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, P1-3 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 P13-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, MEKI-MAPK and P13K-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Butadienes / pharmacology
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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Female
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Fibronectins / metabolism*
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Fibronectins / pharmacology
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Flavonoids / pharmacology
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Humans
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Indoles / pharmacology
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MAP Kinase Kinase 1
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Maleimides / pharmacology
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Matrix Metalloproteinase 9 / metabolism*
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Morpholines / pharmacology
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Neoplasm Invasiveness
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Nitriles / pharmacology
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase C / antagonists & inhibitors
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Tumor Cells, Cultured
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Wortmannin
Substances
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Androstadienes
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Butadienes
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Chromones
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Enzyme Inhibitors
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Fibronectins
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Flavonoids
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Indoles
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Maleimides
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Morpholines
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Nitriles
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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U 0126
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Protein Kinase C
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Matrix Metalloproteinase 9
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bisindolylmaleimide I
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin