Effects of the farnesyltransferase inhibitor UCF-1C/manumycin on growth and p21-ras post-translational processing in NIH3T3 cells.

Examination of the effect of the farnesylprotein transferase (FPTase) inhibitor UCF1-C/manumycin on NIH3T3 cells transfected with a normal N-ras gene and expressing high levels of the corresponding p21-ras protein showed that 10 microm UCF1-C immediately and reversibly inhibited growth in these cells, without modifying cell-death rate, thus acting as a cytostatic. There was also a 98% reduction of p21-ras neofarnesylation and a 3-fold decrease in total content in p21-ras products, yet without gross modification of the relative content in the post-translational products and without accumulation of the native protein to detectable levels. UCF1-C likewise reversibly inhibited growth in parental NIH3T3 cells, as well as in sub-strains expressing a transfected normal or mutated H-ras gene. Together with the fact that the well-developed network of actin stress fibers present in the NIH3T3 (N-ras) cells was not affected by the FPTase inhibitor, these data indicate that its growth-inhibitory effect is not necessarily in direct relation with that exerted on p21-ras processing. Alternatively, it might be causally related to the decreased prenylation of other cellular proteins, perhaps included among the 13 proteins, unrelated to p21-ras, of which the farnesylation was also reduced under UCF1-C treatment. Some cells transformed by a ras or non-ras oncogene might exhibit higher susceptibility towards FPTase inhibitors than normal cells, but this might then be attributable to differences in the pattern of expression and/or in the functional importance of non-ras farnesylated proteins.