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 Chaichana,
Thomas Hartung,
Michael J. Betenbaugh,
Suely K. Marie,
Jin G. Jung,
Tian-Li Wang,
Edward Gabrielson,
Anne Le
Affiliations
Tu Nguyen
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Brian James Kirsch
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
Ryoichi Asaka
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Karim Nabi
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Addison Quinones
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Jessica Tan
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Marjorie Justine Antonio
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Felipe Camelo
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ting Li
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Stephanie Nguyen
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Giang Hoang
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Kiet Nguyen
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Sunag Udupa
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Christos Sazeides
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Yao-An Shen
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Amira Elgogary
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Juvenal Reyes
Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Liang Zhao
Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Andre Kleensang
Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Kaisorn Lee Chaichana
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Thomas Hartung
Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; University of Konstanz, 78464 Konstanz, Germany
Michael J. Betenbaugh
Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
Suely K. Marie
Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil
Jin G. Jung
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Tian-Li Wang
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Edward Gabrielson
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Anne Le
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Summary: 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. : Nguyen et al. show that NAAG is more abundant in higher grade cancers and a source of glutamate in cancers expressing GCPII, the enzyme that hydrolyzes NAAG to glutamate and NAA. The results suggest that GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition. Keywords: N-acetyl-aspartyl-glutamate, NAAG, glutamate carboxypeptidase II, GCPII, glutaminase inhibitor, glutamate deprivation, glutamate reservoir, stable isotope resolved, metabolomics
