影响蛋白通路砒霜可抗肿瘤
来源:《PNAS》 时间:2015/12/29

 

 

上海交通大学和山东大学的一项合作研究证实,砒霜(三氧化二砷,As2O3)可以明显抑制肿瘤细胞中糖酵解通路限速酶己糖激酶2HK2)的活性而影响细胞代谢,最终导致肿瘤细胞的凋亡。相关研究成果近日在线发表于美国《国家科学院院刊》。

As2O3在治疗APL(急性早幼粒细胞白血病)上已获成功,现有研究也表明,它在其他多种恶性肿瘤的治疗方面也有较大的潜力,但相关机制不清楚。

利用包含1.7万个重组人蛋白质的蛋白质组芯片,研究人员发展了一套基于蛋白质组芯片的小分子相互作用蛋白质快速发现技术,发现了360As2O3直接作用蛋白。而此前全世界研究者发现的砷直接相互作用蛋白质总数不超过20个。进一步分析发现As2O3能影响一系列通路,其中最显著的是糖酵解通路,研究表明As2O3能与糖酵解通路中的绝大部分蛋白质发生直接相互作用,进而影响代谢并最终促使肿瘤细胞的凋亡。

此次发现表明了蛋白质芯片平台是快速、全局寻找药物靶标的强有力工具。专家表示,这项研究中找到的众多As2O3靶标蛋白也将为后续As2O3在除APL外的其它肿瘤治疗上的应用提供指引。

该论文共同第一作者分别为上海交通大学系统生物医学研究院博士张海南、杨丽娜以及山东大学教授凌建亚。上海交通大学研究员陶生策与该校医学院附属瑞金医院陈竺院士为本文通讯作者。(来源: 中国科学报  黄辛)

 

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

 

Abstract  Arsenic is highly effective for treating acute promyelocytic leukemia (APL) and has shown significant promise against many other tumors. However, although its mechanistic effects in APL are established, its broader anticancer mode of action is not understood. In this study, using a human proteome microarray, we identified 360 proteins that specifically bind arsenic. Among the most highly enriched proteins in this set are those in the glycolysis pathway, including the rate-limiting enzyme in glycolysis, hexokinase-1. Detailed biochemical and metabolomics analyses of the highly homologous hexokinase-2 (HK2), which is overexpressed in many cancers, revealed significant inhibition by arsenic. Furthermore, overexpression of HK2 rescued cells from arsenic-induced apoptosis. Our results thus strongly implicate glycolysis, and HK2 in particular, as a key target of arsenic. Moreover, the arsenic-binding proteins identified in this work are expected to serve as a valuable resource for the development of synergistic antitumor therapeutic strategies.

 

原文链接:http://www.pnas.org/content/112/49/15084.full.pdf

 

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