TY - JOUR
T1 - LXR stimulates a metabolic switch and reveals cholesterol homeostasis as a statin target in Tasmanian devil facial tumor disease
AU - Ikonomopoulou, Maria P.
AU - Lopez-Mancheño, Yaiza
AU - Novelle, Marta G.
AU - Martinez-Uña, Maite
AU - Gangoda, Lahiru
AU - Pal, Martin
AU - Costa-Machado, Luis Filipe
AU - Fernandez-Marcos, Pablo Jose
AU - Ramm, Grant A.
AU - Fernandez-Rojo, Manuel Alejandro
PY - 2021/3/16
Y1 - 2021/3/16
N2 - 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.
AB - 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.
KW - AKT/mTOR
KW - DFTD
KW - LXR
KW - atorvastatin
KW - cholesterol
KW - energy metabolism
UR - https://www.mendeley.com/catalogue/ea258dac-756e-3f21-9196-3a14cd59b1be/
U2 - 10.1016/j.celrep.2021.108851
DO - 10.1016/j.celrep.2021.108851
M3 - Article
C2 - 33730574
VL - 34
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 11
M1 - 108851
ER -