Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells

Abstract 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 tem...

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Autores principales:	Selva Rupa Christinal Immanuel, Avinash D. Ghanate, Dharmeshkumar S. Parmar, Ritu Yadav, Riya Uthup, Venkateswarlu Panchagnula, Anu Raghunathan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1e7865ffc7db435cb53c095773f326ca
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spelling	oai:doaj.org-article:1e7865ffc7db435cb53c095773f326ca2021-12-02T11:46:10ZIntegrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells10.1038/s41540-020-00161-72056-7189https://doaj.org/article/1e7865ffc7db435cb53c095773f326ca2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41540-020-00161-7https://doaj.org/toc/2056-7189Abstract 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 IC50 value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC50 value of 1.8 mM was thus identified using our integrated systems-based approach.Selva Rupa Christinal ImmanuelAvinash D. GhanateDharmeshkumar S. ParmarRitu YadavRiya UthupVenkateswarlu PanchagnulaAnu RaghunathanNature PortfolioarticleBiology (General)QH301-705.5ENnpj Systems Biology and Applications, Vol 7, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Selva Rupa Christinal Immanuel Avinash D. Ghanate Dharmeshkumar S. Parmar Ritu Yadav Riya Uthup Venkateswarlu Panchagnula Anu Raghunathan Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells
description	Abstract 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 IC50 value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC50 value of 1.8 mM was thus identified using our integrated systems-based approach.
format	article
author	Selva Rupa Christinal Immanuel Avinash D. Ghanate Dharmeshkumar S. Parmar Ritu Yadav Riya Uthup Venkateswarlu Panchagnula Anu Raghunathan
author_facet	Selva Rupa Christinal Immanuel Avinash D. Ghanate Dharmeshkumar S. Parmar Ritu Yadav Riya Uthup Venkateswarlu Panchagnula Anu Raghunathan
author_sort	Selva Rupa Christinal Immanuel
title	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_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_sort	integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1e7865ffc7db435cb53c095773f326ca
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Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells

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