2019•Cell ReportsOpen access
Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer
Tu Nguyen, Brian James Kirsch, Ryoichi Asaka, Karim Nabi, Addison Quinones, Jessica Tan, Marjorie Justine Antonio, Felipe Camelo, Ting Li, Stephanie A. Nguyen, Giang Hoang, Kiet T. Nguyen, Sunag Udupa, Christos Sazeides, Yao Shen, Amira Elgogary, Juvenal Reyes, Liang Zhao, André Kleensang, Kaisorn L. Chaichana, Thomas Härtung, Michael J. Betenbaugh, Suely Kazue Nagahashi Marie, Jin Gyoung Jung, Tian-Li Wang, Edward Gabrielson, Anne Le
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Abstract
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.
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