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Oxidative Stress Induced by the Deubiquitinase Inhibitor b-AP15 Is Associated with Mitochondrial Impairment
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
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: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, article id 1659468Article in journal (Refereed) Published
Abstract [en]

Inhibitors of the 20S proteasome such as bortezomib are cytotoxic to tumor cells and have been proven to be valuable for the clinical management of multiple myeloma. The therapeutic efficacy of bortezomib is, however, hampered by the emergence of acquired resistance. Available data suggest that blocking proteasome activity at the level of proteasome-associated deubiquitinases (DUBs) provides a mechanism to overcome resistance to bortezomib and also to other cancer therapies. The small molecule b-AP15 is an inhibitor of proteasome-associated DUB activity that induces both proteotoxic stress and increases in the levels of reactive oxygen species (ROS) in tumor cells. Antioxidants have been shown to decrease apoptosis induction by b-AP15 and we here addressed the question of the mechanism of redox perturbation by this compound. We show that oxidative stress induction by b-AP15 is abrogated in cells deprived of mitochondrial DNA (rho(0) cells). We also show associations between the level of proteotoxic stress, the degree of mitochondrial dysfunction, and the extent of induction of hemeoxygenase-1 (HO-1), a target of the redox-regulated Nrf-2 transcription factor. Decreased expression of COX5b (cytochrome c oxidase subunit 5b) and TOMM34 (translocase of outer mitochondrial membrane 34) was observed in b-AP15-treated cells. These findings suggest a mitochondrial origin of the increased levels of ROS observed in cells exposed to the DUB inhibitor b-AP15.

Place, publisher, year, edition, pages
HINDAWI LTD , 2019. article id 1659468
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Cell and Molecular Biology
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URN: urn:nbn:se:liu:diva-159013DOI: 10.1155/2019/1659468ISI: 000472879400001PubMedID: 31281566OAI: oai:DiVA.org:liu-159013DiVA, id: diva2:1338099
Note

Funding Agencies|Swedish Cancer Society; Radiumhemmets Forskningsfonder; Vetenskapsradet; Knut och Alice Wallenbergs Stiftelse; Barncancerfonden

Available from: 2019-07-19 Created: 2019-07-19 Last updated: 2019-07-19

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