Liu Xin-Hua, Kirschenbaum Alexander, Lu Min, Yao Shen, Klausner Adam, Preston Chad, Holland James F, Levine Alice C
Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Biochem Biophys Res Commun. 2002 Jan 11;290(1):249-55. doi: 10.1006/bbrc.2001.6188.
Cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. PGE(2) 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 PGE(2) in human PIN cells, activates the IL-6 signaling pathway. We demonstrate an autocrine upregulation of PGE(2) mediated by IL-6 in a human PIN cell line. We further demonstrate that PGE(2) stimulates soluble IL-6 receptor (sIL-6R) release, gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity. These events, induced by PGE(2), lead to increased PIN cell growth. Treatment of PIN cells with a selective COX-2 inhibitor decreases cell growth. Finally, PGE(2)-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/PGE(2) contributes to prostate cancer development and progression via activation of the IL-6 signaling pathway.
环氧化酶（COX）-2的表达以及前列腺素E2（PGE2）的分泌在前列腺上皮内瘤变（PIN）和前列腺癌中均有所增加。由环氧化酶（COX）-2介导的PGE2生物合成在炎症和致癌过程中起着关键作用。前列腺中关键的促炎细胞因子之一是白细胞介素-6（IL-6）。我们推测，COX-2表达增加，导致人PIN细胞中PGE2水平升高，从而激活IL-6信号通路。我们证明了在人PIN细胞系中，IL-6介导了PGE2的自分泌上调。我们进一步证明，PGE2刺激可溶性IL-6受体（sIL-6R）释放、gp130二聚化、Stat-3蛋白磷酸化以及DNA结合活性。这些由PGE2诱导的事件导致PIN细胞生长增加。用选择性COX-2抑制剂处理PIN细胞可降低细胞生长。最后，添加IL-6中和抗体可消除PGE2刺激的PIN细胞生长。这些数据提供了机制证据，表明COX-2/PGE2表达增加通过激活IL-6信号通路促进前列腺癌的发生和发展。
