puc-header

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

47 Pages Posted: 13 Jun 2018 Publication Status: Review Complete

See all articles by Chiaki Tsuge Ishida

Chiaki Tsuge Ishida

Columbia University - Department of Pathology and Cell Biology

Yiru Zhang

Columbia University - Department of Pathology and Cell Biology

Elena Bianchetti

Columbia University - Department of Pathology and Cell Biology; Columbia University - Center for Motor Neuron Biology and Disease

Chang Shu

Columbia University - Department of Pathology and Cell Biology

Maria J. Sanchez-Quintero

Columbia University Medical Center, Department of Neurology

Catarina M. Quinzii

Columbia University Medical Center, Department of Neurology

Mike-Andrew Westhoff

Ulm University - Department of Pediatrics and Adolescent Medicine

Georg Karpel-Massler

Ulm University - Department of Neurosurgery

Peter Canoll

Columbia University - Department of Pathology and Cell Biology

Markus Siegelin

Columbia University - Department of Pathology and Cell Biology

More...

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.

Suggested Citation

Ishida, Chiaki Tsuge and Zhang, Yiru and Bianchetti, Elena and Shu, Chang and Sanchez-Quintero, Maria J. and Quinzii, Catarina M. and Westhoff, Mike-Andrew and Karpel-Massler, Georg and Canoll, Peter and Siegelin, Markus, Activation of Lxrβ Causes Metabolic Reprogramming and Sensitizes Solid Tumors to Bcl-xL Inhibition Mediated Apoptosis (2018). Available at SSRN: https://ssrn.com/abstract=3195357 or http://dx.doi.org/10.2139/ssrn.3195357
This version of the paper has not been formally peer reviewed.

Chiaki Tsuge Ishida

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Yiru Zhang

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Elena Bianchetti

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Columbia University - Center for Motor Neuron Biology and Disease

New York, NY
United States

Chang Shu

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Maria J. Sanchez-Quintero

Columbia University Medical Center, Department of Neurology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032-3784
United States

Catarina M. Quinzii

Columbia University Medical Center, Department of Neurology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032-3784
United States

Mike-Andrew Westhoff

Ulm University - Department of Pediatrics and Adolescent Medicine

Albert-Einstein-Alee 11
Ulm, D-89081
Germany

Georg Karpel-Massler

Ulm University - Department of Neurosurgery

Albert-Einstein-Alee 11
Ulm, D-89081
Germany

Peter Canoll

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Markus Siegelin (Contact Author)

Columbia University - Department of Pathology and Cell Biology ( email )

New York, NY 10032
United States