Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis.
Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis.
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DOI：
10.1038/nature15529
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发表时间：
2015-11-19
期刊：
影响因子：
64.8
通讯作者：
Erez A
中科院分区：
文献类型：
--
作者：
Rabinovich S;Adler L;Yizhak K;Sarver A;Silberman A;Agron S;Stettner N;Sun Q;Brandis A;Helbling D;Korman S;Itzkovitz S;Dimmock D;Ulitsky I;Nagamani SC;Ruppin E;Erez A
癌细胞劫持和重塑现有的代谢途径，以使其受益。精氨琥珀酸合成酶（ASS1）是一种尿素循环酶，其在氮从氨和天冬氨酸到尿素的转化中是必需的。通过肝脏中ASS 1的氮通量减少会导致尿素循环障碍瓜氨酸血症。与ASS1活性丧失对尿素生成的充分研究结果相反，其在多种癌症中的体细胞沉默的目的在很大程度上是未知的。在这里，我们表明，降低活性的ASS 1在癌症中支持增殖，促进嘧啶合成通过CAD（氨甲酰磷酸合酶2，天冬氨酸转氨甲酰酶，和二氢乳清酸酶复合物）激活。我们的研究是通过描述患有两种瓜氨酸血症的人类中ASS 1活性丧失的后果而开始的。我们发现，在瓜氨酸血症I型（CTLN I），这是由于缺乏的ASS 1，有增加的嘧啶合成和增殖相比，瓜氨酸血症II型（CTLN II），其中有减少的底物可用性的ASS 1引起的天冬氨酸转运蛋白的缺乏。在这些结果的基础上，我们证明了癌症中的ASS 1缺陷增加了细胞溶质天冬氨酸水平，这通过上调其底物可用性和通过哺乳动物雷帕霉素靶（mTOR）途径增加S6K1的磷酸化来增加CAD活化。通过阻断柠檬酸蛋白、mTOR信号传导或嘧啶合成来降低CAD活性可降低增殖，因此可作为ASS 1下调的多种癌症的治疗策略。我们的研究结果表明，ASS 1下调是一种支持癌细胞增殖的新机制，它们提供了尿素循环酶和嘧啶合成之间的代谢联系。
Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers whereASS1is downregulated. Our results demonstrate thatASS1downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.