Elevated Asparagine Biosynthesis Drives Brain Tumor Stem Cell Metabolic Plasticity and Resistance to Oxidative Stress

Abstract

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.Implications: This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.

Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy

“…Asparagine can increase the synthesis of purine and pyrimidine by activating mTORC1 signaling when mitochondrial respiration is impaired, and promote tumor cell proliferation 121 . Elevated ASNS expression brought about antioxidative stress and rapid transformation between glycolysis and oxidative phosphorylation, leading to enhanced proliferation and radioresistance in tumor cells 122 .…”

A comparison of different machine-learning techniques for the selection of a panel of metabolites allowing early detection of brain tumors

“…The decrease in aspartate with glioma grade growth is due to the conversion of this AA to asparagine using asparagine synthetase. Asparagine, as Thomas et al 49 proposed, is a crucial factor in brain tumor growth under nutrient-deprived conditions. In parallel to AA metabolism, our study also highlighted the role of lipids in this disease.…”

Amino acid metabolism, redox balance and epigenetic regulation in cancer

“…Asparagine synthetase expression has been associated with poor prognosis in glioma and neuroblastoma. ASNS-high glioma stem cells (GSCs) have higher levels of GSH and a lower GSH:oxidized GSH ratio, which might indicate decreased GSH oxidation and protect GSCs from oxidative stress induced by radiotherapy [68]. PDAC cells also overexpress ASNS, leading to cisplatin-induced apoptosis resistance [69].…”