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

EMBO Mol Med. 2019 Oct;11(10):e10769. doi: 10.15252/emmm.201910769. Epub 2019 Aug 29.

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 phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up-regulates pro-apoptotic Noxa in an ATF4-dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient-derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies.

Keywords: BH3 mimetics; LXR agonist; colon adenocarcinoma; electron transport chain; glioblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzoates / metabolism
  • Benzylamines / metabolism
  • Carcinoma / drug therapy
  • Carcinoma / physiopathology*
  • Cell Proliferation / drug effects
  • Cell Respiration / drug effects*
  • Disease Models, Animal
  • Gene Expression Profiling
  • Glioblastoma / drug therapy
  • Glioblastoma / physiopathology*
  • Humans
  • Indazoles / metabolism
  • Liver X Receptors / agonists*
  • Melanoma / drug therapy
  • Melanoma / physiopathology*
  • Metabolomics
  • Models, Theoretical
  • Treatment Outcome
  • bcl-X Protein / antagonists & inhibitors*

Substances

  • 2-(2-chloro-4-fluorobenzyl)-3-(4-fluorophenyl)-7-(trifluoromethyl)-2H-indazole
  • BCL2L1 protein, human
  • Benzoates
  • Benzylamines
  • GW 3965
  • Indazoles
  • Liver X Receptors
  • bcl-X Protein

Associated data

  • GEO/GSE110151
  • GEO/GSE110152