Journal
CELL REPORTS
Volume 22, Issue 8, Pages 1945-1955Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.01.076
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Funding
- NIH from the National Cancer Institute (NCI) [R01CA213062]
- Ludwig Center at Harvard
- Glenn Foundation for Medical Research
- Takeda Pharmaceutical Company Limited [A19659]
- NIH pre-doctoral training fellowship [F31CA183575]
- NIH from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK103295]
- Paul AMP
- Daisy Soros Fellowship for New Americans
- American Heart Association [15POST25560077]
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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.
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