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Carcinogenesis, Vol. 24, No. 2, 307-315, February 2003
© 2003 Oxford University Press

CARCINOGENESIS

Inverse association between phospholipase A2 and COX-2 expression during mouse colon tumorigenesis

Mei Dong1, Kishore Guda1, Prashant R. Nambiar1, Anahita Rezaie2, Glenn S. Belinsky1, Gérard Lambeau3, Charles Giardina4 and Daniel W. Rosenberg1,5

1 The University of Connecticut Health Center, Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3101, USA,
2 The University of Connecticut Health Center, Department of Internal Medicine, Farmington, CT, USA,
3 The Institute de Pharmacologie Moleculaire et Cellulaire, Valbonne, France and
4 The University of Connecticut, Department of Molecular and Cell Biology, Storrs, CT, USA

Cytosolic phospholipase A2 (cPLA2) releases arachidonic acid (AA) from intracellular phospholipids. We evaluated the status of cPLA2 in azoxymethane (AOM)-induced mouse colon tumors. Despite increased expression of cyclooxygenase 2 (3.7-fold) and PGE2 (3.4-fold) production in tumors, cPLA2 mRNA levels and enzyme activity were significantly reduced (3.6- and 3-fold, respectively). Reduced levels of cPLA2 were also observed in pre-neoplastic aberrant crypt foci (ACF), a distinct morphological alteration that represents an early stage in the pathogenesis of colon tumors. Furthermore, the reciprocal expression patterns of these two genes were found to occur in human colorectal cancers (CRC). Examination of the activity of the secretory phospholipases A2 (sPLA2) and expression of the groups V and X sPLA2s revealed no compensatory increase in tumor tissue. As cPLA2 has been shown to be involved in TNF-{alpha}-induced apoptosis in certain cell types, and TNF-{alpha} expression is significantly enhanced in AOM-induced tumors (2.8-fold), we examined the role of cPLA2 in TNF-{alpha}-induced apoptosis of cultured mouse colonocytes (YAMC). The specific cPLA2 inhibitor, AACOCF3 (arachidonoyl trifluoromethyl ketone), was able to protect colonocytes from TNF-{alpha}-induced apoptosis in vitro. In summary, our data demonstrate an inverse relationship between COX-2 and cPLA2 expression in both AOM-induced mouse colon tumors and human CRC and suggest that down regulation of cPLA2 may attenuate TNF-{alpha} mediated apoptosis during tumorigenesis and facilitate tumor progression.


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