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 1 , Remco J. Molenaar 1 , Krissie Lenting 2 , William P. Leenders 2, * and Cornelis J.F. van Noorden 1, * 1 Department of Medical Biology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands 2 Department of Pathology, Radboudumc, 6500 HB Nijmegen, The Netherlands * These authors jointly supervised this study Correspondence to: Mohammed Khurshed, email: m.khurshed@amc.uva.nl Keywords: glioma, metabolism, isocitrate dehydrogenase 1, glycolysis, glutamate Received: September 23, 2016 Accepted: April 03, 2017 Published: April 13, 2017 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 ( IDH1 MUT ) on expression of genes that encode for metabolic enzymes by data mining The Cancer Genome Atlas. We analyzed 112 IDH1 wild-type ( IDH1 WT ) versus 399 IDH1 MUT low-grade glioma and 157 IDH1 WT versus 9 IDH1 MUT glioblastoma samples. In both glioma types, IDH1 WT was associated with high expression levels of genes encoding enzymes that are involved in glycolysis and acetate anaplerosis, whereas IDH1 MUT glioma overexpress genes encoding enzymes that are involved in the oxidative tricarboxylic acid (TCA) cycle. In vitro , we observed that IDH1 MUT cancer cells have a higher basal respiration compared to IDH1 WT cancer cells and inhibition of the IDH1 MUT shifts the metabolism by decreasing oxygen consumption and increasing glycolysis. Our findings indicate that IDH1 WT glioma have a typical Warburg phenotype whereas in IDH1 MUT glioma the TCA cycle, rather than glycolytic lactate production, is the predominant metabolic pathway. Our data further suggest that the TCA in IDH1 MUT 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 IDH1 MUT and IDH1 WT glioma.