Taniguchi Tomoko, Fujino Hiromichi, Israel Davelene D, Regan John W, Murayama Toshihiko
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Biochem Biophys Res Commun. 2008 Dec 26;377(4):1173-8. doi: 10.1016/j.bbrc.2008.10.140. Epub 2008 Nov 6.
A critical event in tumor development is the formation of new blood vessels to provide oxygen, nutrients and growth factors to the rapidly growing cancer cells. This process of angiogenesis is complex, however, it is well established that vascular endothelial growth factor (VEGF)-mediated signaling is an important early event. Knockout mice studies have implicated the EP3 receptor in tumor development and angiogenesis; however, the signaling mechanism involved with this effect is unclear. We now show that stimulation of the EP3(I) isoform of the human EP3 receptor with prostaglandin E(2) increases the mRNA expression of both VEGF and its cognate receptor VEGF receptor-1 (VEGFR-1). These inductions by the EP3(I) receptor involve the sequential activation of phosphatidylinositol 3-kinase and the extracellular signal-regulated kinases. Up-regulation of VEGF and VEGFR-1 mRNA by the human EP3(I) receptor has not been previously reported and further strengthen the role of this receptor in tumor-associated angiogenesis.
肿瘤发展过程中的一个关键事件是形成新血管，为快速生长的癌细胞提供氧气、营养物质和生长因子。然而，血管生成过程很复杂，不过，血管内皮生长因子（VEGF）介导的信号传导是一个重要的早期事件，这一点已得到充分证实。基因敲除小鼠研究表明EP3受体与肿瘤发展和血管生成有关；然而，这种效应所涉及的信号传导机制尚不清楚。我们现在表明，用前列腺素E2刺激人EP3受体的EP3（I）亚型会增加VEGF及其同源受体VEGF受体-1（VEGFR-1）的mRNA表达。EP3（I）受体的这些诱导作用涉及磷脂酰肌醇3激酶和细胞外信号调节激酶的顺序激活。人EP3（I）受体对VEGF和VEGFR-1 mRNA的上调作用此前尚未见报道，这进一步强化了该受体在肿瘤相关血管生成中的作用。
