title: HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells.
abstract: Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosisin vitroand in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance.Cancer Res; 77(8); 2064-77. ©2017 AACR.
authors.affiliation: The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China.|Center for DAMP Biology, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China.|Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China.|Center for DAMP Biology, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China.|Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China.|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D000093542:Gemcitabine
chemical_list: C497109:ATF4 protein, human; D000964:Antimetabolites, Antineoplastic; C081452:Atf4 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D003841:Deoxycytidine; D051701:Activating Transcription Factor 4; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C000611332:glutathione peroxidase 4, mouse; D000093542:Gemcitabine