Abstract
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 γ-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, γ-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.
Footnotes
- Received March 22, 1999.
- Accepted August 25, 1999.
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Send reprint requests to: Dr. Tse-Hua Tan, Department of Microbiology and Immunology, Baylor College of Medicine, M929, One Baylor Plaza, Houston, TX 77030. E-mail: ttan{at}bcm.tmc.edu
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This work was supported by National Institutes of Health Grants R01-AI38649 and R01-AI42532 (to T.-H.T.). Y.-R.C. was supported by Department of Defense Predoctoral Fellowship DAMD17-97-1-7078 in the Breast Cancer Research Program and is a recipient of Department of Defense Postdoctoral Fellowship DAMA17-99-1-9507) in the Prostate Cancer Research Program. T.-H.T. is a Scholar of the Leukemia Society of America.
- The American Society for Pharmacology and Experimental Therapeutics
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