Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

Abstract

The effects of sarcosine on the processes driving prostate cancer (PCa) development remain still unclear. Herein, we show that a supplementation of metastatic PCa cells (androgen independent PC-3 and androgen dependent LNCaP) with sarcosine stimulates cells proliferation in vitro. Similar stimulatory effects were observed also in PCa murine xenografts, in which sarcosine treatment induced a tumor growth and significantly reduced weight of treated mice (p < 0.05). Determination of sarcosine metabolism-related amino acids and enzymes within tumor mass revealed significantly increased glycine, serine and sarcosine concentrations after treatment accompanied with the increased amount of sarcosine dehydrogenase. In both tumor types, dimethylglycine and glycine-N-methyltransferase were affected slightly, only. To identify the effects of sarcosine treatment on the expression of genes involved in any aspect of cancer development, we further investigated expression profiles of excised tumors using cDNA electrochemical microarray followed by validation using the semi-quantitative PCR. We found 25 differentially expressed genes in PC-3, 32 in LNCaP tumors and 18 overlapping genes. Bioinformatical processing revealed strong sarcosine-related induction of genes involved particularly in a cell cycle progression. Our exploratory study demonstrates that sarcosine stimulates PCa metastatic cells irrespectively of androgen dependence. Overall, the obtained data provides valuable information towards understanding the role of sarcosine in PCa progression and adds another piece of puzzle into a picture of sarcosine oncometabolic potential.

Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

“…Sarcosine one‐carbon metabolism is regulated by the androgen receptor (AR), and androgen supplementation results in increased DNA methylation in prostate cancer . Interestingly, sarcosine upregulates AR expression, indicating a reciprocal regulatory relationship . Although sarcosine is mainly known as a prostate cancer‐associated metabolite, it has also been implicated in a subset of metastatic breast cancer cases.…”

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

“…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).…”

“…Briefly, the organ distribution of 11 C-sarcosine was determined in 2 male and 2 female Sprague-Dawley rats at 5 time points (5,15,30,60, and 90 min) using injected doses of 7.4-28 MBq of 11 C-sarcosine. Groups of animals were sacrificed while under isoflurane anesthesia.…”

“…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). Sarcosine is therefore thought to be a potential oncometabolite rather than a nonproteinogenic amino acid (6).…”

A Biosilification Fusion Protein for a ‘Self‐immobilising’ Sarcosine Oxidase Amperometric Enzyme Biosensor

“…∼1–3 μM in healthy individuals compared with 9–15 μM in patients with prostate cancer) . There is not a consensus on the possible role of sarcosine, but some studies have suggested that sarcosine accumulates in the tumor and exhibits a stimulatory effect on growth in malignant/metastatic prostate cells due to its conversion to serine and glycine .…”