title: AKT activation was not essential for hepatocellular carcinoma cell survival under glucose deprivation.
abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, with a dismal 5-year survival rate less than 15%. The present study aimed to investigate whether AKT inhibition and glucose deprivation could synergistically kill HCC cells and the molecular mechanisms involved. HCC cells were starved in glucose deprivation, and then the resultant cell death was determined by flow cytometry and mitochondrial oxygen consumption rates using a Seahorse XF-24 Extracellular Flux Analyzer. Glucose deprivation reduced mitochondrial oxygen consumption rates for ATP production, enhanced mitochondrial proton leaks, reduced Mcl-1 expression, and subsequently caused significant cell death in the sensitive HepG2 and HCC-M cells. In the resistant Hep3B and Huh7 cells that survived, glucose starvation induced time-dependent AKT activation. However, blockage of AKT activation using chemical inhibitors (ZSTK474 and LY290042) or specific AKT1-targeting siRNAs could not markedly sensitize glucose deprivation-induced cell death. In contrast, AKT inhibitors or AKT1-targeting siRNAs significantly protected the sensitive HepG2 cells from glucose deprivation-induced cell death. More importantly, AKT inhibition mechanically suppressed mTOR activity and induced the prosurvival autophagy pathway in the sensitive HCC cells. Taken together, these data demonstrated that AKT activity was not essential for HCC cell survival during glucose deprivation. The reduction of mTOR activity and induction of the autophagy pathway may hinder the potential application of AKT inhibitors in the cancer therapy of solid tumors such as HCC.
authors.affiliation: aDepartment of Physiology, School of Preclinical Medicine bGuangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease cDepartment of Toxicology, School of Public Health dDepartment of Environmental Medicine, School of Public Health, Guangxi Medical University eDepartment of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, PR China fDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Yue
authors.initials: Y
authors.lastname: Tang
authors.forename: Ze-Jun
authors.initials: ZJ
authors.lastname: Xie
authors.forename: Jing-Ning
authors.initials: JN
authors.lastname: Lu
authors.forename: Jing-Huan
authors.initials: JH
authors.lastname: Deng
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Huang
authors.forename: Shing
authors.initials: S
authors.lastname: Chuan Hooi
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Lu
mesh_terms: D001343:Autophagy / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D005947:Glucose / Q000172:deficiency*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008930:Mitochondria, Liver; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D010101:Oxygen Consumption; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002867:Chromones; C549075:LY 290042; C579095:MCL1 protein, human; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose