Disruption of lipid domain organization in monolayers of complex yeast lipid extracts induced by the lysophosphatidylcholine analogue edelfosine in vivo. (October 2015)

• Record Type: Journal Article
• Authors: Mahadeo, Mark; Nathoo, Safia; Ganesan, Suriakarthiga; Driedger, Michael; Zaremberg, Vanina; Prenner, Elmar J.
• Is Part Of: Chemistry and physics of lipids. Volume 191:(2015)
• Page Start: 153
• Page End: 162
• Publication Date: 2015-10
• Subjects: BAM Brewster angle microscopy -- Ld liquid disordered -- Lo liquid ordered -- LE liquid expanded -- ER endoplasmic reticulum -- PC phosphatidylcholine -- DAG diacylglycerol; Brewster angle microscopy (BAM) -- Antitumor lipids -- Monolayer -- Saccharomyces cerevisiae -- Lysophospholipid -- Lipid domains; Lipids -- Periodicals; Lipids -- Periodicals; Lipides -- Périodiques; Lipids; Periodicals; Electronic journals; 547.77
• DOI: 10.1016/j.chemphyslip.2015.09.004
• Languages: English
• ISSNs: 0009-3084

Abstract

Graphical abstract: Highlights: Effects of the lysophosphatidylcholine analogue edelfosine on membranes were studied using lipid extracts of treated yeast. Edelfosine treatment resulted in a reduction of the number and size of domains compared to controls. Edelfosine addition to control samples post-extraction did not mimic the traits observed with the drug treatment of cells. Reduced edelfosine uptake in lem3 mutant yeast prevented drug effects on the membranes. The changes induced by edelfosine on lateral domain organization are potentially relevant for its mechanism of action. Abstract: The lysophosphatidylcholine analogue edelfosine is a potent antitumor and antiparasitic drug that targets cell membranes. Previous studies have shown that edelfosine alters membrane domain organization inducing internalization of sterols and endocytosis of plasma membrane transporters. These early events affect signaling pathways that result in cell death. It has been shown that edelfosine preferentially partitions into more rigid lipid domains in mammalian as well as in yeast cells. In this work we aimed at investigating the effect of edelfosine on membrane domain organization using monolayers prepared from whole cell lipid extracts of cells treated with edelfosine compared to control conditions. In Langmuir monolayers we were able to detect important differences to the lipid packing of the membrane monofilm. Domain formation visualized by means of Brewster angle microscopy also showed major morphological changes between edelfosine treated versus control samples. Importantly, edelfosine resistant cells defective in drug uptake did not display the same differences. In addition, co-spread samples of control lipid extracts with edelfosine added post extraction did not fully mimic the results obtained with lipid extracts from treated cells. Altogether these results indicate that edelfosine induces changes in membrane domain organization and that these changes depend on drug uptake. Our work also validates the use of monolayers derived from complex cell lipid extracts combined with Brewster angle microscopy, as a sensitive approach to distinguish between conditions associated with susceptibility or resistance to lysophosphatidylcholine analogues.