Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions.
We have found that resveratrol (trans-3,4',5-trihydroxystilbene) induced apoptosis in multiple myeloma (MM) and T-cell leukemia cells through coclustering of Fas/CD95 death receptor and lipid rafts, whereas normal lymphocytes were spared. Tumor necrosis factor-related apoptosis-inducing ligand receptors, Fas-associated death domain-containing protein (FADD), procaspase-8, procaspase-10, c-Jun amino-terminal kinase and Bid were also recruited into lipid rafts on resveratrol incubation with MM and T-cell leukemia cells. Raft disruption inhibited resveratrol-induced apoptosis. Bcl-XL overexpression prevented resveratrol-induced disruption of mitochondrial transmembrane potential (DeltaPsi(m)) and apoptosis. A FADD dominant-negative mutant, that blocked Fas/CD95 downstream signaling, precluded resveratrol-induced DeltaPsi(m) loss and apoptosis, indicating a sequence of Fas/CD95 signaling-->mitochondrion in the apoptotic response triggered by resveratrol. Cells deficient in Fas/CD95 did not undergo resveratrol-induced apoptosis. Pretreatment of MM cells with interferon-gamma upregulated Fas/CD95 and caspase-8, and potentiated resveratrol-induced apoptosis. Our data indicate that recruitment of Fas/CD95 death receptor and downstream signaling molecules into lipid rafts, followed by DeltaPsi(m) disruption, underlies the apoptotic action of resveratrol in MM and T-cell leukemic cells. Combination of resveratrol with perifosine or bortezomib potentiated the apoptotic response induced by each single drug. These results also highlight the role of recruitment of Fas/CD95 signaling in lipid rafts in antimyeloma and antileukemia chemotherapy.
Reis-Sobreiro
M
M
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.
Gajate
C
C
Mollinedo
F
F
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D053455:Caspase 10 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005455:Fluorescent Antibody Technique; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D001897:Boronic Acids; D053200:Fas-Associated Death Domain Protein; D011719:Pyrazines; D013267:Stilbenes; D051020:bcl-X Protein; D019014:fas Receptor; D010767:Phosphorylcholine; C105905:perifosine; D000069286:Bortezomib; D048031:JNK Mitogen-Activated Protein Kinases; D053455:Caspase 10; D053181:Caspase 8; C506438:CASP10 protein, human; D000077185:Resveratrol