The metabolic regulator PGC- 1α links anti- cancer cytotoxic chemotherapy to reactivation of hepatitis B virus

M. Mouler Rechtman, E. O. Burdelova, I. Bar-Yishay, M. Ben-Yehoyada, S. Fishman, Z. Halpern, A. Shlomai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)34-41
Number of pages8
JournalJournal of Viral Hepatitis
Volume20
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Hepatitis B virus
  • chemotherapy
  • peroxisome proliferator- activated receptor- gamma coactivator- 1α
  • reactivation

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