Activation of Lxrβ Causes Metabolic Reprogramming and Sensitizes Solid Tumors to Bcl-xL Inhibition Mediated Apoptosis

Abstract

Liver-X-receptor agonists (LXR) have been shown to bear anti-tumor activity. However, their efficacy is limited and therefore additional strategies to further enhance their anti-cancer activity are warranted. By uncovering novel and unexpected mechanisms through transcriptome and gene set enrichment analysis coupled with global untargeted metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance the anti-proliferative effects of clinically validated as well as novel selective BH3-mimetics in solid tumor malignancies, including glioblastoma, colon carcinoma, melanoma and triple-receptor negative breast cancer. LXR agonists and ABT263 acted in a synergistic fashion to reduce proliferation of cancer cells, which was predominantly mediated by enhanced apoptosis. Inhibition of Bcl-xL was most relevant for the combination treatment to exert its effects. Extracellular flux analysis revealed that activation of LXRβ resulted in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, which occurred independent of cholesterol. Instead, LXR activation engages in a transcriptional program to suppress mitochondrial metabolism. In turn, this leads to a subsequent decline in ATP levels, culminating in endoplasmic reticulum stress with upregulation of pro-apoptotic Noxa in an ATF4 dependent manner. Consistently, siRNA mediated suppression of Noxa rescued from the combination treatment of BH3-mimetics and LXR agonists. In conventional and patient-derived xenograft models of colon carcinoma, melanoma and glioblastoma, the combination treatment of ABT263 and LXR agonists reduced 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.