AI Article Synopsis
- - Sirtuin 3 (SIRT3) is an enzyme that helps regulate metabolism, and its levels decrease with age and in various diseases, including cancer and neurodegeneration.
- - Researchers identified a compound called azaserine that specifically inhibits the growth of cells lacking SIRT3, revealing a unique metabolic weakness in these cells.
- - The study found that cells without SIRT3 rerouted glutamine to produce nucleotides faster, driven by increased mTORC1 activity, and restoring SIRT3 levels slowed down this process, highlighting its potential as a target for cancer treatment.
Article 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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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902027 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2018.01.076 | DOI Listing |
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