Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma

Abstract

Brain tumors actively reprogram their cellular metabolism to survive and proliferate, thus offering potential therapeutic opportunities. Over the past decade, extensive research has been done on mutant IDH enzymes as markers of good prognosis in glioblastoma, a highly aggressive brain tumor in adults with dismal prognosis. Yet, 95% of glioblastoma are IDH wild-type. Here, we review current knowledge about IDH wild-type enzymes and their putative role in mechanisms driving tumor progression. After a brief overview on tumor metabolic adaptation, we present the diverse metabolic function of IDH enzymes and their roles in glioblastoma initiation, progression and response to treatments. Finally, we will discuss wild-type IDH targeting in primary glioblastoma.

Fig. 1. Metabolic properties of wild-type IDH enzymes.

Depending on the isoform, the cofactor, and the localization, IDH enzymes are involved in different cellular processes including mitochondrial energy production, glutamine metabolism, lipogenesis, epigenetic profile, cell responses to hypoxia and cellular redox status. IDH1 performs its function in the cytosol, while IDH2 and IDH3 function as part of the tricarboxylic acid (TCA) cycle in the mitochondria. All three IDH isoforms catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate and carbon dioxide with the production of reducing equivalent NAD(P)H. Whereas this reaction is irreversible through IDH3 within the TCA cycle, IDH1/2 activities are working in a reversible manner.

Fig. 2. Metabolic discrepancies between wild-type and mutant IDH1 in GBM.

Hotspot mutation in IDH1 gene has been identified in GBM occuring at the active site within the catalytic pocket, and resulting in a neomorphic activity leading to the generation of (D)2-Hydroxyglutarate (D2HG) while oxidizing NADPH. D2HG, through structural similarity to αKG, acts as a competitive inhibitor leading to inhibition of αKG-dependent dioxygenases, and resulting to epigenetic alteration, HIF1α stabilization, and alterations in cellular differentiation and response to oxidative stress. Tumors with IDH1/2 mutations have distinctive genetic and clinical characteristics. In particular, patients with mutant IDH1/2 GBM have a better outcome compared to those with wild-type IDH tumor.

Fig. 3. Metabolic functions of wild-type IDH2 and IDH3 in GBM.

IDH2 and IDH3 are located in the mitochondria with the respective production of NADP(H) and NADH. These 2 isoforms act in concert to regulate energy production through modulation of TCA cycle running through an isocitrate/αKG cycle. In this cycle, IDH3 converts isocitrate to αKG while IDH2 converts αKG and NADPH back to isocitrate and NADP⁺. This metabolic cycle allows tumor cells to favor lipid biosynthesis and to cope with mitochondrial oxidative stress. In mitochondria, αKG is provided by the glutamate dehydrogenase (GDH) from glutamine through glutamate. The subunit IDH3α can be found in the cytosol where it interacts with serine hydroxymethyltransferase (cSHMT), an enzyme involved in epigenetic profiling through histone and DNA methylation.