In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma

Abstract

Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) initiate low-grade glioma and secondary glioblastoma and induce a neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). It causes metabolic rewiring that is not fully understood. We investigated the effects of IDH1 mutations (IDH1MUT) on expression of genes that encode for metabolic enzymes by data mining The Cancer Genome Atlas. We analyzed 112 IDH1 wild-type (IDH1WT) versus 399 IDH1MUT low-grade glioma and 157 IDH1WT versus 9 IDH1MUT glioblastoma samples. In both glioma types, IDH1WT was associated with high expression levels of genes encoding enzymes that are involved in glycolysis and acetate anaplerosis, whereas IDH1MUT glioma overexpress genes encoding enzymes that are involved in the oxidative tricarboxylic acid (TCA) cycle. In vitro, we observed that IDH1MUT cancer cells have a higher basal respiration compared to IDH1WT cancer cells and inhibition of the IDH1MUT shifts the metabolism by decreasing oxygen consumption and increasing glycolysis. Our findings indicate that IDH1WT glioma have a typical Warburg phenotype whereas in IDH1MUT glioma the TCA cycle, rather than glycolytic lactate production, is the predominant metabolic pathway. Our data further suggest that the TCA in IDH1MUT glioma is driven by lactate and glutamate anaplerosis to facilitate production of α-KG, and ultimately D-2-HG. This metabolic rewiring may be a basis for novel therapies for IDH1MUT and IDH1WT glioma.

IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

“…We and others showed that IDH1 MUT cells are more dependent on mitochondrial oxphos, as compared to IDH1 WT cells (4,27). In addition, we reported that cells of the patient-derived IDH1 MUT oligodendroglioma xenograft model E478 are packed with mitochondria, suggesting that IDH1 MUT gliomas revert to mitochondrial metabolism (28).…”

“…We previously determined that IDH1 MUT HCT116 cells are more dependent on oxphos than are IDH1 WT HCT116 cells (4). Because cisplatin, but not carboplatin, strongly impairs oxphos and mitochondrial function (37), we investigated whether, besides the reduced NADPH production capacity, the increased sensitivity of IDH1 MUT cells to cisplatin is caused by this metabolic phenotype.…”

“…HCT116 cells, with and without pretreatment with 1 µM AGI-5198, were grown in 5% CO 2 at 37°C, and the oxygen consumption rate (OCR) was measured with a Seahorse XFe96 analyzer (Agilent Technologies, Santa Clara, CA, USA) (4). …”

“…IDH1 MUT leads to reprogramming of cellular metabolism, which is one of the hallmarks of cancer (4, 5). The hotspot mutations in IDH1 , of which IDH1 R132H is the most prevalent, cause loss of enzymatic wild-type IDH1 (IDH1 WT ) function and lead to a neomorphic IDH1 activity that converts α-KG into the oncometabolite d -2-hydroxyglutarate ( d -2HG) (6).…”

A Simple in Silico Approach to Generate Gene-Expression Profiles from Subsets of Cancer Genomics Data

“…IDH1 MUT induces metabolic rewiring that is not fully understood [14,15] but exploration of differences in expression levels of metabolic enzymes is a promising investigational approach. The effects of IDH1 MUT on the expression of genes that encode for metabolic enzymes offer an opportunity to demonstrate the possibilities of the cBioPortal to perform data integration, exploration and analysis.…”