TY - JOUR
T1 - Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer
AU - Nguyen, Tu
AU - Kirsch, Brian James
AU - Asaka, Ryoichi
AU - Nabi, Karim
AU - Quinones, Addison
AU - Tan, Jessica
AU - Antonio, Marjorie Justine
AU - Camelo, Felipe
AU - Li, Ting
AU - Nguyen, Stephanie
AU - Hoang, Giang
AU - Nguyen, Kiet
AU - Udupa, Sunag
AU - Sazeides, Christos
AU - Shen, Yao-An
AU - Elgogary, Amira
AU - Reyes, Juvenal
AU - Zhao, Liang
AU - Kleensang, Andre
AU - Chaichana, Kaisorn Lee
AU - Hartung, Thomas
AU - Betenbaugh, Michael J
AU - Marie, Suely K
AU - Jung, Jin G
AU - Wang, Tian-Li
AU - Gabrielson, Edward
AU - Le, Anne
N1 - Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2019/4/9
Y1 - 2019/4/9
N2 - N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.
AB - N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.
KW - GCPII
KW - N-acetyl-aspartyl-glutamate
KW - NAAG
KW - glutamate carboxypeptidase II
KW - glutamate deprivation
KW - glutamate reservoir
KW - glutaminase inhibitor
KW - metabolomics
KW - stable isotope resolved
UR - http://www.scopus.com/inward/record.url?scp=85063761659&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063761659&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.03.036
DO - 10.1016/j.celrep.2019.03.036
M3 - Article
C2 - 30970252
SN - 2211-1247
VL - 27
SP - 491-501.e6
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -