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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.

SUBMITTER: Khan AP

PROVIDER: S-EPMC3638352 | biostudies-other | 2013 May

REPOSITORIES: biostudies-other

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The role of sarcosine metabolism in prostate cancer progression.

Khan Amjad P AP Rajendiran Thekkelnaycke M TM Ateeq Bushra B Asangani Irfan A IA Athanikar Jyoti N JN Yocum Anastasia K AK Mehra Rohit R Siddiqui Javed J Palapattu Ganesh G Wei John T JT Michailidis George G Sreekumar Arun A Chinnaiyan Arul M AM

Neoplasia (New York, N.Y.) 20130501 5

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 ...[more]

PMID: 23633921

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Project description:The aim of this pilot study is to evaluate sarcosine, uracil, and kynurenic acid in urine as potential biomarkers in prostate cancer detection and progression monitoring. Sarcosine, uracil, and kynurenic acid were measured in urine samples of 32 prostate cancer patients prior to radical prostatectomy, 101 patients with increased prostate-specific antigen prior to ultrasonographically-guided prostatic biopsy collected before and after prostatic massage, and 15 healthy volunteers (controls). The results were related to histopathologic data, Gleason score, and PSA (Prostate Specific Antigen). Metabolites were measured after analysis of urine samples with Ultra-High Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) instrumentation. Multivariate, nonparametric statistical tests including receiver operating characteristics analyses, one-way analysis of variance (Kruskal-Wallis test), parametric statistical analysis, and Pearson correlation, were performed to evaluate diagnostic performance. Decreased median sarcosine and kynurenic acid and increased uracil concentrations were observed for patients with prostate cancer compared to participants without malignancy. Results showed that there was no correlation between the concentration of the studied metabolites and the cancer grade (Gleason score <7 vs. ≥7) and the age of the patients. Evaluation of biomarkers by ROC (Receiving Operating Characteristics) curve analysis showed that differentiation of prostate cancer patients from participants without malignancy was not enhanced by sarcosine or uracil levels in urine. In contrast to total PSA values, kynurenic acid was found a promising biomarker for the detection of prostate cancer particularly in cases where collection of urine samples was performed after prostatic massage. Sarcosine and uracil in urine samples of patients with prostate cancer were not found as significant biomarkers for the diagnosis of prostate cancer. None of the three metabolites can be used reliably for monitoring the progress of the disease.

Project description:BackgroundThe activities of MYC, the androgen receptor, and its associated pioneer factors demonstrate substantial reprogramming between early and advanced prostate cancer. Although previous studies have shown a shift in cellular metabolic requirements associated with prostate cancer progression, the epigenetic regulation of these processes is incompletely described. Here, we have integrated chromatin immunoprecipitation sequencing (ChIP-seq) and whole-transcriptome sequencing to identify novel regulators of metabolism in advanced prostate tumors characterized by elevated MYC activity.ResultsUsing ChIP-seq against MYC, HOXB13, and AR in LNCaP cells, we observed redistribution of co-bound sites suggestive of differential KMT2A activity as a function of MYC expression. In a cohort of 177 laser-capture microdissected foci of prostate tumors, KMT2A expression was positively correlated with MYC activity, AR activity, and HOXB13 expression, but decreased with tumor grade severity. However, KMT2A expression was negatively correlated with these factors in 25 LuCaP patient-derived xenograft models of advanced prostate cancer and 99 laser-capture microdissected foci of metastatic castration-resistant prostate cancer. Stratified by KMT2A expression, ChIP-seq against AR and HOXB13 in 15 LuCaP patient-derived xenografts showed an inverse association with sites involving genes implicated in lipid metabolism, including the arachidonic acid metabolic enzyme PLA2G4F. LuCaP patient-derived xenograft models grown as organoids recapitulated the inverse association between KMT2A expression and fluorine-18 labeled arachidonic acid uptake in vitro.ConclusionsOur study demonstrates that the epigenetic activity of transcription factor oncogenes exhibits a shift during prostate cancer progression with distinctive phenotypic effects on metabolism. These epigenetically driven changes in lipid metabolism may serve as novel targets for the development of novel imaging agents and therapeutics.

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The role of sarcosine metabolism in prostate cancer progression.

Publications

The role of sarcosine metabolism in prostate cancer progression.

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