PT  - JOURNAL ARTICLE
AU  - Yi-Rong Chen
AU  - Guisheng Zhou
AU  - Tse-Hua Tan
TI  - c-Jun N-Terminal Kinase Mediates Apoptotic Signaling Induced by<em>N</em>-(4-Hydroxyphenyl)retinamide
AID  - 10.1124/mol.56.6.1271
DP  - 1999 Dec 01
TA  - Molecular Pharmacology
PG  - 1271--1279
VI  - 56
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/56/6/1271.short
4100  - http://molpharm.aspetjournals.org/content/56/6/1271.full
SO  - Mol Pharmacol1999 Dec 01; 56
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.