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Title: DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer
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.  more » « less
Award ID(s):
1911253
NSF-PAR ID:
10341691
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ;
Date Published:
Journal Name:
Communications Biology
Volume:
4
Issue:
1
ISSN:
2399-3642
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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