A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F2alpha synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signaling pathway.
Cyclooxygenase (COX) enzymes catalyze the biosynthesis of eicosanoids, including prostaglandin (PG) F2alpha. PGF2alpha 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 PGF2alpha-FP receptor interaction in modulating COX-2 expression and PGF2alpha biosynthesis using an endometrial adenocarcinoma cell line stably transfected with the FP receptor cDNA (FPS cells). PGF2alpha-FP receptor activation rapidly induced COX-2 promoter, mRNA, and protein expression in FPS cells. These effects of PGF2alpha 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 PGF2alpha de novo to promote a positive feedback loop to facilitate endometrial tumorigenesis. Finally, we have shown that PGF2alpha could potentiate tumorigenesis in endometrial adenocarcinoma explants by inducing the expression of COX-2 mRNA.
Jabbour
Henry N
HN
Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. h.jabbour@hrsu.mrc.ac.uk
Sales
Kurt J
KJ
Boddy
Sheila C
SC
Anderson
Richard A
RA
Williams
Alistair R W
AR
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D015237:Dinoprost / Q000096:biosynthesis*; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution; D014162:Transfection
D018076:DNA, Complementary; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3