Dendrogenin A drives LXR to trigger lethal autophagy in cancers

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 Voisin, Julia Cherier, Laetitia Ligat, Frederic Lopez, Emmanuel Noguer, Arnaud Rives, Bruno Payré, Talal al Saati, Antonin Lamaziere, Gaëtan Despres, Jean-Marc Lobaccaro, Silvere Baron, Cecile Demur, Fabienne de Toni, Clément Larrue, Helena Boutzen, Fabienne Thomas, Jean-Emmanuel Sarry, Marie Tosolini, Didier Picard, Michel Record, Christian Récher (), Marc Poirot () and Sandrine Silvente-Poirot ()
Additional contact information
Gregory Segala: UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team
Marion David: UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team
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
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

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01948-9

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