Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress

Autor: Rolf Larsson, Stig Linder, Chao Sun, Xiaonan Zhang, Padraig D'Arcy, Slavica Brnjic, Mårten Fryknäs, Magdalena Mazurkiewicz
Rok vydání: 2014
Předmět:
Proteasome Endopeptidase Complex
Transcription
Genetic
Physiology
Blotting
Western
Clinical Biochemistry
Apoptosis
Forum Original Research CommunicationTargeting the Ubiquitin-Proteasome System (A. Ludwig and O. Drews
Eds.)
medicine.disease_cause
Polymerase Chain Reaction
Biochemistry
Deubiquitinating enzyme
Bortezomib
Cell Line
Tumor
medicine
Humans
Protease Inhibitors
Molecular Biology
Piperidones
General Environmental Science
chemistry.chemical_classification
Reactive oxygen species
biology
business.industry
Kinase
Gene Expression Profiling
Cell Biology
Boronic Acids
Oxidative Stress
Proteasome
chemistry
Pyrazines
Immunology
Cancer research
biology.protein
Proteasome inhibitor
General Earth and Planetary Sciences
Ubiquitin-Specific Proteases
Reactive Oxygen Species
business
Oxidative stress
medicine.drug
Zdroj: Antioxidants & Redox Signaling. 21:2271-2285
ISSN: 1557-7716
1523-0864
DOI: 10.1089/ars.2013.5322
Popis: Aims: b-AP15 is a recently described inhibitor of the USP14/UCHL5 deubiquitinases (DUBs) of the 19S proteasome. Exposure to b-AP15 results in blocking of proteasome function and accumulation of polyubiquitinated protein substrates in cells. This novel mechanism of proteasome inhibition may potentially be exploited for cancer therapy, in particular for treatment of malignancies resistant to currently used proteasome inhibitors. The aim of the present study was to characterize the cellular response to b-AP15-mediated proteasome DUB inhibition. Results: We report that b-AP15 elicits a similar, but yet distinct, cellular response as the clinically used proteasome inhibitor bortezomib. b-AP15 induces a rapid apoptotic response, associated with enhanced induction of oxidative stress and rapid activation of Jun-N-terminal kinase 1/2 (JNK)/activating protein-1 signaling. Scavenging of reactive oxygen species and pharmacological inhibition of JNK reduced b-AP15-induced apoptosis. We further report that endoplasmic reticulum (ER) stress is induced by b-AP15 and is involved in apoptosis induction. In contrast to bortezomib, ER stress is associated with induction of α-subunit of eukaryotic initiation factor 2 phosphorylation. Innovation: The findings establish that different modes of proteasome inhibition result in distinct cellular responses, a finding of potential therapeutic importance. Conclusion: Our data show that enhanced oxidative stress and ER stress are major determinants of the strong apoptotic response elicited by the 19S DUB inhibitor b-AP15. Antioxid. Redox Signal. 21, 2271–2285.
Databáze: OpenAIRE
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