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Blood, 15 January 2007, Vol. 109, No. 2, pp. 711-719. Prepublished online as a Blood First Edition Paper on September 26, 2006; DOI 10.1182/blood-2006-04-016824. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-016824v1 109/2/711    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gajate, C. Articles by Mollinedo, F. Search for Related Content PubMed PubMed Citation Articles by Gajate, C. Articles by Mollinedo, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 12, 2006 Accepted August 23, 2006 Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts Consuelo Gajate and Faustino Mollinedo* Universidad de Salamanca-CSIC, Salamanca, Spain * Corresponding author; email: fmollin{at}usal.es. Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain-containing protein and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-XL overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L)-independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft-mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. Garayoa, D. Vilanova, J. C. Montero, N. Mitsiades, C. J. McMullan, et al. Aplidin, a Marine Organism-Derived Compound with Potent Antimyeloma Activity In vitro and In vivo Cancer Res., July 1, 2008; 68(13): 5216 - 5225. [Abstract] [Full Text] [PDF] M. Beneteau, M. Pizon, B. Chaigne-Delalande, S. Daburon, P. Moreau, F. De Giorgi, F. Ichas, A. Rebillard, M.-T. Dimanche-Boitrel, J.-L. Taupin, et al. Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway Mol. Cancer Res., April 1, 2008; 6(4): 604 - 613. [Abstract] [Full Text] [PDF] E. Sharif-Askari, D. Gaucher, R. Halwani, J. Ma, K. Jao, A. Abdallah, E. K. Haddad, and R.-P. Sekaly p56Lck Tyrosine Kinase Enhances the Assembly of Death-inducing Signaling Complex during Fas-mediated Apoptosis J. Biol. Chem., December 7, 2007; 282(49): 36048 - 36056. [Abstract] [Full Text] [PDF] 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] H. A. Elrod, Y.-D. Lin, P. Yue, X. Wang, S. Lonial, F. R. Khuri, and S.-Y. Sun The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway Mol. Cancer Ther., July 1, 2007; 6(7): 2029 - 2038. [Abstract] [Full Text] [PDF] S. L. Kohlhaas, A. Craxton, X.-M. Sun, M. J. Pinkoski, and G. M. Cohen Receptor-mediated Endocytosis Is Not Required for Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis J. Biol. Chem., April 27, 2007; 282(17): 12831 - 12841. [Abstract] [Full Text] [PDF]

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