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Published on: May 10, 2016
Arsenic trioxide targets Hsp60, triggering degradation of p53 and survivin
Xuqiao Hu1, Hongyan Li1, Tiffany Ka-Yan Ip1
1Department of Chemistry and CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong Hong Kong SAR P. R. China hsun@hku.hk.
Abstract:
The mechanisms of action of arsenic trioxide (ATO), a clinically used drug for the treatment of acute promyelocytic leukemia (APL), have been actively studied mainly through characterization of individual putative protein targets. There appear to be no studies at a system level. Herein, we integrate metalloproteomics through a newly developed organoarsenic probe, As-AC (C20H17AsN4O3S2) with quantitative proteomics, allowing 37 arsenic binding and 250 arsenic regulated proteins to be identified in NB4, a human APL cell line. Bioinformatics analysis reveals that ATO disrupts multiple physiological processes, in particular, chaperone-related protein folding and cellular response to stress. Furthermore, we discover heat shock protein 60 (Hsp60) as a vital target of ATO. Through biophysical and cell-based assays, we demonstrate that ATO binds to Hsp60, leading to abolishment of Hsp60 refolding capability. Significantly, the binding of ATO to Hsp60 disrupts the formation of Hsp60-p53 and Hsp60-survivin complexes, resulting in degradation of p53 and survivin. This study provides significant insights into the mechanism of action of ATO at a systemic perspective, and serves as guidance for the rational design of metal-based anticancer drugs.
Insights
Arsenic trioxide (ATO) disrupts protein folding and stress responses in acute promyelocytic leukemia (APL) cells by targeting heat shock protein 60 (Hsp60). This action leads to the degradation of key proteins, offering new insights into ATO
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Arsenic trioxide (ATO) is a treatment for acute promyelocytic leukemia (APL).
- Previous studies focused on individual protein targets of ATO, lacking a systems-level view.
- A comprehensive understanding of ATO's mechanism of action is needed.
Purpose of the Study:
- To investigate the systemic mechanism of action of arsenic trioxide (ATO) in acute promyelocytic leukemia (APL) cells.
- To identify novel arsenic-binding and regulated proteins using an integrated proteomic approach.
- To elucidate the role of heat shock protein 60 (Hsp60) in ATO's anti-leukemic effects.
Main Methods:
- Development and application of a novel organoarsenic probe (As-AC) for metalloproteomics.
- Integration of metalloproteomics with quantitative proteomics in NB4 APL cells.
- Bioinformatics analysis to identify disrupted physiological processes.
- Biophysical and cell-based assays to validate target interactions and functional consequences.
Main Results:
- Identification of 37 arsenic-binding proteins and 250 arsenic-regulated proteins.
- Disruption of chaperone-related protein folding and cellular stress response pathways by ATO.
- Discovery of heat shock protein 60 (Hsp60) as a direct ATO target.
- Demonstration that ATO binding to Hsp60 inhibits its refolding capability and disrupts Hsp60-p53/survivin complex formation, leading to p53 and survivin degradation.
Conclusions:
- ATO exerts its effects through a systems-level disruption of protein homeostasis and stress response pathways.
- Hsp60 is a critical mediator of ATO's action, with its inhibition leading to the degradation of tumor suppressors and survival proteins.
- This study provides a systems-level understanding of ATO's mechanism of action and informs the design of novel metal-based anticancer drugs.
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