Abstract |
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.
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Authors | Y Mizukami, H Ura, T Obara, A Habiro, T Izawa, M Osanai, N Yanagawa, S Tanno, Y Kohgo |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 288
Issue 1
Pg. 198-204
(Oct 19 2001)
ISSN: 0006-291X [Print] United States |
PMID | 11594773
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright 2001 Academic Press. |
Chemical References |
- Amines
- Antineoplastic Agents
- Enzyme Inhibitors
- Farnesol
- farnesylamine
- Alkyl and Aryl Transferases
- Farnesyltranstransferase
- JNK Mitogen-Activated Protein Kinases
- Mitogen-Activated Protein Kinase 8
- Mitogen-Activated Protein Kinases
- oleylamine
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Topics |
- Alkyl and Aryl Transferases
(antagonists & inhibitors)
- Amines
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- Apoptosis
- Enzyme Inhibitors
(pharmacology)
- Farnesol
(analogs & derivatives, pharmacology)
- Farnesyltranstransferase
- Genes, ras
- Humans
- JNK Mitogen-Activated Protein Kinases
- MAP Kinase Signaling System
- Mitogen-Activated Protein Kinase 8
- Mitogen-Activated Protein Kinases
(antagonists & inhibitors, genetics, physiology)
- Mutation
- Pancreatic Neoplasms
(enzymology, pathology)
- Tumor Cells, Cultured
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