Requirement of c-jun N-terminal kinase for apoptotic cell death induced by farnesyltransferase 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 farnesylamine, synthetic isoprenoid-linked with "amine" which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually "cytostatic" rather than "cytotoxic", we speculated another apoptotic machinery of farnesylamine in addition 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 laddering and significantly reduced "cytotoxic" effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without "amine." Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI.
Mizukami
Y
Y
Third Department of Internal Medicine, Asahikawa Medical College, 2-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan. mizu@asahikawa-med.ac.jp
Ura
H
H
Obara
T
T
Habiro
A
A
Izawa
T
T
Osanai
M
M
Yanagawa
N
N
Tanno
S
S
Kohgo
Y
Y
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000588:Amines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D011905:Genes, ras; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000588:Amines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005204:Farnesol; C085171:farnesylamine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C008703:oleylamine