title: Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2α) pathway protect ovarian cancer cells from metformin-induced apoptosis.
abstract: Metformin, an oral biguanide for the treatment of type II diabetes, has been shown to have anticancer effects in ovarian cancer. Energy starvation induced by metformin causes endoplasmic reticulum stress-mediated unfolded protein response (UPR) and autophagy. UPR and autophagy act as a survival or death mechanism in cells. In this study, we observed that metformin-induced apoptosis was relieved by autophagy and the PERK/eIF2α pathway in ovarian cancer cells, but not in peripheral blood mononuclear cells (PBMC) or 'normal' ovarian surface epithelial cells (OSE). Increased PARP cleavage and increased LC3B-II with ATG5-ATG12 complex suggested the induction of apoptosis and autophagy, respectively, in metformin-treated ovarian cancer cells. Accumulation of acidic vacuoles in the cytoplasm and downregulation of p62 further supported late-stage autophagy. Interestingly, metformin induced interdependent activation between autophagy and the UPR, especially the PERK/eIF2α pathway. Inhibition of autophagy-induced PERK inhibition, and vice versa, were demonstrated using small molecular inhibitors (PERK inhibitor I, GSK2606414; autophagy inhibitor, 3-MA, and BafA1). Moreover, autophagy and PERK activation protected ovarian cancer cells against metformin-induced apoptosis. Metformin treatment in the presence of inhibitors of PERK and autophagy, however, had no cytotoxic effects on OSE or PBMC. In conclusion, these results suggest that inhibition of autophagy and PERK can enhance the selective anticancer effects of metformin on ovarian cancer cells. © 2015 Wiley Periodicals, Inc.
authors: Interdisciplinary Program in Cancer Biology, Seoul National University, College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea.
authors: Hee-Sun
authors: HS
authors: Moon
authors: Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea.|Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea.
authors: Boyun
authors: B
authors: Kim
authors: Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea.|Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea.
authors: HyeRan
authors: H
authors: Gwak
authors: Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Dong Hoon
authors: DH
authors: Suh
authors: Interdisciplinary Program in Cancer Biology, Seoul National University, College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea.|Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea.|Department of Obstetrics and Gynecology, Seoul National University, College of Medicine, Seoul, Korea.
authors: Yong Sang
authors: YS
authors: Song
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D007004:Hypoglycemic Agents; D008687:Metformin; D019892:eIF-2 Kinase
keywords: PERK; autophagy; metformin; ovarian cancer