Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 28, pages 3221–3234 (2009)Cite this article

Abstract

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 (ΔΨm) and apoptosis. A FADD dominant-negative mutant, that blocked Fas/CD95 downstream signaling, precluded resveratrol-induced ΔΨm 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-γ 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 ΔΨm 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Ashkenazi A, Holland P, Eckhardt SG . (2008). Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol 26: 3621–3630.

    Article  CAS  Google Scholar 

  • Aziz MH, Kumar R, Ahmad N . (2003). Cancer chemoprevention by resveratrol: in vitro and in vivo studies and the underlying mechanisms (review). Int J Oncol 23: 17–28.

    CAS  PubMed  Google Scholar 

  • Barille-Nion S, Barlogie B, Bataille R, Bergsagel PL, Epstein J, Fenton RG et al. (2003). Advances in biology and therapy of multiple myeloma. Hematology, Am Soc Hematol Educ Program Book 2003: 248–278.

    Article  Google Scholar 

  • Barjot C, Tournaire M, Castagnino C, Vigor C, Vercauteren J, Rossi JF . (2007). Evaluation of antitumor effects of two vine stalk oligomers of resveratrol on a panel of lymphoid and myeloid cell lines: comparison with resveratrol. Life Sci 81: 1565–1574.

    Article  CAS  Google Scholar 

  • Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W et al. (2001). SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98: 13681–13686.

    Article  CAS  Google Scholar 

  • Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U et al. (2007). Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 109: 2293–2302.

    Article  CAS  Google Scholar 

  • Cabaner C, Gajate C, Macho A, Munoz E, Modolell M, Mollinedo F . (1999). Induction of apoptosis in human mitogen-activated peripheral blood T-lymphocytes by the ether phospholipid ET-18-OCH3: involvement of the Fas receptor/ligand system. Br J Pharmacol 127: 813–825.

    Article  CAS  Google Scholar 

  • Christian AE, Haynes MP, Phillips MC, Rothblat GH . (1997). Use of cyclodextrins for manipulating cellular cholesterol content. J Lipid Res 38: 2264–2272.

    CAS  PubMed  Google Scholar 

  • Delmas D, Rebe C, Lacour S, Filomenko R, Athias A, Gambert P et al. (2003). Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J Biol Chem 278: 41482–41490.

    Article  CAS  Google Scholar 

  • Delmas D, Rebe C, Micheau O, Athias A, Gambert P, Grazide S et al. (2004). Redistribution of CD95, DR4 and DR5 in rafts accounts for the synergistic toxicity of resveratrol and death receptor ligands in colon carcinoma cells. Oncogene 23: 8979–8986.

    Article  CAS  Google Scholar 

  • Fulda S, Debatin KM . (2005). Resveratrol-mediated sensitisation to TRAIL-induced apoptosis depends on death receptor and mitochondrial signalling. Eur J Cancer 41: 786–798.

    Article  CAS  Google Scholar 

  • Gajate C, An F, Mollinedo F . (2003). Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. Clin Cancer Res 9: 1535–1545.

    CAS  PubMed  Google Scholar 

  • Gajate C, Del Canto-Janez E, Acuna AU, Amat-Guerri F, Geijo E, Santos-Beneit AM et al. (2004). Intracellular triggering of Fas aggregation and recruitment of apoptotic molecules into Fas-enriched rafts in selective tumor cell apoptosis. J Exp Med 200: 353–365.

    Article  CAS  Google Scholar 

  • Gajate C, Fonteriz RI, Cabaner C, Alvarez-Noves G, Alvarez-Rodriguez Y, Modolell M et al. (2000a). Intracellular triggering of Fas, independently of FasL, as a new mechanism of antitumor ether lipid-induced apoptosis. Int J Cancer 85: 674–682.

    Article  CAS  Google Scholar 

  • Gajate C, Gonzalez-Camacho F, Mollinedo F . (2009a). Involvement of raft aggregates enriched in Fas/CD95 death-inducing signaling complex in the antileukemic action of edelfosine in Jurkat cells. PLoS ONE 4: e5044.

    Article  Google Scholar 

  • Gajate C, Gonzalez-Camacho F, Mollinedo F . (2009b). Lipid raft connection between extrinsic and intrinsic apoptotic pathways. Biochem Biophys Res Commun 380: 780–784.

    Article  CAS  Google Scholar 

  • Gajate C, Mollinedo F . (2001). The antitumor ether lipid ET-18-OCH3 induces apoptosis through translocation and capping of Fas/CD95 into membrane rafts in human leukemic cells. Blood 98: 3860–3863.

    Article  CAS  Google Scholar 

  • Gajate C, Mollinedo F . (2005). Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J Biol Chem 280: 11641–11647.

    Article  CAS  Google Scholar 

  • Gajate C, Mollinedo F . (2007). Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 109: 711–719.

    Article  CAS  Google Scholar 

  • Gajate C, Santos-Beneit AM, Macho A, Lazaro M, Hernandez-De Rojas A, Modolell M et al. (2000b). Involvement of mitochondria and caspase-3 in ET-18-OCH3-induced apoptosis of human leukemic cells. Int J Cancer 86: 208–218.

