Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions

Oncogene. 2009 Sep 10;28(36):3221-34. doi: 10.1038/onc.2009.183. Epub 2009 Jun 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Boronic Acids / pharmacology
  • Bortezomib
  • Caspase 10 / metabolism
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Drug Synergism
  • Fas-Associated Death Domain Protein / metabolism
  • Flow Cytometry / methods
  • Fluorescent Antibody Technique
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Jurkat Cells
  • Leukemia, T-Cell / metabolism
  • Leukemia, T-Cell / pathology
  • Membrane Microdomains / drug effects*
  • Membrane Microdomains / metabolism
  • Microscopy, Confocal
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / pharmacology
  • Pyrazines / pharmacology
  • Resveratrol
  • Signal Transduction / drug effects
  • Stilbenes / pharmacology*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism
  • fas Receptor / metabolism*


  • Antineoplastic Agents
  • BCL2L1 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Boronic Acids
  • Fas-Associated Death Domain Protein
  • Pyrazines
  • Stilbenes
  • bcl-X Protein
  • fas Receptor
  • Phosphorylcholine
  • perifosine
  • Bortezomib
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 10
  • Caspase 8
  • CASP10 protein, human
  • Resveratrol