IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma

Zhang, Chunzhi; Moore, Lynette Marie; Li, Xia; Yung, W. K. Alfred; Zhang, Wei

doi:10.1093/neuonc/not087

Cited by 117 publications

(102 citation statements)

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“…In general, reported kinetic parameters of IDH1 mutants explored to date vary widely, making comparisons difficult. Interestingly, some mutations identified in tumors do not appear to generate D2HG (31,32), suggesting that loss of the normal reaction itself has important consequences, or perhaps that they are simply passenger mutations.…”

Section: Isocitrate Dehydrogenase 1 (Idh1) Catalyzes the Reversible Nadpmentioning

confidence: 99%

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

Matteo

Grunseth

Gonzalez

et al. 2017

Journal of Biological Chemistry

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Edited by John M. Denu Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP؉ -dependent conversion of isocitrate (ICT) to ␣-ketoglutarate (␣KG) in the cytosol and peroxisomes. Mutations in IDH1 have been implicated in >80% of lower grade gliomas and secondary glioblastomas and primarily affect residue 132, which helps coordinate substrate binding. However, other mutations found in the active site have also been identified in tumors. IDH1 mutations typically result in a loss of catalytic activity, but many also can catalyze a new reaction, the NADPH-dependent reduction of ␣KG to D-2-hydroxyglutarate (D2HG). D2HG is a proposed oncometabolite that can competitively inhibit ␣KG-dependent enzymes. Some kinetic parameters have been reported for several IDH1 mutations, and there is evidence that mutant IDH1 enzymes vary widely in their ability to produce D2HG. We report that most IDH1 mutations identified in tumors are severely deficient in catalyzing the normal oxidation reaction, but that D2HG production efficiency varies among mutant enzymes up to ϳ640-fold. Common IDH1 mutations have moderate catalytic efficiencies for D2HG production, whereas rarer mutations exhibit either very low or very high efficiencies. We then designed a series of experimental IDH1 mutants to understand the features that support D2HG production. We show that this new catalytic activity observed in tumors is supported by mutations at residue 132 that have a smaller van der Waals volume and are more hydrophobic. We report that one mutation can support both the normal and neomorphic reactions. These studies illuminate catalytic features of mutations found in the majority of patients with lower grade gliomas.Metabolic changes in tumors have been described for nearly a century (1-3), but only relatively recently have enzymes involved in metabolic processes been established as tumor suppressors or oncoproteins. One of the more striking examples of metabolic enzymes playing a role in tumorigenesis includes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2).3 These homodimeric enzymes are responsible for the reversible NADP ϩ -and Mg 2ϩ -dependent conversion of ICT to ␣KG (Fig. 1A) in the cytosol and peroxisomes (IDH1), or mitochondria (IDH2). IDH3 is responsible for the same reaction within the context of the TCA cycle, although the oxidative decarboxylation catalyzed by this enzyme is non-reversible and NAD ϩ -dependent. Mutations in IDH1 and IDH2 were identified in glioblastoma multiforme in a large sequencing effort (4), and soon Ͼ80% of adult grade II/III gliomas and secondary glioblastomas were found to have IDH1 mutations, commonly R132H or R132C IDH1 (5, 6) (reviewed in Refs. 7-9). Subsequently ϳ10 -20% of acute myeloid leukemias were shown to have primarily IDH2 mutations, typically R140Q or R172K IDH2 (10). Early mechanisms of tumorigenesis focused on deficient conversion of ICT to ␣KG (11), suggesting that IDH serves as a tumor suppressor, in part through altering levels of hypoxia-inducible transcription factor-1␣ (12). However,...

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Section: Isocitrate Dehydrogenase 1 (Idh1) Catalyzes the Reversible Nadpmentioning

confidence: 99%

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

Matteo

Grunseth

Gonzalez

et al. 2017

Journal of Biological Chemistry

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“…In contrast, these mutations rarely occur in primary or de novo glioblastomas (3-21%) (Kim and Liau, 2012;Zhang et al, 2013;Dunn et al, 2013). IDH1 mutations were further identified in the majority of WHO grade II diffuse astrocytoma (59-100%) and WHO grade III anaplastic astrocytomas (approximately 60%), oligodendrogliomas (67-93%), anaplastic oligodendrogliomas (49-86%), and mixed oligoastrocytomas (50-100%).…”

Section: Discussionmentioning

confidence: 99%

“…IDH1 mutations were further identified in the majority of WHO grade II diffuse astrocytoma (59-100%) and WHO grade III anaplastic astrocytomas (approximately 60%), oligodendrogliomas (67-93%), anaplastic oligodendrogliomas (49-86%), and mixed oligoastrocytomas (50-100%). The mutation rate in pilocytic astrocytomas, ependymal tumors, or other less common glial tumors are lower (Kim and Liau, 2012;Zhang et al, 2013;Dunn et al, 2013). The frequency of R132H mutations in gliomas in our series was close to the spectrum described above, as we found this mutation in diffuse astrocytomas (33.3%; 1/3), anaplastic astrocytoma (66.6%; 2/3), oligodendroglioma (50%; 1/2), and anaplastic oligoastrocytoma (66.6%; 2/3).…”

