title: The metabolic regulator PGC-1α links anti-cancer cytotoxic chemotherapy to reactivation of hepatitis B virus.
abstract: Patients with chronic hepatitis B virus (HBV) infection are at an increased risk for a severe and a potentially fatal viral reactivation following anti-cancer therapy. The molecular mechanism for this induction of HBV expression is still unclear. Here, we show that treating hepatoma cell line expressing HBV with various anti-cancer cytotoxic agents results in a significant up-regulation of HBV expression. This HBV induction is at the transcriptional level and is time dependent. Interestingly, treating hepatoma cells with anti-cancer cytotoxic agents results in a robust induction of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a metabolic and energy regulator that is normally induced in the liver under starvation conditions and that has been previously shown to strongly coactivate HBV transcription. Most importantly, HBV up-regulation following anti-cancer therapy depends on PGC-1α induction, because PGC-1α knock-down abolishes HBV induction. Finally, pretreatment of HBV-expressing cells with the antioxidant agent N-acetylcysteine attenuates the induction of both PGC-1α and HBV in response to anti-cancer treatment, suggesting that chemotherapy-associated PGC-1α induction is mediated by cellular oxidative stress that ultimately leads to HBV up-regulation. We conclude that cytotoxic anti-cancer chemotherapy has a direct and an immune system-independent effect on HBV gene expression, which is mediated by PGC-1α. Our results attribute to this metabolic regulator an unexpected role in linking anti-cancer treatment to HBV reactivation and make PGC-1α a potential target for future anti-HBV therapy, especially under conditions in which it is robustly induced, such as following anti-cancer treatment.
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Mouler Rechtman
authors.forename: E O
authors.initials: EO
authors.lastname: Burdelova
authors.forename: I
authors.initials: I
authors.lastname: Bar-Yishay
authors.forename: M
authors.initials: M
authors.lastname: Ben-Yehoyada
authors.forename: S
authors.initials: S
authors.lastname: Fishman
authors.forename: Z
authors.initials: Z
authors.lastname: Halpern
authors.forename: A
authors.initials: A
authors.lastname: Shlomai
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D004249:DNA Damage; D003907:Dexamethasone / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D014775:Virus Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D001761:Bleomycin; D019259:Lamivudine; D005047:Etoposide; D003907:Dexamethasone; D003520:Cyclophosphamide; D000111:Acetylcysteine