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Transcriptional Regulation of Cyclooxygenase-2 Gene Expression: Novel Effects of Nonsteroidal Anti-Inflammatory Drugs

Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892-1830

Cyclooxygenase-2 (COX-2) gene overexpression is suggested to play important roles in colorectal tumorigenesis. Epidemiological studies revealed that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and sulindac, which inhibit COX activity, reduce colorectal cancer mortality. Current investigations have focused on delineating the molecular mechanisms that regulate COX-2 gene expression and the roles of NSAIDs in cancer chemoprevention. COX-2 catalyzes the production of prostaglandins (PGs) from arachidonic acid (AA), generated by phospholipases A₂ (PLA₂s), a family of acyl esterases that cause the release of AA from cellular phospholipids. Pancreatic secretory PLA₂ (sPLA₂), via its receptor (sPLA₂R), transcriptionally activates COX-2 gene expression in several cell types, although a specific transcription factor mediating COX-2 expression has not yet been identified. Here, we report that a transcription factor, CCAAT/enhancer-binding protein ß (C/EBPß), plays a critical role in sPLA₂IB-induced, receptor-mediated COX-2 gene expression in MC3T3E1 and NIH3T3 cells. Furthermore, treatment of these cells with NSAIDs in the presence of sPLA₂IB appears to potentiate the stimulatory effects on COX-2 mRNA and COX-2 protein expression and a concomitant elevation in PG production. Most significantly, NSAID treatment appears to drastically suppress the production of cytosolic PLA₂ (cPLA₂) mRNA. The lack of sPLA₂IB, sPLA₂IIA, and sPLA₂V mRNA expression in both NIH3T3 and MC3T3E1 cells suggests that cPLA₂ is the most likely enzyme that catalyzes the release of AA, the rate-limiting substrate of COX for the production of PGs. Our results suggest that: (a) sPLA₂IB receptor-mediated COX-2 expression is mediated via C/EBPß; (b) NSAIDs in the presence of sPLA₂IB potentiate the stimulatory effects of sPLA₂IB on COX-2 mRNA expression; and (c) despite the apparent stimulation of COX-2 expression by NSAIDs, they strikingly deprive COX-2 of its substrate, AA, by suppressing cPLA₂ mRNA expression. Both AA and PGs regulate many vital biological functions (e.g., motility and invasiveness) that are dysregulated in most cancer cells, and they have profound effects on cellular differentiation. Our results raise the possibility that deprivation of COX-2 of its substrate by the suppression of cPLA₂ mRNA expression is an additional mechanism used by NSAIDs to inhibit tumorigenesis.

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