Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity

Like Many cancer 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-rcactive metabolic enzymes that are upregulated in primary human colorectal tumors,:We identified argininosuccinate synthase 1 (ASS 1) as an upregnlated 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 cancel. through Compromising critical metabolic and metabolite signaling pat ways and demonstrate the Utility of coupling chemoproteomic and metabolomic strategies to map novel metabolic regulators of cancer.