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An inhibitor of ubiquitin conjugation and aggresome formation

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An inhibitor of ubiquitin conjugation and aggresome formation

Content Provider	Royal Society of Chemistry (RSC)
Author	Statsyuk, Alexander V. An, Heeseon
Copyright Year	2015
Abstract	Proteasome inhibitors have revolutionized the treatment of multiple myeloma, and validated the therapeutic potential of the ubiquitin proteasome system (UPS). It is believed that in part, proteasome inhibitors elicit their therapeutic effect by inhibiting the degradation of misfolded proteins, which is proteotoxic and causes cell death. In spite of these successes, proteasome inhibitors are not effective against solid tumors, thus necessitating the need to explore alternative approaches. Furthermore, proteasome inhibitors lead to the formation of aggresomes that clear misfolded proteins via the autophagy–lysosome degradation pathway. Importantly, aggresome formation depends on the presence of polyubiquitin tags on misfolded proteins. We therefore hypothesized that inhibitors of ubiquitin conjugation should inhibit both degradation of misfolded proteins, and ubiquitin dependent aggresome formation, thus outlining the path forward toward more effective anticancer therapeutics. To explore the therapeutic potential of targeting the UPS to treat solid cancers, we have developed an inhibitor of ubiquitin conjugation (ABP A3) that targets ubiquitin and Nedd8 E1 enzymes, enzymes that are required to maintain the activity of the entire ubiquitin system. We have shown that ABP A3 inhibits conjugation of ubiquitin to intracellular proteins and prevents the formation of cytoprotective aggresomes in A549 lung cancer cells. Furthermore, ABP A3 induces activation of the unfolded protein response and apoptosis. Thus, similar to proteasome inhibitors MG132, bortezomib, and carfilzomib, ABP A3 can serve as a novel probe to explore the therapeutic potential of the UPS in solid and hematological malignancies.
Starting Page	5235
Ending Page	5245
Page Count	11
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	6
Issue Number	9
Journal	Chemical Science
DOI	10.1039/c5sc01351h
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Ubiquitin Bortezomib Multiple myeloma Enzyme inhibitor MG132 Tumors of the hematopoietic and lymphoid tissues NEDD8 ABP Unfolded protein response Carfilzomib Proteasome Non-small-cell lung carcinoma Apoptosis
Content Type	Text
Resource Type	Article
Subject	Chemistry

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma

The Mitochondrial Protease LonP1 Promotes Proteasome Inhibitor Resistance in Multiple Myeloma

Predicting the response of multiple myeloma to the proteasome inhibitor Bortezomib by evaluation of the unfolded protein response

Spliced XBP1 Levels Determine Sensitivity of Multiple Myeloma Cells to Proteasome Inhibitor Bortezomib Independent of the Unfolded Protein Response Mediator GRP78

Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition

Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells

Clinical potential of carfilzomib in the treatment of relapsed and refractory multiple myeloma

Proteasome inhibitors bortezomib and carfilzomib used for the treatment of multiple myeloma do not inhibit the serine protease HtrA2/Omi

Cardiac events during treatment with proteasome inhibitor therapy for multiple myeloma

An inhibitor of ubiquitin conjugation and aggresome formation

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