancers. Methods: ALK-positive NSCLC cells and various human ALK-negative cancer cells, especially human colorectal cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells. Results: Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo, supporting the repurposing of brigatinib in CRC, independently of ALK. Conclusion: The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers.	[Zhang, Zhe; Gao, Wei; Zhou, Li; Chen, Yan; Qin, Siyuan; Zhang, Lu; Liu, Jiayang; Han, Junhong; Huang, Canhua; Wei, Xiawei] Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Chengdu 610041, Sichuan, Peoples R China; [Zhang, Zhe; Gao, Wei; Zhou, Li; Chen, Yan; Qin, Siyuan; Zhang, Lu; Liu, Jiayang; He, Yujia; Han, Junhong; Li, Changlong; Huang, Canhua; Wei, Xiawei] Sichuan Univ, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Sichuan, Peoples R China; [Zhang, Zhe; Gao, Wei; Zhou, Li; Chen, Yan; Qin, Siyuan; Zhang, Lu; Liu, Jiayang; Chen, Hai-Ning; Han, Junhong; Zhou, Zong-Guang; Huang, Canhua; Wei, Xiawei] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China; [Lei, Yunlong] Chongqing Med Univ, Dept Biochem & Mol Biol & Mol Med, Chongqing 400016, Peoples R China; [Lei, Yunlong] Chongqing Med Univ, Canc Res Ctr, Chongqing 400016, Peoples R China; [Chen, Hai-Ning; Zhou, Zong-Guang] Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Dept Gastrointestinal Surg, Chengdu 610041, Sichuan, Peoples R China; [Nice, Edouard C.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia		Huang, CH; Wei, XW (corresponding author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Chengdu 610041, Sichuan, Peoples R China.; Huang, CH; Wei, XW (corresponding author), Sichuan Univ, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Sichuan, Peoples R China.; Huang, CH; Wei, XW (corresponding author), Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China.	hcanhua@scu.edu.cn; xiaweiwei@scu.edu.cn	Chen, Hai-Ning/AAR-8059-2021	Chen, Hai-Ning/0000-0003-0104-8498; Zhang, Zhe/0000-0001-7509-6965; Han, Junhong/0000-0002-3371-8698; Lei, Yunlong/0000-0002-7918-0221; , Zongguang/0000-0002-7616-1199	Chinese NSFCNational Natural Science Foundation of China (NSFC) [81430071, 81790251, 81821002, 81672381]; National 973 Basic Research Program of ChinaNational Basic Research Program of China [2013CB911300]	This work was supported by grants from the Chinese NSFC (nos. 81430071, 81790251, 81821002 and 81672381), and National 973 Basic Research Program of China (no. 2013CB911300).	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J	Meng, SS; Xu, JS; Wu, YT; Ding, C				Meng, Songshu; Xu, Jiansheng; Wu, Yantao; Ding, Chan			Targeting autophagy to enhance oncolytic virus-based cancer therapy	EXPERT OPINION ON BIOLOGICAL THERAPY			English	Review						autophagy; cancer therapy; oncolysis; oncolytic virus	HERPES-SIMPLEX-VIRUS; CELL-DEATH; MYXOMA-VIRUS; IN-VIVO; ANTITUMOR-ACTIVITY; COLON-CANCER; STEM-CELLS; REPLICATION; ADENOVIRUS; GLIOMA	Introduction: Autophagy is a conserved catabolic process crucial in maintaining cellular homeostasis. On infection, oncolytic viruses (OVs) perturb the cellular autophagy machinery in infected tumor cells both in vitro and in vivo. Currently, pharmacological modulation of autophagy in OV-infected tumor cells has been shown to augment OV-mediated antitumor effects in preclinical studies. Combination of OVs with autophagy modulators can, therefore, have many potential applications in the future research on targeting autophagy and novel anticancer therapies. Areas covered: This review provides a detailed description of known interactions between OVs and autophagy and summarizes the roles of autophagy in OV replication and cell lysis. The recent literature on targeting autophagy with either the autophagy inducers, such as rapamycin, or autophagy inhibitors, such as chloroquine, to increase OV-induced cytotoxicity is reviewed to help researchers in further investigations. The major challenge for investigators is to understand the molecular mechanism underlying the interplay between OV and the autophagy machinery and its effect on oncolysis. Expert opinion: Targeting the cellular autophagy machinery could be explored as a new therapeutic strategy to enhance OV-mediated antitumor effects in the future.	[Meng, Songshu] Dalian Med Univ, Ctr Canc, Inst Canc Stem Cell, Dalian 116044, Peoples R China; [Xu, Jiansheng; Wu, Yantao] Yangzhou Univ, Coll Vet Med, Minist Educ, Key Lab Avian Prevent Med, Yangzhou 225009, Peoples R China; [Ding, Chan] Chinese Acad Agr Sci, Shanghai Vet Res Inst, Shanghai 200241, Peoples R China		Meng, SS (corresponding author), Dalian Med Univ, Ctr Canc, Inst Canc Stem Cell, 9 Lvshun Rd South, Dalian 116044, Peoples R China.	ssmeng@yzu.edu.cn; shoveldeen@shvri.ac.cn			State Key Laboratory of Veterinary Biotechnology of China [SKLVBF201109]; Program for Changjiang Scholars and Innovative Research Teams in UniversityProgram for Changjiang Scholars & Innovative Research Team in University (PCSIRT) [02738960345k]	This work was supported by grants from the State Key Laboratory of Veterinary Biotechnology of China (SKLVBF201109), the Program for Changjiang Scholars and Innovative Research Teams in University (02738960345k). The authors have no competing interests to declare.	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Biol. Ther.	JUN	2013	13	6					863	873		10.1517/14712598.2013.774365			11	Biotechnology & Applied Microbiology; Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Biotechnology & Applied Microbiology; Research & Experimental Medicine	142LL	WOS:000318798800005	23488666				2022-04-25	
J	Wang, PQ; Zhu, LJ; Sun, DJ; Gan, FH; Gao, SY; Yin, YY; Chen, LX				Wang, Peiqi; Zhu, Lingjuan; Sun, Dejuan; Gan, Feihong; Gao, Suyu; Yin, Yuanyuan; Chen, Lixia			Natural products as modulator of autophagy with potential clinical prospects	APOPTOSIS			English	Review						Natural compounds; Autophagy; Disease; Drug therapy	ENDOPLASMIC-RETICULUM STRESS; ACTIVATED PROTEIN-KINASE; CELL-CYCLE ARREST; COLON-CANCER CELLS; INDUCED APOPTOSIS; ER STRESS; OXIDATIVE STRESS; PROSTATE-CANCER; SIGNALING PATHWAYS; MITOCHONDRIAL ROS	Natural compounds derived from living organisms are well defined for their remarkable biological and pharmacological properties likely to be translated into clinical use. Therefore, delving into the mechanisms by which natural compounds protect against diverse diseases may be of great therapeutic benefits for medical practice. Autophagy, an intricate lysosome-dependent digestion process, with implications in a wide variety of pathophysiological settings, has attracted extensive attention over the past few decades. Hitherto, accumulating evidence has revealed that a large number of natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways and transcriptional regulators. In this review, we summarize natural compounds regulating autophagy in multifarious diseases including cancer, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and immune diseases, hoping to inspire further investigation of the underlying mechanisms of natural compounds and to facilitate their clinical use for multiple human diseases.	