title: Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine.
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.
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stäubert
authors.affiliation: Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden, and.
authors.forename: Hasanuzzaman
authors.initials: H
authors.lastname: Bhuiyan
authors.affiliation: Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden, and.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindahl
authors.affiliation: From the Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden.
authors.forename: Oliver Jay
authors.initials: OJ
authors.lastname: Broom
authors.affiliation: Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden, and.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: the Departments of Medical Biochemistry and Biophysics and.
authors.forename: Saiful
authors.initials: S
authors.lastname: Islam
authors.affiliation: the Departments of Medical Biochemistry and Biophysics and.
authors.forename: Sten
authors.initials: S
authors.lastname: Linnarsson
authors.affiliation: Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden, and.
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.affiliation: 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.
authors.forename: Anders
authors.initials: A
authors.lastname: Nordström
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism; D045744:Cell Line, Tumor; D003524:Cyclosporins / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D005973:Glutamine / Q000502:physiology*; D006019:Glycolysis; D006801:Humans; D007938:Leukemia; D055442:Metabolome; D010084:Oxidation-Reduction; D010205:Pantothenic Acid / Q000378:metabolism; D010480:Perhexiline / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019998:Racemases and Epimerases / Q000378:metabolism; D059467:Transcriptome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003524:Cyclosporins; D005227:Fatty Acids; D012333:RNA, Messenger; C038784:fatty acid oxidation complex; D005973:Glutamine; D010205:Pantothenic Acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases; D010480:Perhexiline; C070272:valspodar; D003630:Daunorubicin
keywords: Drug Resistance; Glutamine; Glycolysis; Leukemia; Mass Spectrometry (MS); Metabolism; Metabolomics; Transcriptomics; β-Oxidation