Section: Discussionmentioning

confidence: 99%

IDH1 and IDH2 mutations in different histologic subtypes and WHO grading gliomas in a sample from Northern Brazil

Pessôa¹,

Sagica²,

Anselmo³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Glioma is a term used to describe tumors derived from glial cells. These tumors are divided into subgroups based on the histological morphology and similarity of their differentiated glia cells. Traditionally, they are classified according to the World Health Organization and include astrocytomas, oligodendrogliomas, ependymomas, and oligoastrocytomas. Like most cancers, gliomas develop as a result of genetic changes that accumulate with tumor progression. Alterations in isocitrate dehydrogenase 1 (IDH1) and IDH2 were found to be relevant in the classification and prognostic of gliomas. Because of the importance of mutations in these genes, particularly in I.A. Pessôa et al. 6534©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 6533-6542 (2015) IDH1, in different proposals of the genesis and progression of gliomas, we analyzed the occurrence of mutations in these genes in samples obtained from patients from Belém (PA, Brazil) using polymerase chain reaction-single-strand conformation polymorphism followed by sequencing. We compared the results obtained from tumors of different malignancy grades, evaluating the significance of the associations between different variables. R132H was the only mutation found in 17.6% (6/34) of cases, including in astrocytomas, anaplastic astrocytomas, oligodendroglioma, and anaplastic oligoastrocytoma. No mutations were found in the IDH2 gene. We found no significant relationship between the identified mutations in IDH1 and the variables. Our data could not confirm that mutations in IDH1/IDH2 are indicative of malignancy and prognosis. However, the results support that the mutation in IDH1 gene was an early event in the development of gliomas, as it was found in tumors of different malignancy grades.

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“…Thus, IDH mutations have been shown to create a gain of function such that α-ketoglutarate is further metabolized to the oncometabolite 2-hydroxyglutarate in a reaction that consumes, rather than produces, NADPH ( Figure 5). 73 Tumors with IDH mutations causing consumption rather than production of NADPH may be particularly sensitive to HD DHEA. Whatever the reason underlying the extreme hypersensitivity of canine CH to HD DHEA, cardiac angiosarcoma is believed to represent the identical disease in humans.…”

Section: Discussionmentioning

confidence: 99%

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

Nyce¹

2017

Transl Med Rep

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Glucose-6-phosphate dehydrogenase (G6PD) is an oncoprotein that is regulated by the p53 tumor suppressor. Mutant p53 loses the ability to inhibit G6PD, and loss of G6PD control clearly plays a role in oncogenesis. The steroid hormone precursor dehydroepiandrosterone (DHEA) is an endogenous uncompetitive inhibitor of G6PD. In humans, and a few other species, the sulfated circulatory form of DHEA (DHEAS) is present at extremely high concentrations -much higher than can be accounted for by DHEA's function as a precursor to steroid hormones. Uncompetitive inhibition is extremely rare in natural systems because it is irreversible in the presence of high concentrations of substrate and inhibitor. What has gone unappreciated is that such uncompetitive inhibition can quickly lead to cell death when the target is an obligatory housekeeping gene such as G6PD. Cells with inactivated p53 not only lose control over G6PD, but also over hexokinase (HK), the enzyme that converts glucose into glucose-6-phosphate (G6P), the substrate of G6PD. Furthermore, loss of p53 function de-represses NFκB activity, resulting in the upregulation of steroid sulfatase (SS) which converts circulating DHEAS into active DHEA. We propose that inactivation of p53 rapidly elevates G6P and DHEA concentrations in affected cells, driving uncompetitive inhibition of G6PD to lethal irreversibility. In animals with circulating DHEAS, this kill-switch mechanism may prevent most cases of p53 inactivation from becoming tumorigenic. Tumors would thus represent instances in which this mechanism had not been triggered, but which might still be triggered by application of DHEA sufficient to uncompetitively inhibit tumor G6PD. To test this hypothesis, we performed a pilot study in which dogs with cardiac hemangiosarcoma were treated with high dose (HD) DHEA supplemented with isoprene precursors to maintain geranylation of Rac GTPase. Tumor regression and longevity observed in these dogs supported the concept that some tumors retain extraordinary sensitivity to uncompetitive inhibition by DHEA.

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IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma

Cited by 117 publications

References 103 publications

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

IDH1 and IDH2 mutations in different histologic subtypes and WHO grading gliomas in a sample from Northern Brazil

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

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