EMT-Derived Alterations in Glutamine Metabolism Sensitize Mesenchymal Breast Cells to mTOR Inhibition.

Autor:	Karvelsson ST; Center for Systems Biology, University of Iceland, Reykjavik, Iceland., Sigurdsson A; Department of Chemistry, Technische Universität Berlin, Berlin, Germany., Seip K; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Grinde MT; Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway., Wang Q; Center for Systems Biology, University of Iceland, Reykjavik, Iceland., Johannsson F; Center for Systems Biology, University of Iceland, Reykjavik, Iceland., Mælandsmo GM; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Moestue SA; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway.; Department of Pharmacy, Nord University, Namsos, Norway., Rolfsson O; Center for Systems Biology, University of Iceland, Reykjavik, Iceland. ottarr@hi.is., Halldorsson S; Center for Systems Biology, University of Iceland, Reykjavik, Iceland.; Institute for Surgical Research, Vilhelm Magnus Laboratory, Oslo University Hospital, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2021 Sep; Vol. 19 (9), pp. 1546-1558. Date of Electronic Publication: 2021 Jun 04.
DOI:	10.1158/1541-7786.MCR-20-0962
Abstrakt:	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 13 C 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. IMPLICATIONS: 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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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