The Role of Sarcosine Metabolism in Prostate Cancer Progression<sup><a href="#FN1" rid="FN1" class=" fn">1</a>,</sup><sup><a href="#FN2" rid="FN2" class=" fn">2</a></sup>

Amjad Khan

Thekkelnaycke Rajendiran

Bushra Ateeq

Irfan Asangani

Ganesh Palapattu+4 authors

Supplementary Figures and Tables:

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^{Michigan Center for Translational Pathology, Ann Arbor, MI}

^{Department of Pathology, University of Michigan, Ann Arbor, MI}

^{Department of Urology, University of Michigan, Ann Arbor, MI}

^{Department of Statistics, University of Michigan, Ann Arbor, MI}

^{Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, TX}

^{Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI}

^{Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI}

Address all correspondence to: Arul M. Chinnaiyan, MD, PhD, Howard Hughes Medical Institute and Department of Pathology, University of Michigan Medical School, 5316 CCGC, 1400 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: ude.hcimu@lura

^{These authors made equal contributions.}

Received 2013 Jan 24; Revised 2013 Feb 22; Accepted 2013 Feb 22.

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.

Abstract

Acknowledgments

We thank V. Vitvitsky from R. Banerjee Laboratory for SAM and SAHA estimations and X. Cao, Robert J. Lonigro, and N. Palanisamy for helpful discussions. We also thank Khalid Suleman and Rong Zhao for technical support.

Acknowledgments

Abbreviations

PCa	prostate cancer
GNMT	glycine N-methyltransferase
SARDH	sarcosine dehydrogenase
PIPOX	pipecolic acid oxidase

Abbreviations

Footnotes

^{This work is supported in part by Early Detection Research Network (UO1}{"type":"entrez-nucleotide","attrs":{"text":"CA111275","term_id":"34964582","term_text":"CA111275"}}CA111275), Prostate Cancer Specialized Program of Research Excellence (P50CA69568), National Institutes of Health (R01CA132874, RO1CA133458, RO3CA139489, UO1CA167234, and R01CA13345), and Department of Defense (W81XWH-12-1-0130). A.M.C. is supported by the Doris Duke Charitable Foundation Clinical Scientist Award, the Prostate Cancer Foundation, and the Howard Hughes Medical Institute. A.M.C. is an American Cancer Society Research Professor and an A. Alfred Taubman Scholar. A.M.C. serves on the Scientific Advisory Board of Metabolon, Inc. Metabolon has licensed sarcosine and other prostate cancer metabolites for diagnostic use in prostate cancer from the University of Michigan. Metabolon was not involved in the development or approval of this study.

^{This article refers to supplementary materials, which are designated by}Table W1 and Figures W1 to W12 and are available online at www.neoplasia.com.

Footnotes

Supplemental Reference

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Supplemental Reference

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