Abstract
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.
Highlights
Diffuse gliomas are the most prevalent brain tumors in adults with an overall unfavorable prognosis
We show that IDH1R132H has differing effects on the redox state between tumor cells and astrocytes, indicating that IDH1R132H could have different effects depending on the stage of malignant transformation
IDH1R132H or IDH1wt showed a strong expression of the transduced protein and expression of the endogenous IDH1 as confirmed with specific antibodies using Western Blot and immunocytochemistry, while cells transduced with an empty vector only showed an expression of the endogenous IDH1 (Supplementary Figures S1b and S6)
Summary
Diffuse gliomas are the most prevalent brain tumors in adults with an overall unfavorable prognosis. Low-grade gliomas and secondary glioblastomas are characterized by mutations in IDH1/2. (isocitrate dehydrogenase 1/2), which are associated with a longer overall survival and better response to therapy compared to IDH-wildtype gliomas [1,2,3,4]. 90% of cases is the amino acid substitution arginine to histidine at codon 132 of the cytoplasmic enzyme isocitrate dehydrogenase 1 (IDH1 c.395G>A; R132H) [1,2]. Other rare IDH1 variants in codon 132 have been described in gliomas, including R132C, R132S, R132G, and R132L, which show similar effects on IDH1 activity [5]. IDH1/2 mutations are assumed to be one of the earliest genetic alterations and are considered to play a key role in glioma development [6].
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