Clinical & Experimental Metastasis

, Volume 18, Issue 5, pp 423–428 | Cite as

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

  • Aye Aye Thant
  • Akihiro Nawa
  • Fumitaka Kikkawa
  • Yasukatu Ichigotani
  • Yangying Zhang
  • Thet Thet Sein
  • A.R.M. Ruhul Amin
  • Michinari Hamaguchi


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.

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


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Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Aye Aye Thant
    • 1
  • Akihiro Nawa
    • 2
  • Fumitaka Kikkawa
    • 2
  • Yasukatu Ichigotani
    • 1
  • Yangying Zhang
    • 1
  • Thet Thet Sein
    • 1
  • A.R.M. Ruhul Amin
    • 1
  • Michinari Hamaguchi
    • 1
  1. 1.Department of Molecular PathogenesisNagoya University School of MedicineNagoyaJapan
  2. 2.Department of Obstetrics and GynecologyNagoya University School of MedicineNagoyaJapan

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