Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl-xL inhibition.

ABSTRACT: Liver-X-receptor (LXR) agonists 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 effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U-¹³ C-glucose and U-¹³ C-glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomen

SUBMITTER: Nguyen TTT 

PROVIDER: S-EPMC6783693 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature