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Endothelin-1-induced Prostaglandin E2-EP2, EP4 Signaling Regulates Vascular Endothelial Growth Factor Production and Ovarian Carcinoma Cell Invasion
Ist Teil von
The Journal of biological chemistry, 2004-11, Vol.279 (45), p.46700-46705
Ort / Verlag
United States: American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
2004
Quelle
MEDLINE
Beschreibungen/Notizen
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.