Cellular Distribution, Post-translational Modification, and Tumorigenic Potential of Human Group III Secreted Phospholipase A2

Human group III secreted phospholipase A2 (sPLA2-III) consists of a central group III sPLA2 domain flanked by unique N- and C-terminal domains. We found that the sPLA2 domain alone was sufficient for its catalytic activity and for its prostaglandin E2 (PGE2)-generating functions in various cell types. In several if not all cell types, the N- and C-terminal domains of sPLA2-III were proteolytically removed, leading to the production of the form containing only the sPLA2 domain, which could be further N-glycosylated at two consensus sites. Immunohistochemistry demonstrated that sPLA2-III was preferentially expressed in the microvascular endothelium in human tissues with inflammation, ischemic injury, and cancer. In support of this, sPLA2-III was induced in cultured microvascular endothelial cells after stimulation with proinflammatory cytokines. Expression of sPLA2-III was also associated with various tumor cells, and colorectal cancer cells transfected with sPLA2-III exhibited enhanced PGE2 production and cell proliferation, which required sPLA2-III catalytic activity. When implanted into nude mice, the sPLA2-III-transfected cells formed larger solid tumors with increased angiogenesis compared with control cells. Moreover, small interfering RNA for sPLA2-III significantly reduced PGE2 production and proliferation of colorectal cancer cells. Taken together, these results reveal unique cell type-specific processing and N-glycosylation of sPLA2-III and the potential role of this enzyme in cancer development by stimulating tumor cell growth and angiogenesis.