结直肠癌
代谢组学
癌症研究
生物
下调和上调
代谢物
精氨琥珀酸合成酶
癌症
生物信息学
生物化学
遗传学
基因
精氨酸
精氨酸酶
氨基酸
作者
Leslie A. Bateman,Wan-min Ku,Martin J. Heslin,Carlo M. Contreras,Christine F. Skibola,Daniel K. Nomura
标识
DOI:10.1021/acschembio.6b01158
摘要
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.
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