Cytoplasmic phospholipase A2 levels correlate with apoptosis in human colon tumorigenesis.
Colon cancers often display perturbations in arachidonic acid metabolism, with elevated levels of cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) production frequently observed. Whereas COX-2 and PGE(2) 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 A(2) (cPLA(2)) and COX-2 expression levels in a panel of human colon tumors by immunohistochemistry. Although high levels of cPLA(2) and COX-2 expression are predicted to facilitate maximal prostaglandin production, tumors frequently displayed a high-COX-2/low-cPLA(2) phenotype. The least represented phenotype was the high expression of cPLA(2), a characteristic predicted to generate the highest levels of intracellular arachidonic acid. The potential proapoptotic role of cPLA(2) was supported by a higher frequency of terminal deoxynucleotidyl transferase-mediated nick end labeling staining in cPLA(2)-positive tumors. Moreover, analysis of preneoplastic aberrant crypt foci from high-risk patients suggests that acquisition of the high-COX-2/low-cPLA(2) phenotype may arise at an early stage of colon carcinogenesis. We additionally inhibited cPLA(2) in HT-29 cells using antisense oligonucleotides. Our results indicate that cPLA(2) plays an important role in tumor necrosis factor alpha-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 cPLA(2) or by a high-COX-2/low-cPLA(2) phenotype.
Dong
Mei
M
Center for Molecular Medicine, Program in Colorectal Cancer, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3101, USA.
Johnson
Michael
M
Rezaie
Anahita
A
Ilsley
Jillian N M
JN
Nakanishi
Masako
M
Sanders
Melinda M
MM
Forouhar
Faripour
F
Levine
Joel
J
Montrose
David C
DC
Giardina
Charles
C
Rosenberg
Daniel W
DW
D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D051546:Cyclooxygenase 2; D003593:Cytoplasm / Q000201:enzymology*; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D011230:Precancerous Conditions / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015232:Dinoprostone