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Submitted on June 30, 2005
Accepted on July 26, 2005
synthesis via the FP receptor and ERK1/2 signalling pathway
MRC Human Reproductive Sciences Unit, Reproductive and Developmental Sciences and Department of Pathology. The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, United Kingdom
* To whom correspondence should be addressed. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.
Cyclooxygenase (COX) enzymes catalyze the biosynthesis of eicosanoids, including prostaglandin (PG) F2
. PGF2 exerts its autocrine/paracrine function by coupling to its G protein-coupled receptor (FP receptor) to initiate cell signaling and target gene transcription. In the present study we found elevated expression of COX-2 and FP receptor, co-localized together within the neoplastic epithelial cells of endometrial adenocarcinomas. We investigated a role for PGF2-FP receptor interaction in modulating COX-2 expression and PGF2 biosynthesis using an endometrial adenocarcinoma cell line stably transfected with the FP receptor cDNA (FPS cells). PGF2-FP receptor activation rapidly induced COX-2 promoter, mRNA and protein expression in FPS cells. These effects of PGF2 upon the expression of COX-2 could be abolished by treatment of FPS cells with an FP receptor antagonist (AL8810) and chemical inhibitor of ERK1/2 kinase (MEK; PD98059), or by inactivation of ERK1/2 signaling with dominant negative mutant isoforms of Ras or MEK. We further confirmed that elevated COX-2 protein in FPS cells could biosynthesise PGF2 de novo to promote a positive feedback loop to facilitate endometrial tumorigenesis. Finally, we have shown that PGF2 could potentiate tumorigenesis in endometrial adenocarcinoma explants by inducing the expression of COX-2 mRNA.
•
FP receptor •
ERK1/2 •
cyclooxygenase •
prostaglandin
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