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

Cytosolic phospholipase A(2) (cPLA(2)) releases arachidonic acid (AA) from intracellular phospholipids. We evaluated the status of cPLA(2) in azoxymethane (AOM)-induced mouse colon tumors. Despite increased expression of cyclooxygenase 2 (3.7-fold) and PGE(2) (3.4-fold) production in tumors, cPLA(2) mRNA levels and enzyme activity were significantly reduced (3.6- and 3-fold, respectively). Reduced levels of cPLA(2) 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 A(2) (sPLA(2)) and expression of the groups V and X sPLA(2)s revealed no compensatory increase in tumor tissue. As cPLA(2) 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 cPLA(2) in TNF-alpha-induced apoptosis of cultured mouse colonocytes (YAMC). The specific cPLA(2) inhibitor, AACOCF(3) (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 cPLA(2) expression in both AOM-induced mouse colon tumors and human CRC and suggest that down regulation of cPLA(2) may attenuate TNF-alpha mediated apoptosis during tumorigenesis and facilitate tumor progression.