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Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic
Hai-Nan Zhang1, Lina Yang2, Jian-Ya Ling3
1Shanghai 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;
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.
Insights
Arsenic inhibits hexokinase-2 (HK2), a key enzyme in cancer cell energy production. This discovery reveals a new anticancer mechanism for arsenic, targeting glycolysis and HK2.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Arsenic is a known treatment for acute promyelocytic leukemia (APL).
- The broader anticancer mechanisms of arsenic beyond APL are not fully understood.
- Identifying arsenic's molecular targets is crucial for developing new cancer therapies.
Purpose of the Study:
- To identify proteins that bind arsenic.
- To elucidate the broader anticancer mode of action of arsenic.
- To investigate the role of glycolysis and hexokinase-2 (HK2) in arsenic's anticancer effects.
Main Methods:
- Human proteome microarray analysis to identify arsenic-binding proteins.
- Biochemical assays to assess enzyme inhibition.
- Metabolomics to analyze cellular metabolic changes.
- Cellular assays to evaluate apoptosis and rescue effects.
Main Results:
- Identified 360 specific arsenic-binding proteins.
- Enriched arsenic-binding proteins were found in the glycolysis pathway, including hexokinase-1.
- Arsenic significantly inhibited hexokinase-2 (HK2), an enzyme overexpressed in many cancers.
- Overexpression of HK2 conferred resistance to arsenic-induced apoptosis.
Conclusions:
- Arsenic's anticancer activity is strongly linked to the inhibition of glycolysis, particularly targeting HK2.
- HK2 is a key molecular target mediating arsenic's effects in cancer cells.
- The identified arsenic-binding proteins provide a resource for developing novel synergistic anticancer strategies.
