We have previously shown that
farnesylamine which acts as a
farnesyltransferase inhibitor (FTI) induces apoptosis in human
pancreatic cancer cells. Since the effect of FTI is usually known as "
cytostatic", another apoptotic machinery of
farnesylamine should be revealed in addition to the inhibition of farnesylation. Considering the chemical formula of
farnesylamine, the "long-chain fatty
amine (LFA)" structure may have a critical role in this mechanism. In this experiment, we examined the cytotoxic effect of LFA with alkyl-chain including
oleylamine. Exposure of human
pancreatic cancer cells to LFAs resulted in cell death, whereas short-chain fatty
amine and
oleylamine-related compounds without "
amine" did not exert cytotoxicity.
Oleylamine-induced cell death was confirmed as apoptosis by
DNA laddering and
caspase-dependent, but numerous cytoplasmic vacuoles, a typical feature of autophagy (type-2 cell death), were also observed. Preceding the apoptosis, strong and sustained activation of
c-jun N-terminal kinase (JNK) and p38 was observed;
caspase inhibitors did not attenuate activities of those
kinases despite significant inhibition of apoptosis. Blockage of JNK activity by dominant-negative mutant completely abrogated the
oleylamine-induced
DNA laddering, but not autophagy. Furthermore,
oleylamine decreased
extracellular signal-regulated kinase (ERK) activity, probably through the activation of
mitogen-activated protein kinase phosphatase-1. Taken together, LFA induces apoptosis through activation of JNK, p38 and
caspase, accompanied with ERK inactivation, in human
pancreatic cancer cells.