Suppression of Intestinal Polyposis in Apc super([delta]716) Knockout Mice by an Additional Mutation in the Cytosolic Phospholipase A sub(2) Gene

• Published in: The Journal of biological chemistry 2000-11, Vol.275 (44), p.34013-34016
• Main Authors: Takaku, K, Sonoshita, M, Sasaki, N, Uozumi, N, Doi, Y, Shimizu, T, Taketo, M M
• Format: Article
• Language: English
• Subjects: Apc gene; familial adenomatous polyposis
• ISSN: 0021-9258

Arachidonic acid is a precursor for biosynthesis of eicosanoids, including prostaglandins, thromboxanes, leukotrienes, and lipoxins. Cytosolic phospholipase A sub(2) (cPLA sub(2)) plays a key role in the release of arachidonic acid as the substrate of cyclooxygenase-1 (COX-1) or COX-2. We found that the level of cPLA sub(2) mRNA was markedly elevated in the polyps and correlated with the polyp size in the small intestine of the Apc super( Delta 716) knockout mouse, a model for human familial adenomatous polyposis. To determine the role of cPLA sub(2) in intestinal tumorigenesis, we then introduced a cPLA sub(2) gene mutation into Apc super( Delta 716) mice. In the compound mutant mice, the size of the small intestinal polyps was reduced significantly, although the numbers remained unchanged. These results provide direct genetic evidence that cPLA sub(2) plays a key role in the expansion of polyps in the small intestine rather than in the initiation process. In contrast, colonic polyps were not affected in either size or number. Interestingly, group X sPLA sub(2) was constitutively expressed in the colon at much higher levels than in the small intestine. These results suggest that in the colon, group X sPLA sub(2) supplies arachidonic acid in both the normal epithelium and the polyps even in the absence of cPLA sub(2).