Abstract 4859: Statin-induced autophagy in prostate cancer cells

Abstract

Abstract Statins, a class of inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are commonly prescribed medications for treatment of hypercholesterolemia. Epidemiological studies have shown that statin use decreases the incidence of advanced prostate cancer. Here we report that atorvastatin (Lipitor), a broadly prescribed statin, induces autophagy and rapid cell death in androgen receptor (AR)-negative prostate cancer PC3 cells. Atorvastatin treatment of PC3 cells for 40 hrs increased expression of LC3-II by more than 10 fold in a dose-dependent manner. Treatment of the cells with pepstatin A and E64-d, the autophagic protease inhibitors, dramatically increased atorvastatin-dependent LC3-II expression level, indicating that atorvastatin induced autophagic flux. In addition, atorvastatin treatment caused rapid death of PC3 cells. Atorvastatin-induced autophagy and rapid cell death were reversed by addition of geranylgeraniol, not farnesol, in culture medium, indicating that atorvastatin-mediated inhibition of geranylgeranyl biosynthesis causes autophagy and cell death. Furthermore, atorvastatin did not induce autophagy or cell death in normal prostate RWPE1 cells and induced only a minor autophagic response in AR-positive prostate cancer LNCaP cells. Thus, our studies demonstrate that statins induce autophagy and autophagy-associated cell death in PC3 cells, likely through inhibition of geranylgeranylation, and suggest that autophagic response to statins may partially underlie the protective effects of statins on prostate cancer. Importantly, these findings highlight additional mechanisms by which statins might be used for therapy of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4859.