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Carcinogenesis Advance Access originally published online on April 11, 2003
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Carcinogenesis, Vol. 24, No. 6, 1067-1075, June 2003
© 2003 Oxford University Press

CANCER BIOLOGY

Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis

Keiji Shimada, Mitsutoshi Nakamura, Eiwa Ishida, Munehiro Kishi and Noboru Konishi1

Department of Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

1 To whom correspondence should be addressed Email: nkonishi{at}naramed-u.ac.jp

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


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