Stäubert, Claudia
- Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences
- University of Leipzig
Abstract
Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid beta-xidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics andRNAexpression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies.
Published in
Journal of Biological Chemistry
2015, volume: 290, number: 13, pages: 8348-8359
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
SLU Authors
Nordström, Anders
- Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences
- Umeå University
- Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences
Global goals (SDG)
SDG3 Good health and well-being
UKÄ Subject classification
Cancer and Oncology
Cell and Molecular Biology
Publication identifier
- DOI: https://doi.org/10.1074/jbc.M114.618769
Permanent link to this page (URI)
https://res.slu.se/id/publ/76083