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Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02
Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068396/ https://www.ncbi.nlm.nih.gov/pubmed/32218815 http://dx.doi.org/10.3892/ol.2020.11362 |
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author | Lohmann, Birthe Le Rhun, Emilie Silginer, Manuela Epskamp, Mirka Weller, Michael |
author_facet | Lohmann, Birthe Le Rhun, Emilie Silginer, Manuela Epskamp, Mirka Weller, Michael |
author_sort | Lohmann, Birthe |
collection | PubMed |
description | Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation, which is currently explored in early clinical trials in newly diagnosed and recurrent glioblastoma. In the present study, human glioma-initiating cell line models were used to explore whether IFN-β modulates the anti-glioma activity of TG02. The present study employed immunoblotting to assess protein levels, several viability assays and gene silencing strategies to assess gene function. Pre-exposure to IFN-β sensitized human glioma models to a subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving caspase activity that was blocked by the anti-apoptotic protein, BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth. Furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02. Consistent with that, caspase 3 gene silencing did not abrogate the effects of TG02 or IFN-β alone or in combination. Finally, it was observed that IFN-β may indeed modulate the effects of TG02 upstream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of the pharmacodynamic activity of TG02, was facilitated when glioma cells were pre-exposed to IFN-β. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth, but that the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic tumor growth inhibition. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel and effective pharmacological approaches to glioblastoma. |
format | Online Article Text |
id | pubmed-7068396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-70683962020-03-26 Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02 Lohmann, Birthe Le Rhun, Emilie Silginer, Manuela Epskamp, Mirka Weller, Michael Oncol Lett Articles Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation, which is currently explored in early clinical trials in newly diagnosed and recurrent glioblastoma. In the present study, human glioma-initiating cell line models were used to explore whether IFN-β modulates the anti-glioma activity of TG02. The present study employed immunoblotting to assess protein levels, several viability assays and gene silencing strategies to assess gene function. Pre-exposure to IFN-β sensitized human glioma models to a subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving caspase activity that was blocked by the anti-apoptotic protein, BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth. Furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02. Consistent with that, caspase 3 gene silencing did not abrogate the effects of TG02 or IFN-β alone or in combination. Finally, it was observed that IFN-β may indeed modulate the effects of TG02 upstream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of the pharmacodynamic activity of TG02, was facilitated when glioma cells were pre-exposed to IFN-β. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth, but that the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic tumor growth inhibition. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel and effective pharmacological approaches to glioblastoma. D.A. Spandidos 2020-04 2020-01-30 /pmc/articles/PMC7068396/ /pubmed/32218815 http://dx.doi.org/10.3892/ol.2020.11362 Text en Copyright: © Lohmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Lohmann, Birthe Le Rhun, Emilie Silginer, Manuela Epskamp, Mirka Weller, Michael Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02 |
title | Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02 |
title_full | Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02 |
title_fullStr | Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02 |
title_full_unstemmed | Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02 |
title_short | Interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, TG02 |
title_sort | interferon-β sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, tg02 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068396/ https://www.ncbi.nlm.nih.gov/pubmed/32218815 http://dx.doi.org/10.3892/ol.2020.11362 |
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