Effectiveness of statin in inducing apoptosis and cell growth arrest via inactivating RhoA in prostate cancer cell lines.

B230

Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl-CoA reductase. Clinically, statins have been approved and effectively used to control hypercholesterolemia. Recent data, however, showed their anti-tumor activity and may be used in preventing and treating human cancers. We conducted this study to evaluate the effectiveness of statins on prostate cancer and to understand the molecular mechanism of their action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines by inducing apoptosis and cell growth arrest at G1 phase. Specifically, lovastatin and simvastatin induced activation of caspase 8 and 3 and to a lesser extent, caspase 9. Lovastatin and simvastatin suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4 and CDK6, but induced p21 and p27 expression in these prostate cancer cells. Molecularly, lovastatin and simvastatin suppressed RhoA activation and then c-JUN expression, but not cycloxygenase-2 (COX-2) expression. The results of the study demonstrated that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest, and that the underlying molecular mechanism is inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G1 cell cycle arrest. In future studies statin and other apoptosis-inducing drugs (e.g., COX-2 inhibitors or curcumin) should be examined together to assess the efficacy of statins in prevention and treatment of prostate cancer.