Regulation of tumor angiogenesis by fastatin, the fourth FAS1 domain of βig-h3, via αvβ3 integrin

Ju Ock Nam, Ha Won Jeong, Byung Heon Lee, Rang Woon Park, In San Kim

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

We previously reported that the FAS1 domains of βig-h3 bear motifs that mediate endothelial cell adhesion and migration via interactions with αvβ3 integrin and regulate angiogenesis. In the present study, we show that the fourth FAS1 domain, designated fastatin, inhibits endothelial adhesion and migration, not only to βig-h3, but also fibronectin and vitronectin, in a RGD-dependent manner. Fastatin and other FAS1 domains suppress endothelial cell tube formation and in vivo neovascularization in a Matrigel plug assay. The antiangiogenic activity of fastatin is associated with antitumor activity in mouse tumor models. Fastatin additionally induces apoptosis in several cells expressing αvβ3 integrin, including endothelial cells. Binding of fastatin to αvβ3 integrin inhibits phosphorylation of focal adhesion kinase, Raf, extracellular signal-regulated kinase, Akt, and mammalian target of rapamycin. Fastatin is thus the first endogenous angiogenesis regulator identified that inhibits both endothelial cell migration and growth by binding to αvβ3 integrin. Our data suggest that FAS1 domains from all possible forms of the four human FAS1 family proteins are potential endogenous regulators for pathologic angiogenesis. Moreover, FAS1 domains such as fastatin may be developed into drugs for blocking tumor angiogenesis.

Original languageEnglish
Pages (from-to)4153-4161
Number of pages9
JournalCancer Research
Volume65
Issue number10
DOIs
Publication statusPublished - 2005 May 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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