Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion.
Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion.
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DOI：
10.1016/j.molcel.2014.08.018
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发表时间：
2014-10-23
期刊：
影响因子：
16
通讯作者：
Thompson, Craig B.
中科院分区：
文献类型：
--
作者：
Zhang, Ji;Fan, Jing;Venneti, Sriram;Cross, Justin R.;Takagi, Toshimitsu;Bhinder, Bhavneet;Djaballah, Hakim;Kanai, Masayuki;Cheng, Emily H.;Judkins, Alexander R.;Pawel, Bruce;Baggs, Julie;Cherry, Sara;Rabinowitz, Joshua D.;Thompson, Craig B.
许多癌细胞消耗大量的谷氨酰胺来维持 TCA 循环回补并支持细胞存活。因此，当 RNAi 筛选揭示抑制柠檬酸合酶 (CS)（第一个 TCA 循环酶）可防止谷氨酰胺撤除诱导的细胞凋亡时，令人感到惊讶。 CS 抑制降低了 TCA 循环活性，并将 CS 的底物草酰乙酸转化为非必需氨基酸天冬氨酸和天冬酰胺的生产。我们发现天冬酰胺对于抑制谷氨酰胺撤药诱导的细胞凋亡是必要且充分的，而不恢复其他非必需氨基酸或 TCA 循环中间体的水平。在完全培养基中，当谷氨酰胺依赖性天冬酰胺合成受到抑制时，表现出高谷氨酰胺消耗率的肿瘤细胞会快速凋亡，并且天冬酰胺合成酶的表达与人类肿瘤的不良预后存在统计学相关性。加上L-天冬酰胺酶成功治疗儿童白血病，数据表明细胞内天冬酰胺是许多人类肿瘤细胞凋亡的关键抑制剂。
Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.
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影响因子：
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