Data from Cyclocreatine Suppresses Creatine Metabolism and Impairs Prostate Cancer Progression

Abstract

<div>Abstract<p>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 <i>in vitro</i> and increased tumor cell proliferation <i>in vivo</i>. Stable isotope tracing revealed that intracellular levels of creatine in prostate cancer cells are predominantly dictated by exogenous availability rather than by <i>de novo</i> synthesis from arginine. Genetic silencing of creatine transporter <i>SLC6A8</i> depleted intracellular creatine levels and reduced the colony-forming capacity of human prostate cancer cells. Accordingly, <i>in vitro</i> 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.</p>Significance:<p>Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.</p></div>