Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands.
ACS Chem Biol. 2013 Oct 18;8(10):2331-8. doi: 10.1021/cb4004332. Epub 2013 Sep 3.
Heparan sulfate (HS), a long linear polysaccharide, is implicated in various steps of tumorigenesis, including angiogenesis. We successfully interfered with HS biosynthesis using a peracetylated 4-deoxy analogue of the HS constituent GlcNAc and studied the compound's metabolic fate and its effect on angiogenesis. The 4-deoxy analogue was activated intracellularly into UDP-4-deoxy-GlcNAc, and HS expression was inhibited up to ∼96% (IC50 = 16 μM). HS chain size was reduced, without detectable incorporation of the 4-deoxy analogue, likely due to reduced levels of UDP-GlcNAc and/or inhibition of glycosyltransferase activity. Comprehensive gene expression analysis revealed reduced expression of genes regulated by HS binding growth factors such as FGF-2 and VEGF. Cellular binding and signaling of these angiogenic factors was inhibited. Microinjection in zebrafish embryos strongly reduced HS biosynthesis, and angiogenesis was inhibited in both zebrafish and chicken model systems. All of these data identify 4-deoxy-GlcNAc as a potent inhibitor of HS synthesis, which hampers pro-angiogenic signaling and neo-vessel formation.
硫酸乙酰肝素 (HS) 是一种长线性多糖，涉及肿瘤发生的多个步骤，包括血管生成。我们成功地使用 HS 成分 GlcNAc 的乙酰化 4-去氧类似物干扰 HS 生物合成，并研究了该化合物的代谢命运及其对血管生成的影响。4-去氧类似物在细胞内被激活为 UDP-4-去氧-GlcNAc，HS 表达被抑制高达约 96%（IC50=16 μM）。HS 链大小减小，但没有检测到 4-去氧类似物的掺入，这可能是由于 UDP-GlcNAc 水平降低和/或糖基转移酶活性抑制。综合基因表达分析显示，与 HS 结合的生长因子（如 FGF-2 和 VEGF）调节的基因表达减少。这些血管生成因子的细胞结合和信号转导受到抑制。在斑马鱼胚胎中的微注射强烈抑制 HS 生物合成，并且在斑马鱼和鸡模型系统中均抑制血管生成。所有这些数据表明 4-脱氧-GlcNAc 是 HS 合成的有效抑制剂，它阻碍了促血管生成信号和新血管形成。
