Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Maddocks, O. D.K. et al. (2017) Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature, 544(7650), pp. 372-376. (doi:10.1038/nature22056) (PMID:28425994)

Maddocks, O. D.K. et al. (2017) Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature, 544(7650), pp. 372-376. (doi:10.1038/nature22056) (PMID:28425994)

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Abstract

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Zhang, Mr Tong and Campbell, Dr Kirsteen and Vincent, Dr David and Athineos, Mr Dimitris and Vousden, Karen and Van Den Broek, Mr Niels and Cheung, Mr Eric and Blyth, Dr Karen and Ceteci, Dr Fatih and Kruiswijk, Dr Flore and Labuschagne, Dr Christiaan Fred and Mackay, Dr Gillian and Maddocks, Dr Oliver and Sansom, Professor Owen
Authors: Maddocks, O. D.K., Athineos, D., Cheung, E. C., Lee, P., Zhang, T., van den Broek, N. J.F., Mackay, G. M., Labuschagne, C. F., Gay, D., Kruiswijk, F., Blagih, J., Vincent, D. F., Campbell, K. J., Ceteci, F., Sansom, O. J., Blyth, K., and Vousden, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:19 April 2017
Copyright Holders:Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Nature 544(7650): 372-376
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
666241Targeting Tumour Metabolism for Cancer Therapy and Diagnosis.Oliver MaddocksCancer Research UK (CRUK)19702RI CANCER SCIENCES