[Oleylamine (long-chain fatty amine)-induced cell death through MAP kinase pathways in human pancreatic cancer cells].
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.
Mizukami
Yusuke
Y
Third Department of Internal Medicine, Asahikawa Medical College, Asahikawa 078-8510, Japan.
D000588:Amines / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000588:Amines; D004791:Enzyme Inhibitors; D005204:Farnesol; C085171:farnesylamine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C008703:oleylamine