[Wang, Peiqi; Zhu, Lingjuan; Sun, Dejuan; Gan, Feihong; Gao, Suyu; Yin, Yuanyuan; Chen, Lixia] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China; [Wang, Peiqi; Gan, Feihong; Yin, Yuanyuan] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610041, Peoples R China		Chen, LX (corresponding author), Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China.	syzyclx@163.com	Chen, Lixia/ABH-1629-2021	Chen, Lixia/0000-0003-2196-1428	National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [31270399, 81603275]; Key Projects of the National Science and Technology Pillar Program [2012BAI30B02]; Fund of the Educational Department of Liaoning Province [L2011177]; Liaoning Baiqianwan Talents Program [2013921043]; Liaoning Province Natural Science FoundationNatural Science Foundation of Liaoning Province [201602689]; Scientific Research Foundation for the Returned Overseas Chinese Scholars of Shenyang Pharmaceutical UniversityScientific Research Foundation for the Returned Overseas Chinese Scholars [GGJJ2015103]; Career Development Program for Young and Middle-aged Teachers of Shenyang Pharmaceutical University [ZQN2015015]	We acknowledge support from the National Natural Science Foundation of China (NSFC) (Grant Number 31270399 and Grant Number 81603275), Key Projects of the National Science and Technology Pillar Program (Grant Number 2012BAI30B02), Fund of the Educational Department of Liaoning Province (Grant Number L2011177), Liaoning Baiqianwan Talents Program (Grant Number 2013921043), Liaoning Province Natural Science Foundation (Grant Number 201602689), Scientific Research Foundation for the Returned Overseas Chinese Scholars of Shenyang Pharmaceutical University (Grant Number GGJJ2015103), and 2015 Career Development Program for Young and Middle-aged Teachers of Shenyang Pharmaceutical University (Grant Number ZQN2015015).	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Cell Biology	EL1GG	WOS:000394367900001	27988811				2022-04-25	
J	Zhou, J; Ji, Q; Li, Q				Zhou, Jing; Ji, Qing; Li, Qi			Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies	JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH			English	Review						Metastatic colorectal cancer; Anti-epidermal growth factor receptor targeted therapies; Drug resistance; Reversal strategies	GROWTH-FACTOR RECEPTOR; PHASE-II TRIAL; WILD-TYPE KRAS; CETUXIMAB PLUS IRINOTECAN; K-RAS MUTATIONS; COLON-CANCER; MONOCLONAL-ANTIBODY; 1ST-LINE TREATMENT; ACQUIRED-RESISTANCE; TGF-ALPHA	Cetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). Cetuximab can prolong survival by 8.2 months in RAS wild-type (WT) mCRC patients. Unfortunately, resistance to targeted therapy impairs clinical use and efficiency. The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. Multiple therapeutic strategies have been investigated extensively to overcome resistance to anti-EGFR mAbs. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. For intrinsic mechanisms, therapies mainly cover the following: new EGFR-targeted inhibitors, a combination of multitargeted inhibitors, and metabolic regulators. In addition, new cytotoxic drugs and small molecule compounds increase the efficiency of cetuximab. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis. The directions include the modification or activation of immune cells and suppression of CAFs and anti-VEGFR agents. In this review, we focus on the mechanisms of resistance to anti-EGFR monoclonal antibodies (anti-EGFR mAbs) and discuss diverse approaches to reverse resistance to this therapy in hopes of identifying more mCRC treatment possibilities.	[Zhou, Jing; Ji, Qing; Li, Qi] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, Shanghai 201203, Peoples R China; [Zhou, Jing; Ji, Qing; Li, Qi] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Inst Canc, Shanghai 201203, Peoples R China; [Li, Qi] Shanghai Univ Tradit Chinese Med, Acad Integrat Med, Shanghai 201203, Peoples R China		Ji, Q; Li, Q (corresponding author), Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, Shanghai 201203, Peoples R China.; Ji, Q; Li, Q (corresponding author), Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Inst Canc, Shanghai 201203, Peoples R China.; Li, Q (corresponding author), Shanghai Univ Tradit Chinese Med, Acad Integrat Med, Shanghai 201203, Peoples R China.	ttt99118@hotmail.com; qili@shutcm.edu.cn		Ji, Qing/0000-0002-1899-0204; Li, Qi/0000-0003-2004-6885	National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81830120, 82074225]; Clinical Research Plan of Shanghai Hospital Development Center [SHDC2020CR4043]	This work was supported by National Science Foundation of China (81830120 to Q.L., 82074225 to Q.J.) and Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR4043 to Y.W.).	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Exp. Clin. Cancer Res.	OCT 18	2021	40	1							328	10.1186/s13046-021-02130-2			17	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	WI6PP	WOS:000708480300001	34663410	Green Published, gold			2022-04-25	
J	Wu, JP; Liu, SL; Chen, XM; Xu, HF; Tang, YP				Wu, Jianping; Liu, Sulai; Chen, Xiaoming; Xu, Hongfei; Tang, Yaoping			Machine learning identifies two autophagy-related genes as markers of recurrence in colorectal cancer	JOURNAL OF INTERNATIONAL MEDICAL RESEARCH			English	Article						Colorectal cancer; machine learning; regression; autophagy; autophagy-related gene; recurrence	BREAST-CANCER; EXPRESSION; MACROAUTOPHAGY; REGULATOR; CELLS; SCORE; RISK	Objective Colorectal cancer (CRC) is the most common cancer worldwide. Patient outcomes following recurrence of CRC are very poor. Therefore, identifying the risk of CRC recurrence at an early stage would improve patient care. Accumulating evidence shows that autophagy plays an active role in tumorigenesis, recurrence, and metastasis. Methods We used machine learning algorithms and two regression models, univariable Cox proportion and least absolute shrinkage and selection operator (LASSO), to identify 26 autophagy-related genes (ARGs) related to CRC recurrence. Results By functional annotation, these ARGs were shown to be enriched in necroptosis and apoptosis pathways. Protein-protein interactions identifiedSQSTM1,CASP8,HSP80AB1,FADD, andMAPK9as core genes in CRC autophagy. Of 26 ARGs,BAXandPARP1were regarded as having the most significant predictive ability of CRC recurrence, with prediction accuracy of 71.1%. Conclusion These results shed light on prediction of CRC recurrence by ARGs. Stratification of patients into recurrence risk groups by testing ARGs would be a valuable tool for early detection of CRC recurrence.	[Wu, Jianping; Chen, Xiaoming; Xu, Hongfei; Tang, Yaoping] Hunan Univ Sci & Engn, 130 Yangzitang Rd, Yongzhou 425100, Peoples R China; [Liu, Sulai] Hunan Normal Univ, Hunan Prov Peoples Hosp, Dept Hepatobiliary Surg, Affiliated Hosp 1, Changsha, Peoples R China		Tang, YP (corresponding author), Hunan Univ Sci & Engn, 130 Yangzitang Rd, Yongzhou 425100, Peoples R China.	