Simvastatin enhances chemotherapy in cervical cancer via inhibition of multiple prenylation-dependent GTPases-regulated pathways.

Abstract

Aberrant activation of GTPases is common in cervical cancer, and their proper biological functions largely depend on a post-translational modification termed prenylation. Simvastatin is a cholesterol-lowering drug via inhibiting HMG-CoA reductase, thereby inhibiting protein prenylation. In this study, we show that simvastatin selectively inhibits proliferation and induces apoptosis in cervical cancer cells while sparing normal cervical epithelial cells. This is achieved by depleting geranylgeranyl pyrophosphate, inhibiting prenylation, decreasing GTPases activities and suppressing the activation of downstream Ras and RhoA signaling. The combination of simvastatin and paclitaxel remarkably augments in vitro as well as in vivo efficacy of either drug alone in cellular system and xenograft mouse model. Importantly, we show that cervical cancer cells have higher level of HMG-CoA reductase and elevated activities of GTPases, suggesting that cervical cancer cells may be more dependent on prenylation than normal cervical epithelial cells. This might explain the selective inhibitory effects of simvastatin in cervical cancer. Since simvastatin is already available for clinic use, these results suggest that simvastatin is a promising drug candidate in combination with chemotherapy for the treatment of cervical cancer. Our findings also emphasize the therapeutic value of prenylation inhibition and provide preclinical evidence to evaluate prenylation-targeted drugs in cervical cancer.