15417786mcr200962-sup-254842_3_supp_7108103_qsvv8z.png (1.05 MB)

Supplementary Figure 1 from EMT-Derived Alterations in Glutamine Metabolism Sensitize Mesenchymal Breast Cells to mTOR Inhibition

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posted on 2023-04-03, 19:42 authored by Sigurdur Trausti Karvelsson, Arnar Sigurdsson, Kotryna Seip, Maria Tunset Grinde, Qiong Wang, Freyr Johannsson, Gunhild Mari Mælandsmo, Siver Andreas Moestue, Ottar Rolfsson, Skarphedinn Halldorsson

NMR data from 1H and 13C labelling experiments of D492 and D492M A) PC 1 scores after Principal Component Analysis of 1H NMR data and B) Corresponding loading plot from PC 1£. C) NMR peak area after incubation with 1-13C-glutamine for 6 hours. The metabolites show integrated peak areas of 1-13C glutamate and 1-13C glutathione (GSH). £: Peak assignment: a: isoleucine, b: leucine, c: valine, d: lactate, e: alanine, f: arginine, g: glutamine, h: glutamate, i: glutathione, j: phosphocholine (10 times higher than shown), k: myo-inositol, l: glycine, m: asparagine, n: proline, o: amp, p: adp, q: atp: r: threonine, s: glucose, t: fumarate, u: tyrosine, v: phenylalanine, w: NAD+, x: NADP, y: NADH.

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ARTICLE ABSTRACT

Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process with strong implications in cancer progression. Understanding the metabolic alterations associated with EMT may open new avenues of treatment and prevention. Here we used 13C carbon analogs of glucose and glutamine to examine differences in their utilization within central carbon and lipid metabolism following EMT in breast epithelial cell lines. We found that there are inherent differences in metabolic profiles before and after EMT. We observed EMT-dependent re-routing of the TCA-cycle, characterized by increased mitochondrial IDH2-mediated reductive carboxylation of glutamine to lipid biosynthesis with a concomitant lowering of glycolytic rates and glutamine-dependent glutathione (GSH) generation. Using weighted correlation network analysis, we identified cancer drugs whose efficacy against the NCI-60 Human Tumor Cell Line panel is significantly associated with GSH abundance and confirmed these in vitro. We report that EMT-linked alterations in GSH synthesis modulate the sensitivity of breast epithelial cells to mTOR inhibitors. EMT in breast cells causes an increased demand for glutamine for fatty acid biosynthesis, altering its contribution to glutathione biosynthesis, which sensitizes the cells to mTOR inhibitors.

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Keywords

Breast Cancer Computational Methods Molecular modeling Drug Mechanisms Cellular responses to anticancer drugs Drug Resistance Glutathione metabolism Stem Cell Biology

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CC BY