Cytoplasmic Phospholipase A2 Levels Correlate with Apoptosis in Human Colon Tumorigenesis

Abstract

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 transferasemediated 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 a a a --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.

Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate

“…Interestingly, the PLA2G2A, PLA2G2C, PLA2G2D, PLA2G2E, PLA2G2F and PLA2G5 genes reside within the same region of human chromosome 1 at p35 -36.1 (Valentin et al, 2000), a region frequently altered in colorectal cancer (Spirio et al, 1996). The decreased expression for PLA2G2D and PLA2G5 appears to be linked (cluster II, Figure 5) to that observed for PLA2G4A, ptgs1, SFRP-1 and RLPA-1, which have been proposed as tumour suppressor genes in colon cancer (Chulada et al, 2000;Shida et al, 2004;Suzuki et al, 2004;Dong et al, 2005).…”

“…These lipid mediators are known to be involved in cell proliferation, cell migration, angiogenesis, and are likely to play a role in the initiation and/or progression of colorectal cancer (Morioka et al, 2000;Krause and DuBois, 2001;Laye and Gill, 2003;Mills and Moolenaar, 2003;Murakami et al, 2005). AA can also participate in apoptosis by activating sphingomyelinases and ceramide production (Dong et al, 2005;Ilsley et al, 2005).…”

Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component

“…14 Expression of phospholipase A2, a key enzyme for prostaglandin synthesis together with COX2, has been associated with TNF-alpha-induced apoptosis in colon cancer cells. 13 As lower COX2 levels have been reported in colorectal carcinoma with MSI, 42 we examined whether COX2 was expressed any differently among the signet group, the mucinous group, and nonmucinous carcinoma, depending on different MSI status. However, we did not observe any significant modifications of COX2 levels due to MSI status among these tumor groups (data not shown).…”

“…4 Both signet ring cell colorectal carcinoma and mucinous colorectal carcinoma are associated with MSI-H. [3][4][5] In addition, frequent BRAF mutation and infrequent KRAS mutation have been reported in mucinous colorectal carcinoma, compared to nonmucinous adenocarcinoma. 4 Cyclooxygenase-2 (COX2) has been shown to be overexpressed in colorectal cancer, 13 and a high level of COX2 expression is associated with poor prognosis. 14 Recently, COX2 has been shown to be a target of mutant KRAS.…”

Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells

“…Seven of these genes were identified as members of the PLA2 family. PLA2 cytoplasmatic level correlates with apoptosis 30 and PLA2 is important for maintaining the phospholipids composition of the membrane especially during oxidative stress. 31 Another interesting link between apoptosis and lipid metabolisms originates from studies on PLD2, which we also identified as upregulated in B-CLL cells.…”