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Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic
Zhang, Hai-nan1,2,3; Yang, Lina1; Ling, Jian-ya4; Czajkowsky, Daniel M.3; Wang, Jing-Fang1; Zhang, Xiao-Wei5; Zhou, Yi-Ming6; Ge, Feng7; Yang, Ming-kun7; Xiong, Qian7; Guo, Shu-Juan1; Le, Huang-Ying1; Wu, Song-Fang1; Yan, Wei1; Liu, Bingya8; Zhu, Heng9,10; Chen, Zhu1,5,11; Tao, Sheng-ce1,2,3,11
2015-12-08
Source PublicationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN0027-8424
Volume112Issue:49Pages:15084-15089
AbstractArsenic 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.
SubtypeArticle
KeywordArsenic Trioxide Human Proteome Microarray Glycolysis Hexokinase-2
DOI10.1073/pnas.1521316112
WOS HeadingsScience & Technology
Funding OrganizationNational High Technology Research and Development Program of China(2012AA020103 ; National High Technology Research and Development Program of China(2012AA020103 ; National Natural Science Foundation of China(31370813 ; National Natural Science Foundation of China(31370813 ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; 2012AA020203) ; 2012AA020203) ; 31370750) ; 31370750) ; National High Technology Research and Development Program of China(2012AA020103 ; National High Technology Research and Development Program of China(2012AA020103 ; National Natural Science Foundation of China(31370813 ; National Natural Science Foundation of China(31370813 ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; 2012AA020203) ; 2012AA020203) ; 31370750) ; 31370750)
Indexed BySCI
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000365989800038
WOS KeywordZINC-FINGER PROTEINS ; ACID COMBINATION THERAPY ; INTERACTION NETWORKS ; MULTIPLE-MYELOMA ; ASCORBIC-ACID ; PHASE-II ; TRIOXIDE ; LEUKEMIA ; CANCER ; GENERATION
Funding OrganizationNational High Technology Research and Development Program of China(2012AA020103 ; National High Technology Research and Development Program of China(2012AA020103 ; National Natural Science Foundation of China(31370813 ; National Natural Science Foundation of China(31370813 ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; 2012AA020203) ; 2012AA020203) ; 31370750) ; 31370750) ; National High Technology Research and Development Program of China(2012AA020103 ; National High Technology Research and Development Program of China(2012AA020103 ; National Natural Science Foundation of China(31370813 ; National Natural Science Foundation of China(31370813 ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant(2013ZX10003006) ; 2012AA020203) ; 2012AA020203) ; 31370750) ; 31370750)
Citation statistics
Cited Times:44[WOS]   [WOS Record]