Team "Cholesterol Metabolism and Therapeutic Innovations", Cancer Research Center of Toulouse, UMR 1037 INSERM-University of Toulouse, Toulouse, France; Cancer Research Center of Toulouse, UMR 1037 INSERM-University of Toulouse, Toulouse, France.
Biochem Pharmacol. 2018 Jul;153:75-81. doi: 10.1016/j.bcp.2018.01.046. Epub 2018 Feb 1.
Dendrogenin A (DDA) is a mammalian cholesterol metabolite recently identified that displays tumor suppressor properties. The discovery of DDA has revealed the existence in mammals of a new metabolic branch in the cholesterol pathway centered on 5,6α-epoxycholesterol and bridging cholesterol metabolism with histamine metabolism. Metabolic studies showed a drop in DDA levels in cancer cells and tumors compared to normal cells, suggesting a link between DDA metabolism deregulation and oncogenesis. Importantly, complementation of cancer cells with DDA induced 1) cancer cell re-differentiation, 2) blockade of 6-oxo-cholestan-3β,5α-diol (OCDO) production, an endogenous tumor promoter and 3) lethal autophagy in tumors. Importantly, by binding the liver X receptor (LXR), DDA activates the expression of genes controlling autophagy. These genes include NR4A1, NR4A3, LC3 and TFEB. The canonical LXR ligands 22(R)hydroxycholesterol, TO901317 and GW3965 did not induce these effects indicating that DDA delineates a new class of selective LXR modulator (SLiM). The induction of lethal autophagy by DDA was associated with the accumulation in cancer cells of lysosomes and of the pro-lysosomal cholesterol precursor zymostenol due to the inhibition of the 3β-hydroxysteroid-ΔΔ-isomerase enzyme (D8D7I). The anti-cancer efficacy of DDA was established on different mouse and human cancers such as breast cancers, melanoma and acute myeloid leukemia, including patient derived xenografts, and did not discriminate bulk cancer cells from cancer cell progenitors. Together these data highlight that the mammalian metabolite DDA is a promising anticancer compound with a broad range of anticancer applications. In addition, DDA and LXR are new actors in the transcriptional control of autophagy and DDA being a "first in line" driver of lethal autophagy in cancers via the LXR.
丹酚酸 A（DDA）是一种最近被发现的哺乳动物胆固醇代谢物，具有肿瘤抑制特性。DDA 的发现揭示了哺乳动物中胆固醇途径的一个新的代谢分支的存在，该分支以 5,6α-环氧胆固醇为中心，并将胆固醇代谢与组氨酸代谢联系起来。代谢研究表明，与正常细胞相比，癌细胞和肿瘤中的 DDA 水平下降，这表明 DDA 代谢失调与癌变之间存在联系。重要的是，用 DDA 补充癌细胞导致 1）癌细胞重新分化，2）阻断内源性肿瘤促进剂 6-氧代-胆甾烷-3β,5α-二醇（OCDO）的产生，以及 3）肿瘤中的致死性自噬。重要的是，通过与肝 X 受体（LXR）结合，DDA 激活控制自噬的基因的表达。这些基因包括 NR4A1、NR4A3、LC3 和 TFEB。DDA 不诱导这些效应的经典 LXR 配体 22(R)羟基胆固醇、TO901317 和 GW3965 表明 DDA 划定了一类新的选择性 LXR 调节剂（SLiM）。DDA 诱导的致死性自噬与癌细胞中溶酶体和前溶酶体胆固醇前体zymostenol 的积累有关，这是由于 3β-羟甾醇-ΔΔ-异构酶（D8D7I）的抑制。DDA 在不同的小鼠和人类癌症（如乳腺癌、黑色素瘤和急性髓系白血病）中的抗癌疗效得到了证实，包括患者来源的异种移植物，并且不区分癌症细胞和癌症细胞祖细胞。这些数据共同表明，哺乳动物代谢物 DDA 是一种很有前途的抗癌化合物，具有广泛的抗癌应用。此外，DDA 和 LXR 是自噬转录控制的新因素，并且 DDA 通过 LXR 成为癌症中致死性自噬的“一线驱动因素”。
