title: Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species.
abstract: BACKGROUND
  Hepatitis C virus (HCV) core protein is known to cause oxidative stress and alter apoptosis pathways. However, the apoptosis results are inconsistent, and the real significance of oxidative stress is not well known. The aim of this study was twofold. First, we wanted to confirm whether core-induced oxidative stress was really significant enough to cause DNA damage, and whether it induced cellular antioxidant responses. Second, we wanted to evaluate whether this core-induced oxidative stress and the antioxidant response to it was responsible for apoptosis changes.
  
  
  METHODS
  HCV core protein was expressed under control of the Tet-Off promoter in Huh-7 cells and HeLa cells. We chose to use deoxycholic acid (DCA) as a model because it is known to produce both reactive oxygen species (ROS) and apoptosis.
  
  
  RESULTS
  Core expression uniformly increased ROS and 8-hydroxy-2'-deoxyguanosine (8-OHdG) under basal and DCA-stimulated conditions. Core protein expression also increased manganese superoxide dismutase levels. Core protein inhibited DCA-mediated mitochondrial membrane depolarization and DCA-mediated activation of caspase-9 and caspase-3, despite the increase in ROS by DCA. Core protein inhibited DCA-mediated apoptosis by increasing Bcl-x(L) protein and decreasing Bax protein, without affecting the proportion of Bax between mitochondria and cytosol, resulting in suppression of cytochrome c release from mitochondria into cytoplasm.
  
  
  CONCLUSIONS
  HCV core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of ROS production. Thus, oxidative stress and apoptosis modulation by core protein are independent of each other.
authors.affiliation: Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hara
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
authors.forename: Michiari
authors.initials: M
authors.lastname: Okuda
authors.forename: Takakazu
authors.initials: T
authors.lastname: Furutani
authors.forename: Isao
authors.initials: I
authors.lastname: Hidaka
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Korenaga
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.forename: Steven A
authors.initials: SA
authors.lastname: Weinman
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Okita
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014758:Viral Core Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C069130:nucleocapsid protein, Hepatitis C virus; D003840:Deoxycholic Acid; D003609:Dactinomycin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045304:Cytochromes c; D013482:Superoxide Dismutase; D003849:Deoxyguanosine