Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB

Recent results have shown that the ability of farnesyltransferase inhibitor s (FTIs) to inhibit malignant cell transformation and Ras prenylation can b e separated. We proposed previously that farnesylated Rho proteins are impo rtant targets for alternation by FTIs, based on studies of RhoB (the FTI-Rh o hypothesis). Cells treated with FTIs exhibit a loss of farnesylated RhoB but a gain of geranylgeranylated RhoB (RhoB-GG), which is associated with l oss of growth-promoting activity. In this study, we tested whether the gain of RhoB-GG elicited by FTI treatment was sufficient to mediate FTI-induced cell growth inhibition. In support of this hypothesis, when expressed in R as-transformed cells RhoB-GG induced phenotypic reversion, cell growth inhi bition, and activation of the cell cycle kinase inhibitor p21WAF1. RhoB-GG did not affect the phenotype or growth of normal cells. These effects mere similar to FTI treatment insofar as they were all induced in transformed ce lls but not in normal cells. RhoB-GG did not promote anoikis of Ras-transfo rmed cells, implying that this response to FTIs involves loss-of-function e ffects. Our findings corroborate the FTI-Rho hypothesis and demonstrate tha t gain-of-function effects on Rho are part of the drug mechanism. Gain of R hoB-GG may explain how FTIs inhibit the growth of human tumor cells that la ck Ras mutations.