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Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

Skrott, Zdenek and Li, Jing and Deshaies, Raymond J. (2017) Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature, 552 (7684). pp. 194-199. ISSN 0028-0836. https://resolver.caltech.edu/CaltechAUTHORS:20171102-125033790

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[img] Image (JPEG) (Extended Data Figure 1 : Epidemiological and pre-clinical data of the anti-cancer effects of DSF) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 2 : CuET is the major anti-cancer metabolite of DSF) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 3 : CuET-induced proteasome inhibition-like response is not due to proteasome inhibition) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 4 : CuET inhibits the p97 pathway and induces cellular UPR) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 5 : CuET kills BTZ-resistant cells) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 6 : CuET targets NPL4, causing immobilization and nuclear clustering of NPL4) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 7 : Immobilized NPL4 forms insoluble protein aggregates) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 8 : NPL4 aggregation immobilizes the p97 binding partner and induces a global cellular HSR) - Supplemental Material
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Abstract

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb–copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram’s tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/nature25016DOIArticle
https://www.nature.com/articles/nature25016PublisherArticle
http://rdcu.be/AJJVPublisherFree ReadCube access
ORCID:
AuthorORCID
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2017 Macmillan Publishers Limited, part of Springer Nature. Received: 01 October 2015; Accepted: 08 November 2017; Published online: 06 December 2017. Data availability: Most data generated or analysed during this study are included in the article and its Supplementary Information. Uncropped images of all gels and blots can be found in Supplementary Fig. 1. Source Data for all graphs are provided in the online version of the paper. Additional datasets generated during and/or analysed during the current study and relevant information are available from the corresponding authors upon reasonable request. We thank J. Škvor, M. Zadinová, J. Večerka and D. Doležal for help with animal experiments, Jana Vrbkova for statistical analysis, D. Fridecky and T. Adam for help with HPLC, I. Protivankova and M. Grønvig Nielsen for technical assistance. This work was supported by grants from the Kellner Family Foundation, Czech National Program of Sustainability, Grant Agency of the Czech Republic, MEYS CR project Czech-BioImaging, the Czech Health Research Council, of the Danish Cancer Society, the Danish National Research Foundation (project CARD), the Danish Council for Independent Research, the Novo Nordisk Foundation, the Czech Cancer League, the Swedish Research Council, Cancerfonden of Sweden, the European Commission (EATRIS), the Czech Ministry of Education, youth and sports (OPVKCZ), Cancer Research Czech Republic and the Howard Hughes Medical Institute. Author Contributions: Z.S., M.Mis., B.C., R.J.D. and J.Barte. conceived the study. Z.S. and M.Mis. performed most biochemical and microscopy experiments and wrote the manuscript. D.M. established the expression cell lines and performed most cytotoxicity tests. T.O., P.D. and I.V. performed the HPLC experiments. K.K.A., S.F. and J.O. performed the epidemiological analyses. J.Bartk. performed the immunohistochemical analyses. J.V. and P.D. performed DARTS experiments. P.M. performed cell death analyses. Z.T. performed cytotoxicity tests and heat-shock response analyses. A.K. performed cytotoxicity tests. A.M. designed and performed phlebotomies of patients treated with Antabuse. M.Mic. performed the ITC. J.G. performed FACS analyses, cell death assays and cell sorting. J.S. performed 20S proteasome assays. J.L. performed 26S proteasome assays. M.K. and C.D. performed the cytotoxicity experiments on myeloid- and patient-derived cell lines. P.P., J.M. and M.H. performed mouse experiments. J.Barte., B.C., Q.P.D. and R.J.D. helped to design the experiments, interpreted the data and wrote/edited the manuscript. All authors approved the manuscript. Competing interests: R.J.D. is a founder of and consultant for Cleave Biosciences. The other authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
Kellner Family FoundationUNSPECIFIED
Czech National Program of SustainabilityUNSPECIFIED
Grant Agency of the Czech RepublicUNSPECIFIED
Ministry of Education, Youth and Sports (MEYS) of the Czech RepublicUNSPECIFIED
Czech Health Research CouncilUNSPECIFIED
Danish Cancer SocietyUNSPECIFIED
Danish National Research FoundationUNSPECIFIED
Danish Council for Independent ResearchUNSPECIFIED
Novo Nordisk FoundationUNSPECIFIED
Czech Cancer LeagueUNSPECIFIED
Swedish Research CouncilUNSPECIFIED
Cancerfonden of SwedenUNSPECIFIED
European CommissionUNSPECIFIED
Cancer Research Czech RepublicUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:7684
Record Number:CaltechAUTHORS:20171102-125033790
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171102-125033790
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:82900
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:14 Dec 2017 21:12
Last Modified:03 Oct 2019 18:59

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