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MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer
Anderton, Brittany1,2; Camarda, Roman1,2; Balakrishnan, Sanjeev1,2; Balakrishnan, Asha1,2,3; Kohnz, Rebecca A.4; Lim, Lionel1,2; Evason, Kimberley J.5,6; Momcilovic, Olga1,2; Kruttwig, Klaus1,2; Huang, Qiang7; Xu, Guowang7; Nomura, Daniel K.4; Goga, Andrei1,2
关键词Cancer Glutathione Metabolism Mirna Myc
刊名EMBO REPORTS
2017-04-01
DOI10.15252/embr.201643068
18页:569-585
收录类别SCI
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine
类目[WOS]Biochemistry & Molecular Biology ; Cell Biology
研究领域[WOS]Biochemistry & Molecular Biology ; Cell Biology
关键词[WOS]GENE-EXPRESSION SIGNATURE ; C-MYC ; HEPATOCELLULAR-CARCINOMA ; OXIDATIVE STRESS ; HUMAN HEPATOCARCINOGENESIS ; METABOLISM ; CELLS ; TUMORS ; PROGRESSION ; PROTEIN
英文摘要How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacylt-RNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors. We find that fewer glutamine-derived carbons are incorporated into GSH in tumor tissue relative to non-tumor tissue. Expression of GCLC, the rate-limiting enzyme of GSH synthesis, is attenuated by the MYC-induced microRNA miR-18a. Inhibition of miR-18a in vivo leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC-driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC-dependent attenuation of GCLC by miR-18a contributes to GSH depletion in vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine.
语种英语
WOS记录号WOS:000399327500011
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文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/152327
专题中国科学院大连化学物理研究所
作者单位1.Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA
2.Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
3.Hannover Med Sch, TWINCORE, Ctr Expt & Clin Infect Res, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany
4.Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA
5.Univ Utah, Dept Pathol, Salt Lake City, UT USA
6.Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA
7.Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, Dalian, Peoples R China
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Anderton, Brittany,Camarda, Roman,Balakrishnan, Sanjeev,et al. MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer[J]. EMBO REPORTS,2017,18:569-585.
APA Anderton, Brittany.,Camarda, Roman.,Balakrishnan, Sanjeev.,Balakrishnan, Asha.,Kohnz, Rebecca A..,...&Goga, Andrei.(2017).MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer.EMBO REPORTS,18,569-585.
MLA Anderton, Brittany,et al."MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer".EMBO REPORTS 18(2017):569-585.
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