Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Gregory Segala 1 Marion David 2 Philippe de Medina 1 Mathias Poirot 1 Nizar Serhan 3 François Vergez 1 Aurélie Mougel 1 Estelle Saland 1 Kévin Carayon 4 Julie Leignadier 1 Nicolas Caron 5 Maud Voisin 1 Julia Cherier 6 Laetitia Ligat 7 Frederic Lopez 1 Emmanuel Noguer 1 Arnaud Rives 8 Bruno Payre 9 Talal Al Saati 10 Antonin Lamaziere 11 Gaëtan Despres 11 Jean-Marc Lobaccaro 12 Silvère Baron 12 Cécile Demur 13 Fabienne de Toni 1 Clément Larrue 1 Héléna Boutzen 1 Fabienne Thomas 14 Jean-Emmanuel Sarry 15 Marie Tosolini 1 Didier Picard 16 Michel Record 17 Christian Recher 18 Marc Poirot 1, * Sandrine Silvente-Poirot 1, *
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.
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Submitted on : Tuesday, November 26, 2019 - 12:17:12 PM
Last modification on : Thursday, November 28, 2019 - 1:19:57 AM

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Gregory Segala, Marion David, Philippe de Medina, Mathias Poirot, Nizar Serhan, et al.. Dendrogenin A drives LXR to trigger lethal autophagy in cancers. Nature Communications, Nature Publishing Group, 2017, 8 (1), pp.1903. ⟨10.1038/s41467-017-01948-9⟩. ⟨inserm-02380591⟩

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