Selective induction of apoptosis by HMG-CoA-reductase inhibitors in hepatoma cells is dependent on p53 expression

Abstract

Background and Aims: HMG-CoA-reductase-inhibitors (statins) are widely used drugs to interfere with cholesterol biosynthesis. Besides this usage, evidence increases that statins might also be useful in therapy of viral infections or cancer. We investigated the effects of statins on primary mouse and human hepatocytes as well as mouse (Hepa1–6) and human (Huh7, HepG2, Hep3B) hepatoma cell lines. Methods: Effects of fluva-, simva-, atorva-, rosuva-, prava- and lovastatin on viability of primary mouse and human hepatocytes as well as mouse (Hepa1–6) and human (Huh7, HepG2, Hep3B) hepatoma cell lines were measured by MTT assay. Stable knockdown of p53 was performed by lentiviral shRNA transfer into Huh7 cells. Prenylation was restored by supplementation of geranyl-geranyl pyrophosphate (GGPP). Results: Fluva-, simva- and lovastatin selectively reduced mouse hepatoma cells viability. Human hepatoma cell lines HepG2 and Hep3B cell lines showed a significant reduction of cell viability, while statins did not reduce viability of Huh7 cells at concentrations not toxic for primary hepatocytes. Stable knockdown of endogenous p53, which is over represented in Huh7 cells in comparison to HepG2 and Hep3B cells, was able to induce susceptibility towards statin-induced toxicity in Huh7 cells. The anti-tumor effect of statins did not depend on a lack of cholesterol, but was restored by supplementation of GGPP, a prerequisite for prenylation of small G proteins. Conclusions: Certain statins display a selective apoptotic effect on human hepatoma cells, with lovastatin being both, most selective for tumor cells and most effective in inducing tumor cell apoptosis. Additionally, our results provide evidence that the p53 expression status seem to be crucial for statin effects on hepatoma cells.