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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.

SUBMITTER: Zhang HN 

PROVIDER: S-EPMC4679019 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Zhang Hai-Nan HN   Yang Lina L   Ling Jian-Ya JY   Czajkowsky Daniel M DM   Wang Jing-Fang JF   Zhang Xiao-Wei XW   Zhou Yi-Ming YM   Ge Feng F   Yang Ming-Kun MK   Xiong Qian Q   Guo Shu-Juan SJ   Le Huang-Ying HY   Wu Song-Fang SF   Yan Wei W   Liu Bingya B   Zhu Heng H   Chen Zhu Z   Tao Sheng-Ce SC  

Proceedings of the National Academy of Sciences of the United States of America 20151123 49

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 glyc  ...[more]

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