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  • 1.
    Stäubert, Claudia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, S-90183 Umea, Sweden; Univ Leipzig, Inst Biochem, Fac Med, D-04103 Leipzig, Germany.
    Bhuiyan, Hasanuzzaman
    Lindahl, Anna
    Broom, Oliver Jay
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Zhu, Yafeng
    Islam, Saiful
    Linnarsson, Sten
    Lehtio, Janne
    Nordström, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, S-90183 Umea, Sweden; Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17177 Stockholm, Sweden.
    Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 13, p. 8348-8359Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Stäubert, Claudia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
    Broom, Oliver Jay
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordström, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 23, p. 19706-19720Article in journal (Refereed)
    Abstract [en]

    Cancer cells exhibit characteristic changes in their metabolism with efforts being made to address them therapeutically. However, targeting metabolic enzymes as such is a major challenge due to their essentiality for normal proliferating cells. The most successful pharmaceutical targets are G protein-coupled receptors (GPCRs), with more than 40% of all currently available drugs acting through them. We show that, a family of metabolite-sensing GPCRs, the Hydroxycarboxylic acid receptor family (HCAs), is crucial for breast cancer cells to control their metabolism and proliferation. We found HCA(1) and HCA(3) mRNA expression were significantly increased in breast cancer patient samples and detectable in primary human breast cancer patient cells. Furthermore, siRNA mediated knock-down of HCA3 induced considerable breast cancer cell death as did knock-down of HCA1, although to a lesser extent. Liquid Chromatography Mass Spectrometry based analyses of breast cancer cell medium revealed a role for HCA3 in controlling intracellular lipid/fatty acid metabolism. The presence of etomoxir or perhexiline, both inhibitors of fatty acid beta-oxidation rescues breast cancer cells with knocked-down HCA3 from cell death. Our data encourages the development of drugs acting on cancer-specific metabolite-sensing GPCRs as novel anti-proliferative agents for cancer therapy.

  • 3.
    Stäubert, Claudia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Forest Genetics and Plant Physiology, Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå; Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Germany.
    Krakowsky, Rosanna
    Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany .
    Bhuiyan, Hasanuzzaman
    Doping Laboratory, Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Witek, Barbara
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lindahl, Anna
    Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
    Broom, Oliver
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordström, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Forest Genetics and Plant Physiology, Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet.
    Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells2016In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 33, no 1, article id 6Article in journal (Refereed)
    Abstract [en]

    The cholesterol metabolism is essential for cancer cell proliferation. We found the expression of genes involved in the cholesterol biosynthesis pathway up-regulated in the daunorubicin-resistant leukemia cell line CEM/R2, which is a daughter cell line to the leukemia cell line CCRF-CEM (CEM). Cellular (H2O)-H-2 labelling, mass spectrometry, and isotopomer analysis revealed an increase in lanosterol synthesis which was not accompanied by an increase in cholesterol flux or pool size in CEM/R2 cells. Exogenous addition of lanosterol had a negative effect on CEM/R2 and a positive effect on sensitive CEM cell viability. Treatment of CEM and CEM/R2 cells with cholesterol biosynthesis inhibitors acting on the enzymes squalene epoxidase and lanosterol synthase, both also involved in the 24,25-epoxycholesterol shunt pathway, revealed a connection of this pathway to lanosterol turnover. Our data highlight that an increased lanosterol flux poses a metabolic weakness of resistant cells that potentially could be therapeutically exploited.

  • 4.
    Stäubert, Claudia
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Le Duc, Diana
    Schoeneberg, Torsten
    Examining the Dynamic Evolution of G Protein-Coupled Receptors2014In: G Protein-Coupled Receptor Genetics: Research and Methods in the Post-Genomic Era / [ed] Craig W. Stevens, Humana Press, 2014, p. 23-43Chapter in book (Refereed)
    Abstract [en]

    The valuable source of large-scale genomic information initiated attempts to identify the origin(s) of G protein-coupled receptors (GPCR), count and categorize those genes, and follow their evolutionary history. Being present in fungi, plants, and unicellular eukaryotes, GPCR must have evolved before the plant-fungi-animal split about 1.5 billion years ago. Phylogenetic analyses revealed several kinds of evolutionary patterns that occurred during GPCR evolution including one-to-one orthologous relationships, species-specific gene expansion, and episodic duplication of the entire GPCR repertoire in certain species lineages. These data document the highly dynamic process of birth and death of GPCR genes since hundreds of millions of years. Genetic drift and selective forces have shaped the individual structure of a given receptor gene but also of the species-specific receptor repertoire - a process that is still ongoing. These processes have left footprints in the genomic sequence that can be detected by bioinformatic methods and may help to interpret receptor function in the light of a given species in its environment. Reasonable intraspecies sequence variability in GPCR is either physiologically tolerated or promotes individual phenotypes and adaptation, but also susceptibilities for diseases. Therefore, the impact of GPCR variants in epistatic networks will be an important task of future GPCR research. The chapter summarizes evolutionary processes working on GPCR genes and sheds light on their consequences at the levels of receptor structure and function.

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