Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity,ACS Chemical Biology

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Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-03-01 00:00:00 , DOI: 10.1021/acschembio.6b01158
Leslie A. Bateman ₁ , Wan-Min Ku , Martin J. Heslin ₂ , Carlo M. Contreras ₂ , Christine F. Skibola ₂ , Daniel K. Nomura ₁

Affiliation

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.

中文翻译：

精氨酸琥珀酸合酶1是结肠直肠癌致病性的代谢调节剂。

像许多类型的癌症一样，大肠癌的新陈代谢失调会促进其致病特征。在这项研究中，我们使用基于活动的蛋白谱化学旋转平台来分析在人类原发性结肠直肠肿瘤中上调的半胱氨酸反应性代谢酶。我们确定精氨酸琥珀酸酯合酶1（ASS1）作为原发性人类结直肠肿瘤中的上调目标，并表明药理学抑制或ASS1的遗传消融损害结直肠癌的致病性。使用代谢组学分析，我们显示出ASS1抑制导致致癌代谢产物富马酸盐水平降低，从而导致支持大肠癌细胞致病性的糖酵解代谢受损。

更新日期：2017-03-01

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