Hoshikawa Hiroshi, Goto Rieko, Mori Terushige, Mitani Tomoo, Mori Nozomu
Department of Otolaryngology, Kagawa University, Kita-gun, Kagawa, Japan.
Int J Oncol. 2009 Mar;34(3):847-52. doi: 10.3892/ijo_00000211.
Prostaglandin E2 (PGE2) can stimulate tumor progression by both direct and indirect mechanisms. However, its influence on cell proliferation is still unclear. The present study characterized expression of subtypes of PGE2 receptors in oral squamous cell carcinomas, while also investigating the effects of EP3 and EP4 selective antagonists on oral carcinoma cell lines. EP1, EP2, EP3 and EP4 receptor mRNAs were detected in 4, 5, 10 and 10 of 11 surgical specimens respectively. Application of an EP3 antagonist (ONO-AE3-240) strongly inhibited cell growth in COX-2 and PGE2 high expression cells (Ca9-22) but not in COX-2 and PGE2 low expression cells (HSC4). The antagonist also reduced the production of endogenous PGE2 and induced G0/G1 phase cell arrest. Addition of exogenous PGE2 only partly abrogated the growth inhibition, indicating that the anti-proliferative effect via EP3 receptor signaling was not only due to PGE2-dependent but also PGE2-independent mechanisms. In contrast, an EP4 antagonist (ONO-AE3-208) did not inhibit growth in either of the cancer cell lines. In summary, PGE2 receptor EP3 signaling probably contributes to development of oral carcinomas and use of EP3 antagonist may be a new therapeutic strategy for head and neck cancer.
前列腺素E2（PGE2）可通过直接和间接机制刺激肿瘤进展。然而，其对细胞增殖的影响仍不清楚。本研究对口腔鳞状细胞癌中PGE2受体亚型的表达进行了表征，同时还研究了EP3和EP4选择性拮抗剂对口腔癌细胞系的影响。在11份手术标本中，分别有4份、5份、10份和10份检测到EP1、EP2、EP3和EP4受体mRNA。应用EP3拮抗剂（ONO-AE3-240）可强烈抑制COX-2和PGE2高表达细胞（Ca9-22）的细胞生长，但对COX-2和PGE2低表达细胞（HSC4）则无抑制作用。该拮抗剂还降低了内源性PGE2的产生，并诱导G0/G1期细胞停滞。添加外源性PGE2仅部分消除了生长抑制，表明通过EP3受体信号传导的抗增殖作用不仅归因于PGE2依赖性机制，还归因于PGE2非依赖性机制。相比之下，EP4拮抗剂（ONO-AE3-208）对两种癌细胞系的生长均无抑制作用。总之，PGE2受体EP3信号传导可能有助于口腔癌的发展，使用EP3拮抗剂可能是头颈癌的一种新治疗策略。
