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Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug
Karolinska Inst, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Karolinska Inst, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
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2019 (English)In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 162, p. 46-54Article in journal (Refereed) Published
Abstract [en]

Auranofin is a gold (1)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical trials for lung and ovarian carcinomas. Both the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase (TrxR) are well documented targets of auranofin. Auranofin was recently reported to also inhibit proteasome activity at the level of the proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14. We here set out to re-examine the molecular mechanism underlying auranofin cytotoxicity towards cultured cancer cells. The effects of auranofin on the proteasome were examined in cells and in vitro, effects on DUB activity were assessed using different substrates. The cellular response to auranofin was compared to that of the 20S proteasome inhibitor bortezomib and the 19S DUB inhibitor b-AP15 using proteomics. Auranofin was found to inhibit mitochondrial activity and to an induce oxidative stress response at IC50 doses. At 2-3-fold higher doses, auranofin inhibits proteasome processing in cells. At such supra-pharmacological concentrations USP14 activity was inhibited. Analysis of protein expression profiles in drug-exposed tumor cells showed that auranofin induces a response distinct from that of the 20S proteasome inhibitor bortezomib and the DUB inhibitor b-AP15, both of which induced similar responses. Our results support the notion that the primary mechanism of action of auranofin is TrxR inhibition and suggest that proteasome DUB inhibition is an off-target effect. Whether proteasome inhibition will contribute to the antineoplastic effect of auranofin in treated patients is unclear but remains a possibility. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

Place, publisher, year, edition, pages
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER , 2019. Vol. 162, p. 46-54
Keywords [en]
Auranofin; Proteasome deubiquitinases; Thioredoxin reductase; Selenocysteine
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-158537DOI: 10.1016/j.biochi.2019.03.015ISI: 000470681600006PubMedID: 30946948OAI: oai:DiVA.org:liu-158537DiVA, id: diva2:1334927
Note

Funding Agencies|Swedish Cancer Society; Radiumhemmets Forskningsfonder; Vetenskapsradet; Barncancerfonden; Knut and Alice Wallenbergs Foundation

Available from: 2019-07-03 Created: 2019-07-03 Last updated: 2019-10-16

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The full text will be freely available from 2020-04-01 09:23
Available from 2020-04-01 09:23

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Selvaraj, KarthikD´arcy, PadraigLinder, Stig
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