Roles of p38 and c-Jun NH2-Terminal Kinase-Mediated Pathways in 2-Methoxyestradiol-Induced p53 Induction and Apoptosis
April 2003
in “
Carcinogenesis
”
Studysummary This study found that 2-methoxyestradiol induces apoptosis in human prostate cancer cells by activating p53 through a pathway dependent on p38/JNK-mediated NFkappaB/AP-1 activation, with JNK-dependent Bcl-2 phosphorylation also playing a critical role.
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The study investigated the molecular mechanisms by which 2-methoxyestradiol (2-ME) induced apoptosis in the human prostate cancer cell line, LNCaP. It was found that 2-ME mediated apoptosis through p53 induction, which was regulated by the p38 and c-jun NH2-terminal kinase (JNK) pathways. Inhibition of p38 or NFkappaB suppressed p53 induction and apoptosis, while JNK inhibition reduced Bcl-2 phosphorylation and almost completely suppressed apoptosis. Additionally, androgen stimulation with dihydrotestosterone inhibited these pathways and apoptosis, suggesting that p53 induction through p38/JNK-dependent NFkappaB/AP-1 activation and JNK-dependent Bcl-2 phosphorylation were crucial for 2-ME-induced apoptosis, and their inhibition may contribute to androgen-mediated resistance to apoptosis.
