Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3.
Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3.
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DOI：
10.1016/j.celrep.2018.01.076
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发表时间：
2018-02-20
期刊：
影响因子：
8.8
通讯作者：
Haigis MC
中科院分区：
文献类型：
--
作者：
Gonzalez Herrera KN;Zaganjor E;Ishikawa Y;Spinelli JB;Yoon H;Lin JR;Satterstrom FK;Ringel A;Mulei S;Souza A;Gorham JM;Benson CC;Seidman JG;Sorger PK;Clish CB;Haigis MC
Sirtuin 3(SIRT3)是一种依赖NAD+的脱乙酰酶，在衰老和与衰老相关的疾病(如癌症和神经退行性变)以及高脂饮食(HFD)诱导的代谢紊乱中下调。在这里，我们进行了小分子筛查，发现了一种与SIRT3缺失相关的意想不到的代谢脆弱性。Azaserine是一种谷氨酰胺类似物，是抑制缺乏SIRT3的细胞生长和增殖的顶级化合物。利用谷氨酰胺的稳定同位素示踪，我们观察到在SIRT3基因敲除(KO)细胞中谷氨酰胺掺入到从头合成核苷酸中的增加。此外，我们发现SIRT3KO细胞通过过度活跃的mTORC1信号上调谷氨酰胺向从头合成核苷酸的转移。在乳腺癌异种移植瘤模型中，过表达SIRT3抑制了mTORC1和体内生长。因此，我们通过使用无偏见的小分子筛查发现了SIRT3缺失细胞的代谢脆弱性。SIRT3在许多病理过程中丢失或下调。SIRT3的缺失会导致细胞增殖增加。Gonzalez Herrera等人。确认谷氨酰胺掺入核苷酸是缺乏SIRT3的细胞增殖增加的驱动力。
Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells. Furthermore, we found that SIRT3 KO cells upregulated the diversion of glutamine into de novo nucleotide synthesis through hyperactive mTORC1 signaling. Overexpression of SIRT3 suppressed mTORC1 and growth in vivo in a xenograft tumor model of breast cancer. Thus, we have uncovered a metabolic vulnerability of cells with SIRT3 loss by using an unbiased small-molecule screen. SIRT3 is lost or downregulated in numerous pathologies. Loss of SIRT3 results in increased cell proliferation. Gonzalez Herrera et al. identify glutamine incorporation into nucleotides to be a driving force behind increased proliferation of cells lacking SIRT3.