The prostaglandin receptor EP2 activates multiple signaling pathways and β-arrestin1 complex formation during mouse skin papilloma development
The prostaglandin receptor EP2 activates multiple signaling pathways and β-arrestin1 complex formation during mouse skin papilloma development
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DOI：
10.1093/carcin/bgp168
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发表时间：
2009-09-01
期刊：
影响因子：
4.7
通讯作者：
Langenbach, Robert
中科院分区：
文献类型：
--
作者：
Chun, Kyung-Soo;Lao, Huei-Chen;Langenbach, Robert
前列腺素 E-2 (PGE(2)) 在许多肿瘤类型中升高，但 PGE(2) 对肿瘤生长的贡献很大程度上未知。为了研究 PGE(2) 的作用，使用小鼠皮肤启动/促进模型研究了其受体之一 EP2 的贡献。初步研究表明，蛋白激酶 A (PKA)、表皮生长因子受体 (EGFR) 和几种效应子 - 环腺苷 3',5'-单磷酸反应元件结合蛋白 (CREB)、H-Ras、Src、蛋白激酶 B (AKT) 和细胞外信号调节激酶 (ERK)1/2 - 在 12-O-十四烷酰佛醇-13-乙酸酯 (TPA) 促进的乳头状瘤和PKA 和 EGFR 抑制（分别为 H89 和 AG1478）减少了乳头状瘤的形成。通过用吲哚美辛 (Indo) 抑制内源性 TPA 诱导的 PGE(2) 产生并同时用 EP2 激动剂 CAY10399 (CAY) 治疗，确定了 EP2 对这些通路激活和乳头状瘤发展的贡献。 CAY 治疗恢复了 TPA/Indo 治疗小鼠的乳头状瘤形成，并通过 p-CREB 形成测量增加了环腺苷 3',5'-单磷酸和 PKA 活化。 CAY 治疗还增加了 EGFR 和 Src 的激活，AG1478 和 PP2 对它们的抑制表明 Src 位于 EGFR 的上游。 CAY 还增加了 H-Ras、ERK1/2 和 AKT 的激活，而 AG1478 降低了它们的激活，表明 EGFR 位于上游。 EP2-/- 小鼠的乳头状瘤减少了 65%，并且 Src、EGFR、H-Ras、AKT 和 ERK1/2 激活减少，这也支持了 EP2 的贡献。据报道，EGFR 的 G 蛋白偶联受体 (GPCR) 激活涉及通过 GPCR-β-arrestin-Src 复合物激活 Src。事实上，β-arrestin1 或 p-Src 的免疫沉淀表明乳头状瘤中存在 EP2-β-arrestin1-p-Src 复合物。数据表明，EP2 通过激活 PKA 和 EGFR 促进肿瘤形成，并且 EP2 与 β-arrestin1 和 Src 形成复合物，从而促进信号传导和/或 EP2 脱敏。
Prostaglandin E-2 (PGE(2)) is elevated in many tumor types, but PGE(2)'s contributions to tumor growth are largely unknown. To investigate PGE(2)'s roles, the contributions of one of its receptors, EP2, were studied using the mouse skin initiation/promotion model. Initial studies indicated that protein kinase A (PKA), epidermal growth factor receptor (EGFR) and several effectors-cyclic adenosine 3',5'-monophosphate response element-binding protein (CREB), H-Ras, Src, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2-were activated in 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas and that PKA and EGFR inhibition (H89 and AG1478, respectively) decreased papilloma formation. EP2's contributions to the activation of these pathways and papilloma development were determined by inhibiting endogenous TPA-induced PGE(2) production with indomethacin (Indo) and concomitantly treating with the EP2 agonist, CAY10399 (CAY). CAY treatment restored papilloma formation in TPA/Indo-treated mice and increased cyclic adenosine 3',5'-monophosphate and PKA activation as measured by p-CREB formation. CAY treatment also increased EGFR and Src activation and their inhibition by AG1478 and PP2 indicated that Src was upstream of EGFR. CAY also increased H-Ras, ERK1/2 and AKT activation, and AG1478 decreased their activation indicating EGFR being upstream. Supporting EP2's contribution, EP2-/- mice exhibited 65% fewer papillomas and reduced Src, EGFR, H-Ras, AKT and ERK1/2 activation. G protein-coupled receptor (GPCR) activation of EGFR has been reported to involve Src's activation via a GPCR-beta-arrestin-Src complex. Indeed, immunoprecipitation of beta-arrestin1 or p-Src indicated the presence of an EP2-beta-arrestin1-p-Src complex in papillomas. The data indicated that EP2 contributed to tumor formation via activation of PKA and EGFR and that EP2 formed a complex with beta-arrestin1 and Src that contributed to signaling and/or EP2 desensitization.