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Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis
Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847333/ https://www.ncbi.nlm.nih.gov/pubmed/24287697 http://dx.doi.org/10.1038/cddis.2013.457 |
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author | Eckhardt, I Roesler, S Fulda, S |
author_facet | Eckhardt, I Roesler, S Fulda, S |
author_sort | Eckhardt, I |
collection | PubMed |
description | Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic. |
format | Online Article Text |
id | pubmed-3847333 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-38473332013-12-03 Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis Eckhardt, I Roesler, S Fulda, S Cell Death Dis Original Article Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic. Nature Publishing Group 2013-11 2013-11-28 /pmc/articles/PMC3847333/ /pubmed/24287697 http://dx.doi.org/10.1038/cddis.2013.457 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Eckhardt, I Roesler, S Fulda, S Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis |
title | Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis |
title_full | Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis |
title_fullStr | Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis |
title_full_unstemmed | Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis |
title_short | Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis |
title_sort | identification of dr5 as a critical, nf-κb-regulated mediator of smac-induced apoptosis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847333/ https://www.ncbi.nlm.nih.gov/pubmed/24287697 http://dx.doi.org/10.1038/cddis.2013.457 |
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