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J Biol Chem. 2015 Mar 27;290(13):8348-59. doi: 10.1074/jbc.M114.618769. Epub 2015 Feb 19.

Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine.

Author information

1
From the Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden, the Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 90183 Umeå, Sweden, the Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany.
2
Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden, and.
3
From the Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden.
4
the Departments of Medical Biochemistry and Biophysics and.
5
From the Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden, the Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 90183 Umeå, Sweden, Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden, and anders.nordstrom@molbiol.umu.se.

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 β-oxidation, 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 and RNA expression 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.

KEYWORDS:

Drug Resistance; Glutamine; Glycolysis; Leukemia; Mass Spectrometry (MS); Metabolism; Metabolomics; Transcriptomics; β-Oxidation

PMID:
25697355
PMCID:
PMC4375488
DOI:
10.1074/jbc.M114.618769
[Indexed for MEDLINE]
Free PMC Article

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