TY - JOUR
T1 - Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis
AU - Flaveny, Colin A.
AU - Griffett, Kristine
AU - El-Gendy, Bahaa El Dien M.
AU - Kazantzis, Melissa
AU - Sengupta, Monideepa
AU - Amelio, Antonio L.
AU - Chatterjee, Arindam
AU - Walker, John
AU - Solt, Laura A.
AU - Kamenecka, Theodore M.
AU - Burris, Thomas P.
N1 - Publisher Copyright:
© 2015 Elsevier Inc..
PY - 2015/7/13
Y1 - 2015/7/13
N2 - Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. Incancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach. Flaveny etal. design a liver-X-receptor (LXR) inverse agonist SR9243 that induces LXR-corepressor interaction. SR9243 displays broad anti-tumor activity and a favorable safety profile by selectively targeting the Warburg effect and lipogenesis.
AB - Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. Incancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach. Flaveny etal. design a liver-X-receptor (LXR) inverse agonist SR9243 that induces LXR-corepressor interaction. SR9243 displays broad anti-tumor activity and a favorable safety profile by selectively targeting the Warburg effect and lipogenesis.
UR - https://www.scopus.com/pages/publications/84937475615
U2 - 10.1016/j.ccell.2015.05.007
DO - 10.1016/j.ccell.2015.05.007
M3 - Article
C2 - 26120082
AN - SCOPUS:84937475615
SN - 1535-6108
VL - 28
SP - 42
EP - 56
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -