期刊
MOLECULAR CANCER RESEARCH
卷 19, 期 8, 页码 1375-1388出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-20-0086
关键词
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资金
- National Institute for Neurological Disorders and Stroke (NIH) [NS 048959]
- FasterCures, a center of the Milken Institute
ASNS gene is copy-number amplified in most glioblastomas, associated with decreased survival. ASNS overexpression leads to metabolic alterations, enhancing cell proliferation, spread, and resistance to stress. This metabolic vulnerability could be therapeutically exploited.
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 (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, 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 that led to radiotherapy 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.
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