Journal
CANCER & METABOLISM
Volume 7, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s40170-019-0198-7
Keywords
IDH mutations; Metabolism; EGCG; Radiotherapy; Glutamate
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Funding
- Dutch Cancer Society [UvA 2014-6839]
- EFRO/GO project Ultrasense NMR
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BackgroundMutations 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 (IDHmut) 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 IDHmut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy.MethodsWe performed C-13-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.ResultsSignificant amounts of C-13 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 IDH1(mut) inhibitor AGI-5198.ConclusionsThis 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 IDHmut cancers.
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