Secreted phospholipases A2 in cancer: diverse mechanisms of action

Secreted phospholipases A2 (sPLA2s) hydrolyse cell and lipoprotein phospholipid membranes to release free fatty acids and lysophospholipids, and can also bind to specific proteins. Several sPLA2s have been associated with various cancers, including prostate, colon, gastric, lung and breast cancers, yet, their role is controversial and seems to be dependent on the cancer type, the local microenvironment and the enzyme studied. There is strong evidence that the expression of some sPLA2s, most notably the group IIA, III and X enzymes, is dysregulated in various malignant tissues, where, as described in a number of in vitro and in vivo studies using mouse models and according to correlations between sPLA2 expression and patient survival, a particular enzyme may exert either a pro- or an anti-tumourigenic role. It is becoming clear that there are multiple, context-dependent mechanisms of action of sPLA2s in different cancers. First, the role of sPLA2s in cancer has traditionally been associated with their enzymatic activity and ability to participate in the release of potent biologically active lipid mediators, in particular arachidonic acid-derived eicosanoids, which promote tumourigenesis by stimulating cell proliferation and cell survival, by abrogating apoptosis and by increasing local inflammation and angiogenesis. Second, several biological effects of sPLA2s were found to be independent of sPLA2 enzymatic activity, arguing for a receptor-mediated mechanism of action. Finally, recent studies have implicated sPLA2s in the regulation of basal lipid metabolism, opening a new window to the understanding of the diverse roles of sPLA2s in cancer. In this short review, we highlight the newest findings on the biological roles of sPLA2s in cancer, with emphasis on their diverse mechanisms of action.