phosphocreatine and Prostatic-Neoplasms

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

Topics: Animals; Creatine; Creatinine; Disease Models, Animal; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Phosphocreatine; Prostatic Neoplasms

To determine whether cancers of the prostate transition zone (TZ) possess a unique metabolic pattern by which they may be identified at proton magnetic resonance (MR) spectroscopic imaging.. Findings in 40 patients who underwent combined endorectal MR imaging and hydrogen 1 MR spectroscopic imaging before radical prostatectomy and who had TZ tumor identified subsequently at step-section pathologic analysis were retrospectively reviewed. Within this population, a subset of 16 patients whose TZ tumor had a largest diameter of 1 cm or greater and was included in the MR spectroscopic imaging excitation volume was identified. In these 16 patients, the ratios of choline-containing compounds (Cho) and creatine/phosphocreatine (Cr) to citrate (Cit) (ie, [Cho + Cr]/Cit), Cho/Cr, and Cho/Cit were compared in tumor and control tissues. The presence of only Cho and the absence of all metabolites were also assessed.. The mean values of (Cho + Cr)/Cit, Cho/Cr, and Cho/Cit were different between TZ cancer and control tissues (P =.001, P =.003, and P =.001, respectively; Wilcoxon signed rank test). Nine (56%) of 16 patients had at least one tumor voxel in which Cho comprised the only detectable peak, while no control voxels showed only Cho (P =.008, McNemar test). The percentage of voxels in which no metabolites were detected did not differ between tumor and control tissues (P =.134, McNemar test).. TZ cancer has a metabolic profile that is different from that of benign TZ tissue; however, the broad range of metabolite ratios observed in TZ cancer precludes the use of a single ratio to differentiate TZ cancer from benign TZ tissue.

Topics: Choline; Citric Acid; Creatine; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Prostate; Prostatic Neoplasms; Retrospective Studies