Liekens S, Leali D, Neyts J, Esnouf R, Rusnati M, Dell'Era P, Maudgal P C, De Clercq E, Presta M
Rega Institute for Medical Research, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium.
Mol Pharmacol. 1999 Jul;56(1):204-13. doi: 10.1124/mol.56.1.204.
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.
碱性成纤维细胞生长因子（FGF - 2）与靶细胞中的高亲和力酪氨酸激酶成纤维细胞生长因子受体（FGFRs）和低亲和力硫酸乙酰肝素蛋白聚糖（HSPGs）相互作用。这两种相互作用对于FGF - 2介导的生物学反应都是必需的。在此，我们报道了具有不同化学结构和分子量（MMs）的新型合成磺酸聚合物的FGF - 2拮抗剂活性。聚（2 - 丙烯酰胺 - 2 - 甲基 - 1 - 丙烷磺酸）（PAMPS），（分子量约7000 - 10000），聚（茴香脑磺酸）（PAS），（分子量约9000 - 11000），聚（4 - 苯乙烯磺酸）（PSS），（分子量 = 70000），以及聚（乙烯磺酸）（分子量 = 2000），抑制了FGF - 2与胎牛主动脉内皮GM 7373细胞中的HSPGs和FGFRs的结合。它们还消除了HSPG/FGF - 2/FGFR三元复合物的形成，这通过它们阻止FGF - 2介导的FGFR - 1过表达、HSPG缺陷的中国仓鼠卵巢细胞与野生型含HSPG细胞的细胞 - 细胞附着的能力得到证明。聚磺酸盐与FGF - 2的直接相互作用通过它们保护生长因子免受蛋白水解切割的能力得到证明。因此，基于FGF - 2与肝素六聚体相互作用的晶体结构的分子建模表明将PAMPS对接至FGF - 2的肝素结合结构域的可行性。与它们的FGF - 2结合能力一致，PSS、PAS和PAMPS抑制了GM 7373细胞和小鼠脑微血管内皮细胞中FGF - 2诱导的细胞增殖。这些化合物的抗增殖活性与FGF - 2诱导的FGFR - 1酪氨酸磷酸化的消除相关。此外，聚磺酸盐PSS和PAS抑制了参与FGF - 2信号转导的丝裂原活化蛋白激酶 - 1/2的FGF - 2诱导的激活。总之，磺酸聚合物通过模拟肝素相互作用结合FGF - 2。这些化合物可能提供一种工具来抑制血管生成和肿瘤生长中FGF - 2诱导的内皮细胞增殖。
