Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells.
Claudia StäubertRosanna KrakowskyHasanuzzaman BhuiyanBarbara WitekAnna LindahlOliver BroomAnders NordströmPublished in: Medical oncology (Northwood, London, England) (2015)
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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- mass spectrometry
- acute myeloid leukemia
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- low density lipoprotein
- single cell
- machine learning
- transcription factor
- risk factors
- high resolution
- ms ms
- young adults
- pulmonary artery
- pulmonary hypertension
- pulmonary arterial hypertension
- binding protein
- childhood cancer