期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01948-9
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资金
- Institut National de la Recherche Medicale
- university of Toulouse III
- Agence Nationale pour la Recherche [ANR-11-RPIB-015-02 DAML, ANR-11-PHUC-0001, ANR-10-LABX-57]
- Ministere de la jeunesse, de l'education nationale et de la Recherche [03L152]
- Onco San Tech (projet DEMODA) [RMN13001BBA]
- Ministere Francais de la Recherche
- Association pour la Recherche sur le Cancer [DOC20110602926]
- Agence Nationale de la Recherche (ANR) [ANR-11-PHUC-0001] Funding Source: Agence Nationale de la Recherche (ANR)
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 3 beta-hydroxysterol-Delta(8,7)-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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