Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells
2016 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 33, no 1, 6Article in journal (Refereed) PublishedText
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
Leukemia, Drug resistance, Cholesterol biosynthesis, LC-MS, Stable isotope labelling mass spectrometry, Cancer
Cancer and Oncology
IdentifiersURN: urn:nbn:se:umu:diva-114568DOI: 10.1007/s12032-015-0717-5ISI: 000367518200006PubMedID: 26698156OAI: oai:DiVA.org:umu-114568DiVA: diva2:903486