Figure 6.

KMT/IDH1 synergistic interaction for targeting GBM energy metabolism. KMT can reduce glucose availability for glycolysis while also interfering with the glutaminolysis pathway. Glutamine-driven mitochondrial substrate-level phosphorylation (mSLP), in the glutaminolysis pathway, is a major source of ATP synthesis for GBM cells (25, 26). The glutaminolysis pathway (red) becomes dominant in tumor cells with inefficient OxPhos and that express the dimeric PKM2 isoform. PKM2 is expressed in GBM and produces less ATP through glycolysis than does the PKM1 isoform (109–111). The elevation of ketone bodies (β-hydroxybutyrate and acetoacetate) through KMT could indirectly reduce ATP synthesis through the succinate CoA ligase (SUCL) reaction by diverting CoA from succinate to acetoacetate. The IDH1 mutation could further reduce ATP synthesis through mSLP by increasing synthesis of 2-hydroxyglutarate from α-ketoglutarate and thus reducing the succinyl CoA substrate for the SUCL reaction (26, 112). Besides its potential effect in reducing glutaminolysis, 2-hydroxyglutarate can also target multiple HIF1α-responsive genes and enzymes in the glycolysis pathway thus limiting synthesis of metabolites and one-carbon metabolism needed for rapid tumor growth (25, 26, 103, 113). The down-regulation of Hif1-α-regulated lactate dehydrogenase A (LDHA), through the action of both KMT and the IDH1 mutation, would reduce extracellular lactate levels thus reducing microenvironment inflammation and tumor cell invasion. Hence, the simultaneous inhibition of glycolysis and glutaminolysis through the synergistic effects of KMT and the IDH1 mutation will stress the majority of signaling pathways necessary for rapid GBM growth. BDH, β-hydroxybutyrate dehydrogenase; FAD, flavin adenine dinucleotide; GLSc, glutaminase, cytosolic; GLSm, glutaminase; mitochondrial; GLUD, glutamate dehydrogenase; GOT2, aspartate aminotransferase; KGDHC, α-ketoglutarate dehydrogenase complex; LDHA, lactate dehydrogenase A; NME, nucleoside diphosphate kinase; OXCT1, succinyl-CoA:3-ketoacid coenzyme A transferase 1; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PEP, phosphoenolpyruvate; PKM2, pyruvate kinase M2; SDH, succinate dehydrogenase; SUCL, succinate-CoA ligase. Reprinted with modifications from Seyfried et al. (26).