MMP production in human fibrosarcoma cells and their invasiveness are regulated by group IB secretory phospholipase A2 receptor-mediated activation of cytosolic phospholipase A2.
Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are expressed in most colonic, gastric, and ovarian carcinomas, and they play a key role in their invasiveness. Previous studies have shown the involvement of arachidonic acid (AA)-derived metabolites in the regulation of MMP expression and cancer dissemination, thus suggesting a role for phospholipase A2, the AA producing enzymes, in these processes. The present study was undertaken to explore the role of phospholipases in MMP production and tumor cell invasiveness. Human fibrosarcoma cells were found to express and secrete type IB, IIA and V sPLA2. The cells were found also to express the M-type sPLA2 receptor. Treatment with an extracellular sPLA2 inhibitor inhibited tumor cell's invasiveness concomitantly with MMP-2/9 production. Correspondingly, adding an exogenous sPLA2-IB (but not IIA) resulted in significant elevation of MMP-2/9 secretion from the fibrosarcoma cells. Time-course determination of AA and oleic acid release by HT-1080 cells suggested that cPLA2 is activated subsequently to sPLA2 action. Accordingly, using Western blot analysis it was found that sPLA2-IB induced cPLA2 phosphorylation, a requirement for its activation, by a receptor-mediated activity, rather than its lipolytic activity. At the same time, sPLA2-IIA did not induce either MMPs secretion or cPLA2 phosphorylation. The results of this study show for the first time that MMP-2/9 production by human fibrosarcoma HT-1080 cells and their invasiveness is regulated by sPLA2-IB acting as a receptor ligand to activate cPLA2, which in turn provides the AA for production of eicosanoids required for MMP expression.
Gorovetz
Michal
M
Department of Pharmacology, Hebrew University School of Pharmacy, Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120.
Schwob
Ouri
O
Krimsky
Miron
M
Yedgar
Saul
S
Reich
Reuven
R
D000818:Animals; D001485:Basement Membrane / Q000201:enzymology; D045744:Cell Line, Tumor; D002633:Chemotaxis; D002809:Chondroitin Sulfates / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D054500:Group IB Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008954:Models, Biological; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism*; D010766:Phosphorylation; D013552:Swine
D002809:Chondroitin Sulfates; D054500:Group IB Phospholipases A2; D054510:Phospholipases A2, Cytosolic; D020782:Matrix Metalloproteinases