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Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival

Multiple myeloma (MM) cells suffer from baseline proteotoxicity as the result of an imbalance between the load of misfolded proteins awaiting proteolysis and the capacity of the ubiquitin-proteasome system to degrade them. This intrinsic vulnerability is at the base of MM sensitivity to agents that...

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Autores principales: Chen, Tianzeng, Ho, Matthew, Briere, Jenna, Moscvin, Maria, Czarnecki, Peter G., Anderson, Kenneth C., Blackwell, T. Keith, Bianchi, Giada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791580/
https://www.ncbi.nlm.nih.gov/pubmed/34649278
http://dx.doi.org/10.1182/bloodadvances.2020003820
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author Chen, Tianzeng
Ho, Matthew
Briere, Jenna
Moscvin, Maria
Czarnecki, Peter G.
Anderson, Kenneth C.
Blackwell, T. Keith
Bianchi, Giada
author_facet Chen, Tianzeng
Ho, Matthew
Briere, Jenna
Moscvin, Maria
Czarnecki, Peter G.
Anderson, Kenneth C.
Blackwell, T. Keith
Bianchi, Giada
author_sort Chen, Tianzeng
collection PubMed
description Multiple myeloma (MM) cells suffer from baseline proteotoxicity as the result of an imbalance between the load of misfolded proteins awaiting proteolysis and the capacity of the ubiquitin-proteasome system to degrade them. This intrinsic vulnerability is at the base of MM sensitivity to agents that perturb proteostasis, such as proteasome inhibitors (PIs), the mainstay of modern-day myeloma therapy. De novo and acquired PI resistance are important clinical limitations that adversely affect prognosis. The molecular mechanisms underpinning PI resistance are only partially understood, limiting the development of drugs that can overcome it. The transcription factor NRF1 is activated by the aspartic protease DNA damage inducible 1 homolog 2 (DDI2) upon proteasome insufficiency and governs proteasome biogenesis. In this article, we show that MM cells exhibit baseline NRF1 activation and are dependent upon DDI2 for survival. DDI2 knockout (KO) is cytotoxic for MM cells, both in vitro and in vivo. Protein structure-function studies show that DDI2 KO blocks NRF1 cleavage and nuclear translocation, causing impaired proteasome activity recovery upon irreversible proteasome inhibition and, thereby, increasing sensitivity to PIs. Add-back of wild-type, but not of catalytically dead DDI2, fully rescues these phenotypes. We propose that DDI2 is an unexplored promising molecular target in MM by disrupting the proteasome stress response and exacerbating proteotoxicity.
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spelling pubmed-87915802022-01-27 Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival Chen, Tianzeng Ho, Matthew Briere, Jenna Moscvin, Maria Czarnecki, Peter G. Anderson, Kenneth C. Blackwell, T. Keith Bianchi, Giada Blood Adv Stimulus Report Multiple myeloma (MM) cells suffer from baseline proteotoxicity as the result of an imbalance between the load of misfolded proteins awaiting proteolysis and the capacity of the ubiquitin-proteasome system to degrade them. This intrinsic vulnerability is at the base of MM sensitivity to agents that perturb proteostasis, such as proteasome inhibitors (PIs), the mainstay of modern-day myeloma therapy. De novo and acquired PI resistance are important clinical limitations that adversely affect prognosis. The molecular mechanisms underpinning PI resistance are only partially understood, limiting the development of drugs that can overcome it. The transcription factor NRF1 is activated by the aspartic protease DNA damage inducible 1 homolog 2 (DDI2) upon proteasome insufficiency and governs proteasome biogenesis. In this article, we show that MM cells exhibit baseline NRF1 activation and are dependent upon DDI2 for survival. DDI2 knockout (KO) is cytotoxic for MM cells, both in vitro and in vivo. Protein structure-function studies show that DDI2 KO blocks NRF1 cleavage and nuclear translocation, causing impaired proteasome activity recovery upon irreversible proteasome inhibition and, thereby, increasing sensitivity to PIs. Add-back of wild-type, but not of catalytically dead DDI2, fully rescues these phenotypes. We propose that DDI2 is an unexplored promising molecular target in MM by disrupting the proteasome stress response and exacerbating proteotoxicity. American Society of Hematology 2022-01-17 /pmc/articles/PMC8791580/ /pubmed/34649278 http://dx.doi.org/10.1182/bloodadvances.2020003820 Text en © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
spellingShingle Stimulus Report
Chen, Tianzeng
Ho, Matthew
Briere, Jenna
Moscvin, Maria
Czarnecki, Peter G.
Anderson, Kenneth C.
Blackwell, T. Keith
Bianchi, Giada
Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival
title Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival
title_full Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival
title_fullStr Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival
title_full_unstemmed Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival
title_short Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival
title_sort multiple myeloma cells depend on the ddi2/nrf1-mediated proteasome stress response for survival
topic Stimulus Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791580/
https://www.ncbi.nlm.nih.gov/pubmed/34649278
http://dx.doi.org/10.1182/bloodadvances.2020003820
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