FGFR1/PI3/AKT signaling pathway is a novel target for anti-angiogenic effects of the cancer drug fumagillin (TNP-470)
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Date
2009-05-15
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Abstract
Fibroblast growth factor-1 (FGF1), a prototypic member of the FGF family, is a
potent angiogenic factor. Although FGF-stimulated angiogenesis has been extensively
studied, the molecular mechanisms regulating FGF1-induced angiogenesis are poorly
understood in vivo. Fumagillin, an antiangiogenic fungal metabolite, has the ability to
inhibit FGF-stimulated angiogenesis in the chicken chorioallantoic membrane (CAM). In
the current study, chicken CAMs were transfected with a signal peptide-containing
version of the FGF1 gene construct (sp-FGF1). Transfected CAMs were then analyzed in
the presence and absence of fumagillin treatment with respect to the mRNA expression
levels and protein activity of the FGF1 receptor protein (FGFR1), PI3K
(phosphatidylinositol 3-kinase), and its immediate downstream target, AKT-1 (protein
kinase B).
Results from the treatment of sp-FGF1-transfected CAMs with fumagillin showed
downregulation of PI3K and AKT-1 proteins at the mRNA and protein levels. In
contrast, no major alterations in FGFR1 mRNA expression level were observed. Similar
patterns of mRNA expression for the above three proteins were observed when the CAMs were treated with recombinant FGF1 protein in place of sp-FGF1 gene
transfection. Investigation using biotin-labeled fumagillin showed that only the FGF1
receptor protein, containing the cytoplasmic domain, demonstrated binding to fumagillin.
Furthermore, I demonstrated endothelial-specificity of the proposed antiangiogenic
signaling cascade using an in vitro system. Based on these findings, I conclude that the
binding of fumagillin to the cytoplasmic domain of the FGF1 receptor inhibited FGF1-
stimulated angiogenesis in vitro and in vivo.
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Keywords
angiogenesis, FGF, FGF1, FGFR1, fumagillin