Cytotoxicity of an anti-cancer lysophospholipid through selective modification of lipid raft composition.
Edelfosine is a prototypical member of the alkylphosphocholine class of antitumor drugs. Saccharomyces cerevisiae was used to screen for genes that modulate edelfosine cytotoxicity and identified sterol and sphingolipid pathways as relevant regulators. Edelfosine addition to yeast resulted in the selective partitioning of the essential plasma membrane protein Pma1p out of lipid rafts. Microscopic analysis revealed that Pma1p moved from the plasma membrane to intracellular punctate regions and finally localized to the vacuole. Consistent with altered sterol and sphingolipid synthesis resulting in increased edelfosine sensitivity, mislocalization of Pma1p was preceded by the movement of sterols out of the plasma membrane. Cells with enfeebled endocytosis and vacuolar protease activities prevented edelfosine-mediated (i) mobilization of sterols, (ii) loss of Pma1p from lipid rafts, and (iii) cell death. The activities of proteins and signaling processes are meaningfully altered by changes in lipid raft biophysical properties. This study points to a novel mode of action for an anti-cancer drug through modification of plasma membrane lipid composition resulting in the displacement of an essential protein from lipid rafts.
Zaremberg
Vanina
V
Department of Pediatrics, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
Gajate
Consuelo
C
Cacharro
Luis M
LM
Mollinedo
Faustino
F
McMaster
Christopher R
CR
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism*; D009154:Mutation; D010742:Phospholipid Ethers / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006180:Proton-Translocating ATPases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013107:Sphingolipids / Q000096:biosynthesis / Q000378:metabolism; D013261:Sterols / Q000096:biosynthesis / Q000378:metabolism
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; D013261:Sterols; C026659:edelfosine; C092477:PMA1 protein, S cerevisiae; D006180:Proton-Translocating ATPases