Requirement of c-jun for testosterone-induced sensitization to N-(4-hydroxyphenyl)retinamide-induced apoptosis.

Androgen stimulation strongly affects the sensitivity to anticancer drug-induced apoptosis in prostate cancer cells. We investigated the influence of androgen stimulation with testosterone on N-(4-hydroxyphenyl)retinamide (4-HPR)-induced apoptosis in the androgen-sensitive prostate cancer cell line LNCaP. Overexpression of a dominant negative form of mitogen-activated protein kinase kinase 7, a specific kinase of c-jun NH(2)-terminal kinase (JNK), significantly inhibited 4-HPR-induced JNK activation and apoptosis and canceled the hormone-dependent sensitization. Testosterone activated extracellular signal-regulated kinase (ERK), activating protein-1, subsequently increased the expression of c-jun. In addition, testosterone significantly enhanced in vivo phosphorylation of c-jun by 4-HPR as well as JNK activation. Transfection with an antisense oligonucleotide of c-jun blocked 4-HPR-induced apoptosis and the testosterone-induced sensitization, suggesting a major contribution of the JNK/c-jun mediated pathway in androgen-dependent sensitization. Interestingly, inhibition of testosterone-induced activation by PD98059 also canceled an upregulation of c-jun and increased apoptosis. These results suggested that modulation of JNK activation and expression of c-jun through ERK might have been essentially involved in androgen-mediated sensitization to 4-HPR-induced apoptosis in prostate cancer cells. Copyright 2003 Wiley-Liss, Inc.