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Cyclooxygenase-1 Is Up-Regulated in Cervical Carcinomas

Autocrine/Paracrine Regulation of Cyclooxygenase-2, Prostaglandin E Receptors, and Angiogenic Factors by Cyclooxygenase-1

Departments of Medical Biochemistry [K. J. S., A. A. K.] and Obstetrics and Gynaecology [B. H., R. P. S.], University of Cape Town Medical School, Cape Town 7925, South Africa, and Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh EH3 9ET, United Kingdom [K. J. S., R. P. M., H. N. J.]

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 E₂ (PGE₂) synthesis. Treatment of HeLa cells overexpressing COX-1 with the dual COX enzyme inhibitor indomethacin or selective COX-2 inhibitor NS-398 significantly reduced PGE₂ 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 PGE₂ 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 PGE₂ receptors (EP1–EP4). We found that the cAMP-linked PGE₂ receptors were significantly up-regulated by COX-1 overexpression coincident with enhanced cAMP responsiveness of these cells to exogenous PGE₂ 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.

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