EP2 signaling mediates suppressive effects of celecoxib on androgen receptor expression and cell proliferation in prostate cancer
EP2 signaling mediates suppressive effects of celecoxib on androgen receptor expression and cell proliferation in prostate cancer
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DOI：
10.1038/pcan.2013.53
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发表时间：
2014-03-01
影响因子：
4.8
通讯作者：
Naito, S.
中科院分区：
文献类型：
--
作者：
Kashiwagi, E.;Shiota, M.;Naito, S.
背景：非甾体类抗炎药可抑制环氧合酶 (COX) 的活性，其使用可降低前列腺癌的风险。塞来昔布是一种选择性 COX-2 抑制剂，据报道可以预防前列腺癌的进展。然而，所涉及的机制仍不清楚。在本研究中，我们研究了塞来昔布对前列腺癌生长的抑制作用，并阐明了抑制途径在前列腺癌细胞系中的生物学相关性。方法：采用Western blotting、实时定量PCR和细胞增殖实验来解析塞来昔布对前列腺癌细胞系PC3、LNCaP及其衍生物的作用机制。结果：塞来昔布诱导细胞凋亡并下调EP2、CREB和雄激素受体（AR）。此外，EP2拮抗剂下调CREB以及COX-2和AR，从而抑制细胞增殖。此外，EP2 和 CREB 敲低诱导 AR 下调，表明塞来昔布对 AR 的抑制是由 EP2/CREB 信号传导介导的。结论：塞来昔布通过 EP2 信号调节 AR 和 COX-2 表达发挥抗肿瘤活性。此外，除了塞来昔布之外，针对 EP2 的疗法也可能有望治疗前列腺癌。
BACKGROUND: Non-steroidal anti-inflammatory drugs inhibit the activity of cyclooxygenases (COXs), and their usage reduces the risks associated with prostate cancer. Celecoxib is a selective COX-2 inhibitor and reported to prevent the progression of prostate cancer. However, the mechanisms involved remain unclear. In this study, we investigated the suppression of prostate cancer growth by celecoxib and elucidated the biological relevance of the inhibited pathway in prostate cancer cell lines.METHODS: Western blotting, quantitative real-time PCR and cell proliferation assay were used to resolve the mechanism of celecoxib in prostate cancer cell line PC3, LNCaP and their derivatives.RESULTS: Celecoxib induced apoptosis and downregulated EP2, CREB and androgen receptor (AR). Moreover, EP2 antagonist downregulated CREB as well as COX-2 and AR, resulting in the suppression of cell proliferation. Furthermore, EP2 and CREB knockdown induced AR downregulation, indicating that AR suppression by celecoxib is mediated by EP2/CREB signaling.CONCLUSIONS: Celecoxib exerts antitumor activity through EP2 signaling regulating AR and COX-2 expression. Furthermore, in addition to celecoxib, therapeutics targeting EP2 may also be promising against prostate cancers.