daiqilai1988@163.com		Liu, Sulai/0000-0002-5257-3922			Bednarczyk M, 2017, J BIOL REG HOMEOS AG, V31, P923; Boga JA, 2019, J PINEAL RES, V66, DOI 10.1111/jpi.12534; Cao QH, 2016, AM J TRANSL RES, V8, P3831; Chen D, 2018, ONCOL LETT, V15, P7104, DOI 10.3892/ol.2018.8206; Coleman MP, 2008, LANCET ONCOL, V9, P730, DOI 10.1016/S1470-2045(08)70179-7; Courtiol P, 2019, NAT MED, V25, P1519, DOI 10.1038/s41591-019-0583-3; Duan X, 2018, APOPTOSIS, V23, P587, DOI 10.1007/s10495-018-1489-0; Feldmann A, 2017, BIOCHEM BIOPH RES CO, V486, P738, DOI 10.1016/j.bbrc.2017.03.112; Friedman J, 2010, J STAT SOFTW, V33, P1, DOI 10.18637/jss.v033.i01; Gil J, 2017, MED ONCOL, V34, DOI 10.1007/s12032-016-0869-y; Gray RG, 2011, J CLIN ONCOL, V29, P4611, DOI 10.1200/JCO.2010.32.8732; Guillaume JD, 2019, METHODS MOL BIOL, V1862, P151, DOI 10.1007/978-1-4939-8769-6_11; Han Q, 2017, SCI REP-UK, V7, DOI 10.1038/s41598-017-04994-x; Han YY, 2018, INT J ONCOL, V52, P1057, DOI 10.3892/ijo.2018.4270; Ianniciello A, 2018, FRONT CELL DEV BIOL, V6, DOI 10.3389/fcell.2018.00120; Jiao YN, 2018, CANCER CELL INT, V18, DOI 10.1186/s12935-018-0646-4; Kinsey CG, 2019, NAT MED, V25, P620, DOI 10.1038/s41591-019-0367-9; Li WL, 2016, EXP THER MED, V11, P1259, DOI 10.3892/etm.2016.3054; Liang ZG, 2018, CANCER MANAG RES, V10, P4125, DOI 10.2147/CMAR.S176536; Lin P, 2018, INT J ONCOL, V53, P603, DOI 10.3892/ijo.2018.4404; Loboda A, 2011, BMC MED GENOMICS, V4, DOI 10.1186/1755-8794-4-9; Ma C, 2018, PLOS ONE, V13, DOI 10.1371/journal.pone.0189452; Ma YB, 2018, EXP THER MED, V15, P4671, DOI 10.3892/etm.2018.5999; Marcuello M, 2019, MOL ASPECTS MED, V69, P107, DOI 10.1016/j.mam.2019.06.002; McGuire S, 2014, ADV NUTR, V5, P456, DOI 10.3945/an.114.006171; Pajares M, 2016, AUTOPHAGY, V12, P1902, DOI 10.1080/15548627.2016.1208889; Renehan AG, 2016, LANCET ONCOL, V17, P174, DOI 10.1016/S1470-2045(15)00467-2; Ritchie ME, 2015, NUCLEIC ACIDS RES, V43, DOI 10.1093/nar/gkv007; Robertson DJ, 2019, GASTROENTEROLOGY, V156, P904, DOI 10.1053/j.gastro.2018.12.012; Sanz-Pamplona R, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0048877; Sing T, 2005, BIOINFORMATICS, V21, P3940, DOI 10.1093/bioinformatics/bti623; Specogna AV, 2020, LANCET, V395, P314, DOI 10.1016/S0140-6736(20)30034-9; Subramanian A, 2005, P NATL ACAD SCI USA, V102, P15545, DOI 10.1073/pnas.0506580102; Sun T, 2017, CELL PHYSIOL BIOCHEM, V44, P716, DOI 10.1159/000485285; Sveen A, 2020, NAT REV CLIN ONCOL, V17, P11, DOI 10.1038/s41571-019-0241-1; Tabernero J, 2015, LANCET ONCOL, V16, P937, DOI 10.1016/S1470-2045(15)00138-2; Tie J, 2019, JAMA ONCOL, V5, P1710, DOI 10.1001/jamaoncol.2019.3616; Tie J, 2018, EXPERT REV MOL DIAGN, V18, P1, DOI 10.1080/14737159.2018.1386558; Venook AP, 2013, J CLIN ONCOL, V31, P1775, DOI 10.1200/JCO.2012.45.1096; Wang C, 2018, CELL DEATH DIS, V9, P1, DOI 10.1038/s41419; Weil J, 2016, NAT IMMUNOL, V17, P277, DOI 10.1038/ni.3365; Wu YQ, 2018, ONCOTARGETS THER, V11, P5621, DOI 10.2147/OTT.S176744; Yu GC, 2012, OMICS, V16, P284, DOI 10.1089/omi.2011.0118; Zhang HX, 2017, ONCOTARGET, V8, P60987, DOI 10.18632/oncotarget.17719; Zhao YX, 2019, ONCOL REP, V41, P27, DOI 10.3892/or.2018.6780; Zheng LQ, 2018, ONCOL LETT, V15, P4837, DOI 10.3892/ol.2018.7971; Zhu FX, 2019, ONCOL LETT, V18, P5310, DOI 10.3892/ol.2019.10881; Zhu HS, 2017, WORLD J SURG ONCOL, V15, DOI 10.1186/s12957-017-1211-7; Zhu J, 2018, MED SCI MONITOR, V24, P7035, DOI 10.12659/MSM.910650	49	0	0	3	8	SAGE PUBLICATIONS LTD	LONDON	1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND	0300-0605	1473-2300		J INT MED RES	J. Int. Med. Res.	OCT	2020	48	10							0300060520958808	10.1177/0300060520958808			13	Medicine, Research & Experimental; Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine; Pharmacology & Pharmacy	OK4XO	WOS:000584655500001	33076720	Green Published, gold			2022-04-25	
J	Zhou, XH; Li, XH; Ma, WJ; Xu, JL				Zhou, Xihan; Li, Xiaohui; Ma, Weijin; Xu, Jiali			Baicalin Improves Intestinal Injury in Mice with Experimental Colitis Via Regulation Autophagy	LATIN AMERICAN JOURNAL OF PHARMACY			English	Article						autophagy; baicalin; Beclin1; LC3B; UC	INFLAMMATORY-BOWEL-DISEASE; CURCUMIN; CANCER; MAINTENANCE; MECHANISMS; EXPRESSION; PROTECTS	The objective was to observe the expression change of autophagy proteins Beclin1 and LC3B in colon tissue of mice with experimental colitis induced by sodium dextran sulfate (DSS), and to explore the role and possible mechanism of baicalin in colitis. Sixty BALB/c mice were randomly divided into normal group, the other group, Model group, baicalin gavage group and mesalazine gavage group, with 15 mice in each group. Except the normal group, the other groups received DSS method to establish colitis models. From the first day of modeling, the baicalin gavage group received baicalin, the mesalazing group was administered with mesalazine suspension, and the Model group and normal groups were gien with normal saline. Modeling period lasted for 21 days, and the mice were sacrificed on the 22nd day with taking the specimens. The general condition of the mice and the pathological damage of the colon were observed and the apoptosis cell number were measured by TUNEL assay. The expression of Beclin1 and LC3B in the colon tissue were detected by immunofluorescence and Western Blot. By HE and TUNEL assay. The histopathological damage score and the positive apoptosis cell number of model group were significantly increased compared with those of normal group (p < 0.001, respectively), and Beclin1 and LC3B proteins expressions were significantly up-regulation by IHC and WB assay (p < 0.001, respectively). With baicalin supplement, the histopathological damage score and the positive apoptosis cell number of baicalin group were significantly improved, and the Beclin1 and LC3B proteins expressions were significantly depressed compared with Model group (p < 0.001, respectively). In conclusion: baicalin improve intestinal injury in mice with experimental colitis via regulation autophagy.	[Zhou, Xihan] Wuhan Fifth Hosp, Dept Gastroenterol, Wuhan 430050, Peoples R China; [Li, Xiaohui] Wuhan Fifth Hosp, Dept Paediat, Wuhan 430050, Peoples R China; [Ma, Weijin] Wuhan Fifth Hosp, Hosp Acquired Infect Control Dept, Wuhan 430050, Peoples R China; [Xu, Jiali] Wuhan Fifth Hosp, Discipline Inspect & Supervis Room, Wuhan 430050, Peoples R China		Xu, JL (corresponding author), Wuhan Fifth Hosp, Discipline Inspect & Supervis Room, Wuhan 430050, Peoples R China.						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Am. J. Pharm.		2021	40	9					2092	2098					7	Pharmacology & Pharmacy	Science Citation Index Expanded (SCI-EXPANDED)	Pharmacology & Pharmacy	WC7SP	WOS:000704454400014					2022-04-25	
