dependent on culture conditions. Prendergast and colleagues (50) showed that when H-Ras transformed Raf-1 fibroblasts are deprived ofsubstratum attachment, FTI treatment induces apoptosis. Similarly, Tamanoi and colleagues (51) found that a reduction in serum growth factors also changes the consequences of FTI treatment from inhibition of mitosis to initiation of programmed cell death. Furthermore, this apoptotic response was specific for K-Ras-transformed normal rat kidney cells and was not seen with their normal counterparts (51). At present, the mechanisms underlying altered responses to FTIs in cells deprived of substratum attachment or growth factors, and the relation of these phenomena to tumor growth, are not understood. Nevertheless, such dramatic alterations in FTI action owing to heterogeneity in the tumor cell environment may partly explain the distinct consequences of FTIs in xenografts vs transgene-induced tumors.
In light of the fact that there are farnesylated proteins other than Ras, the general lack of normal cell toxicity was also an unexpected feature of FTIs. Further, because normal Ras function is believed to be both crucial for normal cell proliferation and dependent on farnesylation, why are FTIs tolerated by normal cells? Although sometimes referred to as anti-Ras drugs, these compounds target FTase and hence potentially act as antagonists of the function of all farnesylated proteins. The nuclear lamins (A and B) are involved in the assembly of the nuclear envelope, yet blocking their farnesylation does not have deleterious effects on cell growth (52). Three proteins that mediate retinal signaling are farnesylated (2), yet impairment of vision has not been documented. The basis for this lack of toxicity is presently not understood. Possible explanations include the retention of function owing to incomplete inhibition of farnesylation, the existence of FTI-insen-sitive proteins that facilitate redundant pathways, and alternative prenylation. The last possibility will be addressed in Section 5.
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