Alteration of Plasma Membrane Organization by an Anticancer Lysophosphatidylcholine Analogue Induces Intracellular Acidification and Internalization of Plasma Membrane Transporters in Yeast*

Autor: Faustino Mollinedo, Vanina Zaremberg, Teshager Bitew, Christopher R. McMaster, Ola Czyz, Álvaro Cuesta-Marbán
Přispěvatelé: European Commission, Natural Sciences and Engineering Research Council of Canada, University of Calgary, Canadian Institutes of Health Research, Ministerio de Economía y Competitividad (España), Red Temática de Investigación Cooperativa en Cáncer (España), Instituto de Salud Carlos III, Junta de Castilla y León
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Intracellular Fluid
Saccharomyces cerevisiae Proteins
media_common.quotation_subject
Antineoplastic Agents
Saccharomyces cerevisiae
Biology
Biochemistry
Cell membrane
03 medical and health sciences
chemistry.chemical_compound
Membrane Microdomains
medicine
Internalization
Molecular Biology
Lipid raft
030304 developmental biology
media_common
Sequence Deletion
0303 health sciences
Plasma membrane organization
Microbial Viability
Cell growth
Endoplasmic reticulum
030302 biochemistry & molecular biology
Cell Membrane
Ubiquitination
Phospholipid Ethers
Cell Biology
Intracellular Membranes
Hydrogen-Ion Concentration
Lipids
3. Good health
Cell biology
Protein Transport
Proton-Translocating ATPases
Lysophosphatidylcholine
medicine.anatomical_structure
chemistry
Nucleotide Transport Proteins
Amino Acid Transport Systems
Basic
lipids (amino acids
peptides
and proteins)
Drug Screening Assays
Antitumor
Edelfosine
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Journal of Biological Chemistry; Vol 288
Popis: 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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
This work was supported in part by a Natural Sciences and Engineering Research Council of Canada discovery grant, a seed grant from the University of Calgary, a Natural Sciences and Engineering Research Council of Canada University Faculty award (to V. Z.), Canadian Institutes of Health Research Grant 14124 (to C. R. M.), Spanish Ministerio de Economia y Competitividad Grants SAF2008-02251 and SAF2011-30518, Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, co-funded by the Fondo Europeo de Desarrollo Regional of the European Union Grants RD06/0020/1037 and RD12/0036/0065, European Community's Seventh Framework Programme FP7-2007-2013 Grant HEALTH-F2-2011-256986, (PANACREAS), and Junta de Castilla y León Grants CSI052A11-2 and CSI221A12-2 (to F. M.).
Databáze: OpenAIRE
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