J	Zhao, HZ; Xi, HQ; Wei, B; Cai, AZ; Wang, T; Wang, Y; Zhao, XD; Song, YJ; Chen, L				Zhao, Huazhou; Xi, Hongqing; Wei, Bo; Cai, Aizhen; Wang, Ting; Wang, Yi; Zhao, Xudong; Song, Yanjing; Chen, Lin			Expression of decorin in intestinal tissues of mice with inflammatory bowel disease and its correlation with autophagy	EXPERIMENTAL AND THERAPEUTIC MEDICINE			English	Article						decorin; inflammatory bowel disease; autophagy	CROHNS-DISEASE; BREAST-CANCER; IBD; INFECTION; FIBROSIS; THERAPY; SURGERY; INJURY; ALPHA	The aim of this study was to investigate the expression of decorin (DCN) in the intestinal tissues of mice with inflammatory bowel disease (IBD) and its correlation with autophagy. The IBD mouse model was created by intrarectal injection of trinitrobenzene sulfonic acid. The pathology of colon tissues of the mice was examined using hematoxylin and eosin staining. Expression of DCN and the proteins associated with autophagy was detected using immunohistochemistry. Normal human colon mucosal epithelial cells (NCM460 cells) were transfected with DCN expression plasmid and the expression of DCN and autophagy-associated proteins was detected by western blot analysis. Cell apoptosis was studied using an Annexin V apoptosis detection assay and intracellular autophagosomes were observed using electron microscopy. The IBD mouse model was successfully established. Thickening, edema and inflammatory cell infiltration of the intestinal wall were observed in the IBD mice. The expression of DCN as well as the autophagy-associated proteins beclin 1 and LC3B, was increased in the intestinal tissues of the IBD mice. Furthermore, in the NCM460 cells transfected with DCN, the expression of beclin 1 and LC3B was upregulated, while p62 expression was downregulated. Intracellular autophagosomes were increased and apoptosis was decreased in the cells with DCN overexpression. Inhibition of autophagy reversed the effects of DCN on apoptosis. Therefore, DCN is able to induce autophagy and protect intestinal cells during the occurrence and development of IBD.	[Zhao, Huazhou; Xi, Hongqing; Wei, Bo; Cai, Aizhen; Wang, Yi; Zhao, Xudong; Song, Yanjing; Chen, Lin] Chinese Peoples Liberat Army, Gen Hosp, Dept Gen Surg, 28 Fuxing Rd, Beijing 100853, Peoples R China; [Zhao, Huazhou; Wang, Yi] Chinese Peoples Liberat Army, Hosp 309, Dept Gen Surg, Beijing 100091, Peoples R China; [Wang, Ting] Beijing Chaoyang Hosp, Med Adm Div, Beijing 100020, Peoples R China		Wei, B (corresponding author), Chinese Peoples Liberat Army, Gen Hosp, Dept Gen Surg, 28 Fuxing Rd, Beijing 100853, Peoples R China.	weibobj301@sina.com; sdc1678@126.com		song, yanjing/0000-0001-7104-0649	National High Technology Research and Development Program of ChinaNational High Technology Research and Development Program of China [2012AA02A504]; Army Medical Science Youth Development Project [13QNP185]	This study was supported by the National High Technology Research and Development Program of China (grant no. 2012AA02A504) and Army Medical Science Youth Development Project (grant no. 13QNP185).	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Ther. Med.	DEC	2016	12	6	B				3885	3892		10.3892/etm.2016.3908			8	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	EG5IC	WOS:000391076500010	28105121	Green Published, Green Submitted, gold			2022-04-25	
J	Liu, ZZ; Liu, XF; Li, Y; Ren, PW; Zhang, CF; Wang, LJ; Du, XJ; Xing, BC				Liu, Zhenzhen; Liu, Xiaofeng; Li, Yuan; Ren, Pengwei; Zhang, Chunfeng; Wang, Lijun; Du, Xiaojuan; Xing, Baocai			miR-6716-5p promotes metastasis of colorectal cancer through downregulating NAT10 expression	CANCER MANAGEMENT AND RESEARCH			English	Article						miR-6716-5p; NAT10; colorectal cancer; CRC; liver metastasis	N-ACETYLTRANSFERASE 10; MICRORNA EXPRESSION; RIBOSOMAL-RNA; HOUSEKEEPING GENE; LIVER METASTASES; COLON-CANCER; WEB SERVER; E-CADHERIN; NORMALIZATION; PROTEIN	Background: Human N-acetyltransferase 10 (NAT10) plays pivotal roles in cellular biological processes, such as senescence, autophagy and cytokinesis. The expression of NAT10 is dysregulated in colorectal cancer (CRC) and is associated with the prognosis of patients. However, it remains unclear how NAT10 is regulated in CRC. Methods: The microRNA(miRNA) regulating NAT10 was predicted by bioinformatics analysis and further validated by real-time quantitative PCR(RT-qPCR), Western blot and dual luciferase reporter assays. The expression of the miRNA regulating NAT10 in CRC tissues was examined using RT-qPCR. Cell proliferation, cell apoptosis, cell migration and cell invasion assays were performed after transfection with miRNA mimic and inhibitor. Results: Here, we report that miR-6716-5p inhibits the expression of NAT10 in CRC. The NAT10 protein level was downregulated by the miR-6716-5p mimic, and was upregulated by the miR-6716-5p inhibitor in CRC cell lines. In addition, miR-6716-5p bound to the 3'-untranslated region of NAT10 mRNA and decreased NAT10 mRNA levels. Significantly, the miR-6716-5p level was higher in the tumor tissues of the CRC patients with liver metastasis than that in the non-metastatic CRC patients. In addition, the miR-6716-5p level was correlated with poor overall survival of CRC patients with liver metastasis. The miR-6716-5p inhibitor inhibited CRC cell migration and invasion. Consistently, the miR-6716-5p mimic significantly promoted cell migration and invasion, and this effect is dependent on NAT10. However, miR-6716-5p had no effect on CRC cell proliferation and apoptosis. We found that miR-6716-5p negatively regulated E-cadherin protein levels. In addition, E-cadherin was upregulated by NAT10 in CRC cells, confirming that miR-6716-5p downregulated E-cadherin levels by inhibiting NAT10 expression. Conclusion: We demonstrated that miR-6716-5p acts as a crucial regulator of NAT10 to promote cell migration and invasion in CRC by inhibiting NAT10 expression. Our data suggest that miR-6716-5p/NAT10 might act as a potential therapeutic target for CRC treatment.	[Liu, Zhenzhen; Liu, Xiaofeng; Li, Yuan; Wang, Lijun; Xing, Baocai] Peking Univ, Sch Oncol, Hepatopancreatobiliary Surg Dept 1,Peking Univ Ca, Key Lab Carcinogenesis & Translat Res,Minist Educ, 52 Fucheng Rd, Beijing 100142, Peoples R China; [Ren, Pengwei; Du, Xiaojuan] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Cell Biol, 38 Xueyuan Rd, Beijing 100191, Peoples R China; [Zhang, Chunfeng] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Med Genet, Beijing 100191, Peoples R China		Xing, BC (corresponding author), Peking Univ, Sch Oncol, Hepatopancreatobiliary Surg Dept 1,Peking Univ Ca, Key Lab Carcinogenesis & Translat Res,Minist Educ, 52 Fucheng Rd, Beijing 100142, Peoples R China.; Du, XJ (corresponding author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Cell Biol, 38 Xueyuan Rd, Beijing 100191, Peoples R China.	duxiaojuan100@bjmu.edu.cn; xingbaocai88@sina.com	Du, Xiaojuan/AAY-1186-2021; Liu, Xiaofeng/AAR-2488-2020	, Xiaofeng/0000-0002-3264-122X	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81672735, 81371868, 81621063]; 973 ProgramNational Basic Research Program of China [2013CB837201]; Chinese Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2018M641118]; Innovation Team of Ministry of Education [IRT13001]	This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81672735, 81371868 and 81621063), the 973 Program (Grant No. 2013CB837201), Chinese Postdoctoral Science Foundation (2018M641118), and grant from the Innovation Team of Ministry of Education (IRT13001).	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Res.		2019	11						5317	5332		10.2147/CMAR.S197733			16	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	IC1EY	WOS:000470703200007	31239781	Green Published, gold, Green Submitted			2022-04-25	
