Cyclocreatine suppresses creatine metabolism and impairs prostate cancer progression

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) (PMCID:PMC9381098)

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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).
Glasgow Author(s) Enlighten ID:Zhang, Mr Tong and Leung, Professor Hing and Rushworth, Dr Linda and Mui, Mr Ernest and Rodgers, Dr Lisa and Sumpton, Mr David and Patel, Dr Rachana and Mackay, Dr Gillian and Sansom, Professor Owen
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 (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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170650Clinical Training AwardIain McNeishCancer Research UK (CRUK)C596/A19493CS - Clinical Research Garscube