Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3
0301 basic medicine
570
QH301-705.5
Glutamine
610
Mice, Nude
Breast Neoplasms
nucleotide synthesis
Mechanistic Target of Rapamycin Complex 1
Article
SIRT3
Small Molecule Libraries
03 medical and health sciences
Cell Line, Tumor
Sirtuin 3
616
Animals
Amino Acid Sequence
Biology (General)
Promoter Regions, Genetic
mTORC1
Azaserine
Cell Proliferation
Mice, Knockout
Nucleotides
Fibroblasts
Up-Regulation
3. Good health
mitochondria
sirtuin
glutamine
Female
Signal Transduction
DOI:
10.1016/j.celrep.2018.01.076
Publication Date:
2018-02-23T15:43:50Z
AUTHORS (16)
ABSTRACT
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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CITATIONS (33)
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