Inhibition of endothelial cell chemotaxis toward FGF-2 by gefitinib associates with downregulation of Fes activity

  • Authors:
    • Shigeru Kanda
    • Alexandra Naba
    • Yasuyoshi Miyata
  • View Affiliations

  • Published online on: December 1, 2009     https://doi.org/10.3892/ijo_00000448
  • Pages: 1305-1312
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Gefitinib inhibits epidermal growth factor-independent angiogenesis, but the molecular mechanism underlying this inhibition has yet to be defined. Here we show that gefitinib dose-dependently inhibited chemotaxis of endothelial cells toward fibroblast growth factor-2 (FGF-2), but not toward vascular endothelial growth factor-A (VEGF-A). Gefitinib inhibited lamellipodium formation by endothelial cells induced by FGF-2, but not by VEGF-A. Gefitinib at 10 µM did not inhibit autophosphorylation of FGF receptor 1 or VEGF receptor 2. A non-receptor protein tyrosine kinase, Fes, has two coiled-coil domains (CCDs) in its N-terminal region. Fes is activated by trans-autophosphorylation through CCD functions. An inactivating mutation in the second CCD abolished FGF-2 activation of Fes, indicating involvement of this CCD in FGF-2-induced Fes activation. Gefitinib-treatment decreased both CCD-independent and FGF-2- or VEGF-A-promoted Fes activity with a maximal decrease at 1 µM. The same results were observed in cells stably expressing kinase-inactive Fes; a dominant negative effect was observed in cells treated with FGF-2, but not with VEGF-A. Taken together, these results indicate that FGF-2 activates Fes via the second CCD, leading to lamellipodium formation and chemotaxis by endothelial cells, and gefitinib may act through Fes as an inhibitor of FGF-2-driven angiogenesis.

Related Articles

Journal Cover

December 2009
Volume 35 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Kanda S, Naba A and Miyata Y: Inhibition of endothelial cell chemotaxis toward FGF-2 by gefitinib associates with downregulation of Fes activity. Int J Oncol 35: 1305-1312, 2009
APA
Kanda, S., Naba, A., & Miyata, Y. (2009). Inhibition of endothelial cell chemotaxis toward FGF-2 by gefitinib associates with downregulation of Fes activity. International Journal of Oncology, 35, 1305-1312. https://doi.org/10.3892/ijo_00000448
MLA
Kanda, S., Naba, A., Miyata, Y."Inhibition of endothelial cell chemotaxis toward FGF-2 by gefitinib associates with downregulation of Fes activity". International Journal of Oncology 35.6 (2009): 1305-1312.
Chicago
Kanda, S., Naba, A., Miyata, Y."Inhibition of endothelial cell chemotaxis toward FGF-2 by gefitinib associates with downregulation of Fes activity". International Journal of Oncology 35, no. 6 (2009): 1305-1312. https://doi.org/10.3892/ijo_00000448