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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