IDH1, lipid metabolism and cancer: Shedding new light on old ideas

Bogdanovic, Elena

doi:10.1016/j.bbagen.2015.04.014

Cited by 35 publications

(27 citation statements)

References 50 publications

(97 reference statements)

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“…Due to the great number of recent reviews on this topic (Guo et al 2011; van Lith et al 2014; Molenaar et al 2014; Bogdanovic 2015; Borodovsky et al 2015; Parker and Metallo 2015), this report will be limited to a brief summary of main observations on IDH mutations and the consequence for cell metabolism in regard to Glu and αKG.…”

Section: Differences Between Idh-wt and Idh-mutant Gliomasmentioning

confidence: 99%

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Glutamate and α-ketoglutarate: key players in glioma metabolism

2016

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Glioblastoma multiforme (GBM), or grade IV astrocytoma, is the most common type of primary brain tumor. It has a devastating prognosis with a 2-year-overall survival rate of only 26 % after standard treatment, which includes surgery, radiation, and adjuvant chemotherapy with temozolomide. Also lower grade gliomas are difficult to treat, because they diffusely spread into the brain, where extensive removal of tissue is critical. Better understanding of the cancer’s biology is a key for the development of more effective therapy approaches. The discovery of isocitrate dehydrogenase (IDH) mutations in leukemia and glioma drew attention to specific metabolic aberrations in IDH-mutant gliomas. In the center of the metabolic alterations is α-ketoglutarate (αKG), an intermediate metabolite in the tricarboxylic acid (TCA) cycle, and the associated amino acid glutamate (Glu). This article highlights the role of these metabolites in glioma energy and lipid production and indicates possible weak spots of IDH-mutant and IDH-wt gliomas.

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Section: Differences Between Idh-wt and Idh-mutant Gliomasmentioning

confidence: 99%

“…It is conceivable that the mutation of IDH leads to an altered ratio of fatty acid products like sphingolipids, or phospholipids. Although no data have been published on this matter, it has been claimed that IDH1 mutations indirectly alter the levels of sphingomyelin in mouse brains (Bogdanovic 2015). …”

Section: Differences Between Idh-wt and Idh-mutant Gliomasmentioning

confidence: 99%

Glutamate and α-ketoglutarate: key players in glioma metabolism

2016

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“…3 The IDH1 mut induces changes in the concentration of tricarboxylic acid (TCA) cycle intermediates and lipid metabolites. 4,5 In vitro and in vivo studies demonstrated that the inhibition of IDH1/2-mutant enzymes decreases intracellular D-2-hydroxyglutarate (D-2HG) levels and reverses epigenetic dysregulation. 6,7 Gene expression profiles of large cohorts of glioma and acute myeloid leukemia have shown that IDH1/2 mutant tumors display a distinct gene expression profile enriched for genes expressed in progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

Metabolic changes related to the IDH1 mutation in gliomas preserve TCA‐cycle activity: An investigation at the protein level

Dekker

Jurriëns

et al. 2020

FASEB j.

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The discovery of the IDH1 R132H (IDH1 mut) mutation in low‐grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA cycle are associated with IDH1 mut. Here, we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism, and the TCA cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate, and enzymes involved in the conversion of α‐ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine, and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA‐cycle activity in IDH1 mut gliomas.

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“…An increased level of IDH1 is also linked to catalase activation, which prevents oxidative stress and apoptosis [4][5][6]. However, it is noteworthy that IDH1 also plays an important role in cellular metabolism, proliferation and production energy by participating in the glutamine metabolism and the glucose secretion pathway as well as in the biosynthesis of fatty acids and lipids [7,8]. Cancer cells are characterized by an accelerated metabolism and an increased demand for glucose and other nutrients.…”

Section: Introductionmentioning

confidence: 99%

The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

Malarz

Mularski

Pacholczyk

et al. 2020

Cancers

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Isocitrate dehydrogenases constitute a class of enzymes that are crucial for cellular metabolism. The overexpression or mutation of isocitrate dehydrogenases are often found in leukemias, glioblastomas, lung cancers, and ductal pancreatic cancer among others. Mutation R132H, which changes the functionality of an enzyme to produce mutagenic 2-hydroxyglutarate instead of a normal product, is particularly important in this field. A series of inhibitors were described for these enzymes of which ivosidenib was the first to be approved for treating leukemia and bile duct cancers in 2018. Here, we investigated the polypharmacological landscape of the activity for known sulfamoyl derivatives that are inhibitors, which are selective towards IDH1 R132H. These compounds appeared to be effective inhibitors of several non-receptor kinases at a similar level as imatinib and axitinib. The antiproliferative activity of these compounds against a panel of cancer cells was tested and is explained based on the relative expression levels of the investigated proteins. The multitargeted activity of these compounds makes them valuable agents against a wide range of cancers, regardless of the status of IDH1.

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IDH1, lipid metabolism and cancer: Shedding new light on old ideas

Cited by 35 publications

References 50 publications

Glutamate and α-ketoglutarate: key players in glioma metabolism

Glutamate and α-ketoglutarate: key players in glioma metabolism

Metabolic changes related to the IDH1 mutation in gliomas preserve TCA‐cycle activity: An investigation at the protein level

The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

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