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

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Item Type:Article
Title:Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations
Creators Name:Fritsche-Guenther, R. and Zasada, C. and Mastrobuoni, G. and Royla, N. and Rainer, R. and Roßner, F. and Pietzke, M. and Klipp, E. and Sers, C. and Kempa, S.
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 BRAF(V600E) and KRAS(G12V) affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRAS(G12V) 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 KRAS(G12V) cells. Carcinoma cells harboring BRAF(V600E) 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 BRAF(V600E) cells counteracts the metabolic predisposition and demonstrates mTOR as a potential target in BRAF(V600E)-driven colorectal carcinomas.
Keywords:AMP-Activated Protein Kinases, Amino Acid Substitution, Biological Models, Caco-2 Cells, Colorectal Neoplasms, Glycolysis, Lactic Acid, Missense Mutation, Physiological Stress, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins p21(ras), Signal Transduction, TOR Serine-Threonine Kinases, Animals, Mice
Source:Scientific Reports
ISSN:2045-2322
Publisher:Nature Publishing Group (U.K.)
Volume:8
Number:1
Page Range:9204
Date:15 June 2018
Official Publication:https://doi.org/10.1038/s41598-018-27394-1
PubMed:View item in PubMed

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