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Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death
Inhibitor of apoptosis (IAP) proteins are frequently expressed at high levels in cancer cells and represent attractive therapeutic targets. We previously reported that the Smac (second mitochondria-derived activator of caspases) mimetic BV6, which antagonizes IAP proteins, sensitizes glioblastoma ce...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2015
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650438/ https://www.ncbi.nlm.nih.gov/pubmed/26379193 http://dx.doi.org/10.1038/cddis.2015.235 |
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author | Marschall, V Fulda, S |
author_facet | Marschall, V Fulda, S |
author_sort | Marschall, V |
collection | PubMed |
description | Inhibitor of apoptosis (IAP) proteins are frequently expressed at high levels in cancer cells and represent attractive therapeutic targets. We previously reported that the Smac (second mitochondria-derived activator of caspases) mimetic BV6, which antagonizes IAP proteins, sensitizes glioblastoma cells to temozolomide (TMZ)-induced cell death in a nuclear factor-κB (NF-κB)-dependent manner. However, BV6-induced NF-κB target genes responsible for this synergistic interaction have remained elusive. Using whole-genome gene expression profiling, we here identify BV6-stimulated, NF-κB-dependent transcriptional upregulation of interferon-β (IFNβ) and IFN-mediated proapoptotic signaling as critical events that mediate BV6/TMZ-induced apoptosis. Knockdown of IFNβ significantly rescues cells from BV6/TMZ-induced cell death. Similarly, silencing of the corresponding receptor IFNα/β receptor (IFNAR) confers a significant protection against apoptosis, demonstrating that IFNβ and IFN signaling are required for BV6/TMZ-mediated cell death. Moreover, BV6 and TMZ cooperate to transcriptionally upregulate the proapoptotic B-cell lymphoma 2 family proteins Bax (Bcl-2-associated X protein) or Puma (p53-upregulated modulator of apoptosis). Knockdown of Bax or Puma significantly decreases BV6/TMZ-induced apoptosis, showing that both proteins are necessary for apoptosis. By identifying IFNβ as a key mediator of BV6/TMZ-induced apoptosis, our study provides novel insights into the underlying molecular mechanisms of Smac mimetic-mediated chemosensitization with important implications for the development of novel treatment strategies for glioblastoma. |
format | Online Article Text |
id | pubmed-4650438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46504382015-12-01 Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death Marschall, V Fulda, S Cell Death Dis Original Article Inhibitor of apoptosis (IAP) proteins are frequently expressed at high levels in cancer cells and represent attractive therapeutic targets. We previously reported that the Smac (second mitochondria-derived activator of caspases) mimetic BV6, which antagonizes IAP proteins, sensitizes glioblastoma cells to temozolomide (TMZ)-induced cell death in a nuclear factor-κB (NF-κB)-dependent manner. However, BV6-induced NF-κB target genes responsible for this synergistic interaction have remained elusive. Using whole-genome gene expression profiling, we here identify BV6-stimulated, NF-κB-dependent transcriptional upregulation of interferon-β (IFNβ) and IFN-mediated proapoptotic signaling as critical events that mediate BV6/TMZ-induced apoptosis. Knockdown of IFNβ significantly rescues cells from BV6/TMZ-induced cell death. Similarly, silencing of the corresponding receptor IFNα/β receptor (IFNAR) confers a significant protection against apoptosis, demonstrating that IFNβ and IFN signaling are required for BV6/TMZ-mediated cell death. Moreover, BV6 and TMZ cooperate to transcriptionally upregulate the proapoptotic B-cell lymphoma 2 family proteins Bax (Bcl-2-associated X protein) or Puma (p53-upregulated modulator of apoptosis). Knockdown of Bax or Puma significantly decreases BV6/TMZ-induced apoptosis, showing that both proteins are necessary for apoptosis. By identifying IFNβ as a key mediator of BV6/TMZ-induced apoptosis, our study provides novel insights into the underlying molecular mechanisms of Smac mimetic-mediated chemosensitization with important implications for the development of novel treatment strategies for glioblastoma. Nature Publishing Group 2015-09 2015-09-17 /pmc/articles/PMC4650438/ /pubmed/26379193 http://dx.doi.org/10.1038/cddis.2015.235 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Marschall, V Fulda, S Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death |
title | Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death |
title_full | Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death |
title_fullStr | Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death |
title_full_unstemmed | Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death |
title_short | Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death |
title_sort | smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650438/ https://www.ncbi.nlm.nih.gov/pubmed/26379193 http://dx.doi.org/10.1038/cddis.2015.235 |
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