Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells

Cell adhesion to the extracellular matrix appears to trigger a cascade of i ntracellular signalings. We have previously shown that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloprotein ase (MMP)-9 secretion and thereby activated the invasiveness of cells via t he FAK/Ras signaling pathway. By use of chemical inhibitors, we investigate d the downstream effectors critical for FN-dependent secretion of MMP-9. Tr eatment of cells with MEK1 inhibitors, U0126 and PD98059, dramatically supp ressed the secretion of MMP-9 activated by FN. Similarly, PI-3 kinase inhib itors, Wortmannin and LY294002, strongly suppressed the FN-dependent secret ion of MMP-9 together with the inhibition of Akt activation. In contrast, a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-d ependent MMP-9 secretion. Moreover, we found that both the MEK1 inhibitor a nd the PI3-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells. Taken together, our results suggest that activa tion of dual signaling pathways, MEK1-MAPK and PI3K-Akt, is required for th e FN-dependent activation of MMP-9 secretion. Our results suggest the impor tance of these signaling molecules as a chemotherapeutic target for cancer.