Cyclocreatine Suppresses Creatine Metabolism and Impairs Prostate Cancer Progression
Patel R, Ford CA, Rodgers L, Rushworth LK, Fleming J, Mui E, Zhang T, Watson D, Lynch V, Mackay G, Sumpton D, Sansom OJ, Vande Voorde J, Leung HY
Cancer research · 36 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Possibly industry funded
- Nonprofit
- Cancer Research UK
- Nonprofit
- CRUK Beatson Institute
- Nonprofit
- CRUK Clinical Research Fellowship
- Authors
- At least one author declares a financial tie to industry
- Grants
- Cancer Research UK (A21139/); Cancer Research UK (A31287); Cancer Research UK (A15151); Cancer Research UK (A25045); Cancer Research UK (A17196/)
Based on 3 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2022-06-08 · Cancer Res · vol. 82 · issue 14 · pp. 2565–2575
- Publisher
- American Association for Cancer Research
- Cited
- 40 citations · more than 95% of similar papers · 3.9× the field average
- Impact
- Top 10% most cited in its field
- References
- 41 works
- Access
- Open access (hybrid journal) · CC-BY-NC-ND
- Research areas
- Muscle metabolism and nutrition · Cancer, Hypoxia, and Metabolism · Metabolism, Diabetes, and Cancer
- Keywords
- Creatine, Prostate cancer, Cancer, Internal medicine, Endocrinology, Biology, Cancer research, Prostate, Cancer cell, Tumor progression, Medicine
- MeSH
- animals, humans, mice, prostatic neoplasms, disease models, animal, creatine, creatinine, phosphocreatine, intracellular signaling peptides and proteins, membrane proteins, male
14 authors
From GB
- Rachana PatelCancer Research UK Scotland Institute
- Catriona A. FordCancer Research UK Scotland Institute
- Lisa Jane RodgersCancer Research UK Scotland Institute; University of Glasgow
- Linda K. RushworthCancer Research UK Scotland Institute; University of Glasgow
- Janis FlemingCancer Research UK Scotland Institute
- Ernest J. MuiCancer Research UK Scotland Institute; University of Glasgow
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 tumor suppressors PTEN and Sprouty2 (SPRY2), 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 tumor 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 SPRY2-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 tumor progression.
Significance
Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC-ND).
Community trust
Loading…
How much do you trust this study's findings?
Comments
Sign in to rate, comment on or flag this study.Sign inSomething wrong here?
Flag this study if its information, labels or funding look wrong. An editor reviews every flag.
Sign in to rate, comment on or flag this study.Sign inEducational information about published research. Not medical advice, and not a recommendation to start or stop anything.