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

Int J Oncol. 2009 Dec;35(6):1305-12. doi: 10.3892/ijo_00000448.


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 microM 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 microM. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Chemotaxis / drug effects*
  • Down-Regulation
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Fibroblast Growth Factor 2 / metabolism
  • Gefitinib
  • Humans
  • Neovascularization, Pathologic / metabolism*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-fes / chemistry
  • Proto-Oncogene Proteins c-fes / drug effects
  • Proto-Oncogene Proteins c-fes / metabolism*
  • Quinazolines / pharmacology*
  • Vascular Endothelial Growth Factor A / metabolism


  • Antineoplastic Agents
  • Quinazolines
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Proto-Oncogene Proteins c-fes
  • Gefitinib