Regulation of tumor angiogenesis by fastatin, the fourth FAS1 domain of betaig-h3, via alphavbeta3 integrin.
We previously reported that the FAS1 domains of betaig-h3 bear motifs that mediate endothelial cell adhesion and migration via interactions with alphavbeta3 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 betaig-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 alphavbeta3 integrin, including endothelial cells. Binding of fastatin to alphavbeta3 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 alphavbeta3 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.
Nam
Ju-Ock
JO
Cell and Matrix Biology National Research Laboratory, Department of Biochemistry, Kyungpook National University School of Medicine, Daegu, Korea.
Jeong
Ha-Won
HW
Lee
Byung-Heon
BH
Park
Rang-Woon
RW
Kim
In-San
IS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*; D019014:fas Receptor; D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta; D019014:fas Receptor; D000099222:betaIG-H3 Protein; C491901:FAS protein, human