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A Positive Feedback Loop that Regulates Cyclooxygenase-2 Expression and Prostaglandin F₂ Synthesis via the F-Series-Prostanoid Receptor and Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway

Medical Research Council Human Reproductive Sciences Unit (H.N.J., K.J.S., S.C.B.), Reproductive and Developmental Sciences (R.A.A.), and Department of Pathology (A.R.W.W.), The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Henry N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. 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 [F-series-prostanoid (FP) receptor] to initiate cell signaling and target gene transcription. In the present study, we found elevated expression of COX-2 and FP receptor colocalized 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 on 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 (PD98059), or by inactivation of ERK1/2 signaling with dominant-negative mutant isoforms of Ras or ERK1/2 kinase. We further confirmed that elevated COX-2 protein in FPS cells could biosynthesize 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.

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