Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells

Abstract

The formation of prostaglandins requires the catalytic activity of cyclooxygenase (COX) which converts arachidonic acid to the prostaglandin endoperoxide PGH2, from which all other prostaglandins are formed. COX-2 is the highly inducible isozyme of COX which is responsible for much of the prostaglandin production in inflammation and is a key factor in colon carcinogenesis. Because COX-2 activity can be rate-limiting in prostaglandin formation, COX-2 expression must be regulated tightly. Numerous factors, including mitogens, tumor promoters, and cytokines have been found to stimulate the transcription of COX-2. We show that fatty acids, prostaglandins, and non-steroidal anti-inflammatory drugs, compounds that are substrates, products, and inhibitors, respectively, of COX enzymatic activity, also increase its expression. These compounds are members of a heterogeneous group of compounds known as peroxisome proliferators, and the prototypical peroxisome proliferator, WY-14,643, also enhanced COX-2 expression. We demonstrate that these compounds increase COX-2 transcription, and we identify a region of the COX-2 promoter containing a peroxisome proliferator response element that is responsible for the enhancement of COX- 2 expression seen with these compounds.