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

[en] IDH1(R132H) (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1(wt) converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP(+)), whereas IDH1(R132H) 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 IDH1(R132H) are still ambiguous. The present study demonstrates that IDH1(R132H) 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 IDH1(R132H) transduction. However, in astrocytes IDH1(R132H) led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1(R132H) 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.

Disciplines :

Oncology

Author, co-author :

Biedermann, Julia; Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.

Preussler, Matthias; Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.

Conde, Marina; Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

Peitzsch, Mirko; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

Richter, Susan; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

Wiedemuth, Ralf; Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

Abou-El-Ardat, Khalil ; Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.

Krüger, Alexander; Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany. ; 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. ; National Center for Tumor Diseases (NCT), Partner site Dresden, 01307 Dresden, Germany. ; German Cancer Consortium (DKTK), Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Meinhardt, Matthias; Institute for Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

Schackert, Gabriele; Department of Neurosurgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. ; National Center for Tumor Diseases (NCT), Partner site Dresden, 01307 Dresden, Germany. ; German Cancer Consortium (DKTK), Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

More authors (10 more)

External co-authors :

yes

Language :

English

Title :

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

Publication date :

16 December 2019

Journal title :

Cancers

eISSN :

2072-6694

Publisher :

Multidisciplinary Digital Publishing Institute (MDPI), Switzerland

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funding number :

RI 2684/1-1; KL 2541/2-1/Deutsche Forschungsgemeinschaft/; 70112014/Deutsche Krebshilfe/; GlioMath-Dresden/European Social Fund/; Else Kröner-Promotionskolleg Dresden/Else Kröner-Fresenius-Stiftung/

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