J	Dabrowska, M; Skoneczny, M; Rode, W				Dabrowska, Magdalena; Skoneczny, Marek; Rode, Wojciech			Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells	TUMOR BIOLOGY			English	Article						High-dose methotrexate; Colorectal adenocarcinoma; Drug-induced senescence; Expression microarrays; Signaling pathways	NITRIC-OXIDE; CELLULAR SENESCENCE; DNA-DAMAGE; DOSE METHOTREXATE; SALVAGE PATHWAY; TETRAHYDROBIOPTERIN; CONTRIBUTES; INVOLVEMENT; ACTIVATION; RESISTANCE	Cellular functions accompanying establishment of premature senescence in methotrexate-treated human colon cancer C85 cells are deciphered in the present study from validated competitive expression microarray data, analyzed with the use of Ingenuity Pathways Analysis (IPA) software. The nitrosative/oxidative stress, inferred from upregulated expression of inducible nitric oxide synthase (iNOS) and mitochondrial dysfunction-associated genes, including monoamine oxidases MAOA and MAOB, beta-amyloid precursor protein (APP) and presenilin 1 (PSEN1), is identified as the main determinant of signaling pathways operating during senescence establishment. Activation of p53-signaling pathway is found associated with both apoptotic and autophagic components contributing to this process. Activation of nuclear factor kappa B (NF-kappa B), resulting from interferon gamma (IFN gamma), integrin, interleukin 1 beta (IL-1 beta), IL-4, IL-13, IL-22, Toll-like receptors (TLRs) 1, 2 and 3, growth factors and tumor necrosis factor (TNF) superfamily members signaling, is found to underpin inflammatory properties of senescent C85 cells. Upregulation of p21-activated kinases (PAK2 and PAK6), several Rho molecules and myosin regulatory light chains MYL12A and MYL12B, indicates acquisition of motility by those cells. Mitogen-activated protein kinase p38 MAPK beta, extracellular signal-regulated kinases ERK2 and ERK5, protein kinase B AKT1, as well as calcium, are identified as factors coordinating signaling pathways in senescent C85 cells.	[Dabrowska, Magdalena; Rode, Wojciech] Polish Acad Sci, Nencki Inst Expt Biol, PL-02093 Warsaw, Poland; [Skoneczny, Marek] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland		Dabrowska, M (corresponding author), Polish Acad Sci, Nencki Inst Expt Biol, Pasteura 3, PL-02093 Warsaw, Poland.	m.dabrowska@nencki.gov.pl	Rode, Wojciech K/A-4891-2008; Skoneczny, Marek/S-5390-2019	Skoneczny, Marek/0000-0001-9922-2276; Dabrowska, Magdalena/0000-0001-7487-8930			Abreu MT, 2010, NAT REV IMMUNOL, V10, P131, DOI 10.1038/nri2707; Bartek J, 2008, NAT CELL BIOL, V10, P887, DOI 10.1038/ncb0808-887; Blagosklonny MV, 2003, EMBO REP, V4, P358, DOI 10.1038/sj.embor.embor806; Cagnol S, 2010, FEBS J, V277, P2, DOI 10.1111/j.1742-4658.2009.07366.x; Campisi J, 2007, NAT REV MOL CELL BIO, V8, P729, DOI 10.1038/nrm2233; Choi K, 2010, CELL DEATH DIFFER, V17, P833, DOI 10.1038/cdd.2009.154; Colasanti M, 2000, TRENDS PHARMACOL SCI, V21, P249, DOI 10.1016/S0165-6147(00)01499-1; Collado M, 2010, NAT REV CANCER, V10, P51, DOI 10.1038/nrc2772; Copeland NG, 2009, TRENDS GENET, V25, P455, DOI 10.1016/j.tig.2009.08.004; Cosentino F, 1999, CARDIOVASC RES, V43, P274, DOI 10.1016/S0008-6363(99)00134-0; Crabtree MJ, 2009, J BIOL CHEM, V284, P28128, DOI 10.1074/jbc.M109.041483; Dabrowska M, 2007, EUR J PHARMACOL, V555, P93, DOI 10.1016/j.ejphar.2006.10.052; Dabrowska M, 2009, PTERIDINES, V20, P143; Dabrowska M, 2009, CANCER LETT, V284, P95, DOI 10.1016/j.canlet.2009.04.015; Dasari A, 2006, CANCER RES, V66, P10805, DOI 10.1158/0008-5472.CAN-06-1236; Delgado MA, 2009, CELL DEATH DIFFER, V16, P976, DOI 10.1038/cdd.2009.40; di Fagagna FD, 2008, NAT REV CANCER, V8, P512, DOI 10.1038/nrc2440; Fridman AL, 2008, ONCOGENE, V27, P5975, DOI 10.1038/onc.2008.213; Fukumura D, 2006, NAT REV CANCER, V6, P521, DOI 10.1038/nrc1910; Fumagalli M, 2009, NAT CELL BIOL, V11, P921, DOI 10.1038/ncb0809-921; Gewirtz DA, 2008, BIOCHEM PHARMACOL, V76, P947, DOI 10.1016/j.bcp.2008.06.024; Gewirtz DA, 2009, AUTOPHAGY, V5, P1232, DOI 10.4161/auto.5.8.9896; Hasegawa H, 2005, MOL GENET METAB, V86, pS2, DOI 10.1016/j.ymgme.2005.09.002; Herman S, 2005, INFLAMM RES, V54, P273, DOI 10.1007/s00011-005-1355-8; Hong Z, 2007, J CELL PHYSIOL, V210, P567, DOI 10.1002/jcp.20919; Iwasa H, 2003, GENES CELLS, V8, P131, DOI 10.1046/j.1365-2443.2003.00620.x; Khan EM, 2006, J BIOL CHEM, V281, P14486, DOI 10.1074/jbc.M509332200; Kinsella AR, 1997, BRIT J CANCER, V75, P935, DOI 10.1038/bjc.1997.164; Kumar MJ, 2003, J BIOL CHEM, V278, P46432, DOI 10.1074/jbc.M306378200; Levine B, 2004, DEV CELL, V6, P463, DOI 10.1016/S1534-5807(04)00099-1; Longo GSA, 2000, ONCOL RES, V12, P309; Manoli I, 2005, FASEB J, V19, P1359, DOI 10.1096/fj.04-3660fje; MARITTO S, 2004, NEUROENDOCRINE IMMUN, P291; Martin SA, 2009, EMBO MOL MED, V1, P323, DOI 10.1002/emmm.200900040; MONCADA S, 1991, PHARMACOL REV, V43, P109; Mruk DD, 2004, ENDOCR REV, V25, P747, DOI 10.1210/er.2003-0022; Novakova Z, 2010, ONCOGENE, V29, P273, DOI 10.1038/onc.2009.318; Passos JF, 2007, PLOS BIOL, V5, P1138, DOI 10.1371/journal.pbio.0050110; Passos JF, 2006, FREE RADICAL RES, V40, P1277, DOI 10.1080/10715760600917151; Passos JF, 2010, MOL SYST BIOL, V6, DOI 10.1038/msb.2010.5; Polyak K, 1997, NATURE, V389, P300, DOI 10.1038/38525; Ramsey MR, 2006, NAT CELL BIOL, V8, P1213, DOI 10.1038/ncb1106-1213; Ravikumar B, 2010, NAT CELL BIOL, V12, P747, DOI 10.1038/ncb2078; Robaey P, 2008, DEV DISABIL RES REV, V14, P211, DOI 10.1002/ddrr.29; Rodier F, 2009, NAT CELL BIOL, V11, P973, DOI 10.1038/ncb1909; Sauer H, 2001, CELL PHYSIOL BIOCHEM, V11, P173, DOI 10.1159/000047804; Scherz-Shouval R, 2007, TRENDS CELL BIOL, V17, P422, DOI 10.1016/j.tcb.2007.07.009; Schulze-Osthoff K, 1998, EUR J BIOCHEM, V254, P439, DOI 10.1046/j.1432-1327.1998.2540439.x; Stuehr D, 2001, J BIOL CHEM, V276, P14533, DOI 10.1074/jbc.R100011200; Swanton C, 2009, BRIT J CANCER, V100, P1517, DOI 10.1038/sj.bjc.6605031; Tesniere A, 2008, CELL DEATH DIFFER, V15, P3, DOI 10.1038/sj.cdd.4402269; Vousden KH, 2007, NAT REV MOL CELL BIO, V8, P275, DOI 10.1038/nrm2147; Woo HA, 2010, CELL, V140, P517, DOI 10.1016/j.cell.2010.01.009; Young ARJ, 2009, GENE DEV, V23, P798, DOI 10.1101/gad.519709; Zarubin T, 2005, CELL RES, V15, P11, DOI 10.1038/sj.cr.7290257; Zelcer S, 2008, PEDIATR BLOOD CANCER, V50, P1176, DOI 10.1002/pbc.21419	56	21	21	1	17	SAGE PUBLICATIONS LTD	LONDON	1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND	1010-4283	1423-0380		TUMOR BIOL	Tumor Biol.	OCT	2011	32	5					965	976		10.1007/s13277-011-0198-x			12	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	808FO	WOS:000293962800014	21678067	hybrid, Green Published			2022-04-25	
