A Positive Feedback Loop that Regulates Cyclooxygenase-2 Expression and Prostaglandin F2α Synthesis via the F-Series-Prostanoid Receptor and Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway

Abstract

Cyclooxygenase (COX) enzymes catalyze the biosynthesis of eicosanoids, including prostaglandin (PG) F2α. PGF2α 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 PGF2α-FP receptor interaction in modulating COX-2 expression and PGF2α biosynthesis using an endometrial adenocarcinoma cell line stably transfected with the FP receptor cDNA (FPS cells). PGF2α-FP receptor activation rapidly induced COX-2 promoter, mRNA, and protein expression in FPS cells. These effects of PGF2α 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 PGF2αde novo to promote a positive feedback loop to facilitate endometrial tumorigenesis. Finally, we have shown that PGF2α could potentiate tumorigenesis in endometrial adenocarcinoma explants by inducing the expression of COX-2 mRNA.