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Control of COX-2 Gene Expression through Peroxisome Proliferator-Activated Receptor in Human Cervical Cancer Cells

Division of Research, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia 30322 [S. H., L. C. F., N. S.], and Department of Pharmacology, National Cardiovascular Center Research Institute, Osaka, 565-8565, Japan [H. I.]

Purpose: The peroxisome proliferator-activated receptor- (PPAR), a ligand-dependent transcription factor belonging to the family of nuclear receptors, has been implicated in the control of cyclooxygenase (COX) 2 expression in some tissue, although the exact mechanism(s) of this activity has not been elucidated. In this study we explored the possible mechanism(s) of control of COX-2 gene expression through PPAR signaling in human cervical cancer.

Experimental Design: Using primary human cervical tissues and the CaSki human cervical cancer cell line, we assayed for PPAR and COX-2 mRNA expression by reverse transcription-PCR. Nuclear protein binding activities to three response elements located in the COX-2 promoter [nuclear factor B (NFB), cyclic AMP response element, and activator protein (AP)-2] were measured by gel mobility shift assays. We used transient transfection assays with COX-2 promoter reporter gene constructs to determine the regulatory sites in this promoter, which mediates PPAR regulation of COX-2 activity.

Results: We showed, for the first time, that primary human cervical cancer tissues express PPAR. Using CaSki cells, we demonstrated that COX-2 and PPAR mRNA levels were inversely regulated by PPAR ligands in that these compounds up-regulated PPAR but down-regulated COX-2. In contrast, epidermal growth factor (EGF), a potent activator of COX-2, decreased PPAR mRNA levels. This down-regulation of PPAR mRNA by EGF was blocked in the presence of NS-398, a selective COX-2 inhibitor. PPAR ligands suppressed the binding activities of AP-1 (binding to CRE) and NFB but not AP-2. Transient transfection results indicated that EGF stimulated whereas PPAR ligands inhibited COX-2 promoter (-327/+59) activity. This effect by PPAR ligands on the COX-2 promoter was blocked when the CRE, but not the NFB, binding site was mutagenized.

Conlcusion: Cervical cancer cells express readily detectable levels of PPAR. There is reciprocal negative regulation between COX-2 and PPAR signaling in human cervical cancer cells. The ability of PPAR ligands to inhibit COX-2 appears to be mediated predominantly through inhibition of AP-1 protein binding to the CRE site in the COX-2 promoter.

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