Farnesyl
protein transferase (FPTase) catalyses the post-translational modification of
proteins by a
farnesyl pyrophosphate. One of the substrates of this
enzyme is p21ras, the product of the ras oncogene. We examined whether
farnesylamine, one of the FPTase inhibitors (FTI), is selectively cytotoxic in
pancreatic carcinoma cells and Ki-ras-transformed fibroblasts. Furthermore, we investigated whether the cytotoxicity of
farnesylamine is caused by the induction of apoptosis in these cells. Using the FPTase assay, we found that
farnesylamine inhibited FPTase in vitro. Immunoprecipitation showed that
farnesylamine inhibited farnesylation of p21ras in vivo. In addition, 24 and 5 microM
farnesylamine were required to achieve 50% cytotoxicity in
pancreatic carcinoma cells containing activated Ki-ras and Ki-ras-transformed NIH/3T3 cells, respectively. The parental NIH/3T3 cells were resistant to the cytotoxic effect of
farnesylamine at concentrations less than 100 microM. After incubation with
farnesylamine, DNA fragmentation was observed in both
pancreatic carcinoma cells and Ki-ras-transformed fibroblasts at cytotoxic doses of this compound but not in NIH/3T3 cells. These results indicate that the mechanism of cell death induced by
farnesylamine is apoptosis, and this apoptosis occurred specifically in
pancreatic carcinoma cells containing mutated Ki-ras and the Ki-ras-transformed cells. Because raf is downstream of ras (p21ras) in the ras-raf-
mitogen-activated protein kinase signaling pathway, we used c-raf-1-transformed fibroblasts, which proved to be resistant to apoptosis induced by
farnesylamine. This supports the theory that inhibition of ras signaling may be related to the induction of apoptosis. These data further suggest that
farnesylamine could be useful as a chemotherapeutic agent in
cancers that very frequently contain a Ki-ras oncogene mutation, e.g.,
pancreatic cancer.