Group III phospholipase A2 promotes colitis and colorectal cancer

Abstract

Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A2 (PLA2) subtypes, which lie upstream of various lipid mediators, have been implicated in the positive or negative regulation of these diseases. Clinical and biochemical evidence suggests that secreted PLA2 group III (sPLA2-III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA2-III-null (Pla2g3 −/−) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3 −/− mice are less susceptible to dextran sulfate-induced colitis, implying that the amelioration of colonic inflammation by sPLA2-III ablation may underlie the protective effect against colon cancer. Lipidomics analysis of the colon revealed significant reduction of pro-inflammatory/pro-tumorigenic lysophosholipids as well as unusual steady-state elevation of colon-protective fatty acids and their oxygenated metabolites in Pla2g3 −/− mice. Overall, our results establish a role of sPLA2-III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA2 enzymes in the gastrointestinal tract, and point to sPLA2-III as a novel druggable target for colorectal diseases.

Group IID, IIE, IIF and III secreted phospholipase A2s

“…PLA2G2F sPLA 2 -IIF Suprabasal keratinocytes Production of lysoplasmalogen Protection from psoriasis, CHS and skin cancer Spontaneous development of psoriasis-like epidermal hyperplasia and alopecia, Exacerbation of skin cancer [45] PLA2G3 sPLA 2 -III Epididymal epithelial cells Sperm membrane phospholipid remodeling Male hypofertility N.D. [93] Mast cells Production of microenvironmental PGD 2 Impaired mast cell maturation and anaphylaxis Increased mast cell maturation and anaphylaxis [34] Colonic epithelial cells Production of LPA and LPI Protection from colonic cancer and colitis N.D. [92] Aorta a Generation of LPC-rich small-dense LDL N.D.…”

“…Evaluation of the enzymatic property using a lipidomics-based natural membrane assay with a mixture of colon-extracted phospholipids as the substrate has demonstrated that sPLA 2 -III hydrolyzes all phospholipid subclasses including PC, PE, PS, PI and PG (i.e. with no apparent polar head group specificity), tending to prefer the sn-2 position of PUFAs [92]. In mice, sPLA 2 -III is distributed in several tissues, showing the highest expression in the colon, skin, and male reproductive organs [92,93].…”

“…with no apparent polar head group specificity), tending to prefer the sn-2 position of PUFAs [92]. In mice, sPLA 2 -III is distributed in several tissues, showing the highest expression in the colon, skin, and male reproductive organs [92,93]. Indeed, mice null for sPLA 2 -III (Pla2g3 −/− ) and those with transgenic overexpression of human sPLA 2 -III (PLA2G3-TG) display several remarkable phenotypes in these tissues, as described below.…”

“…Disturbance of the paracrine sPLA 2 -III-L-PGDS-DP1 circuit hampers the maturation and thereby activation of mast cells, resulting in impairment of allergic responses. (B) The roles of distinct PLA 2 s in the colon [44,92]. cPLA 2 α releases a pool of AA that is converted to PGH 2 by cyclooxygenase-2 (COX-2) and then to PGE 2 by microsomal PGE 2 synthase (mPGES-1).…”

“…shown that sPLA 2 -III is expressed in colonic epithelial cells and that its genetic deletion protects against colon cancer and colitis [92].…”