Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways
Cholesterol sequestration by nystatin enhances the uptake and activity of endostatin in endothelium via regulating distinct endocytic pathways
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DOI：
10.1182/blood-2010-12-322867
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发表时间：
2011-06-09
期刊：
影响因子：
20.3
通讯作者：
Luo, Yongzhang
中科院分区：
文献类型：
--
作者：
Chen, Yang;Wang, Shan;Luo, Yongzhang
内皮抑素特异性内化到内皮细胞中对内皮细胞的生物学功能具有重要意义。然而，内皮抑素内化的机制仍然是难以捉摸的。在这项研究中，我们首次报告，这两个小窝/脂筏和网格蛋白包被的坑参与内皮抑素内化。使用化学抑制剂、小干扰RNA或显性负突变体抑制小窝途径或网格蛋白途径改变了体外内皮抑素内化。有趣的是，胆固醇螯合制霉菌素，一种多烯抗真菌药物，显着提高内皮细胞摄取内皮抑制素通过切换内皮抑制素内化主要是网格蛋白介导的途径。制霉菌素增强内皮抑素的内化也增加其对内皮细胞管形成和迁移的抑制作用。更重要的是，用制霉菌素和内皮抑制素的组合治疗选择性地增强内皮抑制素在肿瘤血管和肿瘤组织中的摄取和生物分布，而不是在荷瘤小鼠的正常组织中，最终导致内皮抑制素在体内的抗血管生成和抗肿瘤功效的提高。总之，我们的数据显示了一种新的内皮抑素内化机制，并支持通过调节不同的内吞途径与胆固醇螯合剂，增强内皮抑素的摄取和治疗效果的潜在应用。（血。2011; 117（23）：6392-6403）
Specific internalization of endostatin into endothelial cells has been proved to be important for its biologic functions. However, the mechanism of endostatin internalization still remains elusive. In this study, we report for the first time that both caveolae/lipid rafts and clathrin-coated pits are involved in endostatin internalization. Inhibition of either the caveolae pathway or the clathrin pathway with the use of chemical inhibitors, small interfering RNAs, or dominant-negative mutants alters endostatin internalization in vitro. Intriguingly, cholesterol sequestration by nystatin, a polyene antifungal drug, significantly enhances endostatin uptake by endothelial cells through switching endostatin internalization predominantly to the clathrin-mediated pathway. Nystatin-enhanced internalization of endostatin also increases its inhibitory effects on endothelial cell tube formation and migration. More importantly, combined treatment with nystatin and endostatin selectively enhances endostatin uptake and biodistribution in tumor blood vessels and tumor tissues but not in normal tissues of tumor-bearing mice, ultimately resulting in elevated antiangiogenic and antitumor efficacies of endostatin in vivo. Taken together, our data show a novel mechanism of endostatin internalization and support the potential application of enhancing the uptake and therapeutic efficacy of endostatin via regulating distinct endocytic pathways with cholesterol-sequestering agents. (Blood. 2011; 117(23): 6392-6403)