Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Gregory Segala (1) , Marion David (2) , Philippe de Médina (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 (1) , Jean-Emmanuel Sarry (14) , Marie Tosolini (1) , Didier Picard (15) , Michel Record (16) , Christian Recher (17) , Marc Poirot (1) , Sandrine Silvente-Poirot (1)

1 CRCT - Centre de Recherches en Cancérologie de Toulouse
2 Laboratoire de biologie clinique [Rouen]
3 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
4 LBPA - Laboratoire de Biologie et de Pharmacologie Appliquée
5 Société de Biotechnologie médicale - Affichem S.A. [Toulouse, France]
6 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
7 SCSV - Surfaces Cellulaires et Signalisation chez les Végétaux
8 LCC - Laboratoire de chimie de coordination
9 CMEAB - Centre de Microscopie Électronique Appliquée à la Biologie
10 ANEXPLO
11 UPMC - Université Pierre et Marie Curie - Paris 6
12 GReD - Génétique, Reproduction et Développement
13 Hematology Laboratory, Oncopole
14 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
15 Département de Biologie Cellulaire genève [Genève, Switzerland]
16 Phospholipides membranaires, signalisation cellulaire et lipoprotéines
17 Service Hématologie - IUCT-Oncopole [CHU Toulouse]

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.

Domaines: Sciences du Vivant [q-bio]; Cancer; Médecine humaine et pathologie; Endocrinologie et métabolisme; Sciences pharmaceutiques; Pharmacologie; Médicaments

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