McGregor, G. H. et al. (2020) Targeting the metabolic response to statin-mediated oxidative stress produces a synergistic anti-tumor response. Cancer Research, 80(2), pp. 175-188. (doi: 10.1158/0008-5472.CAN-19-0644) (PMID:31562248)
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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 |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Nixon, Mr Colin 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 and Campbell, Dr Andrew |
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 > School 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 80(2):175-188 |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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