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  • Original Paper
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Redistribution of CD95, DR4 and DR5 in rafts accounts for the synergistic toxicity of resveratrol and death receptor ligands in colon carcinoma cells

Oncogene volume 23, pages 8979–8986 (2004)Cite this article

Abstract

The natural phytoalexin resveratrol (3, 5, 4′-trihydroxystilbene) exhibits both chemopreventive and antitumor activities through a variety of mechanisms. We have shown previously that resveratrol-induced apoptosis of a human colon cancer cell line involved the redistribution of CD95 (Fas/Apo-1) into lipid rafts. Here, we show that, in colon cancer cells that resist to resveratrol-induced apoptosis, the polyphenol also induces a redistribution of death receptors into lipid rafts. This effect sensitizes these tumor cells to death receptor-mediated apoptosis. In resveratrol-treated cells, tumor necrosis factor (TNF), anti-CD95 antibodies and TNF-related apoptosis-inducing ligand (TRAIL) activate a caspase-dependent death pathway that escapes Bcl-2-mediated inhibition. Resveratrol does not enhance the number of death receptors at the surface of tumor cells but induces their redistribution into lipid rafts and facilitates the caspase cascade activation in response to death receptor stimulation. The cholesterol sequestering agent nystatin prevents resveratrol-induced death receptor redistribution and cell sensitization to death receptor stimulation. Thus, whatever its ability to induce apoptosis in a tumor cell, resveratrol induces redistribution of death receptors into lipid rafts. This redistribution sensitizes the cells to death receptor stimulation. Such a sensitizing effect may be of therapeutic interest if TRAIL agonists are introduced in clinics.

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Acknowledgements

This work was supported by a grant of the Ligue Nationale Contre le Cancer (ES), the BIVB and the ‘Conseil Régional de Bourgogne’ (DD), the Ligue Bourguignonne contre le cancer (NL) and the Association pour la Recherche sur le Cancer (CR). We are grateful to C Humbert (Centre de Microscopie Appliquée à la Biologie, Dijon, France) and A Hamman for excellent technical assistance on confocal laser microscope studies.

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Authors and Affiliations

  1. GDR-CNRS 2583, IFR92 Laboratory of Molecular and Cellular Biology (LBMC), University of Burgundy, 6 Boulevard Gabriel, Dijon, 21000, France

    Dominique Delmas & Norbert Latruffe

  2. INSERM U517, IFR100 Faculty of Medicine, 7 Boulevard Jeanne d'Arc, Dijon, 21000, France

    Cédric Rébé, Olivier Micheau & Eric Solary

  3. INSERM U498, IFR100, CHU Le Bocage, BP1542, Dijon, 21034, France

    Anne Athias & Philippe Gambert

  4. INSERM E9910, Institut Claudius Regaud, Toulouse, 31052, France

    Solène Grazide & Guy Laurent

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  1. Dominique Delmas
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Correspondence to Eric Solary.

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Delmas, D., Rébé, C., Micheau, O. et al. 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 (2004). https://doi.org/10.1038/sj.onc.1208086

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