QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; The University of Queensland, Brisbane, QLD, Australia; Translational Venomics Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain.
Hepatic Regenerative Medicine Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain.
Cell Rep. 2021 Mar 16;34(11):108851. doi: 10.1016/j.celrep.2021.108851.
Devil facial tumor disease (DFTD) and its lack of available therapies are propelling the Tasmanian devil population toward extinction. This study demonstrates that cholesterol homeostasis and carbohydrate energy metabolism sustain the proliferation of DFTD cells in a cell-type-dependent manner. In addition, we show that the liver-X nuclear receptor-β (LXRβ), a major cholesterol cellular sensor, and its natural ligand 24S-hydroxycholesterol promote the proliferation of DFTD cells via a metabolic switch toward aerobic glycolysis. As a proof of concept of the role of cholesterol homeostasis on DFTD proliferation, we show that atorvastatin, an FDA-approved statin-drug subtype used against human cardiovascular diseases that inhibits cholesterol synthesis, shuts down DFTD energy metabolism and prevents tumor growth in an in vivo DFTD-xenograft model. In conclusion, we show that intervention against cholesterol homeostasis and carbohydrate-dependent energy metabolism by atorvastatin constitutes a feasible biochemical treatment against DFTD, which may assist in the conservation of the Tasmanian devil.
恶魔面部肿瘤病（DFTD）及其缺乏可用的治疗方法正在促使塔斯马尼亚恶魔种群走向灭绝。本研究表明胆固醇稳态和碳水化合物能量代谢以细胞类型依赖的方式维持 DFTD 细胞的增殖。此外，我们表明肝 X 核受体-β（LXRβ），一种主要的胆固醇细胞传感器，及其天然配体 24S-羟基胆固醇通过代谢转换促进有氧糖酵解促进 DFTD 细胞的增殖。作为胆固醇稳态对 DFTD 增殖作用的概念验证，我们表明阿托伐他汀，一种 FDA 批准的他汀类药物亚型，用于治疗人类心血管疾病，抑制胆固醇合成，关闭 DFTD 能量代谢，并防止体内 DFTD 异种移植模型中的肿瘤生长。总之，我们表明，阿托伐他汀对胆固醇稳态和碳水化合物依赖的能量代谢的干预构成了针对 DFTD 的可行的生化治疗方法，这可能有助于保护塔斯马尼亚恶魔。
