Inhibition of lysophosphatidic acid-induced RhoA activation and tumor cell invasion by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors.

The mevalonate metabolic pathway is necessary for the isoprenylation of a number of small GTPases. We have previously presented that Rho plays a pivotal role in 1-oleoyl-lysophosphatidic acid (LPA)-induced invasion of rat ascites hepatoma MM1 cells. Herein we report the effect of HMG-CoA reductase inhibitors, fluvastatin and lovastatin, on the in vitro invasion of MM1 cells. Fluvastatin and lovastatin inhibited LPA-induced MM1 cell invasion in a dose-dependent manner. Fluvastatin inhibited LPA-induced translocation of RhoA protein from the cytosol to the membrane and RhoA activation which was measured by pull-down assay for GTP-bound RhoA. Fluvastatin also inhibited the translocation of both endogenous and dominant-active RhoA from the cytosol to the membrane, actin stress fiber assembly and in vitro invasion of the cells expressing dominant-active RhoA (Val14-RhoA). These results indicate that HMG-CoA reductase inhibitors have the potential to reduce RhoA activation and cancer cell invasion by targeting the Rho protein isoprenylation.