Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
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.
Sreekumar
Arun
A
The Michigan Center for Translational Pathology, Ann Arbor, USA.
Poisson
Laila M
LM
Rajendiran
Thekkelnaycke M
TM
Khan
Amjad P
AP
Cao
Qi
Q
Yu
Jindan
J
Laxman
Bharathi
B
Mehra
Rohit
R
Lonigro
Robert J
RJ
Li
Yong
Y
Nyati
Mukesh K
MK
Ahsan
Aarif
A
Kalyana-Sundaram
Shanker
S
Han
Bo
B
Cao
Xuhong
X
Byun
Jaeman
J
Omenn
Gilbert S
GS
Ghosh
Debashis
D
Pennathur
Subramaniam
S
Alexander
Danny C
DC
Berger
Alvin
A
Shuster
Jeffrey R
JR
Wei
John T
JT
Varambally
Sooryanarayana
S
Beecher
Christopher
C
Chinnaiyan
Arul M
AM
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
D000728:Androgens; D050892:Sarcosine Dehydrogenase; D050938:Glycine N-Methyltransferase; D012521:Sarcosine