title: Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1.
abstract: This study was designed to investigate the expression and molecular signaling of cyclooxygenase-1 (COX-1) in cervical carcinomas. Real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis confirmed enhanced expression of COX-1 RNA, and protein in squamous cell carcinomas and adenocarcinoma of the cervix. COX-1 expression in all carcinoma tissues was associated with enhanced expression of COX-2 RNA and protein. The site of COX-1 expression was localized by immunohistochemistry to the neoplastic epithelial cells in all squamous cell carcinomas and adenocarcinomas studied. Minimal COX-1 immunoreactivity was detected in normal cervix. To explore events associated with COX-1 up-regulation, we developed a doxycycline-regulated expression system in HeLa (cervical carcinoma) cells. Overexpression of COX-1 in HeLa cells resulted in induced expression of cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PGES) concomitant with increased prostaglandin E(2) (PGE(2)) synthesis. Treatment of HeLa cells overexpressing COX-1 with the dual COX enzyme inhibitor indomethacin or selective COX-2 inhibitor NS-398 significantly reduced PGE(2) synthesis. Indomethacin, but not NS-398, treatment abolished the up-regulation of expression of COX-2 and PGES in HeLa cells, suggesting that the observed up-regulation of COX-2 and PGES was mediated by COX-1-enzyme products. To assess whether enhanced PGE(2) synthesis after COX-1 induction would act in an autocrine/paracrine manner, we investigated the effect of COX-1 on the expression of the different isoforms of PGE(2) receptors (EP1-EP4). We found that the cAMP-linked PGE(2) receptors were significantly up-regulated by COX-1 overexpression coincident with enhanced cAMP responsiveness of these cells to exogenous PGE(2) ligand. Finally, overexpression of COX-1 was associated with enhanced expression of the angiogenic factors basic fibroblast growth factor, vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2. This up-regulation of angiogenic factor expression was abolished by indomethacin and partially reduced by NS-398. These data indicate that COX-1 up-regulation modulates the expression of factors that may act in an autocrine/paracrine manner to enhance and sustain tumorigenesis in neoplastic cervical epithelial cells. It is likely that similar mechanisms may act in vivo to modulate tumorigenesis of cervical carcinomas.
authors.affiliation: Department of Medical Biochemistry, University of Cape Town Medical School, Cape Town 7925, South Africa.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Sales
authors.forename: Arieh A
authors.initials: AA
authors.lastname: Katz
authors.forename: Bruce
authors.initials: B
authors.lastname: Howard
authors.forename: Robbert P
authors.initials: RP
authors.lastname: Soeters
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
authors.forename: Roggert P
authors.initials: RP
authors.lastname: Soeters
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics; D002584:Cervix Uteri / Q000201:enzymology; D000242:Cyclic AMP / Q000096:biosynthesis; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008222:Lymphokines / Q000096:biosynthesis; D008565:Membrane Proteins; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D043925:Angiogenesis Inducing Agents; D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D018078:Receptors, Prostaglandin E; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone