Cytoplasmic Phospholipase A2 Levels Correlate with Apoptosis in Human Colon Tumorigenesis

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Abstract
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 α–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.