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J. Biol. Chem., Vol. 281, Issue 21, 14833-14840, May 26, 2006

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Differential Targets and Subcellular Localization of Antitumor Alkyl-lysophospholipid in Leukemic Versus Solid Tumor Cells^*

Teresa Nieto-Miguel¹, Consuelo Gajate², and Faustino Mollinedo³

From the Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno and the Unidad de Investigación, Hospital Universitario de Salamanca, E-37007 Salamanca, Spain

Synthetic alkyl-lysophospholipids represent a family of promising anticancer drugs that induce apoptosis in a variety of tumor cells. Here we have found a differential subcellular distribution of the alkyl-lysophospholipid edelfosine in leukemic and solid tumor cells that leads to distinct anticancer responses. Edelfosine induced rapid apoptosis in human leukemic cells, including acute T-cell leukemia Jurkat and Peer cells, but promoted a late apoptotic response, preceded by G₂/M arrest, in human solid tumor cells such as cervix epitheloid carcinoma HeLa cells and lung carcinoma A549 cells. c-Jun amino-terminal kinase (JNK) and caspase-3 were accordingly activated at earlier times in edelfosine-treated Jurkat cells as compared with drug-treated HeLa cells. Both leukemic and solid tumor cells took up this alkyl-lysophospholipid and expressed the two putative edelfosine targets, namely cell surface Fas death receptor (also known as APO-1 or CD95) and endoplasmic reticulum CTP: phosphocholine cytidylyltransferase. However, edelfosine was mainly located to plasma membrane lipid rafts in Jurkat and Peer leukemic cells and to endoplasmic reticulum in solid tumor HeLa and A549 cells. Edelfosine induced translocation of Fas, Fas-associated death domain-containing protein, and JNK into membrane rafts in Jurkat cells, but not in HeLa cells. In contrast, edelfosine inhibited phosphatidylcholine biosynthesis in both HeLa and A549 cells, but not in Jurkat or Peer leukemic cells, before the triggering of apoptosis. These data indicate that edelfosine targets two different subcellular structures in a cell type-dependent manner, namely cell surface lipid rafts in leukemic cells and endoplasmic reticulum in solid tumor cells.

Received for publication, October 17, 2005 , and in revised form, March 14, 2006.

^* This work was supported in part by grants from Fondo de Investigación Sanitaria and European Commission (FIS-FEDER 04/0843, 02/1199), Ministerio de Educación y Ciencia (SAF2005-04293), Fundación de Investigación Médica Mutua Madrileña (FMM), Fundación "la Caixa" (BM05-30-0), and Junta de Castilla y León (CSI04A05). 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 Recipient of a predoctoral fellowship from the Junta de Castilla y León.

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

³ To whom correspondence should be addressed. Tel.: 34-923-294806; Fax: 34-923-294795; E-mail: fmollin{at}usal.es.

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This article has been cited by other articles:

				T. Nieto-Miguel, R. I. Fonteriz, L. Vay, C. Gajate, S. Lopez-Hernandez, and F. Mollinedo Endoplasmic Reticulum Stress in the Proapoptotic Action of Edelfosine in Solid Tumor Cells Cancer Res., November 1, 2007; 67(21): 10368 - 10378. [Abstract] [Full Text] [PDF]

				C. Gajate and F. Mollinedo Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts Blood, January 15, 2007; 109(2): 711 - 719. [Abstract] [Full Text] [PDF]