Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity

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.