Targeting the metabolic response to statin-mediated oxidative stress produces a synergistic anti-tumor response

McGregor, G. H. et al. (2019) Targeting the metabolic response to statin-mediated oxidative stress produces a synergistic anti-tumor response. Cancer Research, (doi:10.1158/0008-5472.CAN-19-0644) (PMID:31562248) (Early Online Publication)

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Abstract

Statins are widely prescribed inhibitors of the mevalonate pathway, acting to lower systemic cholesterol levels. The mevalonate pathway is critical for tumorigenesis and is frequently upregulated in cancer. Nonetheless, reported effects of statins on tumor progression are ambiguous, making it unclear if statins, alone or in combination, can be used for chemotherapy. Here, using advanced mass spectrometry and isotope tracing, we showed that statins only modestly affected cancer cholesterol homeostasis. Instead, they significantly reduced synthesis and levels of another downstream product, the mitochondrial electron carrier coenzyme Q, both in cultured cancer cells and tumors. This compromised oxidative phosphorylation, causing severe oxidative stress. To compensate, cancer cells upregulated antioxidant metabolic pathways, including reductive carboxylation, proline synthesis, and cystine import. Targeting cystine import with an xCT transporter-lowering MEK inhibitor, in combination with statins, caused profound tumor cell death. Thus, statin-induced ROS production in cancer cells can be exploited in a combinatorial regimen.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nixon, Mr Colin and Campbell, Mr Andrew and Fey, Sigrid and Vazquez, Alexei and Tumanov, Dr Sergey and Sumpton, Mr David and Mackay, Dr Gillian and McGregor, Grace and Sansom, Professor Owen and Kamphorst, Dr Jurre
Authors: McGregor, G. H., Campbell, A. D., Fey, S. K., Tumanov, S., Sumpton, D., Rodriguez Blanco, G., Mackay, G., Nixon, C., Vazquez, A., Sansom, O. J., and Kamphorst, J. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:27 September 2019
Copyright Holders:Copyright © 2019 American Association for Cancer Research
First Published:First published in Cancer Research 2019
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170391The effect of tumour microenvironment on the metabolism of pancreatic cancer cellsJurre KamphorstCancer Research UK (CRUK)C50242/A17728CS - Beatson Institute for Cancer Research
190874CR-UK Centre renewalKaren VousdenNot Applicable (NA)C596/A18076Institute of Cancer Sciences