RT Journal Article SR Electronic T1 c-Jun N-Terminal Kinase Mediates Apoptotic Signaling Induced byN-(4-Hydroxyphenyl)retinamide JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1271 OP 1279 DO 10.1124/mol.56.6.1271 VO 56 IS 6 A1 Chen, Yi-Rong A1 Zhou, Guisheng A1 Tan, Tse-Hua YR 1999 UL http://molpharm.aspetjournals.org/content/56/6/1271.abstract AB 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.