Elevated Asparagine Biosynthesis Drives Brain Tumor Stem Cell Metabolic Plasticity and Resistance to Oxidative Stress.
Elevated Asparagine Biosynthesis Drives Brain Tumor Stem Cell Metabolic Plasticity and Resistance to Oxidative Stress.
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DOI：
10.1158/1541-7786.mcr-20-0086
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Yu JS
中科院分区：
文献类型：
--
作者：
Thomas TM;Miyaguchi K;Edwards LA;Wang H;Wollebo H;Aiguo L;Murali R;Wang Y;Braas D;Michael JS;Andres AM;Zhang M;Khalili K;Gottlieb RA;Perez JM;Yu JS
天冬酰胺合成酶（ASNS）是位于7号染色体长臂上的基因，在大多数胶质母细胞瘤中拷贝数扩增。ASNS拷贝数扩增与生存率显著降低相关。使用患者来源的胶质瘤干细胞（GSCs），我们发现当干扰天冬酰胺合成酶的表达时，胶质瘤中会发生显著的代谢改变，这不仅仅局限于氨基酸稳态。高asns的GSCs维持较慢的基础代谢谱，但在需要时，容易转变为大大增加的糖酵解和氧化磷酸化能力。这使得高asn的细胞具有更强的增殖和向脑组织扩散的能力。最后，我们证明，这些变化赋予抵抗细胞应激，特别是氧化应激，通过适应性氧化还原稳态导致辐射抗性。此外，ASNS过表达导致单碳代谢的改变，以促进更抗氧化的肿瘤环境，揭示可能用于治疗的代谢脆弱性。
Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy number amplified in the majority of glioblastomas. ASNS copy number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSCs), we showed significant metabolic alterations occur in gliomas when perturbing the expression of asparagine synthetase, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis which led to radiation resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited.
影响因子：
50.3
作者：
Fine HA
通讯作者：
Fine HA