Requirement of c-Jun N-terminal kinase for apoptotic cell death induced byfarnesyltransferase inhibitor, farnesylamine, in human pancreatic cancer cells

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesy lamine, synthetic isoprenoid-linked with "amine" which acts as a potent FTI , induces apoptosis in human pancreatic cancer cells through the ras signal ing cascade. Since the effect of FTI is usually 'cytostatic' rather than 'c ytotoxic', we speculated another apoptotic machinery of farnesylamine in ad dition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA ladd ering and significantly reduced 'cytotoxic' effect of farnesylamine. Striki ngly similar effect on JNK activation and apoptosis was induced by structur ally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without "amine." Taken together, a poptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI (C) 2001 Academic Press.