期刊
ONCOGENE
卷 28, 期 36, 页码 3221-3234出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.183
关键词
lipid rafts; Fas/CD95 signaling; mitochondrial transmembrane potential; multiple myeloma; T-cell leukemia; resveratrol
资金
- Ministerio de Ciencia e Innovacion [SAF2008-02251, SAF2005-04293, RD06/0020/1037]
- Red Tematica de Investigacion Cooperativa en Cancer, Instituto de Salud Carlos III
- Fondo de Investigacion Sanitaria and European Commission [FIS-FEDER 06/0813, 04/0843]
- Junta de Castilla y Leon [CSI01A08, SAN673/SA32/08]
- Experimental Therapeutics and Translational Oncology Program [GR15]
- Fundacion de Investigacion Medica Mutua Madrilena (FMM)
- Fundacion 'la Caixa' [BM05-30-0]
- Fundacao para a Ciencia e Tecnologia (Ministerio da Ciencia, Tecnologia e Ensino Superior of Portugal)
- Ministerio de Ciencia e Innovacion of Spain
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-X-L overexpression prevented resveratrol-induced disruption of mitochondrial transmembrane potential (Delta Psi(m)) and apoptosis. A FADD dominant-negative mutant, that blocked Fas/CD95 downstream signaling, precluded resveratrol-induced Delta Psi(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 Delta Psi(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. Oncogene (2009) 28, 3221-3234; doi: 10.1038/onc.2009.183; published online 29 June 2009
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