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J. Biol. Chem., Vol. 280, Issue 45, 38047-38058, November 11, 2005

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Cytotoxicity of an Anti-cancer Lysophospholipid through Selective Modification of Lipid Raft Composition^*

Vanina Zaremberg1, Consuelo Gajate2, Luis M. Cacharro3, Faustino Mollinedo, and Christopher R. McMaster4

From the Departments of Pediatrics and Biochemistry & Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada and the Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, E-37007 Salamanca, Spain

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.

Received for publication, March 15, 2005 , and in revised form, September 9, 2005.

^* This work was supported in part by an operating grant from the Cancer Research Society, Inc. (to C. R. M.), Fondo de Investigación Sanitaria Grants FIS04/0843 and FIS02/1199, Fundación de Investigación Médica Mutua Madrileña (FMM), and Junta de Castilla y León Grant CSI04A05 (to F. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Nova Scotia Health Research Foundation Fellowship.

² Supported by the Ramón y Cajal Program from the Ministerio de Educación y Ciencia of Spain.

³ Recipient of a predoctoral Formación de Profesorado Universitario fellowship from the Ministerio de Eduación y Ciencia of Spain.

⁴ Supported by a Canada Research Chair. To whom correspondence should be addressed: 5849 University Ave., Rm. C302, Halifax, Nova Scotia B3H 4H7, Canada. Tel.: 902-494-2953; Fax: 902-494-1394; E-mail: Christopher.mcmaster{at}dal.ca.

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