Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression

Abstract

Multiple, complex molecular events characterize cancer development and progression1,2. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumors, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high throughput liquid and gas chromatography-based mass spectrometry, we profiled more than 1126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer, and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly elevated during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also elevated in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase (GNMT), the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase (SARDH), induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Taken together, we profiled the metabolomic alterations of prostate cancer progression revealing sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.

Efforts to resolve the contradictions in early diagnosis of prostate cancer: a comparison of different algorithms of sarcosine in urine

“…In this study, any of sarcosine algorithms was significantly higher in PCa than in NEM patients not only in all patients (Figures 1a and d) but also in patients with PSA o20 ng ml À1 (data not shown), supporting the report by Sreekumar et al 8 and simultaneously opposing the study by Jentzmik et al 9 As urinary creatinine concentration of patients with NEM did not differ from that of PCa patients in both groups ( Supplementary Figure 1), the creatinine normalization could not be the reason for this contradictory result. These inconsistent results might be explained by differences between the study populations or in pathological evaluation of specimens.…”

“…25 Interestingly, a recent report in Nature by Sreekumar et al 8 demonstrated that sarcosine as one of metabolites offers a promising, non-invasive diagnostic and prognostic test for PCa. However, the first validation study 9 did not support that sarcosine has any advantage over serum PSA, %fPSA, Gleason score and tumor stage.…”

“…3,4 To the best of our knowledge, metabolomic analysis has already been used for identifying metabolic markers in tumors. [5][6][7] Notably, Sreekumar et al 8 demonstrated that sarcosine can be used as a biomarker for PCa and was non-invasively detected in urine, which led to great interest in the scientific community and among potential PCa patients. However, the first independent validation study 9 showed that sarcosine cannot be used as a biomarker to diagnose PCa and predict its aggression.…”

“…Following these observations, letters and replies [10][11][12][13][14][15][16] were published to discuss potential reasons for the contradictions between these two studies. 8,9 Although many possibilities (for example, the analytical method, the biomarker assay, the comparators and the study cohort) were discussed; no data from complete article has been reported.…”

TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer

“…Overexpression of full length, transmembrane TMEFF2 in PCa cells impairs proliferation due to an interaction between the cytoplasmic domain of TMEFF2 and sarcosine dehydrogenase (SARDH). This interaction results in decreased levels of sarcosine (Chen et al, 2011a; Green et al, 2013), an amino acid associated with PCa progression (Sreekumar et al, 2009). Full length TMEFF2 also attenuates the migratory properties of PCa cells (Chen et al, 2014), indicating a tumour suppressor function.…”