Patel, R. et al. (2022) Cyclocreatine suppresses creatine metabolism and impairs prostate cancer progression. Cancer Research, 82(14), pp. 2565-2575. (doi: 10.1158/0008-5472.CAN-21-1301) (PMID:35675421)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
273869.pdf - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. 1MB |
Abstract
Prostate cancer is the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of the tumour suppressors PTEN and SPRY2 (Sprouty 2), we identified enhanced creatine metabolism as a central component of progressive disease. Creatine treatment was associated with enhanced cellular basal respiration in vitro and increased tumour cell proliferation in vivo. Stable isotope tracing revealed that intracellular levels of creatine in prostate cancer cells are predominantly dictated by exogenous availability rather than by de novo synthesis from arginine. Genetic silencing of creatine transporter SLC6A8 depleted intracellular creatine levels and reduced the colony-forming capacity of human prostate cancer cells. Accordingly, in vitro treatment of prostate cancer cells with cyclocreatine, a creatine analog, dramatically reduced intracellular levels of creatine and its derivatives phosphocreatine and creatinine and suppressed proliferation. Supplementation with cyclocreatine impaired cancer progression in the PTEN and SPRY-deficient prostate cancer GEMMs and in a xenograft liver metastasis model. Collectively, these results identify a metabolic vulnerability in prostate cancer and demonstrate a rational therapeutic strategy to exploit this vulnerability to impede tumour progression.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by Cancer Research UK: A17196 - core funding to the CRUK Beatson Institute; A15151 awarded to HYL; A21139, A25045, A17196 and A31287 awarded to OJS. LR received a CRUK Clinical Research Fellowship (A19493). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Mackay, Dr Gillian and Patel, Dr Rachana and Rushworth, Dr Linda and Sansom, Professor Owen and Leung, Professor Hing and Sumpton, Mr David and Mui, Mr Ernest and Rodgers, Dr Lisa and Zhang, Mr Tong |
| Authors: | Patel, R., Ford, C. A., Rodgers, L., Rushworth, L. K., Fleming, J., Mui, E., Zhang, T., Watson, D., Lynch, V., Mackay, G., Sumpton, D., Sansom, O. J., Vande Voorde, J., and Leung, H. Y. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Cancer Research |
| Publisher: | American Association for Cancer Research |
| ISSN: | 0008-5472 |
| ISSN (Online): | 1538-7445 |
| Published Online: | 08 June 2022 |
| Copyright Holders: | Copyright © 2022 American Association for Cancer Research |
| First Published: | First published in Cancer Research 82(14): 2565-2575 |
| Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information