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

Authors: Thant, Aye; Nawa, Akihiro; Kikkawa, Fumitaka; Ichigotani, Yasukatu; Zhang, Yangying; Sein, Thet; Amin, A.R.M.; Hamaguchi, Michinari

Source: Clinical and Experimental Metastasis, Volume 18, Number 5, September 2000 , pp. 423-428(6)

Publisher: Springer

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Abstract:

Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, PI-3 kinase inhibitors, Wortmannin and LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast, a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that both the MEK1 inhibitor and the PI3-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells. Taken together, our results suggest that activation of dual signaling pathways, MEK1-MAPK and PI3K-Akt, is required for the FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic target for cancer.

Keywords: fibronectin; invasion; MAPK; matrix metalloproteinase; ovarian cancer cells; PI-3 kinase

Document Type: Research article

DOI: http://dx.doi.org/10.1023/A:1010921730952

Publication date: 2000-09-01