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

Cell Reports (Apr 2019)

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

Journal volume & issue: Vol. 27, no. 2
pp. 491 – 501.e6

Abstract

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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

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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