title: Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells.
abstract: 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 (2)H2O 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.
authors.affiliation: Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden.|Department of Forest Genetics and Plant Physiology, Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.|Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stäubert
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Krakowsky
authors.affiliation: Doping Laboratory, Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Hasanuzzaman
authors.initials: H
authors.lastname: Bhuiyan
authors.affiliation: Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Witek
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindahl
authors.affiliation: Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Broom
authors.affiliation: Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden. anders.nordstrom@umu.se.|Department of Forest Genetics and Plant Physiology, Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå, Sweden. anders.nordstrom@umu.se.|Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden. anders.nordstrom@umu.se.
authors.forename: Anders
authors.identifier: http://orcid.org/0000-0003-3676-817X
authors.initials: A
authors.lastname: Nordström
mesh_terms: D000903:Antibiotics, Antineoplastic; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003630:Daunorubicin; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D007810:Lanosterol / Q000378:metabolism*; D007938:Leukemia / Q000378:metabolism*; D013058:Mass Spectrometry; D016133:Polymerase Chain Reaction
chemical_list: D000903:Antibiotics, Antineoplastic; D007810:Lanosterol; D003630:Daunorubicin
keywords: Cancer; Cholesterol biosynthesis; Drug resistance; LC–MS; Leukemia; Stable isotope labelling mass spectrometry