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Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma
Recent data suggest that glioblastomas (GBM) activate the c-MET signaling pathway and display increased levels in anti-apoptotic Bcl-2 family members. Therefore, targeting these two deregulated pathways for therapy might yield synergistic treatment responses. We applied extracellular flux analysis t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943348/ https://www.ncbi.nlm.nih.gov/pubmed/29743557 http://dx.doi.org/10.1038/s41598-018-25802-0 |
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author | Zhang, Yiru Ishida, Chiaki Tsuge Shu, Chang Kleiner, Giulio Sanchez-Quintero, Maria J. Bianchetti, Elena Quinzii, Catarina M. Westhoff, Mike-Andrew Karpel-Massler, Georg Siegelin, Markus D. |
author_facet | Zhang, Yiru Ishida, Chiaki Tsuge Shu, Chang Kleiner, Giulio Sanchez-Quintero, Maria J. Bianchetti, Elena Quinzii, Catarina M. Westhoff, Mike-Andrew Karpel-Massler, Georg Siegelin, Markus D. |
author_sort | Zhang, Yiru |
collection | PubMed |
description | Recent data suggest that glioblastomas (GBM) activate the c-MET signaling pathway and display increased levels in anti-apoptotic Bcl-2 family members. Therefore, targeting these two deregulated pathways for therapy might yield synergistic treatment responses. We applied extracellular flux analysis to assess tumor metabolism. We found that combined treatment with ABT263 and Crizotinib synergistically reduces the proliferation of glioblastoma cells, which was dependent on dual inhibition of Bcl-2 and Bcl-xL. The combination treatment led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, c-MET-inhibition results in significant energy deprivation with a reduction in oxidative phosphorylation, respiratory capacity and a suppression of intracellular energy production (ATP). In turn, loss of energy levels suppresses protein synthesis, causing a decline in anti-apoptotic Mcl-1 levels. Silencing of Mcl-1 enhanced ABT263 and MET-inhibitor mediated apoptosis, but marginally the combination treatment, indicating that Mcl-1 is the central factor for the induction of cell death induced by the combination treatment. Finally, combined treatment with BH3-mimetics and c-MET inhibitors results in significantly smaller tumors than each treatment alone in a PDX model system of glioblastoma. These results suggest that c-MET inhibition causes a selective vulnerability of GBM cells to Bcl-2/Bcl-xL inhibition. |
format | Online Article Text |
id | pubmed-5943348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59433482018-05-14 Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma Zhang, Yiru Ishida, Chiaki Tsuge Shu, Chang Kleiner, Giulio Sanchez-Quintero, Maria J. Bianchetti, Elena Quinzii, Catarina M. Westhoff, Mike-Andrew Karpel-Massler, Georg Siegelin, Markus D. Sci Rep Article Recent data suggest that glioblastomas (GBM) activate the c-MET signaling pathway and display increased levels in anti-apoptotic Bcl-2 family members. Therefore, targeting these two deregulated pathways for therapy might yield synergistic treatment responses. We applied extracellular flux analysis to assess tumor metabolism. We found that combined treatment with ABT263 and Crizotinib synergistically reduces the proliferation of glioblastoma cells, which was dependent on dual inhibition of Bcl-2 and Bcl-xL. The combination treatment led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, c-MET-inhibition results in significant energy deprivation with a reduction in oxidative phosphorylation, respiratory capacity and a suppression of intracellular energy production (ATP). In turn, loss of energy levels suppresses protein synthesis, causing a decline in anti-apoptotic Mcl-1 levels. Silencing of Mcl-1 enhanced ABT263 and MET-inhibitor mediated apoptosis, but marginally the combination treatment, indicating that Mcl-1 is the central factor for the induction of cell death induced by the combination treatment. Finally, combined treatment with BH3-mimetics and c-MET inhibitors results in significantly smaller tumors than each treatment alone in a PDX model system of glioblastoma. These results suggest that c-MET inhibition causes a selective vulnerability of GBM cells to Bcl-2/Bcl-xL inhibition. Nature Publishing Group UK 2018-05-09 /pmc/articles/PMC5943348/ /pubmed/29743557 http://dx.doi.org/10.1038/s41598-018-25802-0 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 Zhang, Yiru Ishida, Chiaki Tsuge Shu, Chang Kleiner, Giulio Sanchez-Quintero, Maria J. Bianchetti, Elena Quinzii, Catarina M. Westhoff, Mike-Andrew Karpel-Massler, Georg Siegelin, Markus D. Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma |
title | Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma |
title_full | Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma |
title_fullStr | Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma |
title_full_unstemmed | Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma |
title_short | Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma |
title_sort | inhibition of bcl-2/bcl-xl and c-met causes synthetic lethality in model systems of glioblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943348/ https://www.ncbi.nlm.nih.gov/pubmed/29743557 http://dx.doi.org/10.1038/s41598-018-25802-0 |
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