IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.
IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.
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DOI：
10.1096/fj.201800547r
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发表时间：
2018-06-07
期刊：
影响因子：
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通讯作者：
van Noorden CJF
中科院分区：
文献类型：
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作者：
Khurshed M;Aarnoudse N;Hulsbos R;Hira VVV;van Laarhoven HWM;Wilmink JW;Molenaar RJ;van Noorden CJF
异柠檬酸脱氢酶（IDH 1）-1在各种类型的人类癌症中发生突变，这种突变的存在与实体瘤细胞对放射和化疗的反应改善有关。例如，突变的IDH 1（IDH 1 MUT）酶消耗NADPH以产生d-2-羟基戊二酸（d-2 HG），导致活性氧（ROS）解毒所需的还原能力降低。本研究的目的是研究广泛使用的抗癌药物顺铂在IDH 1 MUT癌细胞中的化学敏感性背后的机制。在IDH 1 MUT HCT 116结肠直肠癌细胞和U251神经胶质瘤细胞中监测顺铂处理引起的氧化应激、DNA损伤和线粒体功能障碍。我们发现，与IDH 1野生型（IDH 1 WT）细胞相比，暴露于顺铂诱导IDH 1 MUT癌细胞中更高水平的ROS、DNA双链断裂（DSB）和细胞死亡。机制研究显示，顺铂处理剂量依赖性地减少IDH 1 MUT细胞中的氧化呼吸，这伴随着线粒体蛋白质稳态紊乱，表明线粒体活性受损。这些作用被IDH 1 MUT抑制剂AGI-5198消除，并通过d-2 HG治疗恢复。因此，我们的研究表明，改变的氧化应激反应和脆弱的氧化代谢是IDH 1 MUT癌细胞对顺铂敏感性的基础。Khurshed，M.，Aarnoudse，N.，赫尔斯博斯河希拉，V. V. V.，货车Laarhoven，H. W. M.，Wilmink，J. W.，莫勒纳尔河J.，货车诺登角J. F. IDH 1突变型癌细胞对顺铂敏感，IDH 1突变型抑制剂抵消了这种敏感性。
Isocitrate dehydrogenase (IDH1)-1 is mutated in various types of human cancer, and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells. Mutated IDH1 (IDH1MUT) enzymes consume NADPH to produce d-2-hydroxyglutarate (d-2HG) resulting in the decreased reducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current study was to investigate the mechanism behind the chemosensitivity of the widely used anticancer agent cisplatin in IDH1MUT cancer cells. Oxidative stress, DNA damage, and mitochondrial dysfunction caused by cisplatin treatment were monitored in IDH1MUT HCT116 colorectal cancer cells and U251 glioma cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double-strand breaks (DSBs), and cell death in IDH1MUT cancer cells, as compared with IDH1 wild-type (IDH1WT) cells. Mechanistic investigations revealed that cisplatin treatment dose dependently reduced oxidative respiration in IDH1MUT cells, which was accompanied by disturbed mitochondrial proteostasis, indicative of impaired mitochondrial activity. These effects were abolished by the IDH1MUT inhibitor AGI-5198 and were restored by treatment with d-2HG. Thus, our study shows that altered oxidative stress responses and a vulnerable oxidative metabolism underlie the sensitivity of IDH1MUT cancer cells to cisplatin.—Khurshed, M., Aarnoudse, N., Hulsbos, R., Hira, V. V. V., van Laarhoven, H. W. M., Wilmink, J. W., Molenaar, R. J., van Noorden, C. J. F. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.