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
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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