J	Lai, HH; Lin, LJ; Hung, LY; Chen, PS				Lai, Hui-Huang; Lin, Li-Jyuan; Hung, Liang-Yi; Chen, Pai-Sheng			Role of Dicer in regulating oxaliplatin resistance of colon cancer cells	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS			English	Article						Oxaliplatin; Dicer; CHIP; Ubiquitination	COLORECTAL-CANCER; BREAST-CANCER; AUTOPHAGY; FLUOROURACIL; LEUCOVORIN	Colorectal cancer (CRC) is a major health problem due to its high mortality rate. The incidence of CRC is increasing in young individuals. Oxaliplatin (OXA) is an approved third-generation drug and is used for first-line chemotherapy in CRC. Although current standard chemotherapy improves the overall survival of CRC patients, an increasing number of reports of OXA resistance in CRC therapy indicates that resistance has become an urgent problem in clinical applications. Dicer is a critical enzyme involved in miRNA maturation. The expression of Dicer has been reported to be involved in the resistance to various drugs in cancer. In the present study, we aimed to investigate the role of Dicer in OXA resistance in CRC. We found that OXA treatment inhibited Dicer expression through decreasing the protein stability. OXA-induced Dicer protein degradation occurred through both proteasomal and lysosomal proteolysis, while the CHIP E3 ligase was involved in OXA-mediated Dicer ubiquitination and degradation. We established stable OXA-resistant clones from CRC cells, and observed that the CHIP E3 ligase was decreased, along with the increased Dicer expression in OXA-resistant cells. Knockdown of Dicer resensitized CRC cells to OXA treatment. In this study, we have revealed the role of miRNA biogenesis factors in OXA resistance in CRC cells. (C) 2018 Elsevier Inc. All rights reserved.	[Lai, Hui-Huang; Chen, Pai-Sheng] Natl Cheng Kung Univ, Inst Basic Med Sci, Coll Med, Tainan, Taiwan; [Lai, Hui-Huang; Chen, Pai-Sheng] Natl Cheng Kung Univ, Dept Med Lab Sci & Biotechnol, Coll Med, 1 Univ Rd, Tainan 701, Taiwan; [Lin, Li-Jyuan; Hung, Liang-Yi] Natl Cheng Kung Univ, Dept Biotechnol & Bioind Sci, Coll Biosci & Biotechnol, Tainan, Taiwan		Chen, PS (corresponding author), Natl Cheng Kung Univ, Dept Med Lab Sci & Biotechnol, Coll Med, 1 Univ Rd, Tainan 701, Taiwan.	bio.benson@gmail.com	Chen, Pai-Sheng/G-2130-2012; Hung, Liang-Yi/AAG-4174-2019	Chen, Pai-Sheng/0000-0003-0513-1467; 	Ministry of Science and Technology, TaiwanMinistry of Science and Technology, Taiwan [MOST 107-2320-B-006-009, MOST 107-2320-B-006-068, MOST 106-2320-B-006-038, MOST 106-2320-B-006-021]	We thank Dr. Ming-Derg Lai for the technical support. This study was supported by the Ministry of Science and Technology, Taiwan (MOST 107-2320-B-006-009, MOST 107-2320-B-006-068, MOST 106-2320-B-006-038, MOST 106-2320-B-006-021).	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Biophys. Res. Commun.	NOV 17	2018	506	1					87	93		10.1016/j.bbrc.2018.10.071			7	Biochemistry & Molecular Biology; Biophysics	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Biophysics	HC6UI	WOS:000451936800014	30336979				2022-04-25	
J	Kim, SM; Ha, E; Kim, J; Cho, C; Shin, SJ; Seo, JH				Kim, Sun Myung; Ha, Eunyoung; Kim, Jinyoung; Cho, Chiheum; Shin, So-Jin; Seo, Ji Hae			NAA10 as a New Prognostic Marker for Cancer Progression	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES			English	Review						acetyltransferase; biomarker; cancer prognosis; NAA10	N-ALPHA-ACETYLTRANSFERASE; ARREST DEFECTIVE 1; TERMINAL ACETYLATION; PROTEIN; ARD1; EXPRESSION; APOPTOSIS; KINASE; IDENTIFICATION; TUMORIGENESIS	N-alpha-acetyltransferase 10 (NAA10) is an acetyltransferase that acetylates both N-terminal amino acid and internal lysine residues of proteins. NAA10 is a crucial player to regulate cell proliferation, migration, differentiation, apoptosis, and autophagy. Recently, mounting evidence presented the overexpression of NAA10 in various types of cancer, including liver, bone, lung, breast, colon, and prostate cancers, and demonstrated a correlation of overexpressed NAA10 with vascular invasion and metastasis, thereby affecting overall survival rates of cancer patients and recurrence of diseases. This evidence all points NAA10 toward a promising biomarker for cancer prognosis. Here we summarize the current knowledge regarding the biological functions of NAA10 in cancer progression and provide the potential usage of NAA10 as a prognostic marker for cancer progression.	[Kim, Sun Myung; Cho, Chiheum; Shin, So-Jin] Keimyung Univ, Sch Med, Dept Gynecol & Obstet, Daegu 42601, South Korea; [Kim, Sun Myung; Cho, Chiheum; Shin, So-Jin] Keimyung Univ, Sch Med, Inst Canc Res, Daegu 42601, South Korea; [Ha, Eunyoung; Seo, Ji Hae] Keimyung Univ, Sch Med, Dept Biochem, Daegu 42601, South Korea; [Kim, Jinyoung] Keimyung Univ, Sch Med, Dept Internal Med, Daegu 42601, South Korea		Shin, SJ (corresponding author), Keimyung Univ, Sch Med, Dept Gynecol & Obstet, Daegu 42601, South Korea.; Shin, SJ (corresponding author), Keimyung Univ, Sch Med, Inst Canc Res, Daegu 42601, South Korea.; Seo, JH (corresponding author), Keimyung Univ, Sch Med, Dept Biochem, Daegu 42601, South Korea.	sun7@snu.ac.kr; eyha@dsmc.or.kr; takgu@dsmc.or.kr; c0035@dsmc.or.kr; sjshinhope2014@kmu.ac.kr; seojh@kmu.ac.kr		Kim, Jin Young/0000-0002-9597-9834	Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2016R1A6A1A03011325, NRF-2020R1I1A3071851]; Korean Government (MSIT)Korean Government [NRF-2019R1C1C1005855]	This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1A6A1A03011325, NRF-2020R1I1A3071851) and the Korean Government (MSIT) (NRF-2019R1C1C1005855).	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J. Mol. Sci.	NOV	2020	21	21							8010	10.3390/ijms21218010			15	Biochemistry & Molecular Biology; Chemistry, Multidisciplinary	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Chemistry	OQ7KW	WOS:000588958400001	33126484	Green Published, gold			2022-04-25	
J	Zhao, Z; Oh, S; Li, DP; Ni, DJ; Pirooz, SD; Lee, JH; Yang, SH; Lee, JY; Ghozalli, I; Costanzo, V; Stark, JM; Liang, CY				Zhao, Zhen; Oh, Soohwan; Li, Dapeng; Ni, Duojiao; Pirooz, Sara Dolatshahi; Lee, Joo-Hyung; Yang, Shunhua; Lee, June-Yong; Ghozalli, Irene; Costanzo, Vincenzo; Stark, Jeremy M.; Liang, Chengyu			A Dual Role for UVRAG in Maintaining Chromosomal Stability Independent of Autophagy	DEVELOPMENTAL CELL			English	Article							COLON-CANCER; DNA; PROTEIN; CENTROSOME; MECHANISM; GENE; PHOSPHORYLATION; INSTABILITY; MUTATIONS; INDUCTION	Autophagy defects have recently been associated with chromosomal instability, a hallmark of human cancer. However, the functional specificity and mechanism of action of autophagy-related factors in genome stability remain elusive. Here we report that UVRAG, an autophagic tumor suppressor, plays a dual role in chromosomal stability, surprisingly independent of autophagy. We establish that UVRAG promotes DNA double-strand-break repair by directly binding and activating DNA-PK in nonhomologous end joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. Furthermore, UVRAG was also found to be localized at centrosomes and physically associated with CEP63, an integral component of centrosomes. Disruption of the association of UVRAG with centrosomes causes centrosome instability and aneuploidy. UVRAG thus represents an autophagy-related molecular factor that also has a convergent role in patrolling both the structural integrity and proper segregation of chromosomes, which may confer autophagy-independent tumor suppressor activity.	