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Cell Cycle, Cell Death, and Senescence

Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway

¹ Université de Bordeaux 2; ² Centre National de la Recherche Scientifique-Unite Mixte de Recherche 5164; ³ IFR66; ⁴ Centre National de la Recherche Scientifique-Unite Mixte de Recherche 5200; ⁵ Institut National de la Sante et de la Recherche Medicale E347, Institut Bergonie; ⁶ Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, Bordeaux, France and ⁷ Institut National de la Sante et de la Recherche Medicale-Unite Mixte de Recherche 620, IFR 140, Université de Rennes 1, Rennes, France

Requests for reprints: Patrick Legembre, Centre National de la Recherche Scientifique-Unite Mixte de Recherche 5164, 146 rue Léo Saignat, 33076 Bordeaux, France. Phone: 33-5-57-57-11-24; Fax: 33-5-57-57-14-72. E-mail: plege{at}u-bordeaux2.fr

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is known to protect tumor cells from apoptosis and more specifically from the Fas-mediated apoptotic signal. The antitumoral agent edelfosine sensitizes leukemic cells to death by inducing the redistribution of the apoptotic receptor Fas into plasma membrane subdomains called lipid rafts. Herein, we show that inhibition of the PI3K signal by edelfosine triggers a Fas-mediated apoptotic signal independently of the Fas/FasL interaction. Furthermore, similarly to edelfosine, blockade of the PI3K activity, using specific inhibitors LY294002 and wortmannin, leads to the clustering of Fas whose supramolecular complex is colocalized within the lipid rafts. These findings indicate that the antitumoral agent edelfosine down-modulates the PI3K signal to sensitize tumor cells to death through the redistribution of Fas into large platform of membrane rafts. (Mol Cancer Res 2008;6(4):604–13)