Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis.
As 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, has been established to cause apoptosis of prostate cancer cells, the downstream effectors of the signaling remain unclear. In the current study, we investigated molecular mechanisms by which 2-ME induces apoptosis in human prostate cancer cell line, LNCaP. It was found that 2-ME mediates apoptosis through p53 induction. Nuclear factor kappaB (NFkappaB) was activated by 2-ME and closely regulated by the mitogen-activated protein kinase, p38. Inhibition of p38 or NFkappaB resulted in suppression of p53 induction and apoptosis. Moreover, we demonstrated that 2-ME activates the c-jun NH2-terminal kinase (JNK)/activation protein (AP)-1 pathway. Interestingly, inhibition of JNK strongly reduced Bcl-2 phosphorylation by 2-ME as well as p53 induction, and almost completely suppressed 2-ME-induced apoptosis. Androgen stimulation with dihydrotestosterone, a major endogenous metabolite of testosterone, also significantly inhibited p38/NFkappaB and JNK/AP-1 activation and apoptosis. The results suggest that not only p53 induction through p38/JNK-dependent NFkappaB/AP-1 activation but also JNK-dependent Bcl-2 phosphorylation are required for 2-ME-induced apoptosis; moreover, inhibition of these pathways may be involved in androgen-mediated resistance to apoptosis.
Shimada
Keiji
K
Department of Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
Nakamura
Mitsutoshi
M
Ishida
Eiwa
E
Kishi
Munehiro
M
Konishi
Noboru
N
D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D013196:Dihydrotestosterone; D004958:Estradiol; D000077584:2-Methoxyestradiol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases