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

Mohammed Khurshed,Cornelis J.F Van Noorden,Krissie Lenting,William P Leenders,Remco J Molenaar

doi:10.18632/oncotarget.17106

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.

Highlights

Diffuse gliomas are infiltrative neoplasms that arise in the cerebral hemispheres of adults and are graded as WHO II-IV based on histopathological characteristics
IDH1 wild-type (IDH1WT) was associated with high expression levels of genes encoding enzymes that are involved in glycolysis and acetate anaplerosis, whereas IDH1 mutations (IDH1MUT) glioma overexpress genes encoding enzymes that are involved in the oxidative tricarboxylic acid (TCA) cycle
GLUT3 expression levels were low in IDH1MUT glioma when compared with IDH1WT glioma, whereas GLUT1 expression did not differ between IDH1MUT and IDH1WT glioma (Figure 1A)

Summary

Introduction

Diffuse gliomas are infiltrative neoplasms that arise in the cerebral hemispheres of adults and are graded as WHO II-IV based on histopathological characteristics. Grade II and III are low-grade gliomas (LGG) of which a subset may progress to secondary glioblastoma (WHO grade IV), whereas others may remain relatively stable for longer periods of time. In contrast to this gradual progression of malignancy, the majority of glioblastomas arise de novo, and are called primary glioblastoma. Complete surgical resection of diffuse glioma is impossible due to their highly invasive nature and without exception residual tumor is a source of recurrence and malignant progression. Despite all efforts to therapeutically target various pathways that are involved in glioma progression, significant improvement in survival has not been achieved since 2005, when temozolomide was added to irradiation as standard therapy [1, 2]

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