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Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3.
Cell Reports ( IF 7.5 ) Pub Date : 2018-Feb-20 , DOI: 10.1016/j.celrep.2018.01.076
Karina N Gonzalez Herrera 1 , Elma Zaganjor 1 , Yoshinori Ishikawa 2 , Jessica B Spinelli 1 , Haejin Yoon 1 , Jia-Ren Lin 3 , F Kyle Satterstrom 4 , Alison Ringel 1 , Stacy Mulei 2 , Amanda Souza 5 , Joshua M Gorham 6 , Craig C Benson 7 , Jonathan G Seidman 6 , Peter K Sorger 3 , Clary B Clish 5 , Marcia C Haigis 1
Cell Reports ( IF 7.5 ) Pub Date : 2018-Feb-20 , DOI: 10.1016/j.celrep.2018.01.076
Karina N Gonzalez Herrera 1 , Elma Zaganjor 1 , Yoshinori Ishikawa 2 , Jessica B Spinelli 1 , Haejin Yoon 1 , Jia-Ren Lin 3 , F Kyle Satterstrom 4 , Alison Ringel 1 , Stacy Mulei 2 , Amanda Souza 5 , Joshua M Gorham 6 , Craig C Benson 7 , Jonathan G Seidman 6 , Peter K Sorger 3 , Clary B Clish 5 , Marcia C Haigis 1
Affiliation
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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.
中文翻译：
小分子筛查表明从头合成核苷酸是缺乏SIRT3的细胞的脆弱性。
Sirtuin 3（SIRT3）是一种NAD +依赖性脱乙酰基酶，在衰老和与年龄相关的疾病（如癌症和神经退行性疾病）以及高脂饮食（HFD）引起的代谢紊乱中被下调。在这里，我们进行了一个小分子筛查，并发现了与SIRT3丢失相关的意外代谢脆弱性。谷氨酰胺类似物Azaserine是抑制缺少SIRT3的细胞生长和增殖的顶级化合物。使用谷氨酰胺的稳定同位素示踪，我们观察到其在SIRT3基因敲除（KO）细胞中从头合成核苷酸的掺入增加。此外，我们发现SIRT3 KO细胞通过高活性的mTORC1信号传导上调了谷氨酰胺向新生核苷酸合成的转移。SIRT3的过表达抑制了乳腺癌异种移植肿瘤模型中的mTORC1和体内生长。因此，
更新日期：2018-02-25
中文翻译：
小分子筛查表明从头合成核苷酸是缺乏SIRT3的细胞的脆弱性。
Sirtuin 3（SIRT3）是一种NAD +依赖性脱乙酰基酶，在衰老和与年龄相关的疾病（如癌症和神经退行性疾病）以及高脂饮食（HFD）引起的代谢紊乱中被下调。在这里，我们进行了一个小分子筛查，并发现了与SIRT3丢失相关的意外代谢脆弱性。谷氨酰胺类似物Azaserine是抑制缺少SIRT3的细胞生长和增殖的顶级化合物。使用谷氨酰胺的稳定同位素示踪，我们观察到其在SIRT3基因敲除（KO）细胞中从头合成核苷酸的掺入增加。此外，我们发现SIRT3 KO细胞通过高活性的mTORC1信号传导上调了谷氨酰胺向新生核苷酸合成的转移。SIRT3的过表达抑制了乳腺癌异种移植肿瘤模型中的mTORC1和体内生长。因此，
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