Dataset Information
Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate.
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ABSTRACT: Background
Mutations in isocitrate dehydrogenase 1 (IDH1) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of D-2-hydroxyglutarate (D-2-HG) at the expense of ?-ketoglutarate (?-KG) and NADPH. To overcome metabolic stress induced by these alterations, IDH-mutated (IDH mut ) cancers utilize rescue mechanisms comprising pathways in which glutaminase and glutamate dehydrogenase (GLUD) are involved. We hypothesized that inhibition of glutamate processing with the pleiotropic GLUD-inhibitor epigallocatechin-3-gallate (EGCG) would not only hamper D-2-HG production, but also decrease NAD(P)H and ?-KG synthesis in IDH mut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy.Methods
We performed 13C-tracing studies to show that HCT116 colorectal cancer cells with an IDH1 R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D-2-HG. We treated HCT116 cells, HCT116-IDH1 R132H cells, and HT1080 cells (carrying an IDH1 R132C mutation) with EGCG and evaluated D-2-HG production, cell proliferation rates, and sensitivity to radiotherapy.Results
Significant amounts of 13C from glutamate accumulate in D-2-HG in HCT116-IDH1 wt/R132H but not in HCT116-IDH1 wt/wt . Preventing glutamate processing in HCT116-IDH1 wt/R132H cells with EGCG resulted in reduction of D-2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1 mut cells and at high doses sensitized cancer cells to ionizing radiation. Effects of EGCG in IDH-mutated cell lines were diminished by treatment with the IDH1mut inhibitor AGI-5198.Conclusions
This work shows that glutamate can be directly processed into D-2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for IDH mut cancers.
SUBMITTER: Peeters TH
PROVIDER: S-EPMC6526618 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
<i>Isocitrate dehydrogenase 1</i>-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate.
Cancer & metabolism 20190520
<h4>Background</h4>Mutations in isocitrate dehydrogenase 1 (<i>IDH1</i>) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of <i>D</i>-2-hydroxyglutarate (<i>D-</i>2-HG) at the expense of α-ketoglutarate (α-KG) and NADPH. To overcome metabolic stress induced by these alterations, <i>IDH</i>-mutated (<i>IDH</i> <sup><i>mut</i></sup> ) cancers utilize rescue mechanisms comprising pathways in which glutaminase and glutama ...[more]
