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

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

  • Commun Biol. 2021 Nov 16;4(1):1289. doi: 10.1038/s42003-021-02805-8.
Ning Shen  # 1 2,  Sovannarith Korm  # 1,  Theodoros Karantanos 2 3,  Dun Li 1 2,  Xiaoyu Zhang 4,  Eleni Ritou 5,  Hanfei Xu 4,  Andrew Lam 1,  Justin English 1,  Wei-Xing Zong 6,  Ching-Ti Liu 4,  Orian Shirihai 5,  Hui Feng 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
  • 2 Department of Medicine, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
  • 3 Department of Medical Oncology, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
  • 4 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • 5 Department of Medicine, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • 6 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
  • 7 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA. [email protected].
  • 8 Department of Medicine, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 34785772 DOI: 10.1038/s42003-021-02805-8
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.

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