Dendrogenin A drives LXR to trigger lethal autophagy in cancers.
Gregory SegalaMarion DavidPhilippe de MedinaMathias C PoirotNizar SerhanFrançois VergezAurelie MougelEstelle SalandKevin CarayonJulie LeignadierNicolas CaronMaud VoisinJulia CherierLaetitia LigatFrederic LopezEmmanuel NoguerArnaud RivesBruno PayréTalal Al SaatiAntonin LamaziereGaëtan DespresJean Marc A LobaccaroSilvere BaronCecile DemurFabienne de ToniClément LarrueHelena BoutzenFabienne ThomasJean-Emmanuel SarryMarie TosoliniDidier PicardMichel RecordChristian RécherMarc PoirotSandrine Silvente-PoirotPublished in: Nature communications (2017)
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.
Keyphrases
- cell death
- acute myeloid leukemia
- endoplasmic reticulum stress
- oxidative stress
- signaling pathway
- allogeneic hematopoietic stem cell transplantation
- clinical evaluation
- cell cycle arrest
- diabetic rats
- high glucose
- pi k akt
- simultaneous determination
- tandem mass spectrometry
- solid phase extraction
- high resolution mass spectrometry