EP1 Prostanoid Receptor Coupling to Gi/o Up-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway
EP1 Prostanoid Receptor Coupling to Gi/o Up-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway
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DOI：
10.1124/mol.110.063933
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发表时间：
2010-06-01
影响因子：
3.6
通讯作者：
Regan, John W.
中科院分区：
文献类型：
--
作者：
Ji, Ruyue;Chou, Chih-Ling;Regan, John W.
EP1前列腺素受体是前列腺素E_2(PGE(2))为其同源生理配体的四种亚型之一。它是G蛋白偶联受体家族中的一员，已知可以激活钙信号，尽管对E型前列腺素受体(EP)1受体信号的其他方面知之甚少。在表达人EP1受体的人胚胎肾(HEK)细胞中，我们发现PGE(2)刺激EP1受体上调低氧诱导因子-1(HIF-1α)的表达，该表达可被百日咳毒素完全阻断，表明偶联到G I/O。这种HIF-1α的上调在常氧条件下发生，并可被Wortmannin、Akt抑制剂和雷帕霉素抑制，这分别与磷酸肌醇-3激酶/Akt/哺乳动物雷帕霉素靶(MTOR)信号通路的激活一致。与低氧诱导的HIF-1上调类似于蛋白质降解减少相反，与EP1受体类似的HIF-1上调与核糖体蛋白S6(RpS6)的磷酸化有关，这表明核糖体S6激酶的激活和翻译的增加。人肝癌细胞中内源性EP1受体的刺激重现了HEK细胞中HIF-1α的正常上调，对百日咳毒素敏感，并参与了mTOR信号通路的激活和rpS6的磷酸化。此外，用EP1选择性激动剂舒前列酮处理HepG2细胞后，血管内皮生长因子-C的mRNA表达上调，这是一种受HIF调节的基因。众所周知，HIF-1α可以促进肿瘤的生长和转移，并且在癌症中经常上调。我们的发现提供了一个潜在的机制，通过增加PGE(2)的生物合成可以上调HIF-1α的表达，促进肿瘤的发生。
The EP1 prostanoid receptor is one of four subtypes whose cognate physiological ligand is prostaglandin-E2 (PGE(2)). It is in the family of G-protein-coupled receptors and is known to activate Ca2+ signaling, although relatively little is known about other aspects of E-type prostanoid receptor (EP) 1 receptor signaling. In human embryonic kidney (HEK) cells expressing human EP1 receptors, we now show that PGE(2) stimulation of the EP1 receptor up-regulates the expression of hypoxia-inducible factor-1 similar to (HIF-1 alpha), which can be completely blocked by pertussis toxin, indicating coupling to G i/o. This up-regulation of HIF-1 alpha occurs under normoxic conditions and could be inhibited with wortmannin, Akt inhibitor, and rapamycin, consistent with the activation of a phosphoinositide-3 kinase/Akt/ mammalian target of rapamycin (mTOR) signaling pathway, respectively. In contrast to the hypoxia-induced up-regulation of HIF-1 similar to which involves decreased protein degradation, the up-regulation of HIF-1 similar to by the EP1 receptor was associated with the phosphorylation of ribosomal protein S6 (rpS6), suggesting activation of the ribosomal S6 kinases and increased translation. Stimulation of endogenous EP1 receptors in human HepG2 hepatocellular carcinoma cells recapitulated the normoxic up-regulation of HIF-1 alpha observed in HEK cells, was sensitive to pertussis toxin, and involved the activation of mTOR signaling and phosphorylation of rpS6. In addition, treatment of HepG2 cells with sulprostone, an EP1-selective agonist, up-regulated the mRNA expression of vascular endothelial growth factor-C, a HIF-regulated gene. HIF-1 alpha is known to promote tumor growth and metastasis and is often up-regulated in cancer. Our findings provide a potential mechanism by which increased PGE(2) biosynthesis could up-regulate the expression of HIF-1 alpha and promote tumorigenesis.