Sensitisation of cancer cells to radiotherapy by serine and glycine starvation Journal Article
| Authors: | Falcone, M.; Uribe, A. H.; 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.; Maddocks, O. D. K. |
| Article Title: | Sensitisation of cancer cells to radiotherapy by serine and glycine starvation |
| 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. © 2022, The Author(s). |
| Keywords: | adult; human tissue; human cell; nonhuman; pancreatic neoplasms; animal cell; mouse; phenotype; animal; metabolism; animals; mice; cell death; dna damage; cell cycle; serine; radiotherapy; in vivo study; cancer cell culture; in vitro study; transcriptomics; radiation response; immunocytochemistry; cancer cell; pancreas tumor; reactive oxygen metabolite; amino acid; antioxidant; antioxidants; amino acids; clonogenic assay; fluorescence activated cell sorting; histone h2ax; diet restriction; radiosensitization; glycine; cone beam computed tomography; x ray; clonogenesis; citric acid cycle; metabolomics; liquid chromatography-mass spectrometry; nucleotide metabolism; malonaldehyde; carbon metabolism; human; female; article; rna sequencing; colorectal cancer cell line; breast cancer cell line; organoid; pancreatic cancer cell line; hct 116 cell line; kpc cell line; 4t1 cell line; mda-mb-231 cell line; mda-mb-468 cell line; dld-1 cell line; sw480 cell line; eo771 cell line |
| Journal Title: | British Journal of Cancer |
| Volume: | 127 |
| Issue: | 10 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-11-09 |
| Start Page: | 1773 |
| End Page: | 1786 |
| Language: | English |
| DOI: | 10.1038/s41416-022-01965-6 |
| PUBMED: | 36115879 |
| PROVIDER: | scopus |
| PMCID: | PMC9643498 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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