FARNESYLTRANSFERASE INHIBITION CAUSES MORPHOLOGICAL REVERSION OF RAS-TRANSFORMED CELLS BY A COMPLEX MECHANISM THAT INVOLVES REGULATION OF THE ACTIN CYTOSKELETON

A potent and specific small molecule inhibitor of farnesyl-protein tra nsferase, L-739,749, caused rapid morphological reversion and growth i nhibition of ras-transformed fibroblasts (Rat1/ras cells). Morphologic al reversion occurred within 18 h of L-739,749 addition. The reverted phenotype was stable for several days in the absence of inhibitor befo re the transformed phenotype reappeared. Cell enlargement and actin st ress fiber formation accompanied treatment of both Rat1/ras and normal Rat1 cells. Significantly, inhibition of Ras processing did not corre late with the initiation or maintenance of the reverted phenotype. Whi le a single treatment with L-739,749 was sufficient to morphologically revert Rat1/ras cells, repetitive inhibitor treatment was required to significantly reduce cell growth rate. Thus, the effects of L-739,749 on transformed cell morphology and cytoskeletal actin organization co uld be separated from effects on cell growth, depending on whether exp osure to a farnesyl-protein transferase inhibitor was transient or rep etitive. In contrast, L-739,749 had no effect on the growth, morpholog y, or actin organization of v-raf-transformed cells. Taken together, t he results suggest that the mechanism of morphological reversion is co mplex and may involve farnesylated proteins that control the organizat ion of cytoskeletal actin.