[Zhao, Zhen; Oh, Soohwan; Li, Dapeng; Ni, Duojiao; Pirooz, Sara Dolatshahi; Lee, Joo-Hyung; Yang, Shunhua; Lee, June-Yong; Ghozalli, Irene; Liang, Chengyu] Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA; [Costanzo, Vincenzo] London Res Inst, Clare Hall Labs, Genome Stabil Unit, London EN6 3LD, England; [Stark, Jeremy M.] Beckman Res Inst City Hope, Dept Radiat Biol, Duarte, CA 91010 USA		Liang, CY (corresponding author), Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA.	chengyu.liang@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; Lee, June-Yong/0000-0002-4476-725X; LIANG, CHENGYU/0000-0001-6082-2143; Costanzo, Vincenzo/0000-0002-2920-9508	National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [E14TG2a.4, AC0571, R01 CA140964, R21 AI083841, R01 CA120954]; National Cancer Institute Cancer CenterUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [5 P30 CA014089]; USC; Baxter Foundation; American Cancer SocietyAmerican Cancer Society [RSG-11-121-01-CCG]; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [NIAID U19AI083025]; Norris Cancer Center [P30CA014089-34]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA014089, R21CA161436, R01CA140964, R01CA120954] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [U19AI083025, R21AI083841] Funding Source: NIH RePORTER	The authors acknowledge the National Institutes of Health (NIH)-sponsored Mutant Mouse Regional Resource Center National System as the source of genetically altered UVRAG<SUP>+/+</SUP> (E14TG2a.4) and UVRAG<SUP>+/-</SUP> (AC0571) mouse embryonic stem cells 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 also thank Ross Tomaino for mass spectrometry analysis. We acknowledge the University of Southern California Broad CIRM Center Flow Cytometry Core Facility, supported by the National Cancer Institute Cancer Center Shared Grant 5 P30 CA014089 and the USC Provost Funds in BCC CU Accounts, for flow cytometry study. We thank Drs. J.U. Jung, M. Liber, B. Levine, S. Virgin, S. Field, T. Yoshimori, and Y. Ohsumi for providing reagents. This work is supported by the Baxter Foundation, the American Cancer Society (grant RSG-11-121-01-CCG to C.L.), the NIH (grants R01 CA140964 and R21 AI083841 to C.L. and grant R01 CA120954 to J.M.S.), and core services performed through the National Institute of Allergy and Infectious Diseases grant NIAID U19AI083025 and Norris Cancer Center grant P30CA014089-34 (to C.L.).	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Cell	MAY 15	2012	22	5					1001	1016		10.1016/j.devcel.2011.12.027			16	Cell Biology; Developmental Biology	Science Citation Index Expanded (SCI-EXPANDED)	Cell Biology; Developmental Biology	945QS	WOS:000304291700013	22542840	Green Accepted, Bronze			2022-04-25	
J	Feidantsis, K; Georgoulis, I; Giantsis, IA; Michaelidis, B				Feidantsis, Konstantinos; Georgoulis, Ioannis; Giantsis, Ioannis A.; Michaelidis, Basile			Treatment with ascorbic acid normalizes the aerobic capacity, antioxidant defence, and cell death pathways in thermally stressed Mytilus galloprovincialis	COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY			English	Article						Ascorbic acid; Antioxidant response; Cell death pathways; Energy capacity; Heat stress; Mediterranean mussel	SUPEROXIDE-DISMUTASE ACTIVITY; COLON-CANCER CELLS; OXIDATIVE STRESS; VITAMIN-C; INDUCED APOPTOSIS; REFERENCE GENES; CLIMATE-CHANGE; BCL-2 FAMILY; AUTOPHAGY; OXIDASE	Considering temperature's upcoming increase due to climate change, combined with the fact that Mediterranean mussels Mytilus galloprovincialis (Lamarck, 1819) live at their upper limits [critical temperatures (Tc) beyond 25 degrees C], we cannot be sure of this species' sustainable future in the Mediterranean Sea. Deviation from optimum temperatures leads to cellular damage due to oxidative stress. Although ascorbic acid (AA) is a major scavenger of reactive oxygen species (ROS), its capacity to minimize oxidative stress effects is scarcely studied in aquatic organisms. Thus, treatment with 5 mM and 10 mM AA of thermally stressed molluscs had been employed in order to examine its antioxidant capacity. While 5 mM had no effect, 10 mM normalized COXI and ND2 relative mRNA levels, and superoxide dismutase (SOD), catalase, and glutathione reductase (GR) enzymatic activity levels in both examined tissues: posterior adductor muscle (PAM) and mantle. ATP levels, probably providing the adequate energy for antioxidant defence in thermally stressed mussels, is also normalized under 10 mM AA treatment. Moreover, autophagic indicators such as LC3 II/I and SQSTMl1/p62 levels are normalized, indicating autophagy amelioration. Apoptosis also seems to be inhibited since both Bax/Bcl-2 and cleaved caspase substrate levels decrease with 10 mM AA treatment. Therefore, treatment of mussels with AA seems to produce threshold effects, although the precise underlying mechanisms must be elucidated in future studies. These findings show that treatment of mussels with effective antioxidants can be useful as a strategic approach for the reduction of the deleterious effects on mussels' summer mortality in aquaculture zones.	[Feidantsis, Konstantinos; Georgoulis, Ioannis; Michaelidis, Basile] Aristotle Univ Thessaloniki, Sch Biol, Dept Zool, Lab Anim Physiol, GR-54124 Thessaloniki, Greece; [Giantsis, Ioannis A.] Univ Western Macedonia, Fac Agr Sci, Dept Anim Sci, Florina 53100, Greece		Feidantsis, K (corresponding author), Aristotle Univ Thessaloniki, Sch Biol, Dept Zool, Lab Anim Physiol, GR-54124 Thessaloniki, Greece.	kfeidant@bio.auth.gr	Giantsis, Ioannis A./D-4382-2013	Giantsis, Ioannis A./0000-0002-6323-2955	European UnionEuropean Commission; Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Special Actions AQUACULTURE -INDUSTRIAL MATERIALS -OPEN INNOVATION IN CULTURE [T6YBPi-00388]	This research has been co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Special Actions AQUACULTURE -INDUSTRIAL MATERIALS -OPEN INNOVATION IN CULTURE (project code: T6YB Pi-00388; Project acronym: SmartMussel).	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Biochem. Physiol. B-Biochem. Mol. Biol.	AUG-SEP	2021	255								110611	10.1016/j.cbpb.2021.110611		MAY 2021	11	Biochemistry & Molecular Biology; Zoology	Science Citation Index Expanded (SCI-EXPANDED)	Biochemistry & Molecular Biology; Zoology	SJ4NX	WOS:000655511800014	33965617				2022-04-25	
