title: Modulation of fibroblast growth factor-2 receptor binding, signaling, and mitogenic activity by heparin-mimicking polysulfonated compounds.
abstract: Basic fibroblast growth factor (FGF-2) interacts with high-affinity tyrosine-kinase fibroblast growth factor receptors (FGFRs) and low-affinity heparan sulfate proteoglycans (HSPGs) in target cells. Both interactions are required for FGF-2-mediated biological responses. Here we report the FGF-2 antagonist activity of novel synthetic sulfonic acid polymers with distinct chemical structures and molecular masses (MMs). PAMPS [poly(2-acrylamido-2-methyl-1-propanesulfonic acid)], (MM approximately 7,000-10,000), PAS [poly(anetholesulfonic acid)], (MM approximately 9,000-11,000), PSS [poly(4-styrenesulfonic acid)], (MM = 70,000), and poly(vinylsulfonic acid) (MM = 2,000), inhibited FGF-2 binding to HSPGs and FGFRs in fetal bovine aortic endothelial GM 7373 cells. They also abrogated the formation of the HSPG/FGF-2/FGFR ternary complex, as evidenced by their capacity to prevent FGF-2-mediated cell-cell attachment of FGFR-1-overexpressing, HSPG-deficient Chinese hamster ovary cells to wild-type HSPG-bearing cells. Direct interaction of the polysulfonates with FGF-2 was demonstrated by their ability to protect the growth factor from proteolytic cleavage. Accordingly, molecular modeling, based on the crystal structure of the interaction of FGF-2 with a heparin hexamer, showed the feasibility of docking PAMPS into the heparin-binding domain of FGF-2. In agreement with their FGF-2-binding capacity, PSS, PAS, and PAMPS inhibited FGF-2-induced cell proliferation in GM 7373 cells and murine brain microvascular endothelial cells. The antiproliferative activity of these compounds was associated with the abrogation of FGF-2-induced tyrosine phosphorylation of FGFR-1. Moreover, the polysulfonates PSS and PAS inhibited FGF-2-induced activation of mitogen-activated protein kinase-1/2, involved in FGF-2 signal transduction. In conclusion, sulfonic acid polymers bind FGF-2 by mimicking heparin interaction. These compounds may provide a tool to inhibit FGF-2-induced endothelial cell proliferation in angiogenesis and tumor growth.
authors.affiliation: Rega Institute for Medical Research, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium. Liekens@rega.kuleuven.ac.be
authors.forename: S
authors.initials: S
authors.lastname: Liekens
authors.forename: D
authors.initials: D
authors.lastname: Leali
authors.forename: J
authors.initials: J
authors.lastname: Neyts
authors.forename: R
authors.initials: R
authors.lastname: Esnouf
authors.forename: M
authors.initials: M
authors.lastname: Rusnati
authors.forename: P
authors.initials: P
authors.lastname: Dell'Era
authors.forename: P C
authors.initials: PC
authors.lastname: Maudgal
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: M
authors.initials: M
authors.lastname: Presta
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002417:Cattle; D002478:Cells, Cultured; D003198:Computer Simulation; D006224:Cricetinae; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D011108:Polymers / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013451:Sulfonic Acids / Q000494:pharmacology; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology*; D014357:Trypsin / Q000378:metabolism
chemical_list: D011108:Polymers; D017468:Receptors, Fibroblast Growth Factor; D013451:Sulfonic Acids; D013457:Sulfur Compounds; C077118:poly(2-acrylamido-2-methyl-1-propanesulfonic acid); C077115:poly(anetholesulfonic acid); D006493:Heparin; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D014357:Trypsin; C077114:styrenesulfonic acid polymer