Chang Sung-Hee, Liu Catherine H, Wu Ming-Tao, Hla Timothy
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, 06030-3501, USA.
Prostaglandins Other Lipid Mediat. 2005 May;76(1-4):48-58. doi: 10.1016/j.prostaglandins.2004.12.001. Epub 2005 Mar 17.
Prostaglandin E(2) (PGE(2)), a major metabolite of the cyclooxygenase pathway in the mammary gland, induces angiogenesis during mammary tumor progression. To better define the molecular mechanisms involved, we examined the role of the G protein-coupled receptors (GPCR) for PGE(2) in mammary tumor cell lines isolated from MMTV-cyclooxygenase-2 (COX-2) transgenic mice. Expression of the EP2 subtype of the PGE(2) receptor was correlated with the tumorigenic phenotype and the ability to induce vascular endothelial growth factor (VEGF). Overexpression of EP2 by adenoviral transduction into EP2-null cells resulted in the induction of VEGF expression in response to PGE(2) and CAY10399, an EP2 receptor agonist. The induction of VEGF by the EP2 receptor did not require the hypoxia inducible factor (HIF)-1alpha pathway, MAP kinase pathway, or phosphoinositide-3-kinase/Akt pathway, but required the cAMP/protein kinase A pathway. These results suggest that EP2 receptor is a critical element for PGE(2) mediated VEGF induction in mouse mammary tumor cells.
前列腺素E(2)（PGE(2)）是乳腺中环氧化酶途径的主要代谢产物，在乳腺肿瘤进展过程中诱导血管生成。为了更好地确定其中涉及的分子机制，我们研究了PGE(2)的G蛋白偶联受体（GPCR）在从MMTV-环氧化酶-2（COX-2）转基因小鼠分离的乳腺肿瘤细胞系中的作用。PGE(2)受体EP2亚型的表达与致瘤表型以及诱导血管内皮生长因子（VEGF）的能力相关。通过腺病毒转导将EP2过表达至EP2缺失细胞中，导致细胞在PGE(2)和EP2受体激动剂CAY10399作用下诱导VEGF表达。EP2受体诱导VEGF并不需要缺氧诱导因子（HIF）-1α途径、丝裂原活化蛋白激酶途径或磷酸肌醇-3-激酶/蛋白激酶B途径，但需要环磷酸腺苷/蛋白激酶A途径。这些结果表明，EP2受体是PGE(2)介导小鼠乳腺肿瘤细胞中VEGF诱导的关键因素。
