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Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Author

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  • Gregory Segala

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team
    Département de Biologie Cellulaire, Université de Genève)

  • Marion David

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team
    UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia)

  • Philippe de Medina

    (AFFICHEM)

  • Mathias C. Poirot

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Nizar Serhan

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • François Vergez

    (Service d’Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse)

  • Aurelie Mougel

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Estelle Saland

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia)

  • Kevin Carayon

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Julie Leignadier

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Nicolas Caron

    (AFFICHEM)

  • Maud Voisin

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Julia Cherier

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Laetitia Ligat

    (UMR 1037-CRCT, Pole Technologique)

  • Frederic Lopez

    (UMR 1037-CRCT, Pole Technologique)

  • Emmanuel Noguer

    (AFFICHEM)

  • Arnaud Rives

    (AFFICHEM)

  • Bruno Payré

    (Centre de Microscopie Electronique Appliquée à la Biologie)

  • Talal al Saati

    (INSERM-US006 ANEXPLO/CREFRE F-31024)

  • Antonin Lamaziere

    (Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités-UPMC, CHU Saint-Antoine)

  • Gaëtan Despres

    (Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités-UPMC, CHU Saint-Antoine)

  • Jean-Marc Lobaccaro

    (Université de Clermont Auvergne, CNRS, INSERM, GReD)

  • Silvere Baron

    (Université de Clermont Auvergne, CNRS, INSERM, GReD)

  • Cecile Demur

    (Service d’Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse)

  • Fabienne de Toni

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia)

  • Clément Larrue

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia)

  • Helena Boutzen

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia)

  • Fabienne Thomas

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Dose Individualisation of Anticancer Drugs Team)

  • Jean-Emmanuel Sarry

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia)

  • Marie Tosolini

    (UMR 1037-CRCT, Pole Technologique)

  • Didier Picard

    (Département de Biologie Cellulaire, Université de Genève)

  • Michel Record

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Christian Récher

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia
    Service d’Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse)

  • Marc Poirot

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

  • Sandrine Silvente-Poirot

    (UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team)

Abstract

Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressor properties. Here, we explored its efficacy and mechanism of cell death in melanoma and acute myeloid leukemia (AML). We found that DDA induced lethal autophagy in vitro and in vivo, including primary AML patient samples, independently of melanoma Braf status or AML molecular and cytogenetic classifications. DDA is a partial agonist on liver-X-receptor (LXR) increasing Nur77, Nor1, and LC3 expression leading to autolysosome formation. Moreover, DDA inhibited the cholesterol biosynthesizing enzyme 3β-hydroxysterol-Δ8,7-isomerase (D8D7I) leading to sterol accumulation and cooperating in autophagy induction. This mechanism of death was not observed with other LXR ligands or D8D7I inhibitors establishing DDA selectivity. The potent anti-tumor activity of DDA, its original mechanism of action and its low toxicity support its clinical evaluation. More generally, this study reveals that DDA can direct control a nuclear receptor to trigger lethal autophagy in cancers.

Suggested Citation

  • Gregory Segala & Marion David & Philippe de Medina & Mathias C. Poirot & Nizar Serhan & François Vergez & Aurelie Mougel & Estelle Saland & Kevin Carayon & Julie Leignadier & Nicolas Caron & Maud Vois, 2017. "Dendrogenin A drives LXR to trigger lethal autophagy in cancers," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01948-9
    DOI: 10.1038/s41467-017-01948-9
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