title: 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.
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai 200240, China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Hai-Nan
authors.initials: HN
authors.lastname: Zhang
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Jinan 250100, China;
authors.forename: Jian-Ya
authors.initials: JY
authors.lastname: Ling
authors.affiliation: School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Czajkowsky
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zhang
authors.affiliation: National Engineering Research Center for Beijing Biochip Technology, Beijing 102206, China;
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;
authors.forename: Feng
authors.initials: F
authors.lastname: Ge
authors.affiliation: Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;
authors.forename: Ming-Kun
authors.initials: MK
authors.lastname: Yang
authors.affiliation: Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiong
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Guo
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Huang-Ying
authors.initials: HY
authors.lastname: Le
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Song-Fang
authors.initials: SF
authors.lastname: Wu
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205; The High-Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Heng
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Collaborative Innovation Center of Systems Biomedicine, Shanghai 200240, China zchen@stn.sh.cn taosc@sjtu.edu.cn.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai 200240, China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Collaborative Innovation Center of Systems Biomedicine, Shanghai 200240, China zchen@stn.sh.cn taosc@sjtu.edu.cn.
authors.forename: Sheng-Ce
authors.initials: SC
authors.lastname: Tao
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000378:metabolism / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002352:Carrier Proteins / Q000032:analysis* / Q000378:metabolism; D019295:Computational Biology; D006019:Glycolysis; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D006801:Humans; D055432:Metabolomics; D008969:Molecular Sequence Data; D010087:Oxides / Q000494:pharmacology; D020543:Proteome
chemical_list: D001152:Arsenicals; D002352:Carrier Proteins; D010087:Oxides; D020543:Proteome; D006593:Hexokinase; D001151:Arsenic; D000077237:Arsenic Trioxide
keywords: arsenic trioxide; glycolysis; hexokinase-2I; human proteome microarray