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Prostaglandin E(2) (PGE(2)) plays an important role in promoting carcinogenesis. Cytosolic phospholipase A(2) (cPLA(2)) and cyclooxygenase 2 (COX-2) are both key enzymes for PGE(2) biosynthesis. Recent evidence suggests that the coordinated function of cPLA(2) and COX-2 in the arachidonic acid pathway may contribute to the process of carcinogenesis in various tissue types. However, the concomitant effect of these enzymes on oral carcinogenesis remains unclear. In this study,we evaluated the expression of cPLA(2) and COX-2 in normal oral mucosa, dysplastic oral mucosa and squamous carcinoma (SCC) using immunohistochemistry. In an in vitro assay, Tca8113 and KB oral cancer cells were treated with NS-398 (a selective inhibitor of COX-2) for varying time intervals: 6, 12, 24, 48 and 72 h. The levels of cPLA(2) and COX-2 expression were evaluated by Western blot, and PGE(2) production was analyzed by radioimmunoassay. We found that cPLA(2) and COX-2 were expressed at higher levels in oral dysplasia and SCC than in normal oral mucosa. cPLA(2) expression was also found to correlate closely with COX-2 expression. Moreover, the enzymatic activities of cPLA(2) and COX-2 were gradually downregulated with longer durations of treatment with NS-398, as demonstrated by a reduction in the amount of PGE(2) production over time. Our data suggest that the coordinated activity of cPLA(2) and COX-2 contribute to the process of oral carcinogenesis, thus identifying cPLA(2) as a potential target for the prevention and treatment of oral cancers., (Copyright 2008 S. Karger AG, Basel.)