title: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
abstract: Multiple, complex molecular events characterize cancer development and progression. 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.
authors.affiliation: The Michigan Center for Translational Pathology, Ann Arbor, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.forename: Laila M
authors.initials: LM
authors.lastname: Poisson
authors.forename: Thekkelnaycke M
authors.initials: TM
authors.lastname: Rajendiran
authors.forename: Amjad P
authors.initials: AP
authors.lastname: Khan
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
authors.forename: Bharathi
authors.initials: B
authors.lastname: Laxman
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Nyati
authors.forename: Aarif
authors.initials: A
authors.lastname: Ahsan
authors.forename: Shanker
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.forename: Gilbert S
authors.initials: GS
authors.lastname: Omenn
authors.forename: Debashis
authors.initials: D
authors.lastname: Ghosh
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.forename: Danny C
authors.initials: DC
authors.lastname: Alexander
authors.forename: Alvin
authors.initials: A
authors.lastname: Berger
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Shuster
authors.forename: John T
authors.initials: JT
authors.lastname: Wei
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Christopher
authors.initials: C
authors.lastname: Beecher
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000728:Androgens / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D050938:Glycine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D055432:Metabolomics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012521:Sarcosine / Q000032:analysis / Q000378:metabolism* / Q000652:urine; D050892:Sarcosine Dehydrogenase / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000728:Androgens; D050892:Sarcosine Dehydrogenase; D050938:Glycine N-Methyltransferase; D012521:Sarcosine