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标题：Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic
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作者：Hai-nan Zhang ; Lina Yang ; Jian-ya Ling 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：15084-15089
DOI：10.1073/pnas.1521316112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceArsenic holds promise for treating a wide range of tumors. To understand arsenic's antitumor mechanism further, we identified 360 arsenic-binding proteins using a human proteome microarray and found proteins of glycolysis to be highly enriched. In-depth in vitro and in vivo analysis revealed that glycolysis in general and the rate-limiting enzyme hexokinase-2 of the glycolytic pathway in particular play a key role in mediating the anticancer activity of arsenic. These findings shed light on the mode of action of arsenic, and the newly identified arsenic-binding proteins may serve as a rich resource for future studies. 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.
关键词：arsenic trioxide ; human proteome microarray ; glycolysis ; hexokinase-2I