Alteration of plasma membrane organization by an anticancer lysophosphatidylcholine analogue induces intracellular acidification and internalization of plasma membrane transporters in yeast.
The lysophosphatidylcholine analogue edelfosine is a potent antitumor lipid that targets cellular membranes. The underlying mechanisms leading to cell death remain controversial, although two cellular membranes have emerged as primary targets of edelfosine, the plasma membrane (PM) and the endoplasmic reticulum. In an effort to identify conditions that enhance or prevent the cytotoxic effect of edelfosine, we have conducted genome-wide surveys of edelfosine sensitivity and resistance in Saccharomyces cerevisiae presented in this work and the accompanying paper (Cuesta-Marbán, Á., Botet, J., Czyz, O., Cacharro, L. M., Gajate, C., Hornillos, V., Delgado, J., Zhang, H., Amat-Guerri, F., Acuña, A. U., McMaster, C. R., Revuelta, J. L., Zaremberg, V., and Mollinedo, F. (January 23, 2013) J. Biol. Chem. 288,), respectively. Our results point to maintenance of pH homeostasis as a major player in modulating susceptibility to edelfosine with the PM proton pump Pma1p playing a main role. We demonstrate that edelfosine alters PM organization and induces intracellular acidification. Significantly, we show that edelfosine selectively reduces lateral segregation of PM proteins like Pma1p and nutrient H(+)-symporters inducing their ubiquitination and internalization. The biology associated to the mode of action of edelfosine we have unveiled includes selective modification of lipid raft integrity altering pH homeostasis, which in turn regulates cell growth.
Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
Ola
O
Czyz
Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
Teshager
T
Bitew
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Alvaro
A
Cuesta-Marbán
Department of Pharmacology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada.
Christopher R
CR
McMaster
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain. Electronic address: fmollin@usal.es.
Faustino
F
Mollinedo
Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada. Electronic address: vzarembe@ucalgary.ca.
Vanina
V
Zaremberg
D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D050296:Microbial Viability / Q000187:drug effects; D033704:Nucleotide Transport Proteins / Q000378:metabolism*; D010742:Phospholipid Ethers / Q000494:pharmacology*; D021381:Protein Transport; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D054875:Ubiquitination / Q000187:drug effects
D026923:Amino Acid Transport Systems, Basic; D000970:Antineoplastic Agents; C502212:CAN1 protein, S cerevisiae; C035528:FUR4 protein, S cerevisiae; D033704:Nucleotide Transport Proteins; D010742:Phospholipid Ethers; D029701:Saccharomyces cerevisiae Proteins; C026659:edelfosine; C092477:PMA1 protein, S cerevisiae; D006180:Proton-Translocating ATPases