Glutathione biosynthesis is upregulated at the initiation of MYCN-driven neuroblastoma tumorigenesis

被引:20
作者
Carter, Daniel R. [1 ,2 ]
Sutton, Selina K. [1 ]
Pajic, Marina [3 ,4 ]
Murray, Jayne [1 ]
Sekyere, Eric O. [5 ]
Fletcher, Jamie [1 ]
Beckers, Anneleen [6 ]
De Preter, Katleen [6 ]
Speleman, Frank [6 ]
George, Rani E. [7 ,8 ]
Haber, Michelle [1 ]
Norris, Murray D. [1 ,9 ]
Cheung, Belamy B. [1 ,2 ]
Marshall, Glenn M. [1 ,10 ]
机构
[1] Univ New S Wales, Lowy Canc Res Ctr, Childrens Canc Inst, Randwick, NSW 2031, Australia
[2] UNSW Australia, Sch Womens & Childrens Hlth, Randwick, NSW 2031, Australia
[3] Univ New S Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St, Sydney, NSW 2010, Australia
[4] Univ New S Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW 2010, Australia
[5] Endeavour Coll Nat Hlth, Sydney, NSW 2000, Australia
[6] Univ Ghent, Ctr Med Genet CMGG, Med Res Bldg MRB1,De Pintelaan 185, B-9000 Ghent, Belgium
[7] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Hematol & Oncol, Boston, MA USA
[8] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA
[9] Univ New S Wales, Ctr Childhood Canc Res, Randwick, NSW 2031, Australia
[10] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW 2031, Australia
基金
澳大利亚国家健康与医学研究理事会;
关键词
Neuroblastoma; MYCN; Glutathione; Metabolomics; Tumorigenesis; BSO; MULTIDRUG-RESISTANCE; N-MYC; EXPRESSION; AMPLIFICATION; METABOLISM; PROTEIN; GENES; CELLS; PHOSPHORYLATION; TRANSCRIPTION;
D O I
10.1016/j.molonc.2016.02.004
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The MYCN gene is amplified and overexpressed in a large proportion of high stage neuroblastoma patients and has been identified as a key driver of tumorigenesis. However, the mechanism by which MYCN promotes tumor initiation is poorly understood. Here we conducted metabolic profiling of pre-malignant sympathetic ganglia and tumors derived from the TH-MYCN mouse model of neuroblastoma, compared to non-malignant ganglia from wildtype littermates. We found that metabolites involved in the biosynthesis of glutathione, the most abundant cellular antioxidant, were the most significantly upregulated metabolic pathway at tumor initiation, and progressively increased to meet the demands of tumorigenesis. A corresponding increase in the expression of genes involved in ribosomal biogenesis suggested that MYCN-driven transactivation of the protein biosynthetic machinery generated the necessary substrates to drive glutathione biosynthesis. Pre-malignant sympathetic ganglia from TH-MYCN mice had higher antioxidant capacity and required glutathione upregulation for cell survival, when compared to wildtype ganglia. Moreover, in vivo administration of inhibitors of glutathione biosynthesis significantly delayed tumorigenesis when administered prophylactically and potentiated the anticancer activity of cytotoxic chemotherapy against established tumors. Together these results identify enhanced glutathione biosynthesis as a selective metabolic adaptation required for initiation of MYCN-driven neuroblastoma, and suggest that glutathione-targeted agents may be used as a potential preventative strategy, or as an adjuvant to existing chemotherapies in established disease. Crown Copyright (C) 2016 Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. All rights reserved.
引用
收藏
页码:866 / 878
页数:13
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