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

Proc Natl Acad Sci U S A
Authors
Keywords
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.

Year of Publication
2001
Journal
Proc Natl Acad Sci U S A
Volume
98
Issue
7
Pages
3935-9
Date Published
2001 Mar 27
ISSN
0027-8424
DOI
10.1073/pnas.051635898
PubMed ID
11274413
PubMed Central ID
PMC31157
Links
Grant list
DK38452 / DK / NIDDK NIH HHS / United States
DK39773 / DK / NIDDK NIH HHS / United States
NS10828 / NS / NINDS NIH HHS / United States