Endothelin-1-induced Prostaglandin E2-EP2, EP4 Signaling Regulates Vascular Endothelial Growth Factor Production and Ovarian Carcinoma Cell Invasion

Abstract

Cyclooxygenase (COX)-1-and COX-2-derived prostaglandins are implicated in the development and progression of several malignancies. We have recently demonstrated that treatment of ovarian carcinoma cells with endothelin-1 (ET-1) induces expression of both COX-1 and COX-2, which contributes to vascular endothelial growth factor (VEGF) production. In this study, we show that in HEY and OVCA 433 ovarian carcinoma cells, ET-1, through the binding with ET A receptor (ET A R), induces prostaglandin E2 (PGE 2 ) production, as the more represented PG types, and increases the expression of PGE 2 receptor type 2 (EP2) and type 4 (EP4). The use of pharmacological EP agonists and antagonists indicates that ET-1 and PGE 2 stimulate VEGF production principally through EP2 and EP4 receptors. At the mechanistic level, we prove that the induction of PGE 2 and VEGF by ET-1 involves Src-mediated epidermal growth factor receptor transactivation. Finally, we demonstrate that ET A R-mediated activation of PGE 2 -dependent signaling participates in the regulation of the invasive behavior of ovarian carcinoma cells by activating tumor-associated matrix metalloproteinase. These results implicate EP2 and EP4 receptors in the induction of VEGF expression and cell invasiveness by ET-1 and provide a mechanism by which ET A R/ET-1 can promote and interact with PGE 2 -dependent machinery to amplify its proangiogenic and invasive phenotype in ovarian carcinoma cells. Pharmacological blockade of ET A R can therefore represent an additional strategy to control PGE 2 signaling, which has been associated with ovarian carcinoma progression.

Lysophosphatidic acid receptor 2 and Gi/Src pathway mediate cell motility through cyclooxygenase 2 expression in CAOV-3 ovarian cancer cells

“…Next, we determined the effect of LPA on PGE2 production. Like other ovarian cancer HEY or OVCAR-433 cells (Spinella et al, 2004), CAOV-3 cells secrete more than 100 pg/ml of PGE2 even without any treatment. When the cells were stimulated with LPA, PGE2 secretion was dramatically increased.…”

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

“…3A and B), and this effect was more pronounced when ZD4054 was added in combination with paclitaxel. In ovarian carcinoma cells, ET-1 increases VEGF, COX-1, and COX-2 expression through the ET A R, and these modulate invasive behavior (17,18). Therefore, we also tested the therapeutic efficacy of ZD4054 alone or in combination with paclitaxel on the endogenous production of VEGF and on COX-1/-2 expression.…”

“…We have demonstrated previously that the tumorpromoting effects of ET-1 through the ET A R in ovarian carcinoma cells also includes the secretion and activation of MMPs, such as MMP-2 and MMP-9, which are highly relevant in angiogenesis as well as in tumor cell invasion and metastasis (18,19). Thus, we investigated whether ZD4054 may inhibit ET-1 -induced MMP secretion and activity in ovarian carcinoma cells.…”

Altered Endothelin-1 Signaling in Production of Thromboxane A2 in Kupffer Cells from Bile Duct Ligated Rats

“…ET-1 induced the phosphorylation of cPLA 2 at ser505 in KCs from BDL and sham animals; however, the effect was significantly greater in KCs from BDL animals. In other cell types, ET-1 has been demonstrated to activate cPLA 2 and the release of various eicosanoids including TXA 2 , via binding to Gq/G11 and Gi coupled ET (A) and ET (B) receptors, subsequently inducing the activation of ERK1/2 or p38 MAPK through PLC or PKC mediated signaling pathways (38,39,41,42,44,45,47,(55)(56)(57)(58)(59)(60)(61). Therefore, the purposes of the present study were to delineate the signaling pathways induced via stimulation of Gq/G11 and Gi coupled ETBRs and the relative roles of intermediates in the activation of cPLA 2 and production of TXA 2 in KCs in response to ET-1, and determine whether the hepatic stress of early stage fibrosis alters the signaling pathways through modifications in the expressions or activities of signaling intermediates.…”