Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells.
OBJECTIVE
During glutaminolysis, glutamine is catabolized to glutamate and incorporated into citric acid cycle and lipogenesis. Serum glutamate levels were measured in patients with primary prostate cancer or metastatic castrate-resistant prostate cancer (mCRPCa) to establish clinical relevance. The effect of glutamate deprivation or blockade by metabotropic glutamate receptor 1 (GRM1) antagonists was investigated on prostate cancer cells' growth, migration, and invasion to establish biologic relevance.


METHODS
Serum glutamate levels were measured in normal men (n = 60) and patients with primary prostate cancer (n = 197) or mCRPCa (n = 109). GRM1 expression in prostatic tissues was examined using immunohistochemistry (IHC). Cell growth, migration, and invasion were determined using cell cytotoxicity and modified Boyden chamber assays, respectively. Apoptosis was detected using immunoblotting against cleaved caspases, PARP, and γ-H2AX.


RESULTS
Univariate and multivariate analyses showed significantly higher serum glutamate levels in Gleason score ≥ 8 than in the Gleason score ≤ 7 and in African Americans than in the Caucasian Americans. African Americans with mCRPCa had significantly higher serum glutamate levels than those with primary prostate cancer or benign prostate. However, in Caucasian Americans, serum glutamate levels were similar in normal research subjects and patients with mCRPC. IHC showed weak or no expression of GRM1 in luminal acinar epithelial cells of normal or hyperplastic glands but high expression in primary or metastatic prostate cancer tissues. Glutamate deprivation or blockade decreased prostate cancer cells' proliferation, migration, and invasion and led to apoptotic cell death.


CONCLUSIONS
Glutamate expression is mechanistically associated with and may provide a biomarker of prostate cancer aggressiveness.
Department of Cancer Genetics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. Shahriar.Koochekpour@Roswellpark.org
Shahriar
S
Koochekpour
Sunipa
S
Majumdar
Gissou
G
Azabdaftari
Kristopher
K
Attwood
Ray
R
Scioneaux
Dhatchayini
D
Subramani
Charles
C
Manhardt
Giovanni D
GD
Lorusso
Stacey S
SS
Willard
Hillary
H
Thompson
Mojgan
M
Shourideh
Katayoon
K
Rezaei
Oliver
O
Sartor
James L
JL
Mohler
Robert L
RL
Vessella
D000328:Adult; D001741:Black or African American; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018698:Glutamic Acid / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood* / Q000378:metabolism / Q000473:pathology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology; D044465:White People
D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D019782:Riluzole