Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations

Abstract Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAFV600E and KRASG12V affect cell metabolism, stress resistance and signaling in colorectal carci...

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Autores principales:	Raphaela Fritsche-Guenther, Christin Zasada, Guido Mastrobuoni, Nadine Royla, Roman Rainer, Florian Roßner, Matthias Pietzke, Edda Klipp, Christine Sers, Stefan Kempa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ba89ec86c64648e088f3642d09599e61
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spelling	oai:doaj.org-article:ba89ec86c64648e088f3642d09599e612021-12-02T15:08:54ZAlterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations10.1038/s41598-018-27394-12045-2322https://doaj.org/article/ba89ec86c64648e088f3642d09599e612018-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-27394-1https://doaj.org/toc/2045-2322Abstract Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAFV600E and KRASG12V affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRASG12V expressing cells are characterized by the induction of glycolysis, accumulation of lactic acid and sensitivity to glycolytic inhibition. Notably mathematical modelling confirmed the critical role of MCT1 designating the survival of KRASG12V cells. Carcinoma cells harboring BRAFV600E remain resistant towards alterations of glucose supply or application of signaling or metabolic inhibitors. Altogether these data demonstrate that an oncogene-specific decoupling of mTOR from AMPK or AKT signaling accounts for alterations of resistance mechanisms and metabolic phenotypes. Indeed the inhibition of mTOR in BRAFV600E cells counteracts the metabolic predisposition and demonstrates mTOR as a potential target in BRAFV600E-driven colorectal carcinomas.Raphaela Fritsche-GuentherChristin ZasadaGuido MastrobuoniNadine RoylaRoman RainerFlorian RoßnerMatthias PietzkeEdda KlippChristine SersStefan KempaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-17 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Raphaela Fritsche-Guenther Christin Zasada Guido Mastrobuoni Nadine Royla Roman Rainer Florian Roßner Matthias Pietzke Edda Klipp Christine Sers Stefan Kempa Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
description	Abstract Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAFV600E and KRASG12V affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRASG12V expressing cells are characterized by the induction of glycolysis, accumulation of lactic acid and sensitivity to glycolytic inhibition. Notably mathematical modelling confirmed the critical role of MCT1 designating the survival of KRASG12V cells. Carcinoma cells harboring BRAFV600E remain resistant towards alterations of glucose supply or application of signaling or metabolic inhibitors. Altogether these data demonstrate that an oncogene-specific decoupling of mTOR from AMPK or AKT signaling accounts for alterations of resistance mechanisms and metabolic phenotypes. Indeed the inhibition of mTOR in BRAFV600E cells counteracts the metabolic predisposition and demonstrates mTOR as a potential target in BRAFV600E-driven colorectal carcinomas.
format	article
author	Raphaela Fritsche-Guenther Christin Zasada Guido Mastrobuoni Nadine Royla Roman Rainer Florian Roßner Matthias Pietzke Edda Klipp Christine Sers Stefan Kempa
author_facet	Raphaela Fritsche-Guenther Christin Zasada Guido Mastrobuoni Nadine Royla Roman Rainer Florian Roßner Matthias Pietzke Edda Klipp Christine Sers Stefan Kempa
author_sort	Raphaela Fritsche-Guenther
title	Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
title_short	Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
title_full	Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
title_fullStr	Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
title_full_unstemmed	Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
title_sort	alterations of mtor signaling impact metabolic stress resistance in colorectal carcinomas with braf and kras mutations
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/ba89ec86c64648e088f3642d09599e61
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Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations

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