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.