Cyclocreatine Suppresses Creatine Metabolism and Impairs Prostate Cancer Progression

Overview

Journal Cancer Res

Specialty Oncology

Date 2022 Jun 8

PMID 35675421

Authors

Rachana Patel

Catriona A Ford

Lisa Rodgers

Linda K Rushworth

Janis Fleming

Ernest Mui

Tong Zhang

David Watson

Victoria Lynch

Gillian Mackay

David Sumpton

Owen J Sansom

Johan Vande Voorde

Hing Y Leung

Affiliations

Soon will be listed here.

Abstract

Significance: Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.

Citing Articles

Atractylenolide I ameliorated the growth and enzalutamide resistance of castration-resistant prostate cancer by targeting KIF15.

Han C, Yang B, Deng Y, Hu P, Hu B, Liu X Chin Med. 2025; 20(1):35.

PMID: 40087774 DOI: 10.1186/s13020-025-01086-1.

It Is Not Just About Storing Energy: The Multifaceted Role of Creatine Metabolism on Cancer Biology and Immunology.

Geng Y, DeLay S, Chen X, Miska J Int J Mol Sci. 2025; 25(24).

PMID: 39769038 PMC: 11678534. DOI: 10.3390/ijms252413273.

Part II. Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?.

Antonio J, Brown A, Candow D, Chilibeck P, Ellery S, Forbes S J Int Soc Sports Nutr. 2024; 22(1):2441760.

PMID: 39720835 PMC: 11703406. DOI: 10.1080/15502783.2024.2441760.

A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress.

Katz J, Geng Y, Billingham L, Sadagopan N, DeLay S, Subbiah J Sci Rep. 2024; 14(1):21959.

PMID: 39304717 PMC: 11415369. DOI: 10.1038/s41598-024-73051-1.

Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial.

Coletta A, Simon L, Maslana K, Taylor S, Larson K, Hansen P BMC Cancer. 2024; 24(1):493.

PMID: 38637770 PMC: 11025211. DOI: 10.1186/s12885-024-12260-3.

References

Vande Voorde J, Ackermann T, Pfetzer N, Sumpton D, Mackay G, Kalna G . Improving the metabolic fidelity of cancer models with a physiological cell culture medium. Sci Adv. 2019; 5(1):eaau7314. PMC: 6314821. DOI: 10.1126/sciadv.aau7314. View

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

Ben-Sahra I, Puissant A . HER2 Signaling Hijacks the Creatine Shuttle to Fuel Breast Cancer Cell Growth. Cell Metab. 2018; 28(6):805-807. DOI: 10.1016/j.cmet.2018.11.009. View

Fairman C, Kendall K, Newton R, Hart N, Taaffe D, Chee R . Examining the effects of creatine supplementation in augmenting adaptations to resistance training in patients with prostate cancer undergoing androgen deprivation therapy: a randomised, double-blind, placebo-controlled trial. BMJ Open. 2019; 9(9):e030080. PMC: 6756416. DOI: 10.1136/bmjopen-2019-030080. View

Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I . Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A. 2019; 116(23):11428-11436. PMC: 6561293. DOI: 10.1073/pnas.1902651116. View

Patel R, Brzezinska E, Repiscak P, Ahmad I, Mui E, Gao M . Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer. Cancer Res. 2019; 80(3):576-590. DOI: 10.1158/0008-5472.CAN-19-1684. View

Patel R, Fleming J, Mui E, Loveridge C, Repiscak P, Blomme A . Sprouty2 loss-induced IL6 drives castration-resistant prostate cancer through scavenger receptor B1. EMBO Mol Med. 2018; 10(4). PMC: 5887544. DOI: 10.15252/emmm.201708347. View

Li Q, Liu M, Sun Y, Jin T, Zhu P, Wan X . SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress. J Exp Clin Cancer Res. 2021; 40(1):168. PMC: 8120850. DOI: 10.1186/s13046-021-01933-7. View

Wallimann T . Bioenergetics. Dissecting the role of creatine kinase. Curr Biol. 1994; 4(1):42-6. DOI: 10.1016/s0960-9822(00)00008-7. View

10.

Kurth I, Yamaguchi N, Andreu-Agullo C, Tian H, Sridhar S, Takeda S . Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels. Sci Adv. 2021; 7(41):eabi7511. PMC: 8494442. DOI: 10.1126/sciadv.abi7511. View

11.

Gao M, Patel R, Ahmad I, Fleming J, Edwards J, McCracken S . SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis. EMBO Mol Med. 2012; 4(8):776-90. PMC: 3494076. DOI: 10.1002/emmm.201100944. View

12.

Qian X, Li Y, Gu F, Liu F, Li W, Zhang X . Overexpression of ubiquitous mitochondrial creatine kinase (uMtCK) accelerates tumor growth by inhibiting apoptosis of breast cancer cells and is associated with a poor prognosis in breast cancer patients. Biochem Biophys Res Commun. 2012; 427(1):60-6. DOI: 10.1016/j.bbrc.2012.08.147. View

13.

Kornacker M, Schlattner U, Wallimann T, Verneris M, Negrin R, Kornacker B . Hodgkin disease-derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis. Int J Cancer. 2001; 94(4):513-9. DOI: 10.1002/ijc.1502. View

14.

Ellington W . Evolution and physiological roles of phosphagen systems. Annu Rev Physiol. 2001; 63:289-325. DOI: 10.1146/annurev.physiol.63.1.289. View

15.

Zhang L, Bu P . The two sides of creatine in cancer. Trends Cell Biol. 2021; 32(5):380-390. DOI: 10.1016/j.tcb.2021.11.004. View

16.

Lohiya V, Aragon-Ching J, Sonpavde G . Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer. Clin Med Insights Oncol. 2016; 10(Suppl 1):57-66. PMC: 5065075. DOI: 10.4137/CMO.S34535. View

17.

Kazak L, Rahbani J, Samborska B, Lu G, Jedrychowski M, Lajoie M . Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity. Nat Metab. 2019; 1(3):360-370. PMC: 6544051. DOI: 10.1038/s42255-019-0035-x. View

18.

Zhang L, Zhu Z, Yan H, Wang W, Wu Z, Zhang F . Creatine promotes cancer metastasis through activation of Smad2/3. Cell Metab. 2021; 33(6):1111-1123.e4. DOI: 10.1016/j.cmet.2021.03.009. View

19.

Sousa C, Biancur D, Wang X, Halbrook C, Sherman M, Zhang L . Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016; 536(7617):479-83. PMC: 5228623. DOI: 10.1038/nature19084. View

20.

Taylor B, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver B . Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010; 18(1):11-22. PMC: 3198787. DOI: 10.1016/j.ccr.2010.05.026. View