In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 7 ( 2001-03-27), p. 3935-3939
Abstract:
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 convert arachidonic acid (AA) to prostaglandins (PGs). Therefore, NSAIDs may suppress tumorigenesis by inhibiting PG
synthesis. However, various experimental studies have suggested the possibility of PG-independent mechanisms. Notably, disruption of the
mouse group IIA secretory phospholipase A 2 locus
( Pla2g2a ), a potential source of AA for COX-2, increases
tumor number despite the fact that the mutation has been predicted to decrease PG production. Some authors have attempted to reconcile the
results by suggesting that the level of the precursor (AA), not the products (PGs), is the critical factor. To clarify the role of AA in
tumorigenesis, we have examined the effect of deleting the group IV cytosolic phospholipase A 2 (cPLA 2 ) locus
(Pla2g4). We report that Apc Min/+ ,
cPLA 2 −/− mice show an 83% reduction in tumor
number in the small intestine compared with littermates with genotypes Apc Min/+ , cPLA 2 +/− and
Apc Min/+ , cPLA 2 +/+ . This tumor
phenotype parallels that of COX-2 knockout mice, suggesting that cPLA 2 is the predominant source of AA for COX-2 in the
intestine. The protective effect of cPLA 2 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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.051635898
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2001
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink