Cysteine Catabolism: A Novel Metabolic Pathway Contributing to Glioblastoma Growth

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 3; pp. 787 - 796
• Main Authors: Prabhu, Antony, Sarcar, Bhaswati, Kahali, Soumen, Yuan, Zhigang, Johnson, Joseph J., Adam, Klaus-Peter, Kensicki, Elizabeth, Chinnaiyan, Prakash
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2014
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; Cysteine - analogs & derivatives; Cysteine - metabolism; Cysteine - pharmacology; Cysteine Dioxygenase - antagonists & inhibitors; Cysteine Dioxygenase - genetics; Cysteine Dioxygenase - metabolism; Disease Models, Animal; Enzyme Activation - drug effects; Gene Expression; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Medical sciences; Metabolic Networks and Pathways; Mice; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Grading; Neurology; Pharmacology. Drug treatments; Pyruvate Dehydrogenase Complex - metabolism; Tumor Burden - drug effects; Tumor Burden - genetics; Tumors; Tumors of the nervous system. Phacomatoses; Sulfur containing aminoacid; Malignant glioma; Nervous system diseases; Thiol; Cysteine; Growth; Central nervous system disease; Glioblastoma; Catabolism; Metabolic pathway; Malignant tumor; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-1423

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. Cancer Res; 74(3); 787–96. ©2013 AACR.