Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma

Abstract 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 a...

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Autores principales:	Yiru Zhang, Chiaki Tsuge Ishida, Chang Shu, Giulio Kleiner, Maria J. Sanchez-Quintero, Elena Bianchetti, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c7b64c32e50d4b209c3d47ac8b498b63
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spelling	oai:doaj.org-article:c7b64c32e50d4b209c3d47ac8b498b632021-12-02T12:32:09ZInhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma10.1038/s41598-018-25802-02045-2322https://doaj.org/article/c7b64c32e50d4b209c3d47ac8b498b632018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25802-0https://doaj.org/toc/2045-2322Abstract 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.Yiru ZhangChiaki Tsuge IshidaChang ShuGiulio KleinerMaria J. Sanchez-QuinteroElena BianchettiCatarina M. QuinziiMike-Andrew WesthoffGeorg Karpel-MasslerMarkus D. SiegelinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yiru Zhang Chiaki Tsuge Ishida Chang Shu Giulio Kleiner Maria J. Sanchez-Quintero Elena Bianchetti Catarina M. Quinzii Mike-Andrew Westhoff Georg Karpel-Massler Markus D. Siegelin Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma
description	Abstract 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	article
author	Yiru Zhang Chiaki Tsuge Ishida Chang Shu Giulio Kleiner Maria J. Sanchez-Quintero Elena Bianchetti Catarina M. Quinzii Mike-Andrew Westhoff Georg Karpel-Massler Markus D. Siegelin
author_facet	Yiru Zhang Chiaki Tsuge Ishida Chang Shu Giulio Kleiner Maria J. Sanchez-Quintero Elena Bianchetti Catarina M. Quinzii Mike-Andrew Westhoff Georg Karpel-Massler Markus D. Siegelin
author_sort	Yiru Zhang
title	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_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_sort	inhibition of bcl-2/bcl-xl and c-met causes synthetic lethality in model systems of glioblastoma
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/c7b64c32e50d4b209c3d47ac8b498b63
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Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma

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