Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway.
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.
Bénéteau
Marie
M
Centre National de la Recherche Scientifique-Unite Mixte de Recherche 5164, 33076 Bordeaux, France.
Pizon
Mathieu
M
Chaigne-Delalande
Benjamin
B
Daburon
Sophie
S
Moreau
Patrick
P
De Giorgi
Francesca
F
Ichas
François
F
Rebillard
Amélie
A
Dimanche-Boitrel
Marie-Thérèse
MT
Taupin
Jean-Luc
JL
Moreau
Jean-François
JF
Legembre
Patrick
P
D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010742:Phospholipid Ethers / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism*
D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010742:Phospholipid Ethers; D051057:Proto-Oncogene Proteins c-akt; D019014:fas Receptor; C026659:edelfosine