Pegylated interferon's anti‐hepatoma effect is mediated by β‐catenin inhibition

Abstract

Aberrant β-catenin activation, a main component of the Wnt pathway, has been implicated in liver cancer. It also promotes cell proliferation and hence is a logical therapeutic target in cancers. Here, we investigate the effect of Ribavirin & Pegasys, alone or in combination, on β-catenin. Other reports have shown an anti-tumor role of these anti-HCV agents, however their effect on Wnt/β-catenin pathway is unknown. This is of particular relevance based on recent observations of decreased HCC incidence in HCV patients undergoing anti-HCV treatment. We examined the effect of these drugs on morphology of hepatoma cells & on the Wnt pathway components. Short-term experiments failed to detect any effect of Ribavirin on morphology or total & nuclear β-catenin. Administration of 3 doses of pegylated interferon demonstrated a 50% decrease in nuclear β-catenin protein. Based on these results, Hep3B and HepG2 cells were treated long-term (10–12 doses) with Pegasys (+/− Ribavirin). A loss of cell viability was observed at 6–8 doses. Western blot exhibited a dramatic decrease in total & active β-catenin protein. GSK3β, a kinase that phosphorylates β-catenin to induce its degradation, underwent a significant activation following the combination therapy only. Also, Pegasys significantly affected β-catenin gene expression to 20% of the control by real time PCR. Thus Pegasys alone or in combination with Ribavirin significantly inhibits hepatoma cell growth and viability and appears to do so at least in part by β-catenin inhibition via multi-factorial mechanisms.