Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer

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2019
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Nguyen, Tu
Kirsch, Brian James
Asaka, Ryoichi
Nabi, Karim
Quinones, Addison
Tan, Jessica
Antonio, Marjorie Justine
Camelo, Felipe
Li, Ting
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Cell reports. 2019, 27(2), pp. 491-501.e6. ISSN 2211-1247. eISSN 2211-1247. Available under: doi: 10.1016/j.celrep.2019.03.036
Zusammenfassung

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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ISO 690NGUYEN, Tu, Brian James KIRSCH, Ryoichi ASAKA, Karim NABI, Addison QUINONES, Jessica TAN, Marjorie Justine ANTONIO, Felipe CAMELO, Ting LI, Thomas HARTUNG, Anne LE, 2019. Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer. In: Cell reports. 2019, 27(2), pp. 491-501.e6. ISSN 2211-1247. eISSN 2211-1247. Available under: doi: 10.1016/j.celrep.2019.03.036
BibTex
@article{Nguyen2019Uncov-47107,
  year={2019},
  doi={10.1016/j.celrep.2019.03.036},
  title={Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer},
  number={2},
  volume={27},
  issn={2211-1247},
  journal={Cell reports},
  pages={491--501.e6},
  author={Nguyen, Tu and Kirsch, Brian James and Asaka, Ryoichi and Nabi, Karim and Quinones, Addison and Tan, Jessica and Antonio, Marjorie Justine and Camelo, Felipe and Li, Ting and Hartung, Thomas and Le, Anne}
}
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