title: HBx regulates fatty acid oxidation to promote hepatocellular carcinoma survival during metabolic stress.
abstract: Due to a high rate of nutrient consumption and inadequate vascularization, hepatocellular carcinoma (HCC) cells constantly undergo metabolic stress during tumor development. Hepatitis B virus (HBV) X protein (HBx) has been implicated in the pathogenesis of HBV-induced HCC. In this study, we investigated the functional roles of HBx in HCC adaptation to metabolic stress. Up-regulation of HBx increased the intracellular ATP and NADPH generation, and induced the resistance to glucose deprivation, whereas depletion of HBx via siRNA abolished these effects and conferred HCC cells sensitive to glucose restriction. Though HBx did not affect the glycolysis and oxidative phosphorylation capacity of HCC cells under normal culture conditions, it facilitated fatty acid oxidation (FAO) in the absence of glucose, which maintained NADPH and ATP levels. Further investigation showed that HBx expression, under glucose deprivation, stimulated phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) via a calcium/CaMKK-dependent pathway, which was required for the activation of FAO. Conversely, inhibition of FAO by etomoxir (ETO) restored the sensitivity of HBx-expressing cells to glucose deficiency in vitro and retarded xenograft tumor formation in vivo. Finally, HBx-induced activation of the AMPK and FAO pathways were also observed in xenograft tumors and HBV-associated HCC specimens. Our data suggest that HBx plays a key role in the maintenance of redox and energy homeostasis by activating FAO, which is critical for HCC cell survival under conditions of metabolic stress and might be exploited for therapeutic benefit.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Ming-Da
authors.initials: MD
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Wu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.
authors.forename: Hui-Lu
authors.initials: HL
authors.lastname: Zhang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Chen-Jie
authors.initials: CJ
authors.lastname: Qin
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Ling-Hao
authors.initials: LH
authors.lastname: Zhao
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Gong-Bo
authors.initials: GB
authors.lastname: Fu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Shan-Hua
authors.initials: SH
authors.lastname: Tang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Cao
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Lin-Na
authors.initials: LN
authors.lastname: Guo
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China.|National Center for Liver Cancer Research, Shanghai 201805, P.R. China.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200032, P.R. China.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D006019:Glycolysis; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D013312:Stress, Physiological; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D005227:Fatty Acids; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D009249:NADP; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: cell survival; energy homeostasis; fatty acid oxidation; hepatitis B virus X protein; metabolic stress