Heparan sulfate proteoglycans play a dual role in regulating fibroblast growth factor-2 mitogenic activity in human breast cancer cells.
Heparan sulfate proteoglycans play a dual role in regulating fibroblast growth factor-2 mitogenic activity in human breast cancer cells.
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硫酸乙酰肝素蛋白聚糖在调节人乳腺癌细胞中成纤维细胞生长因子-2 有丝分裂活性中发挥双重作用。
DOI：
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发表时间：
1996
影响因子：
3.7
通讯作者：
H. Hondermarck
中科院分区：
文献类型：
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作者：
M. Delehedde;E. Deudon;Benoni Boilly;H. Hondermarck
人乳腺癌细胞系MCF-7和MDA-MB-231对成纤维细胞生长因子-2 （FGF-2）的反应性不同。这种生长因子刺激分化良好的MCF-7细胞的增殖，而分化较差的MDA-MB-231细胞对这种分子不敏感。为了研究硫酸肝素蛋白多糖（HSPG）对FGF-2有丝分裂活性的潜在调节作用，我们用糖胺聚糖降解酶或蛋白聚糖硫酸化代谢抑制剂氯酸钠处理人乳腺癌细胞。通过检测125I-FGF-2与乳腺癌细胞培养物以及负载HSPG的阳离子膜的结合，研究了FGF-2与蛋白聚糖之间的相互作用。在MCF-7细胞中，我们发现肝素酶处理抑制了FGF-2与HSPG的结合，并完全消除了FGF-2诱导的生长；氯酸盐处理MCF-7细胞降低了FGF-2与HSPG的结合，并以剂量依赖的方式降低了细胞反应性。这表明，在MCF-7细胞上，FGF-2的促生长活性需要充分硫酸化的HSPG。高侵袭性MDA-MB-231细胞产生的HSPG是MCF-7细胞的两倍，通常对外源添加的FGF-2没有反应，氯酸盐处理降低了FGF-2与HSPG的结合并诱导了FGF-2的有丝分裂作用。这种氯酸盐效应是剂量依赖性的，在浓度为10-30 mM时观察到；较高的氯酸盐浓度完全消除了FGF-2的作用。这说明硫酸化的HSPG水平也可以负向调节FGF-2的生物活性。综上所述，这些结果表明HSPG在乳腺癌细胞增殖中FGF-2有丝分裂活性的阳性和阴性控制中都起着至关重要的作用。
The human breast cancer cell lines MCF-7 and MDA-MB-231 differ in their responsiveness to fibroblast growth factor-2 (FGF-2). This growth factor stimulates proliferation in well-differentiated MCF-7 cells, whereas the less well-differentiated MDA-MB-231 cells are insensitive to this molecule. To investigate the potential regulation of FGF-2 mitogenic activity by heparan sulfate proteoglycans (HSPG), we have treated human breast cancer cells by glycosaminoglycan degrading enzymes or a metabolic inhibitor of proteoglycan sulfation: sodium chlorate. The interaction between FGF-2 and proteoglycans was assayed by examining the binding of 125I-FGF-2 to breast cancer cell cultures as well as to cationic membranes loaded with HSPG. Using MCF-7 cells, we showed that heparinase treatment inhibited FGF-2 binding to HSPG and completely abolished FGF-2 induced growth; chlorate treatment of MCF-7 cells decreased FGF-2 binding to HSPG and cell responsiveness in a dose-dependent manner. This demonstrates a requirement of adequately sulfated HSPG for FGF-2 growth-promoting activity on MCF-7 cells. In highly invasive MDA-MB-231 cells which produce twice as much HSPG as MCF-7 cells and which are not normally responsive to exogenously added FGF-2, chlorate treatment decreased FGF-2 binding to HSPG and induced FGF-2 mitogenic effect. This chlorate effect was dose dependent and observed at concentrations of 10-30 mM; higher chlorate concentrations completely abolished the FGF-2 effect. This shows that the HSPG level of sulfation can also negatively regulate the biological activity of FGF-2. Taken together, these results demonstrate a crucial role for HSPG in both positive and negative control of FGF-2 mitogenic activity in breast cancer cell proliferation.