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

Ning Shen, Sovannarith Korm, Theodoros Karantanos, Dun Li, Xiaoyu Zhang, Eleni Ritou, Hanfei Xu, Andrew Lam, Justin English, Wei Xing Zong, Ching Ti Liu, Orian Shirihai, Hui Feng

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Article number1289
JournalCommunications Biology
Volume4
Issue number1
DOIs
StatePublished - 1 Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Agricultural and Biological Sciences (all)

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