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Article: Arsenic trioxide targets Hsp60, triggering degradation of p53 and survivin

TitleArsenic trioxide targets Hsp60, triggering degradation of p53 and survivin
Authors
Issue Date2021
Citation
Chemical Science, 2021, v. 12, n. 32, p. 10893-10900 How to Cite?
AbstractThe 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. This journal is
Persistent Identifierhttp://hdl.handle.net/10722/313032
ISSN
2023 Impact Factor: 7.6
2023 SCImago Journal Rankings: 2.333
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHu, Xuqiao-
dc.contributor.authorLi, Hongyan-
dc.contributor.authorIp, Tiffany Ka Yan-
dc.contributor.authorCheung, Yam Fung-
dc.contributor.authorKoohi-Moghadam, Mohamad-
dc.contributor.authorWang, Haibo-
dc.contributor.authorYang, Xinming-
dc.contributor.authorTritton, Daniel N.-
dc.contributor.authorWang, Yuchuan-
dc.contributor.authorWang, Yi-
dc.contributor.authorWang, Runming-
dc.contributor.authorNg, Kwan Ming-
dc.contributor.authorNaranmandura, Hua-
dc.contributor.authorTse, Eric Wai Choi-
dc.contributor.authorSun, Hongzhe-
dc.date.accessioned2022-05-26T07:00:08Z-
dc.date.available2022-05-26T07:00:08Z-
dc.date.issued2021-
dc.identifier.citationChemical Science, 2021, v. 12, n. 32, p. 10893-10900-
dc.identifier.issn2041-6520-
dc.identifier.urihttp://hdl.handle.net/10722/313032-
dc.description.abstractThe 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. This journal is-
dc.languageeng-
dc.relation.ispartofChemical Science-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleArsenic trioxide targets Hsp60, triggering degradation of p53 and survivin-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1039/d1sc03119h-
dc.identifier.scopuseid_2-s2.0-85113256536-
dc.identifier.volume12-
dc.identifier.issue32-
dc.identifier.spage10893-
dc.identifier.epage10900-
dc.identifier.eissn2041-6539-
dc.identifier.isiWOS:000674876800001-

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