title: Hepatitis B virus X protein enhances cisplatin-induced hepatotoxicity via a mechanism involving degradation of Mcl-1.
abstract: Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatitis B virus (HBV)-associated liver diseases. However, whether HBx has the ability to disturb the susceptibility of hepatocytes to common chemotherapeutic agents remains incompletely understood. Here we demonstrate that HBx enhances cisplatin-induced hepatotoxicity by a mechanism involving degradation of Mcl-1, an antiapoptotic member of the Bcl-2 family. Ectopic expression of HBx sensitized hepatocytes to cisplatin-induced apoptosis, which was accompanied by a marked downregulation of Mcl-1 but not of Bcl-2 or Bcl-xL. Overexpression of Mcl-1 prevented HBx-induced proapoptotic and proinflammatory effects during cisplatin treatment both in vitro and in vivo. HBx-induced dysregulation of Mcl-1 resulted mainly from posttranslational degradation rather than transcription repression. Moreover, a caspase-3 inhibitor effectively abrogated HBx-enhanced Mcl-1 degradation and cell death. Importantly, antioxidants blocked activation of caspase-3 and acceleration of Mcl-1 loss, as well as cell death, in HBx-expressing hepatocytes upon cisplatin exposure in vitro and in vivo. Collectively, these data implicate oxidative stress-dependent caspase-3-mediated degradation of Mcl-1 as a mechanism contributing to HBx-mediated sensitization of cisplatin-induced hepatotoxicity. A combination of cisplatin and antioxidants might provide more advantage than cisplatin alone in the treatment of cancer patients with chronic HBV infection.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Hanyong
authors.initials: H
authors.lastname: Sun
authors.forename: Guangzhen
authors.initials: G
authors.lastname: Yang
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Chang
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Tu
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D006515:Hepatitis B virus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000473:pathology* / Q000821:virology*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D037521:Virulence Factors; C057628:hepatitis B virus X protein; D053148:Caspase 3; D002945:Cisplatin