Evidence that porcine pancreatic phospholipase A2 via its high affinity receptor stimulates extracellular matrix invasion by normal and cancer cells.

Cellular migration and extracellular matrix (ECM) invasion are some of the critical steps in embryonic implantation, inflammation, wound healing, and cancer metastasis. Extracellular phospholipases A2 (PLA2s), belonging to either group I (PLA2-I) or group II (PLA2-II), play an essential role in the generation of proinflammatory lipid mediators (e.g. prostaglandins, leukotrienes, etc.). Recent reports indicate that PLA2-I, in addition to its digestive function, has receptor-mediated effects. For instance, PLA2-I, via its receptor, can induce cell proliferation and airway as well as vascular smooth muscle contraction. Here, we report that both porcine pancreatic and Naja naja PLA2s, in a dose-dependent manner, stimulate dramatic invasion of an artificial ECM (MatrigelTM) by NIH 3T3, mouse fibrosarcoma, and sarcoma cells in vitro, but it has no such effect on lymphoma and mastocytoma cells. That this is a receptor-mediated process is strongly suggested by the following findings. (a) While NIH 3T3, mouse fibrosarcoma, and sarcoma cells, which respond to PLA2-I stimulation, express high affinity PLA2-I receptor mRNA and protein, this receptor expression is not detectable in nonresponder lymphoma and mastocytoma cells. (b) There is a close correlation between the Kd values for 125I-PLA2-I binding to its receptor and the ED50 values for PLA2-I-induced ECM-invasion. (c) Catalytically inactivated PLA2-I is as effective as the active enzyme in stimulating invasion. (d) Suppression of PLA2-I receptor expression in responder cells causes inhibition of ECM invasion. (e) Treatment of the same cells with PLA2-I receptor-antibody also produces virtually identical effects. Taken together, our results identify a novel receptor-mediated function of PLA2-I and raises the possibility that extracellular PLA2s play important physiological as well as pathological roles via this receptor. To our knowledge, this is the first report of this novel receptor-mediated effect (i.e. ECM invasion) of PLA2-I on normal as well as malignant cancer cells.