DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE
    • Publication Information:
      Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]-
    • Subject Terms:
      Cell Proliferation* ; Citric Acid Cycle*; Acyltransferases/*metabolism ; Glutamine/*metabolism ; Triple Negative Breast Neoplasms/*enzymology; Cell Cycle ; Cell Line, Tumor ; Humans ; Metabolomics
    • Abstract:
      Triple-negative breast cancer (TNBC) is traditionally considered a glycolytic tumor with a poor prognosis while lacking targeted therapies. Here we show that high expression of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, predicts poor overall and recurrence-free survival among TNBC patients. DLST depletion suppresses growth and induces death in subsets of human TNBC cell lines, which are capable of utilizing glutamine anaplerosis. Metabolomics profiling reveals significant changes in the TCA cycle and reactive oxygen species (ROS) related pathways for sensitive but not resistant TNBC cells. Consequently, DLST depletion in sensitive TNBC cells increases ROS levels while N-acetyl-L-cysteine partially rescues cell growth. Importantly, suppression of the TCA cycle through DLST depletion or CPI-613, a drug currently in clinical trials for treating other cancers, decreases the burden and invasion of these TNBC. Together, our data demonstrate differential TCA-cycle usage in TNBC and provide therapeutic implications for the DLST-dependent subsets.
      (© 2021. The Author(s).)
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    • Grant Information:
      R01 CA224550 United States CA NCI NIH HHS; K99 CA134743 United States CA NCI NIH HHS; R56 CA215059 United States CA NCI NIH HHS; T32 HL007501 United States HL NHLBI NIH HHS; R01 CA129536 United States CA NCI NIH HHS; R00 CA134743 United States CA NCI NIH HHS; R01 CA232246 United States CA NCI NIH HHS; R01 CA215059 United States CA NCI NIH HHS
    • Accession Number:
      0RH81L854J (Glutamine)
      EC 2.3.- (Acyltransferases)
      EC 2.3.1.61 (dihydrolipoamide succinyltransferase)
    • Publication Date:
      Date Created: 20211117 Date Completed: 20211220 Latest Revision: 20220716
    • Publication Date:
      20240829
    • Accession Number:
      PMC8595664
    • Accession Number:
      10.1038/s42003-021-02805-8
    • Accession Number:
      34785772