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Inositolhexakisphosphate (InsP6): an antagonist of fibroblast growth factor receptor binding and activity
1Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Abstract:
Fibroblast growth factors (FGF), which have been implicated in tumor cell growth and angiogenesis, have biological activities that appear to be mediated by both heparinlike extracellular matrix sites and transmembrane tyrosine kinase receptor sites. In the present study, we demonstrated that inositolhexakisphosphate (InsP6) inhibits basic FGF (bFGF) binding to heparin. Our spectrofluorometric analyses demonstrated that InsP6 not only bound to bFGF, presumably within the bFGF heparin-binding domain, but also protected bFGF from degradation by trypsin. Also, InsP6 inhibited the cellular binding of bFGF and other fibroblast growth factor family members such as acidic FGF (aFGF) and K-FGF in a saturable and dose-dependent manner. Furthermore, concentrations as low as 100 microM InsP6 inhibited bFGF-induced DNA synthesis in AKR-2B fibroblasts, as well as the growth of bFGF- and K-FGF-transfected NIH/3T3 cells. Together, these results indicate that InsP6 may serve as a useful antagonist of FGF activity.
Insights
Inositolhexakisphosphate (InsP6) inhibits fibroblast growth factor (FGF) binding to heparin and cellular uptake. This suggests InsP6 can act as an antagonist to block FGF
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Fibroblast growth factors (FGFs) are implicated in tumor growth and angiogenesis.
- FGF biological activity involves heparin-like extracellular matrix and tyrosine kinase receptors.
Purpose of the Study:
- To investigate the inhibitory effects of inositolhexakisphosphate (InsP6) on basic FGF (bFGF) activity.
- To determine if InsP6 can antagonize FGF binding and cellular functions.
Main Methods:
- Spectrofluorometric analysis to assess bFGF binding to heparin.
- Cellular binding assays for bFGF and related FGFs.
- Assays for bFGF-induced DNA synthesis and cell growth in transfected cell lines.
Main Results:
- InsP6 demonstrated binding to bFGF, inhibiting its interaction with heparin.
- InsP6 protected bFGF from trypsin degradation.
- InsP6 inhibited cellular binding of bFGF, acidic FGF, and K-FGF in a dose-dependent manner.
- Low concentrations of InsP6 inhibited bFGF-induced DNA synthesis and cell proliferation.
Conclusions:
- InsP6 acts as an inhibitor of FGF binding to heparin and cellular receptors.
- InsP6 effectively antagonizes FGF-mediated cellular responses, including DNA synthesis and cell growth.
- InsP6 shows potential as a therapeutic antagonist for FGF-driven processes.