James Wood
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
Authors
Salah Abdelrazig
Sergey Evseev
Catherine Ortori
Marcos Castellanos-Uribe
Professor SEAN MAY SEAN.MAY@NOTTINGHAM.AC.UK
Professor of Plant Cyber Infrastructure
David A. Barrett
Mohammed Diksin
Sajib Chakraborty
DONG-HYUN KIM Dong-hyun.Kim@nottingham.ac.uk
Associate Professor
RICHARD GRUNDY richard.grundy@nottingham.ac.uk
Professor of Paediatric Neuro-Oncology
RUMAN RAHMAN RUMAN.RAHMAN@NOTTINGHAM.AC.UK
Associate Professor
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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Lipoprotein Deprivation In Paediatric Diffuse Glioma 2022
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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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