p53-mediated adaptation to serine starvation is retained by a common tumour-derived mutant

Humpton, T. J., Hock, A. K., Maddocks, O. D.K. and Vousden, K. H. (2018) p53-mediated adaptation to serine starvation is retained by a common tumour-derived mutant. Cancer and Metabolism, 6, 18. (doi:10.1186/s40170-018-0191-6) (PMID:30524726) (PMCID:PMC6276204)

Humpton, T. J., Hock, A. K., Maddocks, O. D.K. and Vousden, K. H. (2018) p53-mediated adaptation to serine starvation is retained by a common tumour-derived mutant. Cancer and Metabolism, 6, 18. (doi:10.1186/s40170-018-0191-6) (PMID:30524726) (PMCID:PMC6276204)

[img]
Preview
Text
177800.pdf - Published Version
Available under License Creative Commons Attribution.

2MB

Abstract

Background: In response to oncogenic stress, the tumour suppressor protein p53 can induce the elimination of cells through induction of cell death or senescence, helping to restrain malignant progression. Conversely, under nutrient stress, p53 can protect cells by supporting metabolic adaptation. Many cancers express mutant p53 proteins that have lost the cell-elimination properties of wild-type p53. However, a previous report showed that a tumour-derived mutant can retain the ability to support cells under glutamine starvation. Results: We show that a commonly occurring p53 mutant, R248W, retains wild-type ability to support survival under serine starvation. R248W, but not R175H, can engage p21 and MDM2, which both function to limit oxidative stress and facilitate the switch to de novo serine synthesis. In vivo, the growth of R248W-expressing tumours is resistant to dietary depletion of serine and glycine, correlating with an increased capacity to limit ROS compared to tumours expressing R175H. Human cancers expressing this p53 mutant show a worse outcome. Conclusion: Our work shows that mutant p53s can selectively retain wild-type p53 functions that allow adaptation to serine starvation through the activation of antioxidant defence pathways. Tumours containing this p53 mutation are resistant to serine-limited conditions and less responsive to therapy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hock, Dr Andreas and Maddocks, Dr Oliver and Vousden, Karen
Authors: Humpton, T. J., Hock, A. K., Maddocks, O. D.K., and Vousden, K. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer and Metabolism
Publisher:BioMed Central
ISSN:2049-3002
ISSN (Online):2049-3002
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cancer and Metabolism 6: 18
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

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