UroToday - In the February 12, 2009 issue of Nature, the group of Dr. Arul Chinnaiyan identified sarcosine, an N-methyl derivative of the amino acid glycine as a metabolite that is highly increased during prostate cancer (CaP) progression.

The scientists used liquid and gas chromatography coupled with mass spectrometry to interrogate the relative levels of 1,126 metabolites from 262 prostate-related biospecimens (42 tissue samples and 110 matched plasma and post-digital rectal examination urine samples). Metabolomic profiles from urine or plasma did not identify differences between biopsy-positive and biopsy-negative individuals. For tissue, benign adjacent prostate (16 samples), clinically localized CaP (12 samples) and metastatic CaP (14 samples) were studied. A total of 69 metabolites were found in CaP and/or metastatic samples but not in benign prostate samples. After further analysis, 6 metabolites were found to be significantly increased on disease progression from benign to CaP to metastatic disease.

They focused on sarcosine, as it is involved in the amino acid metabolism and methylation processes that are enriched during CaP progression. Sarcosine was markedly elevated in 79% of metastatic samples, 42% of localized samples but no benign prostate samples. They developed an assay to measure as little as 10 fetomoles of sarcosine, and in an independent tissue sample set it was significantly elevated in metastatic CaP compared to organ-confined CaP compared to benign tissue. Regarding the predictive value for the assay among patients with a PSA between 2 and 10ngml, sarcosine performed better than PSA.

Evaluation of CaP cell lines revealed increased sarcosine levels compared to benign prostate cell lines. Overexpression of the histone methyltransferase EZH2 (which can mediate cell invasion and neoplastic progression) in benign prostate epithelial cells increased sarcosine levels, whereas its knockdown diminished sarcosine levels. Addition of sarcosine to non-invasive prostate cells resulted in an invasive phenotype and increased motility. Using siRNA to block the enzyme GNMT that converts glycine to sarcosine resulted in significant reduction in cell invasion and 3-fold decrease in sarcosine levels.

Furthermore, the ETS family of fusion genes known to be involved in CaP progression was found to be directly linked to the sarcosine pathway. Induced ETS related gene expression resulted in a 3-fold increase in sarcosine expression in benign prostate cells and knockdown in aggressive cells resulted in a 3-fold reduction in sarcosine. This links the sarcosine pathway to androgen signaling and ETS gene fusion regulation. Thus, sarcosine may have both a diagnostic and therapeutic role in prostate cancer.

Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM

Nature. 2009 Feb 12;457(7231):910-4
10.1038/nature07762

UroToday Contributing Editor Christopher P. Evans, MD, FACS

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