FARNESYL TRANSFERASE INHIBITORS INDUCE APOPTOSIS OF RAS-TRANSFORMED CELLS DENIED SUBSTRATUM ATTACHMENT

Farnesyl transferase inhibitors (FTIs) are a novel class of antitumor drugs that block the oncogenic activity of Ras. Because FTIs lack sign ificant cell toxicity in vitro and in vivo, a significant question is how they cause tumor regression, We now report that FTIs are in fact p otent activators of apoptosis in Ras-transformed cells if attachment t o substratum is prevented, When cultured at high density or on polyHEM A, a nonadherent substrate, Ras-transformed cells exhibited massive DN A degradation and cell death within 24 h of treatment with the FTI L-7 39,749. Death was p53-independent and was inhibited by the apoptosis s uppressor BCL-X(L). Furthermore, apoptosis was significantly attenuate d by ectopic expression of a farnesyl-independent form of RhoB, a Rho protein previously implicated as a critical target for inhibition by F TIs, The findings suggest a link between FTIs and Rho-dependent adhesi on signaling, Furthermore, our work indicates that FTIs revert cells t o a state in which cell-substratum attachment is necessary for viabili ty and suggests that apoptosis forms the basis for drug-induced tumor regression.