Abstract
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. © 2003 Wiley‐Liss, Inc.