Deletion of cytosolic phospholipase A(2) suppresses Apc(Min)-induced tumorigenesis

Although nonsteroidal antiinflammatory drugs (NSAIDs) show great promise as therapies for colon cancer, a dispute remains regarding their mechanism of action, NSAIDs are known to inhibit cyclooxygenase (COX) enzymes, which co nvert arachidonic acid (AA) to prostaglandins (PGs). Therefore, NSAIDs may suppress tumorigenesis by inhibiting PC synthesis, However, various experim ental studies have suggested the possibility of PC-independent mechanisms, Notably, disruption of the mouse group IIA secretory phospholipase Az locus (Pla2g2a), a potential source of AA for COX-2, increases tumor number desp ite the fact that the mutation has been predicted to decrease PG production , Some authors have attempted to reconcile the results by suggesting that t he level of the precursor (AA), not the products (PGs), is the critical fac tor. To clarify the role of AA in tumorigenesis, we have examined the effec t of deleting the group IV cytosolic phospholipase Az (cPLA(2)) locus (Pla2 g4). We report that Apc(Min/+), cPLA(2)(-/-) mice show an 83% reduction in tumor number in the small intestine compared with littermates with genotype s Apc(Min/+), cPLA(2)(+/-) and Apc(Min/+), cPLA(2)(+/+). This tumor phenoty pe parallels that of COX-2 knockout mice, suggesting that cPLA2 is the pred ominant source of AA for COX-2 in the intestine. The protective effect of c PLA2 deletion is thus most likely attributed to a decrease in the AA supply to COX-2 and a resultant decrease in PG synthesis. The tumorigenic effect of sPLA(2) mutations is likely to be through a completely different pathway .