SIRT1 Sensitizes Hepatocellular Carcinoma Cells Expressing Hepatitis B Virus X Protein to Oxidative Stress-Induced Apoptosis

Biochem Biophys Res Commun. 2012 Dec 7;429(1-2):45-50. doi: 10.1016/j.bbrc.2012.10.102. Epub 2012 Nov 5.

Abstract

We previously showed that SIRT1 deacetylase inhibits proliferation of hepatocellular carcinoma cells expressing hepatitis B virus (HBV) X protein (HBX), by destabilization of β-catenin. Here, we report another role for SIRT1 in HBX-mediated resistance to oxidative stress. Ectopic expression and enhanced activity of SIRT1 sensitize Hep3B cells stably expressing HBX to oxidative stress-induced apoptosis. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for sensitization of oxidation-mediated apoptosis. Furthermore, ectopic expression of SIRT1 and treatment with resveratrol (a SIRT1 activator) attenuated JNK phosphorylation, which is a prerequisite for resistance to oxidative stress-induced apoptosis. Conversely, suppression of SIRT1 activity with nicotinamide inhibited the effect of resveratrol on JNK phosphorylation, leading to restoration of resistance to oxidation-induced apoptosis. Taken together, these results suggest that up-regulation of SIRT1 under oxidative stress may be a therapeutic strategy for treatment of hepatocellular carcinoma cells related to HBV through inhibition of JNK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Apoptosis*
  • Carcinoma, Hepatocellular / enzymology*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Humans
  • Liver Neoplasms / enzymology*
  • MAP Kinase Kinase 4 / metabolism
  • Oxidative Stress*
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Resveratrol
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Stilbenes / pharmacology
  • Trans-Activators / biosynthesis*
  • Up-Regulation*

Substances

  • Antioxidants
  • RNA, Small Interfering
  • Stilbenes
  • Trans-Activators
  • hepatitis B virus X protein
  • MAP Kinase Kinase 4
  • SIRT1 protein, human
  • Sirtuin 1
  • Resveratrol