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Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells

The recurrence of Glioblastoma is partly attributed to the highly resistant subpopulation of glioma stem cells. A novel therapeutic approach focuses on restoring apoptotic programs in these cancer stem cells, as they are often deregulated. BH3-mimetics, targeting anti-apoptotic Bcl-2 family members,...

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Autores principales: Vera, Mariana Belén, Morris-Hanon, Olivia, Nogueiras, Germán Ignacio, Ripari, Luisina Belén, Esquivel, Myrian Inés, Perez-Castro, Carolina, Romorini, Leonardo, Sevlever, Gustavo Emilio, Scassa, María Elida, Videla-Richardson, Guillermo Agustín
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587994/
https://www.ncbi.nlm.nih.gov/pubmed/36273072
http://dx.doi.org/10.1038/s41598-022-20910-4
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author Vera, Mariana Belén
Morris-Hanon, Olivia
Nogueiras, Germán Ignacio
Ripari, Luisina Belén
Esquivel, Myrian Inés
Perez-Castro, Carolina
Romorini, Leonardo
Sevlever, Gustavo Emilio
Scassa, María Elida
Videla-Richardson, Guillermo Agustín
author_facet Vera, Mariana Belén
Morris-Hanon, Olivia
Nogueiras, Germán Ignacio
Ripari, Luisina Belén
Esquivel, Myrian Inés
Perez-Castro, Carolina
Romorini, Leonardo
Sevlever, Gustavo Emilio
Scassa, María Elida
Videla-Richardson, Guillermo Agustín
author_sort Vera, Mariana Belén
collection PubMed
description The recurrence of Glioblastoma is partly attributed to the highly resistant subpopulation of glioma stem cells. A novel therapeutic approach focuses on restoring apoptotic programs in these cancer stem cells, as they are often deregulated. BH3-mimetics, targeting anti-apoptotic Bcl-2 family members, are emerging as promising compounds to sensitize cancer cells to antineoplastic treatments. Herein, we determined that the most abundantly expressed anti-apoptotic Bcl-2 family members, Bcl-xL and Mcl-1, are the most relevant in regulating patient-derived glioma stem cell survival. We exposed these cells to routinely used chemotherapeutic drugs and BH3-mimetics (ABT-263, WEHI-539, and S63845). We observed that the combination of BH3-mimetics targeting Bcl-xL with chemotherapeutic agents caused a marked increase in cell death and that this sensitivity to Bcl-xL inhibition correlated with Noxa expression levels. Interestingly, whereas co-targeting Bcl-xL and Mcl-1 led to massive cell death in all tested cell lines, down-regulation of Noxa promoted cell survival only in cell lines expressing higher levels of this BH3-only. Therefore, in glioma stem cells, the efficacy of Bcl-xL inhibition is closely associated with Mcl-1 activity and Noxa expression. Hence, a potentially effective strategy would consist of combining Bcl-xL inhibitors with chemotherapeutic agents capable of inducing Noxa, taking advantage of this pro-apoptotic factor.
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spelling pubmed-95879942022-10-24 Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells Vera, Mariana Belén Morris-Hanon, Olivia Nogueiras, Germán Ignacio Ripari, Luisina Belén Esquivel, Myrian Inés Perez-Castro, Carolina Romorini, Leonardo Sevlever, Gustavo Emilio Scassa, María Elida Videla-Richardson, Guillermo Agustín Sci Rep Article The recurrence of Glioblastoma is partly attributed to the highly resistant subpopulation of glioma stem cells. A novel therapeutic approach focuses on restoring apoptotic programs in these cancer stem cells, as they are often deregulated. BH3-mimetics, targeting anti-apoptotic Bcl-2 family members, are emerging as promising compounds to sensitize cancer cells to antineoplastic treatments. Herein, we determined that the most abundantly expressed anti-apoptotic Bcl-2 family members, Bcl-xL and Mcl-1, are the most relevant in regulating patient-derived glioma stem cell survival. We exposed these cells to routinely used chemotherapeutic drugs and BH3-mimetics (ABT-263, WEHI-539, and S63845). We observed that the combination of BH3-mimetics targeting Bcl-xL with chemotherapeutic agents caused a marked increase in cell death and that this sensitivity to Bcl-xL inhibition correlated with Noxa expression levels. Interestingly, whereas co-targeting Bcl-xL and Mcl-1 led to massive cell death in all tested cell lines, down-regulation of Noxa promoted cell survival only in cell lines expressing higher levels of this BH3-only. Therefore, in glioma stem cells, the efficacy of Bcl-xL inhibition is closely associated with Mcl-1 activity and Noxa expression. Hence, a potentially effective strategy would consist of combining Bcl-xL inhibitors with chemotherapeutic agents capable of inducing Noxa, taking advantage of this pro-apoptotic factor. Nature Publishing Group UK 2022-10-22 /pmc/articles/PMC9587994/ /pubmed/36273072 http://dx.doi.org/10.1038/s41598-022-20910-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Vera, Mariana Belén
Morris-Hanon, Olivia
Nogueiras, Germán Ignacio
Ripari, Luisina Belén
Esquivel, Myrian Inés
Perez-Castro, Carolina
Romorini, Leonardo
Sevlever, Gustavo Emilio
Scassa, María Elida
Videla-Richardson, Guillermo Agustín
Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells
title Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells
title_full Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells
title_fullStr Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells
title_full_unstemmed Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells
title_short Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells
title_sort noxa and mcl-1 expression influence the sensitivity to bh3-mimetics that target bcl-xl in patient-derived glioma stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587994/
https://www.ncbi.nlm.nih.gov/pubmed/36273072
http://dx.doi.org/10.1038/s41598-022-20910-4
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