title: Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity.
abstract: Like many cancer types, colorectal cancers have dysregulated metabolism that promotes their pathogenic features. In this study, we used the activity-based protein profiling chemoproteomic platform to profile cysteine-reactive metabolic enzymes that are upregulated in primary human colorectal tumors. We identified argininosuccinate synthase 1 (ASS1) as an upregulated target in primary human colorectal tumors and show that pharmacological inhibition or genetic ablation of ASS1 impairs colorectal cancer pathogenicity. Using metabolomic profiling, we show that ASS1 inhibition leads to reductions in the levels of oncogenic metabolite fumarate, leading to impairments in glycolytic metabolism that supports colorectal cancer cell pathogenicity. We show here that ASS1 inhibitors may represent a novel therapeutic approach for attenuating colorectal cancer through compromising critical metabolic and metabolite signaling pathways and demonstrate the utility of coupling chemoproteomic and metabolomic strategies to map novel metabolic regulators of cancer.
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bateman
authors.forename: Wan-Min
authors.initials: WM
authors.lastname: Ku
authors.affiliation: The University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Heslin
authors.affiliation: The University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Contreras
authors.affiliation: The University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Christine F
authors.initials: CF
authors.lastname: Skibola
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Daniel K
authors.identifier: 0000-0003-1614-8360
authors.initials: DK
authors.lastname: Nomura
mesh_terms: D001124:Argininosuccinate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D055442:Metabolome; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D001124:Argininosuccinate Synthase