title: Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer.
abstract: Metformin, which is widely used as an anti-diabetic drug, reduces cancer related morbidity and mortality. However, the role of metformin in cancer is not fully understood. Here, we first describe that the anti-cancer effect of metformin is mediated by cyclin D1 deregulation via AMPK/GSK3β axis in ovarian cancer cells. Metformin promoted cytotoxic effects only in the cancer cells irrespective of the p53 status and not in the normal primary-cultured cells. Metformin induced the G1 cell cycle arrest, in parallel with a decrease in the protein expressions of cyclin D1 without affecting its transcriptional levels. Using a proteasomal inhibitor, we could address that metformin-induced decrease in cyclin D1 through the ubiquitin/proteasome process. Cyclin D1 degradation by metformin requires the activation of GSK3β, as determined based on the treatment with GSK3β inhibitors. The activation of GSK3β correlated with the inhibitory phosphorylation by Akt as well as p70S6K through AMPK activation in response to metformin. These findings suggested that the anticancer effects of metformin was induced due to cyclin D1 degradation via AMPK/GSK3β signaling axis that involved the ubiquitin/proteasome pathway specifically in ovarian cancer cells. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: HyeRan
authors.initials: H
authors.lastname: Gwak
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Youngmin
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Haein
authors.initials: H
authors.lastname: An
authors.affiliation: Department of Cell Biology, Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Danny N
authors.initials: DN
authors.lastname: Dhanasekaran
authors.affiliation: Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Song
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; 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; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D019938:Cyclin D1; D008687:Metformin; D000071679:Glycogen Synthase Kinase 3 beta; D055372:AMP-Activated Protein Kinases
keywords: AMPK; GSK3β; cyclin D1; metformin; ovarian cancer