期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 49, 页码 15084-15089出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1521316112
关键词
arsenic trioxide; human proteome microarray; glycolysis; hexokinase-2
资金
- National High Technology Research and Development Program of China [2012AA020103, 2012AA020203]
- National Natural Science Foundation of China [31370813, 31370750]
- Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health Grant [2013ZX10003006]
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.
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