DECIPHERING THE SIGNALING NETWORKS UNDERLYING SIMVASTATIN-INDUCED APOPTOSIS IN HUMAN CANCER CELLS

Abstract

Statins are widely used as cholesterol-lowering drugs that selectively inhibit the enzyme HMG-CoA reductase and block cholesterol biosynthesis. Recent studies show that statins induce apoptotic cell death in several types of cancer cells. However, the underlying molecular mechanisms are still unclear. In this study, we showed that simvastatin activated the mitochondrial death pathway and inhibited colony-forming ability of HCT116 colorectal cancer cells. Exogenously added mevalonate or geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP), in combination with simvastatin prevented the growth-inhibitory effect of simvastatin. These data suggest that simvastatin exerts effects via inhibition of the mevalonate pathway and by modulating the functions of its downstream geranylgeranylated proteins, such as Rho GTPases. We then explored the signaling cascade downstream of inhibition of protein geranylgeranylation in simvastatin-treated HCT116 colorectal cancer cells.