J	Maclean, KH; Dorsey, FC; Cleveland, JL; Kastan, MB				Maclean, Kirsteen H.; Dorsey, Frank C.; Cleveland, John L.; Kastan, Michael B.			Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis	JOURNAL OF CLINICAL INVESTIGATION			English	Article							MYC-INDUCED LYMPHOMAGENESIS; CYTOCHROME-C RELEASE; BCL-X-L; SIGNALING PATHWAYS; INDUCED APOPTOSIS; TRANSGENIC MICE; AUTOPHAGY; P53; ATM; PHOSPHORYLATION	Despite great interest in cancer chemoprevention, effective agents are few. Here we show that chloroquine, a drug that activates the stress-responsive Atm-p53 tumor-suppressor pathway, preferentially enhances the death of Myc oncogene-overexpressing primary mouse B cells and mouse embryonic fibroblasts (MEFs) and impairs Myc-induced lymphomagenesis in a transgenic mouse model of human Burkitt lymphoma. Chloroquine-induced cell death in primary MEFs and human colorectal cancer cells was dependent upon p53, but not upon the p53 modulators Atm or Arf. Accordingly, chloroquine impaired spontaneous lymphoma development in Atm-deficient mice, a mouse model of ataxia telangiectasia, but not in p53-deficient mice. Chloroquine treatment enhanced markers of both macroautophagy and apoptosis in MEFs but ultimately impaired lysosomal protein degradation. Interestingly, chloroquine-induced cell death was not dependent on caspase-mediated apoptosis, as neither overexpression of the antiapoptotic protein Bcl-2 nor deletion of the proapoptotic Bax and Bak affected chloroquine-induced MEF death. However, when both apoptotic and autophagic pathways were blocked simultaneously, chloroquine-induced killing of Myc-overexpressing cells was blunted. Thus chloroquine induces lysosomal stress and provokes a p53-dependent cell death that does not require caspase-mediated apoptosis. These fmdings specifically demonstrate that intermittent chloroquine use effectively prevents cancer in mouse models of 2 genetically distinct human cancer syndromes, Burkitt lymphoma and ataxia telangiectasia, suggesting that agents targeting lysosome-mediated degradation may be effective in cancer prevention.	[Dorsey, Frank C.; Cleveland, John L.] Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA; [Maclean, Kirsteen H.; Kastan, Michael B.] St Jude Childrens Res Hosp, Dept Oncol, Div Mol Therapeut, Memphis, TN 38105 USA		Kastan, MB (corresponding author), St Jude Childrens Res Hosp, Dept Oncol, Div Mol Therapeut, 332 N Lauderdale St, Memphis, TN 38105 USA.	jcleve@scripps.edu; michael.kastan@stjude.org			NCI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01 CA071387, R01 CA076379, CA21765, CA76379, P30 CA021765, CA71387] Funding Source: Medline; NIEHS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [R37 ES005777, ES05777, R01 ES005777] Funding Source: Medline; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA021765, R01CA071387, R01CA076379] Funding Source: NIH RePORTER		ADAMS JM, 1985, NATURE, V318, P533, DOI 10.1038/318533a0; 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Clin. Invest.	JAN	2008	118	1					79	88		10.1172/JCI33700			10	Medicine, Research & Experimental	Science Citation Index Expanded (SCI-EXPANDED)	Research & Experimental Medicine	248AE	WOS:000252122900011	18097482	Green Published, Bronze			2022-04-25	
J	Duan, L; Deng, LJ; Wang, DB; Ma, SC; Li, CM; Zhao, D				Duan, Ling; Deng, Leijiao; Wang, Dabin; Ma, Shoucheng; Li, Chunmei; Zhao, Da			Treatment mechanism of matrine in combination with irinotecan for colon cancer	ONCOLOGY LETTERS			English	Article						matrine; irinotecan; colon cancer; HT29 cells; apoptosis	CELLS; APOPTOSIS; PROLIFERATION; MITOCHONDRIA; METASTASIS; INHIBITION; AUTOPHAGY; P38	The inhibitory effect of matrine (MA) was studied in combination with irinotecan (CPT-11) on proliferation of human colon carcinoma cell line HT29. We also explored the mechanism of cell apoptosis induction in HT29. HT29 cells were treated with different concentrations of MA and CPT-11 alone and in combination. The growth inhibition in HT29 cells was evaluated using MTT assay. Apoptosis was detected using AV-PI double staining flow cytometry. Transmission electron microscopy was used to detect structural changes in cells. Topoisomerase (TOPO) I, Bax and Caspase-3 expression levels were evaluated using western blot analysis. MA and CPT-11 alone and in combination, inhibited the proliferation of HT29 cells, whereas the combination treatment exhibited higher inhibitory effect (P<0.01). This suggests the existence of synergistic cytotoxicity. Compared with each treatment alone, the combination treatment caused more significant damage to cell structure, and caused a significantly higher apoptosis rate (P<0.01). Additionally, the combination treatment increased TOPO I, Bax and Caspase-3 expression levels (P<0.01). In conclusion, MA in combination with CPT-11 synergistically inhibited HT29 cell proliferation and induced apoptosis in these cells. The mechanism may be related to upregulation of the TOPO I, Bax and Caspase-3 protein expression.	[Duan, Ling; Ma, Shoucheng; Li, Chunmei; Zhao, Da] Lanzhou Univ, Hosp 1, Dept Oncol, 1 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China; [Deng, Leijiao] Lanzhou Univ, Hosp 1, Dept Pharm, Lanzhou 730000, Gansu, Peoples R China; [Wang, Dabin] Peoples Hosp Gansu Prov, Dept Anesthesiol, Lanzhou 730000, Gansu, Peoples R China		Zhao, D (corresponding author), Lanzhou Univ, Hosp 1, Dept Oncol, 1 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China.	zbo662@163.com					Chen MC, 2017, ENVIRON TOXICOL, V32, P669, DOI 10.1002/tox.22268; Chui CH, 2004, ACAD THI MED U, V26, P778; Fang XL, 2009, CHIN J CLIN RATION D, V2, P8; Gordon MB, 2016, CASE REP ENDOCRINOL, V2016; Heit B, 2011, AM J PHYSIOL-CELL PH, V300, pC33, DOI 10.1152/ajpcell.00139.2010; [黄建 HUANG Jian], 2007, [中草药, Chinese Traditional and Herbal Drugs], V38, P1210; Indran IR, 2011, BBA-BIOENERGETICS, V1807, P735, DOI 10.1016/j.bbabio.2011.03.010; Ismaili N, 2011, WORLD J SURG ONCOL, V9, DOI 10.1186/1477-7819-9-154; Jeong JC, 2009, NEUROCHEM RES, V34, P991, DOI 10.1007/s11064-008-9868-5; Lee YS, 2002, CANCER LETT, V186, P83, DOI 10.1016/S0304-3835(02)00260-4; Li HL, 2010, AM J CHINESE MED, V38, P1115, DOI 10.1142/S0192415X10008512; Li Z, 2010, CELL, V141, P859, DOI 10.1016/j.cell.2010.03.053; Lujan HJ, 2002, DIS COLON RECTUM, V45, P491, DOI 10.1007/s10350-004-6227-8; Phelps MA, 2014, J CLIN ONCOL, V32, P2287, DOI 10.1200/JCO.2014.56.3387; Pommier Y, 2006, NAT REV CANCER, V6, P789, DOI 10.1038/nrc1977; Ren HT, 2014, ACTA BIOCH BIOPH SIN, V46, P1049, DOI 10.1093/abbs/gmu101; Sileri P, 2009, SOUTH MED J, V102, P733, DOI 10.1097/SMJ.0b013e3181a93c39; Venkatesan P, 2012, LIFE SCI, V91, P789, DOI 10.1016/j.lfs.2012.08.024; Zhang JQ, 2010, WORLD J GASTROENTERO, V16, P4281, DOI 10.3748/wjg.v16.i34.4281; Zhang JQ, 2011, ONCOL REP, V26, P115, DOI 10.3892/or.2011.1277; Zhang LP, 2001, LEUKEMIA RES, V25, P793, DOI 10.1016/S0145-2126(00)00145-4; Zhang Ming-Qian, 2015, Asian Pac J Cancer Prev, V16, P1993; Zhang Y, 2009, CYTOTECHNOLOGY, V59, P191, DOI 10.1007/s10616-009-9211-2	23	15	18	2	7	SPANDIDOS PUBL LTD	ATHENS	POB 18179, ATHENS, 116 10, GREECE	1792-1074	1792-1082		ONCOL LETT	Oncol. Lett.	AUG	2017	14	2					2300	2304		10.3892/ol.2017.6407			5	Oncology	Science Citation Index Expanded (SCI-EXPANDED)	Oncology	FE0IS	WOS:000407904600152	28781667	Green Submitted, Green Published, gold			2022-04-25	
