Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells

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• 作者：Claudia Stäubert ; Rosanna Krakowsky ; Hasanuzzaman Bhuiyan…
• 关键词：Leukemia ; Drug resistance ; Cholesterol biosynthesis ; LC–MS ; Stable isotope labelling mass spectrometry ; Cancer
• 刊名：Medical Oncology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：33
• 期：1
• 全文大小：1,348 KB
• 刊物主题：Oncology; Hematology; Pathology; Internal Medicine;
• 出版者：Springer US
• ISSN：1559-131X

文摘

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 2H₂O 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.