c-Jun N-terminal kinase mediates apoptotic signaling induced by N-(4-hydroxyphenyl)retinamide.
N-(4-Hydroxyphenyl)retinamide (4-HPR), a retinoic acid analog, induces apoptosis in several cell types. The mechanism by which 4-HPR initiates apoptosis remains poorly understood. We examined the effects of 4-HPR on two prostate carcinoma cell lines, LNCaP (an androgen-sensitive, p53(+/+) cell line) and PC-3 (an androgen-insensitive, p53(-/-) cell line). 4-HPR caused sustained c-Jun N-terminal kinase (JNK) activation and apoptosis in LNCaP cells but not in PC-3 cells at the dosages tested. Activation of JNK by 4-HPR was independent of caspases because a pan-caspase inhibitor failed to suppress JNK activation. Ultraviolet-C and gamma-radiation induced JNK activation in both LNCaP and PC-3 cells, suggesting that the failure of PC-3 cells to respond to 4-HPR was due to defects upstream of the JNK pathway. Furthermore, gamma-radiation-induced JNK activation was suppressed by an antioxidant, but 4-HPR-induced JNK activation was not, indicating that these two stimuli induced JNK activation through different mechanisms. Forced expression of JNK1, but not a JNK1 mutant, caused apoptosis in both LNCaP and PC-3 cells, suggesting that p53 is not required for JNK-mediated apoptosis. 4-HPR-induced apoptosis in LNCaP cells was suppressed by curcumin, which inhibits JNK activation. Expression of dominant-negative mutants in the JNK pathway also inhibited 4-HPR-induced apoptosis in human embryonic kidney 293 cells. Collectively, these results suggest that the JNK pathway mediates 4-HPR-induced apoptotic signaling.
Chen
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YR
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
Zhou
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G
Tan
T H
TH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002478:Cells, Cultured; D004789:Enzyme Activation; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017313:Fenretinide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases