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Cytoplasmic phospholipase A2 deletion enhances colon tumorigenesis.

Abstract：

:Cellular pools of free arachidonic acid are tightly controlled through enzymatic release of the fatty acid and subsequent utilization by downstream enzymes including the cyclooxygenases. Arachidonic acid cleavage from membrane phospholipids is accomplished by the actions of phospholipase A(2) (PLA(2)). Upon release, free arachidonic acid provides substrate for the synthesis of eicosanoids. However, under certain conditions, arachidonic acid may participate in ceramide-mediated apoptosis. Disruption of arachidonic acid homeostasis can shift the balance of cell turnover in favor of tumorigenesis, via overproduction of tumor-promoting eicosanoids or alternatively by limiting proapoptotic signals. In the following study, we evaluated the influence of genetic deletion of a key intracellular phospholipase, cytoplasmic PLA(2) (cPLA(2)), on azoxymethane-induced colon tumorigenesis. Heterozygous and null mice, upon treatment with the organotropic colon carcinogen, azoxymethane, developed a significant (P < 0.05) increase in colon tumor multiplicity (7.2-fold and 5.5-fold, respectively) relative to their wild-type littermates. This enhanced tumor sensitivity may be explained, in part, by the attenuated levels of apoptosis observed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining within the colonic epithelium of heterozygous and null mice ( approximately 50% of wild type). The lower frequency of apoptotic cells corresponded with reduced ceramide levels (69% and 46% of wild-type littermates, respectively). Remarkably, increased tumorigenesis resulting from cPLA(2) deletion occurred despite a significant reduction in prostaglandin E(2) production, even in cyclooxygenase-2-overexpressing tumors. These data contribute new information that supports a fundamental role of cPLA(2) in the control of arachidonic acid homeostasis and cell turnover. Our findings indicate that the proapoptotic role of cPLA(2) in the colon may supercede its contribution to eicosanoid production in tumor development.

journal_name

Cancer Res

journal_title

Cancer research

authors

Ilsley JN,Nakanishi M,Flynn C,Belinsky GS,De Guise S,Adib JN,Dobrowsky RT,Bonventre JV,Rosenberg DW

doi

10.1158/0008-5472.CAN-04-3446

subject

Has Abstract

pub_date

2005-04-01 00:00:00

pages

2636-43

issue

eissn

0008-5472

issn

1538-7445

pii

65/7/2636

journal_volume

pub_type

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Cytoplasmic phospholipase A2 deletion enhances colon tumorigenesis.