Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzymeA reductase inhibitors

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors preven t the conversion of HMG-CoA to mevalonate and thereby inhibit the synthesis of other products derived from this metabolite, This includes a number of small prenylated GTPases involved in cell growth, motility, and invasion, W e studied the effect of HMG-CoA reductase inhibitors (fluvastatin and lovas tatin) on in vitro invasion of human pancreatic cancer PANC-1 cells. Epider mal growth factor (EGF) induced a dose-dependent increase of PANG-1 cell in vasion in a modified Boyden chamber assay. Stimulation of cancer cells with EGF induced translocation of RhoA from the cytosol to the membrane fractio n acid actin stress fiber assembly, Furthermore, Clostridium botulinum C3 t ransferase, a specific inhibitor of Rho, inhibited the ability of EGF to pr omote invasion, indicating that EGF-indnced cancer cell invasion is regulat ed by Rho signaling, Treatment of PANG-1 cells with fluvastatin markedly at tenuated EGF-induced translocation of RhoA from the cytosol to the membrane traction and actin stress fiber assembly, whereas it did not inhibit the t yrosine phosphorylation of EGF receptor and c-erbB-2, The induction of canc er cell invasion by EGF was inhibited by the addition of fluvastatin or lov astatin in a dose-dependent manner. The effects of fluvastatin or lovastati n on cell morphology and invasion were reversed by the addition of all-tran s-geranylgeraniol but not by the addition of all-trans-farnesol, These resu lts suggest that HMG-CoA reductase inhibitors affect RhoA activation by pre venting geranylgeranylation, which results in inhibition of EGF-induced inv asiveness of human pancreatic cancer cells.