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Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells
Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794364/ https://www.ncbi.nlm.nih.gov/pubmed/33420045 http://dx.doi.org/10.1038/s41540-020-00161-7 |
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author | Immanuel, Selva Rupa Christinal Ghanate, Avinash D. Parmar, Dharmeshkumar S. Yadav, Ritu Uthup, Riya Panchagnula, Venkateswarlu Raghunathan, Anu |
author_facet | Immanuel, Selva Rupa Christinal Ghanate, Avinash D. Parmar, Dharmeshkumar S. Yadav, Ritu Uthup, Riya Panchagnula, Venkateswarlu Raghunathan, Anu |
author_sort | Immanuel, Selva Rupa Christinal |
collection | PubMed |
description | Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines. The genetic basis of this metabolic adaptation was characterized by whole exome sequencing that identified mutations in signaling pathway regulators of growth and energy metabolism. Remarkably, our integrated approach identified rewiring in glycolysis, TCA cycle, malate aspartate shunt, and oxidative phosphorylation pathways. The differential killing of TMZ resistant NSP by Rotenone at low concentrations with an IC(50) value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC(50) value of 1.8 mM was thus identified using our integrated systems-based approach. |
format | Online Article Text |
id | pubmed-7794364 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77943642021-01-21 Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells Immanuel, Selva Rupa Christinal Ghanate, Avinash D. Parmar, Dharmeshkumar S. Yadav, Ritu Uthup, Riya Panchagnula, Venkateswarlu Raghunathan, Anu NPJ Syst Biol Appl Article Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines. The genetic basis of this metabolic adaptation was characterized by whole exome sequencing that identified mutations in signaling pathway regulators of growth and energy metabolism. Remarkably, our integrated approach identified rewiring in glycolysis, TCA cycle, malate aspartate shunt, and oxidative phosphorylation pathways. The differential killing of TMZ resistant NSP by Rotenone at low concentrations with an IC(50) value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC(50) value of 1.8 mM was thus identified using our integrated systems-based approach. Nature Publishing Group UK 2021-01-08 /pmc/articles/PMC7794364/ /pubmed/33420045 http://dx.doi.org/10.1038/s41540-020-00161-7 Text en © The Author(s) 2021, corrected publication 2021 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 Immanuel, Selva Rupa Christinal Ghanate, Avinash D. Parmar, Dharmeshkumar S. Yadav, Ritu Uthup, Riya Panchagnula, Venkateswarlu Raghunathan, Anu Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells |
title | Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells |
title_full | Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells |
title_fullStr | Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells |
title_full_unstemmed | Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells |
title_short | Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells |
title_sort | integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794364/ https://www.ncbi.nlm.nih.gov/pubmed/33420045 http://dx.doi.org/10.1038/s41540-020-00161-7 |
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