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.
Highlights
Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressor properties
In the melanoma cell lines B16F10 and SKMEL-28, dendrogenin A (DDA) induced tumor cell accumulation in sub G0/G1, and the appearance of characteristics of apoptosis (Supplementary Fig. 1c–g), DDA cytotoxicity measured for 48 and 72 h was not blocked by general caspase inhibitors or antioxidants which blocked lipoperoxidation and cholesterol epoxidation (Fig. 1c), suggesting that cell death is independent of apoptosis and cholesterol epoxide hydrolase (ChEH) inhibition
Analyses of the oxysterol profile of cells treated with DDA showed no accumulation in 5,6-EC as opposed to what was found with other ChEH inhibitors Tam and PBPE (Supplementary Fig. 1h)
Summary
Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressor properties. DDA inhibited the cholesterol biosynthesizing enzyme 3β-hydroxysterol-Δ8,7isomerase (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. UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Cholesterol Metabolism and Therapeutic Innovations Team, Toulouse, F-31037, France. 3 UMR 1037-CRCT, Université de Toulouse, INSERM, UPS, Chemoresistance, Stem Cells and Metabolism in Acute Myeloid Leukemia, Toulouse, F-31037, France. ChEH inhibitors such as the anticancer drug Tamoxifen (Tam), have been shown to induce tumor cell differentiation and death and survival macroautophagy (hereafter referred as to autophagy)[11,12,13,14,15,16]. We report the potent anti-tumor activity of DDA against human melanoma and acute myeloid leukemia (AML) both in vitro and in vivo, including primary tumors from AML patients. We describe its original mechanism of cytotoxicity, which involves the direct control of a nuclear receptor to trigger lethal autophagy
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