title: GRIM-19 inhibition induced autophagy through activation of ERK and HIF-1α not STAT3 in Hela cells.
abstract: Gene associated with retinoid-interferon-induced mortality (GRIM-19), an important subunit of mitochondrial complex I, has been identified as a tumor suppressor, and its reduced expression has been reported to be associated with tumorigenesis and metastasis. Autophagy has been proposed as a protective mechanism for cell survival under various stresses, including chemotherapy. However, it remains unknown whether GRIM-19 is linked to autophagy and chemotherapy resistance. Here, we showed that suppression of GRIM-19 by shRNA enhanced cell-type-dependent autophagy by activating extracellular regulated protein kinase (ERK) and hypoxia inducible factor-1a (HIF-1a) in a reactive oxygen species (ROS)-mediated manner, and thereby conferred resistance to paclitaxel. Besides, the antioxidant N-acetyl-L-cysteine (NAC) and autophagy inhibitor 3-MA could in part overcome this resistance. We also found that GRIM-19 expression was significantly correlated with clinical stage and grade in patients with cervical cancers. Taken together, our results indicated that GRIM-19 inhibition induced autophagy and chemotherapy resistance, which could affect prognosis of cervical cancers. Our study has identified new function of GRIM-19 and its underlying mechanism, and it will provide possible avenues for therapeutic targeting in cervical cancers.
authors.affiliation: Clinical Research Center, Wuhan Medical and Healthcare Center for Women and Children, No. 100 Hongkong Rd, Wuhan, Hubei, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yue
authors.affiliation: Clinical Research Center, Wuhan Medical and Healthcare Center for Women and Children, No. 100 Hongkong Rd, Wuhan, Hubei, China.
authors.forename: Peiwei
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, China.
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Pathology, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, Hubei, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pathology, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, Hubei, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Public Health, Wuhan University, Wuhan, China.
authors.forename: Yaogui
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Oncology, Renmin Hospital, Wuhan University, Wuhan, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liang
authors.affiliation: Clinical Research Center, Wuhan Medical and Healthcare Center for Women and Children, No. 100 Hongkong Rd, Wuhan, Hubei, China. hexuelian2013@hotmail.com.
authors.forename: Xuelian
authors.initials: X
authors.lastname: He
mesh_terms: D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000494:pharmacology; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017239:Paclitaxel
keywords: Autophagy; Cervical cancer; Chemotherapy; ERK; GRIM-19; HIF-1a
references.citation: J Virol. 2008 Jan;82(2):1011-20
references.pmid: 17928352
references.citation: Oncotarget. 2015 Mar 20;6(8):5877-88
references.pmid: 25788272
references.citation: J Virol. 2002 Sep;76(17):8797-807
references.pmid: 12163600
references.citation: Apoptosis. 2014 Apr;19(4):555-66
references.pmid: 24415198
references.citation: PLoS One. 2013 Apr 22;8(4):e61677
references.pmid: 23630608
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9342-7
references.pmid: 12867595
references.citation: Cell Death Differ. 2007 Feb;14(2):327-37
references.pmid: 16826196
references.citation: Pharmacol Res. 2015 Oct;100:170-4
references.pmid: 26276086
references.citation: Cell Death Dis. 2013 Oct 10;4:e838
references.pmid: 24113172
references.citation: J Hum Genet. 2010 Aug;55(8):507-11
references.pmid: 20505682
references.citation: Oncotarget. 2015 Apr 20;6(11):8621-34
references.pmid: 25940701
references.citation: Cell Cycle. 2011 May 15;10(10):1528-32
references.pmid: 21471732
references.citation: J Hematol Oncol. 2014 Oct 17;7:73
references.pmid: 25322986
references.citation: Nature. 2010 Jul 1;466(7302):38-40
references.pmid: 20596005
references.citation: J Biol Chem. 2015 Apr 3;290(14):9101-10
references.pmid: 25681445
references.citation: EMBO J. 2003 Mar 17;22(6):1325-35
references.pmid: 12628925
references.citation: J Biol Chem. 2005 May 13;280(19):19021-6
references.pmid: 15753091
references.citation: J Biol Chem. 2000 Oct 27;275(43):33416-26
references.pmid: 10924506
references.citation: J Biol Chem. 2012 Aug 3;287(32):27227-35
references.pmid: 22665480
references.citation: Mol Cell Biol. 2004 Oct;24(19):8447-56
references.pmid: 15367666
references.citation: Autophagy. 2007 Sep-Oct;3(5):496-8
references.pmid: 17617738
references.citation: Hum Pathol. 2015 Dec;46(12):1815-20
references.pmid: 26363526
references.citation: Nat Rev Drug Discov. 2013 Jun;12(6):465-83
references.pmid: 23666487
references.citation: Nat Rev Drug Discov. 2009 Jul;8(7):579-91
references.pmid: 19478820
references.citation: Br J Cancer. 2005 May 23;92(10):1892-8
references.pmid: 15841082
references.citation: Cell Death Dis. 2014 Aug 14;5:e1367
references.pmid: 25118927
references.citation: Carcinogenesis. 2013 Aug;34(8):1728-36
references.pmid: 23580587
references.citation: Mol Cell Biol. 2007 Sep;27(18):6420-32
references.pmid: 17636012
references.citation: J Biol Chem. 2001 Oct 19;276(42):38345-8
references.pmid: 11522775