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Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells
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.
Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany .
Doping Laboratory, Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
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2016 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 33, no 1, 6Article in journal (Refereed) Published
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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.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2016. Vol. 33, no 1, 6
Keyword [en]
Leukemia, Drug resistance, Cholesterol biosynthesis, LC-MS, Stable isotope labelling mass spectrometry, Cancer
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Cancer and Oncology
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URN: urn:nbn:se:umu:diva-114568DOI: 10.1007/s12032-015-0717-5ISI: 000367518200006PubMedID: 26698156OAI: oai:DiVA.org:umu-114568DiVA: diva2:903486
Available from: 2016-02-16 Created: 2016-01-25 Last updated: 2017-11-30Bibliographically approved

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Stäubert, ClaudiaWitek, BarbaraBroom, OliverNordström, Anders

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