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Cytoplasmic Phospholipase A₂ Levels Correlate with Apoptosis in Human Colon Tumorigenesis

¹ Center for Molecular Medicine, Program in Colorectal Cancer; Departments of ² Internal Medicine, ³ Pathology, and ⁴ Medicine, Division of Gastroenterology, Program in Colorectal Cancer, University of Connecticut Health Center, Farmington, Connecticut; and ⁵ Department of Molecular and Cellular Biology, University of Connecticut-Storrs, Storrs, Connecticut

Requests for reprints: Daniel W. Rosenberg, Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3101. Phone: 860-679-8704; Fax: 860-679-7639; E-mail: rosenberg{at}nso2.uchc.edu.

Colon cancers often display perturbations in arachidonic acid metabolism, with elevated levels of cyclooxygenase (COX)-2 expression and prostaglandin E₂ (PGE₂) production frequently observed. Whereas COX-2 and PGE₂ are associated with cancer cell survival and tumor angiogenesis, arachidonic acid itself is a strong apoptotic signal that may facilitate cancer cell death. To further explore how cancer cells exploit the progrowth actions of prostaglandins while suppressing the proapoptotic actions of intracellular arachidonic acid, we determined the cytoplasmic phospholipase A₂ (cPLA₂) and COX-2 expression levels in a panel of human colon tumors by immunohistochemistry. Although high levels of cPLA₂ and COX-2 expression are predicted to facilitate maximal prostaglandin production, tumors frequently displayed a high-COX-2/low-cPLA₂ phenotype. The least represented phenotype was the high expression of cPLA₂, a characteristic predicted to generate the highest levels of intracellular arachidonic acid. The potential proapoptotic role of cPLA₂ was supported by a higher frequency of terminal deoxynucleotidyl transferase–mediated nick end labeling staining in cPLA₂-positive tumors. Moreover, analysis of preneoplastic aberrant crypt foci from high-risk patients suggests that acquisition of the high-COX-2/low-cPLA₂ phenotype may arise at an early stage of colon carcinogenesis. We additionally inhibited cPLA₂ in HT-29 cells using antisense oligonucleotides. Our results indicate that cPLA₂ plays an important role in tumor necrosis factor –induced apoptosis in human colon cancer cells. Our data further support the model in which colon cancer growth is favored when intracellular arachidonic acid levels are suppressed by inhibition of cPLA₂ or by a high-COX-2/low-cPLA₂ phenotype.

Key Words: cytosolic phospholipase A2 • cyclooxygenase 2 • TNF • apoptosis • arachidonic acid

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