Fibroblast growth factor 2-antagonist activity of a long-pentraxin 3-derived anti-angiogenic pentapeptide.
Bottom Line: In all the assays the mutated Ac-ARPSA-NH(2) peptide was ineffective.In keeping with the observation that hydrophobic interactions dominate the interface between FGF2 and the FGF-binding domain of the Ig-like loop D2 of FGFR1, amino acid substitutions in Ac-ARPCA-NH(2) and saturation transfer difference-nuclear magnetic resonance analysis of its mode of interaction with FGF2 implicate the hydrophobic methyl groups of the pentapeptide in FGF2 binding.These results will provide the basis for the design of novel PTX3-derived anti-angiogenic FGF2 antagonists.
Affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy.Show MeSH
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Mentions: PTX3 is able to inhibit the mitogenic activity exerted by FGF2 and by other members of the FGF family on endothelial cells, without affecting the activity of unrelated mitogens . On this basis, ARPCA was assessed for its capacity to affect the proliferation of endothelial GM7373 cells exposed to different mitogenic stimuli. In these and following biological experiments, the inactive Ac-ARPSA-NH2 (hereafter referred to as ARPSA) was used as a negative control peptide. As shown in Fig. 1(A), ARPCA inhibits GM7373 cell proliferation triggered by FGF2, FGF8b and with a less efficiency by FGF1, whereas it does not affect the mitogenic activity of VEGF, EGF, DAG, TPA and serum. No inhibition was instead exerted by control peptide ARPSA on any mitogen. Moreover, in keeping with the capacity of FGF2 to interact with all four members of the FGFR family , ARPCA, but not ARPSA, inhibits the proliferation triggered by FGF2 in CHO cells stably transfected with the FGFR1, FGFR2, FGFR3 or FGFR4 isoforms  (Fig. 1B). These data demonstrate that, as for PTX3, the inhibitory activity of ARPCA is limited to the FGF/FGFR system and it is not due to a generic antiproliferative/toxic effect.
Affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy.