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 2 H 2 O 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.

New Bis-Alkenoic Acid Derivatives from a Marine-Derived Fungus Fusarium solani H915

“…The antifungal activity against tea pathogenic fungi P. theae and C. gloeosporioides was evaluated according to a previously described method [10,11]. Petri plates were used in the test.…”

“…To date, reports on bioactive compounds against tea pathogenic fungi are limited. Previously, we identified two new macrolactins [10,11] from Bacillus subtilis B5, a bacterium isolated from the 3000 m deep sea sediment of the Pacific Ocean that exhibit antifungal activity against P. theae and C. gloeosporioides . In the present study, Fusarium solani H915, a fungal strain that originated from the mangrove sediment of the Zhangjiangkou Mangrove National Nature Reserve, was found to possess antifungal activity.…”

GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism

“…While deregulated cellular metabolism appears to be an emerging hallmark of cancer drug resistance [12][13][14][15], deregulated energetics involving alterations in cellular metabolism to support neoplastic proliferation is a fundamental hallmark of cancer [16]. Central to this metabolic deregulation is Warburg's discovery of aerobic glycolysis, where glucose is converted to lactate even when oxygen supply is sufficient to support oxidative phosphorylation.…”

Separation and purification of lanosterol, dihydrolanosterol, and cholesterol from lanolin by high‐performance counter‐current chromatography dual‐mode elution method

“…Lanosterol is an intermediate of sterol biosynthesis and plays an important physiological role such as cancer prevention activity , a metabolic weakness of resistant cells , and potential activity in cataract treatment . The most potential application of lanosterol is its ability to reverse the aggregation of intracrystalline proteins, which can be used in the treatment of cataracts.…”

“…Lanosterol is an intermediate of sterol biosynthesis [1] and plays an important physiological role such as cancer prevention activity [2], a metabolic weakness of resistant cells [3,4], and potential activity in cataract treatment [5,6]. The most potential application of lanosterol is its ability to reverse the aggregation of intracrystalline proteins, which can be used Article Related Abbreviations: CCC, counter-current chromatography; DAD, diode-array detector; ELSD, evaporative light scattering detector; HPCCC, high-performance counter-current chromatography; K, partition coefficient; L-I-H, lower phase as mobile phase elute in head-to-tail mode; U-O-T, upper phase as mobile phase elute in the tail-to-head mode.…”