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.
Shimada
Keiji
K
Second Department of Pathology, Nara Medical University, Nara, Japan.
Nakamura
Mitsutoshi
M
Ishida
Eiwa
E
Kishi
Munehiro
M
Konishi
Noboru
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017313:Fenretinide / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction; D013739:Testosterone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017313:Fenretinide; D013739:Testosterone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one