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 (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.

Keywords

Leukemia; Drug resistance; Cholesterol biosynthesis; LC-MS; Stable isotope labelling mass spectrometry; Cancer

Published in

Medical Oncology
2016, volume: 33, article number: 6
Publisher: HUMANA PRESS INC

SLU Authors

• Stäubert, Claudia

  • Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences
    
  • Umeå University
  • University of Leipzig

• Nordström, Anders

  • Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences
    
  • Karolinska Institute
  • Umeå University

Global goals (SDG)

SDG3 Good health and well-being

UKÄ Subject classification

Cancer and Oncology

Publication identifier

• DOI: https://doi.org/10.1007/s12032-015-0717-5

Permanent link to this page (URI)

https://res.slu.se/id/publ/83023