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

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.

Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC

“…The identification of new markers in cancer is crucial to develop better forecasts on prognosis and to find new therapy options [ 5 , 7 , 19 , 32 ]. In this field of research, CSC markers are very prominent, although some are linked to a better and some to a worse prognosis, whereas the literature is controversial for some markers [ 12 , 13 , 33 , 34 ].…”

Transcriptome Analysis of Porcine Granulosa Cells in Healthy and Atretic Follicles: Role of Steroidogenesis and Oxidative Stress

“…This assumption is further supported by the decreased mRNA content of IDH1 in AA follicles. IDH1 is an important generator of NADPH in cells, essential for the regeneration of GSH from GSSH [ 42 ]. By means of single cell sequencing, the analysis of cell-type-specific aging-associated transcriptional changes uncovered that granulosa cells in the aged non-human primate ovary prone to higher oxidative stress, had a lower IDH1 expression compared with the younger controls.…”

ZWINT: A potential therapeutic biomarker in patients with glioblastoma correlates with cell proliferation and invasion

“…GBM patients present with only a 15-to 19-month median overall survival rate due to chemoradiotherapy resistance and recurrence (1). Recent studies have identified several molecular alterations involved in GBM carcinogenesis, progression, chemotherapeutic resistance and recurrence, such as IDH1, 1p/19q, MGMT, ATRX and PTEN, but the precise mechanisms underlying this malignancy and its rapid recurrence have not been fully elucidated (2)(3)(4). Targeting key genes and signaling pathways is considered a promising approach for the diagnosis and treatment of cancer.…”