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Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

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Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
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Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany
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National Center for Tumor Diseases (NCT), Partner site Dresden, 01307 Dresden, Germany
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German Cancer Consortium (DKTK), Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Institute for Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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Department of Biochemistry, Radboud University Medical Center, 6525 Nijmegen, The Netherlands
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Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
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Department of Oncology, NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), L-1526 Luxembourg, Luxembourg
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Department of Biomedicine, University of Bergen, 5020 Bergen, Norway
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Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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National Center of Genetics (NCG), Laboratoire national de santé (LNS), L-3555 Dudelange, Luxembourg
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(12), 2028; https://doi.org/10.3390/cancers11122028
Received: 9 October 2019 / Revised: 13 November 2019 / Accepted: 5 December 2019 / Published: 16 December 2019
IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas. View Full-Text
Keywords: IDH-mutation; IDH1; glioma; redox state; metabolism; NAD-synthesis IDH-mutation; IDH1; glioma; redox state; metabolism; NAD-synthesis
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Biedermann, J.; Preussler, M.; Conde, M.; Peitzsch, M.; Richter, S.; Wiedemuth, R.; Abou-El-Ardat, K.; Krüger, A.; Meinhardt, M.; Schackert, G.; Leenders, W.P.; Herold-Mende, C.; Niclou, S.P.; Bjerkvig, R.; Eisenhofer, G.; Temme, A.; Seifert, M.; Kunz-Schughart, L.A.; Schröck, E.; Klink, B. Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin. Cancers 2019, 11, 2028.

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