HBx regulates fatty acid oxidation to promote hepatocellular carcinoma survival during metabolic stress
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Ming-Da Wang1,2,*, Han Wu1,*, Shuai Huang1, Hui-Lu Zhang1, Chen-Jie Qin1,2, Ling-Hao Zhao1,3, Gong-Bo Fu1,2, Xu Zhou1,2, Xian-Ming Wang1,2, Liang Tang1, Wen Wen1,2, Wen Yang1,2, Shan-Hua Tang1,2, Dan Cao1,2, Lin-Na Guo1,2, Min Zeng1,2, Meng-Chao Wu3, He-Xin Yan1,2, Hong-Yang Wang1,2,4
1International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, P.R. China
2National Center for Liver Cancer Research, Shanghai 201805, P.R. China
3Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, P.R. China
4State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, Shanghai 200032, P.R. China
*These authors have contributed equally to this work
Hong-Yang Wang, e-mail: [email protected]
He-Xin Yan, e-mail: [email protected]
Keywords: hepatitis B virus X protein, fatty acid oxidation, energy homeostasis, metabolic stress, cell survival
Received: June 01, 2015 Accepted: December 29, 2015 Published: January 4, 2016
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.
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