Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway
Molecular Cancer Research. 2008-03-14; 6(4): 604-613
DOI: 10.1158/1541-7786.mcr-07-0331
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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.