Mimetic peptide of ubiquitin-interacting motif of epsin as a cancer therapeutic-perspective in brain tumor therapy through regulating VEGFR2 signaling.
Mimetic peptide of ubiquitin-interacting motif of epsin as a cancer therapeutic-perspective in brain tumor therapy through regulating VEGFR2 signaling.
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DOI：
10.20517/2574-1209.2016.01
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Dong Y;Wu H;Dong J;Song K;Rahman HA;Towner R;Chen H
Epsins，泛素化受体内化所需的内吞衔接蛋白，通常在人类癌症中上调。已经表征了内皮中缺乏胰蛋白酶的小鼠通过失调血管内皮生长因子受体-2（VEGFR 2）信号传导和非生产性肿瘤血管生成来抑制肿瘤生长。epsin泛素（Ub）相互作用基序（UIM）与泛素化VEGFR 2的结合是epsin依赖性VEGFR 2内吞和降解的关键机制，表明epsin UIM是潜在的治疗靶点。利用计算机辅助药物设计的方法来创建UIM模拟肽的泛素化VEGFR 2中的epsin结合位点在体内的功能竞争。化学合成的嵌合UIM肽UPI特异性靶向肿瘤血管系统中的VEGFR 2，在几种肿瘤模型中引起非功能性肿瘤血管生成，延缓肿瘤生长，并提高存活率。作者表明，UPI结合泛素化的VEGFR 2，以Ub依赖的方式形成超复合物。总的来说，UPI靶向策略为对当前抗血管生成疗法有抗性的癌症患者提供了一种潜在的新型治疗方法。在这篇综述中，作者概述了这项研究的要点，特别是作为一个潜在的应用胶质瘤肿瘤治疗。
Epsins, endocytic adaptor proteins required for internalization of ubiquitylated receptors, are generally upregulated in human cancers. It has been characterized that mice deficient of epsins in the endothelium inhibit tumor growth by dysregulating vascular endothelial growth factor receptor-2 (VEGFR2) signaling and non-productive tumor angiogenesis. Binding of the epsin ubiquitin (Ub)-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and degradation, indicative of epsin UIM as a potential therapeutic target. A Computer Assisted Drug Design approach was utilized to create the UIM mimetic peptides for the functional competition of epsin binding sites in ubiquitylated VEGFR2 in vivo. Specifically targeting VEGFR2 in the tumor vasculature, the chemically synthesized chimeric UIM peptide, UPI, causes non-functional tumor angiogenesis, retards tumor growth, and increases survival rates in several tumor models. The authors showed that UPI binds ubiquitylated VEGFR2 to form a supercomplex in an Ub-dependent fashion. Collectively, the UPI targeting strategy offers a potentially novel treatment for cancer patients who are resistant to current anti-angiogenic therapies. In this review, the authors outline the main points of this research specifically as a potential application for glioma tumor therapy.