Medical Oncology · 2015 · 22 citations · 40 references
Life SciencesBiochemistryPharmacologyCellular MetabolismChemotherapyMetabolismCancer MetabolismCholesterol BiosynthesisCholesterol MetabolismLipid MetabolismSteroid BiosynthesisSterol MetabolismCancer Cell Proliferation InhibitionIsotopomer AnalysisLanosterol MetabolismLanosterol SynthaseMetabolic BurdenPharmacological Inhibition Of Cholesterol BiosynthesisSqualene EpoxidaseSqualene Synthase
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.
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Tracking the clonal origin of lethal prostate cancer
Michael C. Haffner, Timothy L. Mosbruger, David Esopi et al. · Journal of Clinical Investigation · 2013 · 506 citations