Selective inhibition of cancer cell invasion by a geranylgeranyltransferase-I inhibitor

A number of small GTPases are involved in cancer cell proliferation, migration and invasion. They need to be prenylated for full biological functions. We have recently reported that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which block the biosynthesis of farnesylpyrophosphate and geranylgeranylpyrophosphate, inhibit in vitro invasion of human pancreatic cancer cells. In the present study, we examined the effects of two selective inhibitors of prenylation, a farnesyltransferase inhibitor (FTI-277) and a geranylgeranyltransferase type I inhibitor (GGTI-298), on in vitro invasion of cancer cells in a modified Boyden chamber assay. The invasion of COLO 320DM human colon cancer cells was inhibited potently by HMG-CoA reductase inhibitor lovastatin and GGTI-298 but weakly by FTI-277. The treatment of cancer cells with GGTI-298 markedly caused RhoA to decrease in the membrane fraction and accumulate in the cytosolic fraction, whereas it had almost no effect on the translocation of Ras. FTI-277 markedly inhibited membrane localization of Ras, but its inhibitory effect on cancer cell invasion occurred only at doses that affected membrane localization of RhoA. FTI-277 and GGTI-298 decreased the growth potential of COLO 320DM cells, but the inhibitory effect of GGTI-298 was rather selective toward invasion in association with changes in cell morphology and RhoA localization. These results suggest that geranylgeranylation of RhoA by geranylgeranyltransferase type I is critical for cancer cell invasion, and inhibition of geranylgeranyltransferase type I activity should offer a novel approach to the treatment of invasion and metastasis of cancer cells resistant to farnesyltransferase inhibitors.