The Role of Sarcosine Metabolism in Prostate Cancer Progression

Abstract

Metabolomic profiling of prostate cancer (PCa) progression identified markedly elevated levels of sarcosine (N-methyl glycine) in metastatic PCa and modest but significant elevation of the metabolite in PCa urine. Here, we examine the role of key enzymes associated with sarcosine metabolism in PCa progression. Consistent with our earlier report, sarcosine levels were significantly elevated in PCa urine sediments compared to controls, with a modest area under the receiver operating characteristic curve of 0.71. In addition, the expression of sarcosine biosynthetic enzyme, glycine N-methyltransferase (GNMT), was elevated in PCa tissues, while sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), which metabolize sarcosine, were reduced in prostate tumors. Consistent with this, GNMT promoted the oncogenic potential of prostate cells by facilitating sarcosine production, while SARDH and PIPOX reduced the oncogenic potential of prostate cells by metabolizing sarcosine. Accordingly, addition of sarcosine, but not glycine or alanine, induced invasion and intravasation in an in vivo PCa model. In contrast, GNMT knockdown or SARDH overexpression in PCa xenografts inhibited tumor growth. Taken together, these studies substantiate the role of sarcosine in PCa progression.

Metabolomic signatures of aggressive prostate cancer

“…Chen et al [20] showed that expression of the tumor suppressor TMEFF2 reduced sarcosine levels in a model of aggressive prostate cancer and Dahl et al [21] showed that addition of exogenous sarcosine induced HER2/neu expression in androgendependent prostate cancer cells. Recently, Khan et al [22] have recapitulated the earlier findings that sarcosine in post-DRE urine sediments is a biomarker of prostate cancer, that the enzymes that produce and catabolize sarcosine are dysregulated in aggressive prostate cancer, and finally that modulation of the sarcosine metabolic pathway results in concordant modulation of prostate cancer aggressiveness, both in vitro and in animal models.…”

Determination of common urine substances as an assay for improving prostate carcinoma diagnostics

“…probability to suffer from non-aggressive prostate carcinoma with a lower ability to produce sarcosine due to dysregulation of the enzymes producing and catabolizing sarcosine (57). The current hypothesis is that most aged men have prostate cancer, and they have cells in their prostates that if observed on a needle biopsy would be diagnosed as prostate cancer (58).…”

Preclinical Evaluation of 11C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer

“…We considered 11 C-sarcosine for prostate cancer imaging because metabolomic data indicated strongly elevated tissue levels in localized prostate cancer, particularly in metastatic disease (3). Also, the mere addition of sarcosine to cultured benign prostate epithelial cells induced an invasive phenotype (4). Although the sarcosine metabolism is well-characterized, its metabolic functions in the human body are still poorly understood and are currently under active investigation (5,22).…”

“…Tissue sarcosine levels have also been shown to increase during prostate cancer progression to metastatic disease (3), and knockdown of glycine-N-methyltransferase-the enzyme that generates sarcosine from glycine-attenuates prostate cancer invasion. The addition of exogenous sarcosine, or knockdown of the mitochondrial enzyme that leads to sarcosine degradation (sarcosine dehydrogenase [SARDH]), induces an invasive phenotype in benign prostate epithelial cells (4). Furthermore, there is evidence for a strong sarcosine-related induction of genes involved particularly in cell cycle progression (5).…”