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Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug.
Biochimie. 2019 Jul; 162:46-54.B

Abstract

Auranofin is a gold (I)-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.

Authors+Show Affiliations

Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden.Department of Medical and Health Sciences, Linköping University, SE-581 83, Linköping, Sweden.Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry I, Karolinska Institutet, SE-171 77, Stockholm, Sweden.Department of Medical and Health Sciences, Linköping University, SE-581 83, Linköping, Sweden.Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry I, Karolinska Institutet, SE-171 77, Stockholm, Sweden.Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77, Stockholm, Sweden.Department of Oncology-Pathology, Karolinska Institutet, SE-171 76, Stockholm, Sweden; Department of Medical and Health Sciences, Linköping University, SE-581 83, Linköping, Sweden. Electronic address: Stig.Linder@ki.se.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30946948

Citation

Zhang, Xiaonan, et al. "Repurposing of Auranofin: Thioredoxin Reductase Remains a Primary Target of the Drug." Biochimie, vol. 162, 2019, pp. 46-54.
Zhang X, Selvaraju K, Saei AA, et al. Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug. Biochimie. 2019;162:46-54.
Zhang, X., Selvaraju, K., Saei, A. A., D'Arcy, P., Zubarev, R. A., Arnér, E. S., & Linder, S. (2019). Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug. Biochimie, 162, 46-54. https://doi.org/10.1016/j.biochi.2019.03.015
Zhang X, et al. Repurposing of Auranofin: Thioredoxin Reductase Remains a Primary Target of the Drug. Biochimie. 2019;162:46-54. PubMed PMID: 30946948.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug. AU - Zhang,Xiaonan, AU - Selvaraju,Karthik, AU - Saei,Amir Ata, AU - D'Arcy,Padraig, AU - Zubarev,Roman A, AU - Arnér,Elias Sj, AU - Linder,Stig, Y1 - 2019/04/01/ PY - 2019/02/06/received PY - 2019/03/24/accepted PY - 2019/4/5/pubmed PY - 2019/4/5/medline PY - 2019/4/5/entrez KW - Auranofin KW - Proteasome deubiquitinases KW - Selenocysteine KW - Thioredoxin reductase SP - 46 EP - 54 JF - Biochimie JO - Biochimie VL - 162 N2 - Auranofin is a gold (I)-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. SN - 1638-6183 UR - https://www.unboundmedicine.com/medline/citation/30946948/Repurposing_of_auranofin:_Thioredoxin_reductase_remains_a_primary_target_of_the_drug_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300-9084(19)30084-7 DB - PRIME DP - Unbound Medicine ER -