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Lipoprotein Deprivation Reveals a Cholesterol-Dependent Therapeutic Vulnerability in Diffuse Glioma Metabolism

Wood, James; Abdelrazig, Salah; Evseev, Sergey; Ortori, Catherine; Castellanos-Uribe, Marcos; May, Sean T.; Barrett, David A.; Diksin, Mohammed; Chakraborty, Sajib; Kim, Dong Hyun; Grundy, Richard G.; Rahman, Ruman

Lipoprotein Deprivation Reveals a Cholesterol-Dependent Therapeutic Vulnerability in Diffuse Glioma Metabolism Thumbnail


Authors

James Wood

Salah Abdelrazig

Sergey Evseev

Catherine Ortori

Marcos Castellanos-Uribe

David A. Barrett

Mohammed Diksin

Sajib Chakraborty

RICHARD GRUNDY richard.grundy@nottingham.ac.uk
Professor of Paediatric Neuro-Oncology



Abstract

Poor outcomes associated with diffuse high-grade gliomas occur in both adults and children, despite substantial progress made in the molecular characterisation of the disease. Targeting the metabolic requirements of cancer cells represents an alternative therapeutic strategy to overcome the redundancy associated with cell signalling. Cholesterol is an integral component of cell membranes and is required by cancer cells to maintain growth and may also drive transformation. Here, we show that removal of exogenous cholesterol in the form of lipoproteins from culture medium was detrimental to the growth of two paediatric diffuse glioma cell lines, KNS42 and SF188, in association with S-phase elongation and a transcriptomic program, indicating dysregulated cholesterol homeostasis. Interrogation of metabolic perturbations under lipoprotein-deficient conditions revealed a reduced abundance of taurine-related metabolites and cholesterol ester species. Pharmacological reduction in intracellular cholesterol via decreased uptake and increased export was simulated using the liver X receptor agonist LXR-623, which reduced cellular viability in both adult and paediatric models of diffuse glioma, although the mechanism appeared to be cholesterol-independent in the latter. These results provide proof-of-principle for further assessment of liver X receptor agonists in paediatric diffuse glioma to complement the currently approved therapeutic regimens and expand the options available to clinicians to treat this highly debilitating disease.

Citation

Wood, J., Abdelrazig, S., Evseev, S., Ortori, C., Castellanos-Uribe, M., May, S. T., …Rahman, R. (2022). Lipoprotein Deprivation Reveals a Cholesterol-Dependent Therapeutic Vulnerability in Diffuse Glioma Metabolism. Cancers, 14(16), Article 3873. https://doi.org/10.3390/cancers14163873

Journal Article Type Article
Acceptance Date Aug 9, 2022
Online Publication Date Aug 11, 2022
Publication Date Aug 1, 2022
Deposit Date Aug 11, 2022
Publicly Available Date Aug 11, 2022
Journal Cancers
Electronic ISSN 2072-6694
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 14
Issue 16
Article Number 3873
DOI https://doi.org/10.3390/cancers14163873
Keywords diffuse glioma, metabolism, lipoprotein, cholesterol, LXR agonists
Public URL https://nottingham-repository.worktribe.com/output/9903352
Publisher URL https://www.mdpi.com/2072-6694/14/16/3873

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