Activation of LXR? Inhibits Tumor Respiration and is Synthetically Lethal with Bcl-xL Inhibition

ABSTRACT: Liver-X-receptor agonists (LXR) are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effects of BH3-mimetics in solid tumor malignancies. Extracellular flux analysis and carbon tracing experiments (U-13C-Glucose and U-13C-Glutamine) reveal that within 5h activation of LXRb results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing

SUBMITTER: Dr. Trang Nguyen 

PROVIDER: S-SCDT-EMM-2019-10769 | biostudies-other |

REPOSITORIES: biostudies-other