Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study

Cerivastatin is used in the treatment of hypercholesterolemia to inhibit 3- hydroxy 3-methylglutaryl coenzyme A reductase and thus prevent the synthesi s of cholesterol precursors, such as farnesyl pyrophosphate (FPP) and geran ylgeranyl pyrophosphate (GGPP), responsible, respectively, for translocatio n of Ras and Rho to the cell membrane, a step required for their cell signa ling, leading to cell proliferation and migration. Recently, it has been su ggested that non lipid-related effects of statins could play a beneficial r ole in cancer therapy. In this study, we have investigated the mechanisms b y which statins inhibit cancer and the types of cancers which could benefit from this therapy. In MDA-MB-231 cells, an aggressive breast cancer cell l ine with spontaneous activation of Ras and NF kappaB and overexpression of RhoA, cerivastatin induced inhibition of both cell proliferation and invasi on through Matrigel. This anti-proliferative effect was related to G(1)/S a rrest due to an increase in p21(Waf1/Cip1). The anti-invasive effect was ob served from 18 h and could be explained by RhoA delocalization from the cel l membrane, resulting in disorganization of the actin fibers and disappeara nce of focal adhesion sites. The importance of RhoA inactivation in both th ese inhibitory effects was proved by their reversion by GGPP but not by FPP . Moreover, cerivastatin was also shown to induce inactivation of NF kappaB , in a RhoA inhibition-dependent manner, resulting in a decrease in urokina se and metalloproteinase-9 expression, two proteases involved in cell migra tion. The participation of Ras inactivation is considered a subsidiary mech anism for the effects of cerivastatin, as they were not rescued by FPP. Pro longed treatment of MDA-MB-231 cells with high doses of cerivastatin induce d a loss of cell attachment. Interestingly, the effect of cerivastatin was considerably lower on poorly invasive MCF-7 cells. In conclusion, our resul ts suggest that cerivastatin inhibits cell signaling pathways involved in t he invasiveness and metastatic properties of highly invasive cancers.