    Article  CAS  Google Scholar 

  • Gill C, Walsh SE, Morrissey C, Fitzpatrick JM, Watson RW . (2007). Resveratrol sensitizes androgen independent prostate cancer cells to death-receptor mediated apoptosis through multiple mechanisms. Prostate 67: 1641–1653.

    Article  CAS  Google Scholar 

  • Harder T, Scheiffele P, Verkade P, Simons K . (1998). Lipid domain structure of the plasma membrane revealed by patching of membrane components. J Cell Biol 141: 929–942.

    Article  CAS  Google Scholar 

  • Hofmann TG, Moller A, Hehner SP, Welsch D, Droge W, Schmitz ML . (2001). CD95-induced JNK activation signals are transmitted by the death-inducing signaling complex (DISC), but not by Daxx. Int J Cancer 93: 185–191.

    Article  CAS  Google Scholar 

  • Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW et al. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275: 218–220.

    Article  CAS  Google Scholar 

  • Lonial S . (2007). Multiple myeloma: novel approaches for relapsed disease. Clin Lymphoma Myeloma 8 (Suppl 1): S18–S23.

    Article  CAS  Google Scholar 

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490.

    Article  CAS  Google Scholar 

  • Mollinedo F . (2007). Antitumor ether lipids: proapoptotic agents with multiple therapeutic indications. Expert Opin Ther Pat 17: 385–405.

    Article  CAS  Google Scholar 

  • Mollinedo F, Burgaleta C, Velasco G, Arroyo AG, Acevedo A, Barasoain I . (1992). Enhancement of human neutrophil functions by a monoclonal antibody directed against a 19-kDa antigen. J Immunol 149: 323–330.

    CAS  PubMed  Google Scholar 

  • Mollinedo F, Gajate C . (2006a). Fas/CD95 death receptor and lipid rafts: new targets for apoptosis-directed cancer therapy. Drug Resist Updat 9: 51–73.

    Article  CAS  Google Scholar 

  • Mollinedo F, Gajate C . (2006b). FasL-independent activation of Fas. In: Wajant H (ed). Fas Signaling. Landes Bioscience and Springer Science: Georgetown, TX. Chapter 2, pp 13–27.

    Chapter  Google Scholar 

  • Nieto-Miguel T, Gajate C, Gonzalez-Camacho F, Mollinedo F . (2008). Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy. Oncogene 27: 1779–1787.

    Article  CAS  Google Scholar 

  • Nieto-Miguel T, Gajate C, Mollinedo F . (2006). Differential targets and subcellular localization of antitumor alkyl-lysophospholipid in leukemic versus solid tumor cells. J Biol Chem 281: 14833–14840.

    Article  CAS  Google Scholar 

  • Orlowski RZ, Kuhn DJ . (2008). Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14: 1649–1657.

    Article  CAS  Google Scholar 

  • Schon A, Freire E . (1989). Thermodynamics of intersubunit interactions in cholera toxin upon binding to the oligosaccharide portion of its cell surface receptor, ganglioside GM1. Biochemistry 28: 5019–5024.

    Article  CAS  Google Scholar 

  • Shima Y, Nishimoto N, Ogata A, Fujii Y, Yoshizaki K, Kishimoto T . (1995). Myeloma cells express Fas antigen/APO-1 (CD95) but only some are sensitive to anti-Fas antibody resulting in apoptosis. Blood 85: 757–764.

    CAS  PubMed  Google Scholar 

  • Westendorf JJ, Lammert JM, Jelinek DF . (1995). Expression and function of Fas (APO-1/CD95) in patient myeloma cells and myeloma cell lines. Blood 85: 3566–3576.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Ministerio de Ciencia e Innovación (SAF2008-02251, SAF2005-04293, RD06/0020/1037 – Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III), Fondo de Investigación Sanitaria and European Commission (FIS-FEDER 06/0813, 04/0843), Junta de Castilla y León (CSI01A08, SAN673/SA32/08, and GR15-Experimental Therapeutics and Translational Oncology Program), Fundación de Investigación Médica Mutua Madrileña (FMM) and Fundación ‘la Caixa’ (BM05-30-0). MRS is recipient of a predoctoral fellowship from the Fundação para a Ciencia e Tecnologia (Ministério da Ciencia, Tecnología e Ensino Superior of Portugal). CG is supported by the Ramón y Cajal Program from the Ministerio de Ciencia e Innovación of Spain. We thank Lienhard Schmitz (University of Bern, Switzerland) for providing the stably transfected Jurkat FADD-DN cell line.

Author information

Authors and Affiliations

  1. Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain

    M Reis-Sobreiro, C Gajate & F Mollinedo

  2. Unidad de Investigación, Hospital Universitario de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain

    C Gajate

Authors
  1. M Reis-Sobreiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Gajate
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Mollinedo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Mollinedo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reis-Sobreiro, M., Gajate, C. & Mollinedo, F. Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions. Oncogene 28, 3221–3234 (2009). https://doi.org/10.1038/onc.2009.183

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.183

Keywords

This article is cited by

Search

Advanced search

Quick links