Prostaglandin E₂ stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway

Cyclooxygenase (COX)-2 expression and prostaglandin E₂ (PGE₂) secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. PGE₂ biosynthesis by cyclooxygenase (COX)-2 plays a pivotal role in inflammation and carcinogenesis. One of the critical proinflammatory cytokines in the prostate is interleukin-6 (IL-6). We hypothesized that increased expression of COX-2, with resultant increased levels of PGE₂ in human PIN cells, activates the IL-6 signaling pathway. We demonstrate an autocrine up-regulation of PGE₂ mediated by IL-6 in a human PIN cell line. We further demonstrate that PGE₂ stimulates soluble IL-6 receptor (sIL-6R) release, gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity. These events, induced by PGE₂, lead to increased PIN cell growth. Treatment of PIN cells with a selective COX-2 inhibitor decreases cell growth. Finally, PGE₂-stimulated PIN cell growth was abrogated by the addition of IL-6 neutralizing antibodies. These data provide mechanistic evidence that increased expression of COX-2/PGE₂ contributes to prostate cancer development and progression via activation of the IL-6 signaling pathway.