Journal Article

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

Canoll, Peter, Zhang, Yiru, Torrini, Consuelo, Ishida, Chiaki Tsuge, Quinzii, Catarina M, Sanchez‐Quintero, Maria J, Kleiner, Giulio, Shang, Enyuan, Karpel‐Massler, Georg, Westhoff, Mike‐Andrew, Bianchetti, Elena, Shu, Chang, Siegelin, Markus D, Nguyen, Trang Thi Thu

2019

Overview

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. Synopsis Liver‐X‐receptor agonists display limited anti‐tumor activity. The present study uncovers the synthetic lethality triggered by combining activation of liver‐X‐receptor and Bcl‐xL inhibition. Activation of LXR‐receptors resulted in suppression of gene‐sets related to mitochondrial translation, metabolism, transcription and regulators of intrinsic apoptosis associated, with an increase in cholesterol efflux signature. In the TCGA datasets, high levels of the LXR target ABCA1 correlated with low levels of group of genes related to mitochondrial transcription, translation and metabolism. Liver‐X‐receptors activation led to early reprogramming of oxidative energy metabolism, resulting in energy deprivation and solid tumor cells sensitization to glucose withdrawal. Suppression of the electron transport chain by LXRβ activation lowered the apoptotic threshold and sensitized solid tumor cells to the cytotoxic effects of BH3‐mimetics. The combination treatment of ABT263 and LXR623 reduced tumor growth in patient‐derived xenograft model systems. Graphical Abstract Liver‐X‐receptor agonists display limited anti‐tumor activity. The present study uncovers the synthetic lethality triggered by combining activation of liver‐X‐receptor and Bcl‐xL inhibition.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Agonists / Analysis / Animals / Apoptosis / Apoptosis - drug effects / Astrocytes / bcl-X Protein - antagonists & inhibitors / Benzoates - metabolism / Benzylamines - metabolism / BH3 mimetics / Brain cancer / Brain research / Cancer / Carcinoma - drug therapy / Carcinoma - physiopathology / Care and treatment / Cell death / Cell Proliferation - drug effects / Cell Respiration - drug effects / Cellular stress response / Cholesterol / Colon / colon adenocarcinoma / Colon cancer / Colorectal cancer / Disease Models, Animal / electron transport chain / EMBO03 / EMBO08 / EMBO21 / FDA approval / Gene expression / Gene Expression Profiling / Genes / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - physiopathology / Gliomas / Glutamine / Humans / Indazoles - metabolism / Liver X Receptors - agonists / LXR agonist / Melanoma / Melanoma - drug therapy / Melanoma - physiopathology / Metabolism / Metabolites / Metabolomics / Mitochondria / Models, Theoretical / Nucleotides / Phosphorylation / Physiological aspects / Regulation / Respiration / Scholarships & fellowships / Solid tumors / Statistical analysis / Treatment Outcome / Tumors / Xenografts