Journal Article

Roles of p38- and c-jun NH<sub>2</sub>-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis

Keiji Shimada, Mitsutoshi Nakamura, Eiwa Ishida, Munehiro Kishi and Noboru Konishi

in Carcinogenesis

Volume 24, issue 6, pages 1067-1075
Published in print June 2003 | ISSN: 0143-3334
Published online June 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg058
Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis

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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 (NFκB) was activated by 2-ME and closely regulated by the mitogen-activated protein kinase, p38. Inhibition of p38 or NFκB 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/NFκB and JNK/AP-1 activation and apoptosis. The results suggest that not only p53 induction through p38/JNK-dependent NFκB/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.

Keywords: AP, activation protein; DHT, dihydrotestosterone; Hyg B, Hygromycin B; JNK, c-jun NH2-terminal kinase; 2-ME, 2-methoxyestradiol; MAP, mitogen-activated protein; PARP, poly-ADP ribose polymerase.

Journal Article.  6765 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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