Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer
Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer
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DOI：
10.7554/elife.28083
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发表时间：
2017-10-02
期刊：
影响因子：
7.7
通讯作者：
Papagiannakopoulos, Thales
中科院分区：
文献类型：
--
作者：
Sayin, Volkan I.;LeBoeuf, Sarah E.;Papagiannakopoulos, Thales
在肿瘤发生过程中，癌细胞的高代谢需求导致活性氧的产生增加。为了维持氧化稳态，肿瘤细胞通过过度激活NRF 2途径增加抗氧化剂的产生，从而促进肿瘤细胞生长。尽管NRF 2驱动的代谢重新布线的广泛表征，很少有人知道这种重新编程产生的代谢负债。在这里，我们表明，在小鼠或人癌细胞中，NRF 2的激活，导致增加对外源性谷氨酰胺的依赖性，通过增加消耗谷氨酸的谷胱甘肽合成和谷氨酸分泌的x（c）（-）反向转运蛋白系统。总之，这限制了三羧酸循环和其他生物合成反应的谷氨酸盐可用性，从而产生代谢瓶颈。具有NRF 2抗氧化剂途径的遗传或药理学激活的癌症在支持增加的抗氧化能力与中心碳代谢之间具有代谢失衡，这可以在治疗上加以利用。
During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by x(c)(-) antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.