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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<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. 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<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1128\/jvi.01841-10","type":"journal-article","created":{"date-parts":[[2011,1,13]],"date-time":"2011-01-13T03:48:51Z","timestamp":1294890531000},"page":"3214-3228","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1"],"prefix":"10.1128","volume":"85","author":[{"given":"Liang","family":"Hu","sequence":"first","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"HanYong","family":"Sun","sequence":"additional","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"GuangZhen","family":"Yang","sequence":"additional","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YanXin","family":"Chang","sequence":"additional","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"QianQian","family":"Tu","sequence":"additional","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MengChao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"HongYang","family":"Wang","sequence":"additional","affiliation":[{"name":"International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute"},{"name":"State Key Laboratory for Oncogenes and Related Genes, Cancer Institute of Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.23.12725-12734.2004"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2003.50472"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1177\/106002809302700408"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304202200"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00172-07"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-1221"},{"key":"e_1_3_3_8_2","first-page":"358","volume":"50","year":"2009","unstructured":"Chen, L., et al. 2009. 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