Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton.

Abstract

A potent and specific small molecule inhibitor of farnesyl-protein transferase, L-739,749, caused rapid morphological reversion and growth inhibition of ras-transformed fibroblasts (Ratl/ras cells). Morphological reversion occurred within 18 h of L-739,749 addition. The reverted phenotype was stable for several days in the absence of inhibitor before the transformed phenotype reappeared. Cell enlargement and actin stress fiber formation accompanied treatment of both Ratl/ras and normal Ratl cells. Significantly, inhibition of Ras processing did not correlate with the initiation or maintenance of the reverted phenotype. While a single treatment with L-739,749 was sufficient to morphologically revert Ratl/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 could be separated from effects on cell growth, depending on whether exposure to a farnesyl-protein transferase inhibitor was transient or repetitive. In contrast, L-739,749 had no effect on the growth, morphology, or actin organization of v-raf-transformed cells. Taken together, the results suggest that the mechanism of morphological reversion is complex and may involve farnesylated proteins that control the organization of cytoskeletal actin.

Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines

“…This is consistent with previous reports by Prendergast et al (1994), and SeppLorenzino et al (1995). In Colo357, A-549 and Calu-1 cells, K-Ras prenylation is inhibited only by cotreatment with FTI-277 and GGTI-298.…”

Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts

“…Furthermore, our soft agar results are consistent with those of Sepp-Lorenzino et al (1995) who showed that the ability of FTase inhibitors to inhibit human tumor cell line growth in soft agar does not correlate with their Ras mutation status. In addition, others have demonstrated that the ability of FTase inhibitors to reverse morphological transformation did not correlate with their ability to inhibit Ras prenylation (Prendergast et al, 1994). Taken together these results suggest that farnesylated protein(s) other than oncogenic K-Ras, that are pivotal to transformation, are targets for FTase inhibitors.…”

“…Furthermore, CAAX peptidomimetics inhibited the anchorage-dependent growth of ras-transformed cells but had little e ect on the growth of normal cells (Kohl et al, 1993;James et al, 1993). However, the ability of FTase inhibitors to reverse morphological transformation was shown not to correlate with their ability to inhibit Ras prenylation (Prendergast et al, 1994), and the Ras mutation status did not predict the sensitivity of human tumor cell growth in soft agar (SeppLorenzino et al, 1995).…”

Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer

“…Candidates that could ful®ll this role are a family of protein tyrosine phosphatases (PRL1) with oncogenic properties, an inositol phosphatase and members of the Ras-like superfamily, like RhoB, RhoE, Rheb. In fact, Prendergast and others have proposed that RhoB might be the target responsible for changes in morphologic transformation induced by the FTI 43,44,47,48 as was observed in TSU-Pr1 cells.…”