title: Glycogen synthase kinase-3β antagonizes ROS-induced hepatocellular carcinoma cell death through suppression of the apoptosis signal-regulating kinase 1.
abstract: Glycogen synthase kinase-3β (GSK-3β), a multifunctional kinase, is an important regulator of cancer cell survival. Apoptosis signal-regulating kinase 1 (ASK1) is also a key factor for controlling several cellular events including the cell cycle, senescence, and apoptosis, in response to reactive oxygen species (ROS). The role of GSK-3β regulating the activity and protein level of ASK1 in the cancer cells remains largely unexplored. In this study, we showed that GSK-3β inhibits ROS-induced hepatocellular carcinoma cell death by suppressing ASK1. We first found that ectopic expression of GSK-3β suppressed hydrogen peroxide (H2O2)-induced cell death in HepG2 cells and knockdown of endogenous GSK-3β expression exhibited opposite effects. Moreover, GSK-3β expression clearly inhibited H2O2-induced phosphorylation of ASK1 in HepG2 cells, in association with a decrease in ASK1 protein level. Further exploration revealed that GSK-3β induced ubiquitination and proteasome-dependent degradation of ASK1 via inhibition of ubiquitin-specific protease USP9X. Our results thus suggest that GSK-3β is a key factor involved in ASK1 activation and ROS-induced cell death.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Tian Tan Xi Li, Beijing, 100050, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Tian Tan Xi Li, Beijing, 100050, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Tian Tan Xi Li, Beijing, 100050, China.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Tian Tan Xi Li, Beijing, 100050, China.
authors.forename: Danqing
authors.initials: D
authors.lastname: Song
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Tian Tan Xi Li, Beijing, 100050, China. hdeng@imb.pumc.edu.cn.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Deng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C506234:USP9X protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D043222:Ubiquitin Thiolesterase
keywords: ASK1; Glycogen synthase kinase-3β; ROS; Ubiquitination