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Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells

Oncogene volume 29, pages 2712–2723 (2010)Cite this article

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Abstract

Cholesterol is a structural component of lipid rafts within the plasma membrane. These domains, used as platforms for various signaling molecules, regulate cellular processes including cell survival. Cholesterol contents are tightly correlated with the structure and function of lipid rafts. Liver X receptors (LXRs) have a central role in the regulation of cholesterol homeostasis within the cell. Therefore, we investigated whether these nuclear receptors could modulate lipid raft signaling and consequently alter prostate cancer (PCa) cell survival. Treatment with the synthetic LXR agonist T0901317 downregulated the AKT survival pathway and thus induced apoptosis of LNCaP PCa cells in both xenografted nude mice and cell culture. The decrease in tumor cholesterol content resulted from the upregulation of ABCG1 and the subsequent increase in reverse cholesterol transport. RNA interference experiments showed that these effects were mediated by LXRs. Atomic force microscopy scanning of the inner plasma membrane sheet showed smaller and thinner lipid rafts after LXR stimulation, associated with the downregulation of AKT phosphorylation in these lipid rafts. Replenishment of cell membranes with exogenous cholesterol antagonized these effects, showing that cholesterol is a key modulator in this process. Altogether, pharmacological modulation of LXR activity could thus reduce prostate tumor growth by enhancing apoptosis in a lipid raft-dependent manner.

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Acknowledgements

This study was supported by Association de Recherche sur les Tumeurs Prostatiques, Ligue Allier contre le Cancer, FRM and Fondation BNP-Paribas research grants. A Pommier and E Viennois are funded by MNERT and Région Auvergne grants, respectively, and G Alves is funded by Région Auvergne program. We are grateful to ICCF—Imagerie Confocale Clermont-Ferrand—for the help in confocal analyses. We thank JP Saru and A De Haze for molecular biology technical assistance, and C Puchol and S Plantade for animal facilities. We also thank Dr P Val, Dr A Martinez, Dr L Morel and Dr C White for their help in the editing of the paper and for fruitful scientific discussions.

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Author notes

  1. S Baron and J M A Lobaccaro: These authors contributed equally to this work.

Authors and Affiliations

  1. Clermont Université, Université Blaise Pascal, Génétique Reproduction et Développement, Clermont-Ferrand, France

    A J C Pommier, G Alves, E Viennois, C Damon, F Caira, S Baron & J M A Lobaccaro

  2. CNRS, UMR 6247, GReD, Aubiere, France

    A J C Pommier, G Alves, E Viennois, G Marceau, C Damon, F Caira, S Baron & J M A Lobaccaro

  3. Centre de Recherche en Nutrition Humaine d’Auvergne, Clermont-Ferrand, France

    A J C Pommier, G Alves, E Viennois, F Caira, S Baron & J M A Lobaccaro

  4. UPR 2228 CNRS, Université Paris Descartes, Paris, France

    S Bernard

  5. Département d′Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France

    Y Communal

  6. Equipe d’Accueil EA975, Université d’Auvergne, Clermont-Ferrand, France

    B Sion

  7. Clermont Université, Université d’Auvergne, Génétique Reproduction et Développement, Clermont-Ferrand, France

    G Marceau

  8. Service de Biochimie, Centre Hospitalier Universitaire, Clermont-Ferrand, France

    G Marceau

  9. Service de Biochimie, Centre Hospitalier Universitaire, Nimes, France

    K Mouzat

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Correspondence to J M A Lobaccaro.

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Pommier, A., Alves, G., Viennois, E. et al. Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. Oncogene 29, 2712–2723 (2010). https://doi.org/10.1038/onc.2010.30

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