Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate

Cancer & Metabolism

Arno van Rooij¹  Ron Wevers¹  Paul N. Span²  Sanne A. M. van Lith³  Arend Heerschap³  Tom H. Peeters³  Vincent Breukels³  Remco Molenaar⁴  Krissie Lenting⁵  Corina N. A. M. van den Heuvel⁵  William P. J. Leenders⁵ 

[1] 0000 0004 0444 9382, grid.10417.33, Department of Laboratory Medicine, Radboud university medical center, PO Box 9101, 6500, Nijmegen, HB, The Netherlands;0000 0004 0444 9382, grid.10417.33, Department of Radiation Oncology, Radiotherapy and OncoImmunology Laboratory, Radboud university medical center, PO Box 9101, 6500, Nijmegen, HB, The Netherlands;0000 0004 0444 9382, grid.10417.33, Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, 6500, Nijmegen, HB, The Netherlands;0000000404654431, grid.5650.6, Department of Medical Biology, Cancer Center Amsterdam at the Academic Medical Center, Meibergdreef 15, 1105, Amsterdam, AZ, The Netherlands;grid.461760.2, Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 26, 6525, Nijmegen, GA, The Netherlands;

关键词: IDH mutations;    Metabolism;    EGCG;    Radiotherapy;    Glutamate;   

DOI  :  10.1186/s40170-019-0198-7

来源: publisher

【 摘 要 】

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 α-ketoglutarate (α-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 α-KG synthesis in IDHmut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy.MethodsWe performed 13C-tracing studies to show that HCT116 colorectal cancer cells with an IDH1R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D-2-HG. We treated HCT116 cells, HCT116-IDH1R132H cells, and HT1080 cells (carrying an IDH1R132C mutation) with EGCG and evaluated D-2-HG production, cell proliferation rates, and sensitivity to radiotherapy.ResultsSignificant amounts of 13C from glutamate accumulate in D-2-HG in HCT116-IDH1wt/R132H but not in HCT116-IDH1wt/wt. Preventing glutamate processing in HCT116-IDH1wt/R132H cells with EGCG resulted in reduction of D-2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1mut 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.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.

【 授权许可】

CC BY