Sensitisation of cancer cells to radiotherapy by serine and glycine starvation

Falcone, M. et al. (2022) Sensitisation of cancer cells to radiotherapy by serine and glycine starvation. British Journal of Cancer, 127(10), pp. 1773-1786. (doi: 10.1038/s41416-022-01965-6) (PMID:36115879)

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Abstract

Background: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells. Methods: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq. Results: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle. Conclusion: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Newman, Dr Alice and Blyth, Professor Karen and Athineos, Mr Dimitris and Falcone, Dr Mattia and Chalmers, Professor Anthony and Huerta Uribe, Mr Alejandro and Maddocks, Professor Oliver and Papalazarou, Vasileios and Stevenson, Mrs Katrina
Authors: Falcone, M., Huerta Uribe, A., Papalazarou, V., Newman, A. C., Athineos, D., Stevenson, K., Sauvé, C.-E. G., Gao, Y., Kim, J. K., Del Latto, M., Kierstead, M., Wu, C., Smith, J. J., Romesser, P. B., Chalmers, A. J., Blyth, K., and Maddocks, O. D.K.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:British Journal of Cancer
Publisher:Springer Nature
ISSN:0007-0920
ISSN (Online):1532-1827
Published Online:17 September 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in British Journal of Cancer 127(10): 1773-1786
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190874CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076Institute of Cancer Sciences
171982Targeting Tumour Metabolism for Cancer Therapy and Diagnosis.Oliver MaddocksCancer Research UK (CRUK)C53309/A19702Institute of Cancer Sciences
306407Glasgow RadNet CentreAnthony ChalmersCancer Research UK (CRUK)C16583/A28803CS - Clinical Trials Research