Hominoid-specific enzyme GLUD2 promotes growth of IDH1 ^R132H glioma

Abstract

Somatic mutation of isocitrate dehydrogenase 1 (IDH1) is now recognized as the most common initiating event for secondary glioblastoma, a brain tumor type arising with high frequency in the frontal lobe. A puzzling feature of IDH1 mutation is the selective manifestation of glioma as the only neoplasm frequently associated with early postzygotic occurrence of this genomic alteration. We report here that IDH1 R132H exhibits a growth-inhibitory effect that is abrogated in the presence of glutamate dehydrogenase 2 (GLUD2), a hominoid-specific enzyme purportedly optimized to facilitate glutamate turnover in human forebrain. Using murine glioma progenitor cells, we demonstrate that IDH1R132H exerts a growth-inhibitory effect that is paralleled by deficiency in metabolic flux from glucose and glutamine to lipids. Examining human gliomas, we find that glutamate dehydrogenase 1 (GLUD1) and GLUD2 are overexpressed in IDH1-mutant tumors and that orthotopic growth of an IDH1-mutant glioma line is inhibited by knockdown of GLUD1/2. Strikingly, introduction of GLUD2 into murine glioma progenitor cells reverses deleterious effects of IDH1 mutation on metabolic flux and tumor growth. Further, we report that glutamate, a substrate of GLUD2 and a neurotransmitter abundant in mammalian neocortex, can support growth of glioma progenitor cells irrespective of IDH1 mutation status. These findings suggest that specialization of human neocortex for high glutamate neurotransmitter flux creates a metabolic niche conducive to growth of IDH1 mutant tumors.tumor metabolism | astrocytoma | oligodendroglioma

Mice carrying a human GLUD2 gene recapitulate aspects of human transcriptome and metabolome development

“…Instead, metabolic differences between GLUD2 + and control mice center on the metabolic pathways surrounding the TCA cycle. In agreement with this, it has been reported that overexpression of human GLUD2, but not GLUD1, in mutant murine glioma progenitor cells results in shunting of carbon into lipid biosynthesis via the TCA cycle (12). Our data further show that metabolic differences between GLUD2…”

“…However, the connection between the emergence of the GLUD2 gene in the ancestors of apes and humans and changes in brain function remains elusive. To date, the only direct insights into GLUD2 function come from a rare GLUD2 mutation linked to the onset of Parkinson's disease (11) and from glioma cells carrying a mutated isocitrate dehydrogenase 1 gene (IDH1) where GLUD2 expression reverses the effects of the IDH1 mutation by reactivation of the metabolic flux from glucose and glutamine to lipids by way of the TCA cycle (12).…”

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

“…In all, our results suggest that altered oxidative stress response is the most likely downstream element of causing mitochondrial ROS (54). In addition, other Achilles' heels in IDH MT metabolism could be exploited, such as mitochondrial dysfunction (50), increased dependence on glutaminolysis (2,(55)(56)(57)(58)(59) and oxidative phosphorylation (42,43). These vulnerabilities can be pharmacologically targeted via BCL-2 inhibitors, chloroquine, and metformin, respectively.…”

Metabolic consequences of oncogenic IDH mutations

“…For example, a glioblastoma cell line and transformed astrocytes both exhibited increased sensitivity to pharmacological or siRNA-mediated inhibition of glutaminase (Seltzer et al, 2010). In addition, Chen et al recently observed that gliomas harboring IDH1 mutations overexpressed glutamate dehydrogenase 1 and 2 ( GLUD1 and GLUD2 ), and orthotopic growth of mutant glioma lines were sensitive to GLUD1 or GLUD2 knockdown (Chen et al, 2014). We observed a similar increase in the dependence of IDH1 mutant cells on glutaminolysis in our analysis of a panel of HCT116 cells, providing evidence that these changes arise due to a direct impact on metabolism rather than indirectly through cell lineage-specific mechanisms (Grassian et al, 2014).…”