GCLM公司
谷胱甘肽
GCLC公司
IDH1
异柠檬酸脱氢酶
癌症研究
胶质瘤
生物
突变体
生物化学
基因
酶
作者
Yang Liu,Yanxin Lu,Orieta Celiku,Aiguo Li,Chunzhang Yang
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2019-11-01
卷期号:21 (Supplement_6): vi83-vi83
标识
DOI:10.1093/neuonc/noz175.338
摘要
Abstract BACKGROUND Mutations in isocitrate dehydrogenase (IDH1/2) are frequent genetic abnormalities in human malignancies. IDH1/2-mutated cancers are a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism and resistance to therapy. Molecular targeting approaches against this disease cluster remain limited. METHODS We investigated the redox homeostasis in IDH1 mutant-transduced cells and patient-derived brain tumor initiating cells. The importance of antioxidant genes was confirmed through COX regression analysis on a large cohort of lower grade glioma. We investigated the biologic impact of Nuclear factor erythroid 2-related factor 2 (NRF2) on the glutathione de novo synthesis in IDH1-mutated cells. Finally, we evaluated the value of targeting NRF2/glutathione metabolic pathway as a potential synthetic lethality approach for IDH1-mutated cell in vitro and in vivo. RESULTS We discovered that acquisition of cancer-associated IDH1 mutants results in constitutive activation of NRF2-governed cytoprotective pathways through decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM and SLC7A11, which strengthens the glutathione de novo synthesis, and relieves the metabolic burden derived from IDH1 mutant neomorphic activity. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic reactive oxygen species, which results in overwhelming oxidative damage in IDH1-mutated cells, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION Our findings suggest that blockade of the NRF2/glutathione synthetic pathway is a novel targeting strategy for IDH1-mutated malignancies.
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