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 PGH 2 , 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.

Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

“…A previous study demonstrated that COX-2 contains a PPRE in the promoter region and is a target for PPAR-mediated transactivation in epithelial cells 65 and immortalized keratinocytes 66 . Importantly, COX-2 induction has been implicated in UV-mediated processes ranging from carcinogenesis to local and systemic immunosuppression 29,30,[67][68][69] .…”

Endothelial Cell Confluence Regulates Cyclooxygenase-2 and Prostaglandin E2 Production That Modulate Motility

“…ulating cyclooxygenase-2 in our systems because inhibitors of cyclooxygenase-2 catalytic activity, including NS-398, themselves induce cyclooxygenase protein expression (12).…”

“…Endothelial cells express cyclooxygenase-2 in response to diverse soluble agonists ranging from serum (32) to endotoxin (8) to cytokines (7,9) to lipid agonists of peroxisome proliferator-activated receptors (12,33). Cyclooxygenase-2 expression has not been characterized as a response to environmental stimuli such as intercellular contacts, although prostaglandin production from arachidonate by endothelial cells is modulated by the number of population doublings (34), and cell density has been shown to affect the amount of PGE 2 made in response to IL-1 stimulation of an osteoblast-like cell line (35).…”

“…Cyclooxgenase-2 typically is absent from endothelial cells and white blood cells but accumulates to high levels in endothelial cells over several hours in response to IL-1␤ (7), lipopolysaccharide (8), phorbol myristate acetate (8), TNF␣ (9), and oxidized phospholipids (10). Accordingly, cyclooxygenase-2 has numerous transcriptional regulatory elements in its 5Ј-regulatory region (11,12) and also is subject to post-transcriptional control (13).…”

Role of COX-2, thromboxane A2 synthase, and prostaglandin I2 synthase in papillary thyroid carcinoma growth

“…COX-2 expression is increased by various substances including mitogens, 2 tumor promoters, 3,4 cytokines, 1,2,5,6 serum, 5 and free fatty acids. 7 Other studies have shown that COX-2 is also regulated by nonsteroidal antiinflammatory drugs (NSAIDs) or by selective COX-2 inhibitors. [7][8][9][10] COX-2 is expressed in many types of cancers including colon, 11,12 pancreas, 8,13,14 stomach, [15][16][17] lung, 12,18 breast, 12,19 prostate, 20 cervix, 6 head and neck, 21 esophagus, 22 bladder, 23 glioma, 24 and melanomas.…”