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Proteasome inhibition blocks necroptosis by attenuating death complex aggregation

Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apop...

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Autores principales: Ali, Mohammad, Mocarski, Edward S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832869/
https://www.ncbi.nlm.nih.gov/pubmed/29497034
http://dx.doi.org/10.1038/s41419-018-0371-x
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author Ali, Mohammad
Mocarski, Edward S.
author_facet Ali, Mohammad
Mocarski, Edward S.
author_sort Ali, Mohammad
collection PubMed
description Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis. Proteasome inhibition leads to the induction of apoptotic markers such as activated caspase-3 rather than necroptotic markers such as phosphorylated-MLKL in all cell lines tested. In HT-29 cells, Cf attenuates the late RIPK1 interaction with TNFR1 during TNF-induced necroptosis without altering the sensitivity of cIAP antagonists. Cf treatment results in decreased translocation of death signaling components RIPK1, FADD, caspase-8, cFLIP, and RIPK3 to detergent insoluble fractions. Our results show that proteasome inhibition with Cf impairs necroptosis and favors apoptosis even in cells with intact necroptotic machinery. Following the induction of TNFR1-mediated necroptosis, proteasome activity stabilizes effective aggregation and activation of ripoptosome/necrosome complexes.
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spelling pubmed-58328692018-03-05 Proteasome inhibition blocks necroptosis by attenuating death complex aggregation Ali, Mohammad Mocarski, Edward S. Cell Death Dis Article Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis. Proteasome inhibition leads to the induction of apoptotic markers such as activated caspase-3 rather than necroptotic markers such as phosphorylated-MLKL in all cell lines tested. In HT-29 cells, Cf attenuates the late RIPK1 interaction with TNFR1 during TNF-induced necroptosis without altering the sensitivity of cIAP antagonists. Cf treatment results in decreased translocation of death signaling components RIPK1, FADD, caspase-8, cFLIP, and RIPK3 to detergent insoluble fractions. Our results show that proteasome inhibition with Cf impairs necroptosis and favors apoptosis even in cells with intact necroptotic machinery. Following the induction of TNFR1-mediated necroptosis, proteasome activity stabilizes effective aggregation and activation of ripoptosome/necrosome complexes. Nature Publishing Group UK 2018-03-01 /pmc/articles/PMC5832869/ /pubmed/29497034 http://dx.doi.org/10.1038/s41419-018-0371-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ali, Mohammad
Mocarski, Edward S.
Proteasome inhibition blocks necroptosis by attenuating death complex aggregation
title Proteasome inhibition blocks necroptosis by attenuating death complex aggregation
title_full Proteasome inhibition blocks necroptosis by attenuating death complex aggregation
title_fullStr Proteasome inhibition blocks necroptosis by attenuating death complex aggregation
title_full_unstemmed Proteasome inhibition blocks necroptosis by attenuating death complex aggregation
title_short Proteasome inhibition blocks necroptosis by attenuating death complex aggregation
title_sort proteasome inhibition blocks necroptosis by attenuating death complex aggregation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832869/
https://www.ncbi.nlm.nih.gov/pubmed/29497034
http://dx.doi.org/10.1038/s41419-018-0371-x
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