Abstract
The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Through metabolomic profiling using a combination of high-throughput liquid and gas chromatography–based mass spectrometry on a total of 69 patient-derived glioma specimens, this report documents the discovery of a parallel pathway involving cysteine catabolism that results in the accumulation of cysteine sulfinic acid (CSA) in glioblastoma. These studies identified CSA to rank as one of the top metabolites differentiating glioblastoma from low-grade glioma. There was strong intratumoral concordance of CSA levels with expression of its biosynthetic enzyme cysteine dioxygenase 1 (CDO1). Studies designed to determine the biologic consequence of this metabolic pathway identified its capacity to inhibit oxidative phosphorylation in glioblastoma cells, which was determined by decreased cellular respiration, decreased ATP production, and increased mitochondrial membrane potential following pathway activation. CSA-induced attenuation of oxidative phosphorylation was attributed to inhibition of the regulatory enzyme pyruvate dehydrogenase. Studies performed in vivo abrogating the CDO1/CSA axis using a lentiviral-mediated short hairpin RNA approach resulted in significant tumor growth inhibition in a glioblastoma mouse model, supporting the potential for this metabolic pathway to serve as a therapeutic target. Collectively, we identified a novel, targetable metabolic pathway involving cysteine catabolism contributing to the growth of aggressive high-grade gliomas. These findings serve as a framework for future investigations designed to more comprehensively determine the clinical application of this metabolic pathway and its contributory role in tumorigenesis.
Highlights
Gliomas represent a common type of primary brain tumor that arises from glial cells in the brain, which includes astrocytes, oligodendrocytes, and ependymal cells
A comprehensive study of glioma metabolism was recently performed using global metabolomic profiling on patient-derived tumors. These investigations identified unique metabolic subtypes in glioma, with the metabolic signature of glioblastoma being consistent with anabolic metabolism [9]. Through this line of investigation, we identified the metabolic intermediate of cystine catabolism cysteine sulfinic acid (CSA) as a novel metabolite associated with glioblastoma, demonstrating a more than 23-fold increase in accumulation when compared with grade 2 glioma
Both GSH and hypotaurine demonstrated significant differences between glioma grade, which were 3.2- (P = 0.01) and 6.63-fold (P < 0.001) higher in glioblastoma, respectively. These studies identified a more than 23-fold increase in CSA levels in glioblastoma when compared with grade 2 glioma (P < 0.001), which ranked as the metabolite with the highest relative accumulation in glioblastoma when compared with grade 2 glioma (Fig. 1A and B)
Summary
Gliomas represent a common type of primary brain tumor that arises from glial cells in the brain, which includes astrocytes, oligodendrocytes, and ependymal cells. Common molecular alterations identified in low-grade oligodendrogliomas and astrocytomas are allelic loss of 1p and 19q and mutations in p53, respectively, whereas grade 3 and 4 astrocytomas typically are driven by alterations in phosphoinositide 3-kinase (PI3K), EGFR, VEGF, and PTEN signaling [2]. Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) have been identified in low-grade glioma and secondary glioblastoma, which were discovered to form the oncometabolite 2-hydroxyglutarate (2-HG) that demonstrated the capacity to regulate global epigenetic programs in these tumors [3,4,5]
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