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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. Shen and Korm et al. investigate the role of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, in the metabolic heterogeneity of triple negative breast cancer (TNBC) cell lines. They show that either depletion or inhibition of DLST in the dependent cells leads to decreased invasion and metastasis in vitro and in vivo.

SUBMITTER: Shen N

PROVIDER: S-EPMC8595664 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We recently established c-Abl as a potent suppressor of triple-negative breast cancer (TNBC) progression through its reactivation of a p53:p21 signaling axis coupled to senescence. Moreover, we observed co-expression of p53 and c-Abl to be essential for normal mammary epithelial cell physiology, as this relationship is lost upon breast cancer progression. Cytoplasmic c-Abl activity is markedly increased in some TNBCs and contributes to disease progression; however, the mechanisms underlying these events remain largely unknown. In addressing this question, we show here that c-Abl is predominantly restricted to the cytoplasm of human MDA-MB-231 TNBC cells, and to the nucleus of human MCF-7 luminal A cells. TTK is a mitotic protein kinase that phosphorylates c-Abl on Thr735, thereby creating a recognition binding motif for 14-3-3 adaptor proteins in response to oxidative stress. By interrogating the METABRIC database, we observed a significant correlation between p53 expression and that of c-Abl and TTK in basal-like breast cancers. Moreover, heterologous expression of TTK in MCF-7 cells significantly stimulated their growth in part via a c-Abl-dependent mechanism. Conversely, depleting TTK expression in MDA-MB-231 cells not only inhibited their organoid growth in 3D-cultures, but also sensitized them to the tumor suppressing activities of c-Abl independent of its subcellular localization. Moreover, we show that mutant p53 forms cytoplasmic complexes with c-Abl, thereby dictating the subcellular localization of c-Abl and the sensitivity of MDA-MB-231 cells to Imatinib. In response to nutrient deprivation, c-Abl:p53 complexes readily accumulate in the nucleus, resulting in the hyperactivation of c-Abl and initiation of its anti-tumor activities. Collectively, we identified a novel mutant p53:c-Abl cytoplasmic signaling complex that promotes MDA-MB-231 cell growth and highlights the contextual cues that confer oncogenic activity to c-Abl in breast cancer.

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

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