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 Nguyen, Giang Hoang, Kiet Nguyen, Sunag Udupa, Christos Sazeides, Yao-An Shen, Amira Elgogary, Juvenal Reyes, Liang Zhao, Andre Kleensang, Kaisorn Lee ChaichanaThomas Hartung, Michael J Betenbaugh, Suely K Marie, Jin G Jung, Tian-Li Wang, Edward Gabrielson, Anne Le

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)491-501.e6
JournalCell Reports
Volume27
Issue number2
DOIs
Publication statusPublished - Apr 9 2019
Externally publishedYes

Keywords

  • GCPII
  • N-acetyl-aspartyl-glutamate
  • NAAG
  • glutamate carboxypeptidase II
  • glutamate deprivation
  • glutamate reservoir
  • glutaminase inhibitor
  • metabolomics
  • stable isotope resolved

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Nguyen, T., Kirsch, B. J., Asaka, R., Nabi, K., Quinones, A., Tan, J., Antonio, M. J., Camelo, F., Li, T., Nguyen, S., Hoang, G., Nguyen, K., Udupa, S., Sazeides, C., Shen, Y-A., Elgogary, A., Reyes, J., Zhao, L., Kleensang, A., ... Le, A. (2019). Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer. Cell Reports, 27(2), 491-501.e6. https://doi.org/10.1016/j.celrep.2019.03.036