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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Abate-Shen, C. & Shen, M. M. Molecular genetics of prostate cancer. Genes Dev. 14, 2410–2434 (2000)
Ruijter, E. et al. Molecular genetics and epidemiology of prostate carcinoma. Endocr. Rev. 20, 22–45 (1999)
Lawton, K. A. et al. Analysis of the adult human plasma metabolome. Pharmacogenomics 9, 383–397 (2008)
Rhodes, D. R. et al. Molecular concepts analysis links tumors, pathways, mechanisms, and drugs. Neoplasia 9, 443–454 (2007)
Tomlins, S. A. et al. Integrative molecular concept modeling of prostate cancer progression. Nature Genet. 39, 41–51 (2007)
Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002)
van der Vlag, J. & Otte, A. P. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nature Genet. 23, 474–478 (1999)
Laible, G. et al. Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. EMBO J. 16, 3219–3232 (1997)
Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002)
Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003)
Varambally, S. et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695–1699 (2008)
Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005)
Eisen, M. B. & Brown, P. O. DNA arrays for analysis of gene expression. Methods Enzymol. 303, 179–205 (1999)
Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)
Klemke, R. L. et al. Regulation of cell motility by mitogen-activated protein kinase. J. Cell Biol. 137, 481–492 (1997)
Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002)
Yu, J. et al. A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res. 67, 10657–10663 (2007)
Storey, J. D. A direct approach to false discovery rates. J. R. Stat. Soc. [Ser B] 64, 479–498 (2002)
Yu, J. et al. Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer. Cancer Cell 12, 419–431 (2007)
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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).
Supplementary information
Supplementary Information
This file contains Supplementary Methods, a Supplementary Discussion, Supplementary References and Supplementary Tables 1-10 (PDF 540 kb)
Supplementary Figures
This files contains Supplementary Figures 1-26 with Legends (PDF 1648 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature07762
This article is cited by
-
Identification of changes in bile composition in pancreaticobiliary reflux based on liquid chromatography/mass spectrometry metabolomics
BMC Gastroenterology (2024)
-
Multi-omics approaches for drug-response characterization in primary biliary cholangitis and autoimmune hepatitis variant syndrome
Journal of Translational Medicine (2024)
-
Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer proliferation and survival
Communications Biology (2024)
-
Unveiling the Therapeutic Potential: Metabolomics Insights into Medicinal Plants and Their Antidiabetic Effects
Current Food Science and Technology Reports (2024)
-
Changes in secondary metabolites of grape skins in response to different postharvest dehydration temperatures as evaluated by UPLC-Q-TOF-MS
Journal of Food Measurement and Characterization (2024)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.