Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression

  • A Corrigendum to this article was published on 05 June 2013
  • A Corrigendum to this article was published on 05 June 2013

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 tumours, 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 1,126 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 increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, 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, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.

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Figure 1: Metabolomic profiling of prostate cancer.
Figure 2: Metabolomic alterations of prostate cancer progression.
Figure 3: Sarcosine levels in prostate cancer and its association with cell invasion.
Figure 4: A role for sarcosine in androgen signalling and prostate cancer cell invasion.

Change history

  • 05 June 2013

    Nature 457, 910–914 (2009); doi:10.1038/nature07762 In Fig. 4b of this Article, a typographical error was made in reporting sarcosine levels in the DU145 cell line represented. The y axis values should be in the scale of 0–50 pmoles per 106 cells, rather than 0–500 pmoles per 106 cells. This error has been verified and does not affect the conclusion of the paper.

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Acknowledgements

We thank J. Granger for help in manuscript preparation, J. Siddiqui and R. Varambally for help with the clinical database, and A. Vellaichamy and S. Pullela for technical assistance. We thank K. Pienta for access to metastatic prostate cancer samples from the University of Michigan Prostate SPORE rapid autopsy programme. This work is supported in part by the Early Detection Research Network (A.M.C., J.T.W.), National Institutes of Health (A.S., S.P., J.B., T.M.R., D.G., G.S.O. and A.M.C.) and an MTTC grant (G.S.O. and A.S.). A.M.C. is supported by a Clinical Translational Science Award from the Burroughs Welcome Foundation. A.S. is supported by a grant from the Fund for Discovery of the University of Michigan Comprehensive Cancer Center. L.M.P. is supported by the University of Michigan Cancer Biostatistics Training Grant. A.M.C and S.P. are supported by the Doris Duke Charitable Foundation.

Author Contributions A.S., L.M.P. and A.M.C. wrote the manuscript. A.S. and A.M.C. conceptualized, designed and interpreted the data. L.M.P., R.J.L., S.K.-S., D.G. and D.C.A. performed data analysis. T.M.R., G.S.O., J.B. S.P., J.R.S., A.B. and C.B. carried out the mass spectrometry studies. A.P.K., J.Y., Q.C., B.L., Y.L., M.K.N., A.A., X.C. and S.V. performed biochemical experiments. R.M., B.H., A.M.C. and J.T.W. coordinated the clinical and pathology components of the study.

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Correspondence to Arul M. Chinnaiyan.

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Competing interests

C.B. was previously an employee of Metabolon. C.B., D.C.A., J.R.S. and A.B. own equity in Metabolon. A.M.C. joined the Scientific Advisory Board of Metabolon in July 2008. The University of Michigan has licensed the diagnostic field of use of the metabolomic biomarkers discussed in this manuscript to Metabolon (A.M.C. and A.S. are named as inventors).

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Sreekumar, A., Poisson, L., Rajendiran, T. et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910–914 (2009). https://doi.org/10.1038/nature07762

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