Liver X receptor inhibition potentiates mitotane-induced adrenotoxicity in ACC.
- Warde KM Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
- Schoenmakers E Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science-University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
- Ribes Martinez E Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
- Lim YJ Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
- Leonard M Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
- Lawless SJ Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
- O'Shea P Department of Clinical Biochemistry, Galway University Hospitals, Saolta Hospitals Group, Galway, Ireland.
- Chatterjee KV Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science-University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
- Gurnell M Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science-University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
- Hantel C Department of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.
- Dennedy MC Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
- 2020-04-11
Published in:
- Endocrine-related cancer. - 2020
English
Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first-line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40 and 50 µM) induced dose-dependent cell death; however, in MUC-1, this only occurred at a supratherapeutic concentration (200 µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1; however, combination treatment with mitotane attenuated this effect. Intracellular free-cholesterol levels were associated with increased cytotoxicity in H295R (r2 = 0.5210) and MUC-1 (r2 = 0.9299) cells. While both cell lines exhibited similar levels of free cholesterol at baseline, H295R were cholesterol ester rich, whereas MUC-1 were cholesterol ester poor. We highlight the importance of LXRα mediated cholesterol metabolism in the management of ACC, drawing attention to its role in the therapeutics of mitotane sensitive tumours. We also demonstrate significant differences in cholesterol storage between mitotane sensitive and resistant disease.
- Language
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- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1530/ERC-20-0031
- PMID 32276262
- Persistent URL
- https://sonar.ch/global/documents/47723
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