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

研究成果: 雜誌貢獻文章

5 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)491-501.e6
期刊Cell Reports
27
發行號2
DOIs
出版狀態已發佈 - 四月 9 2019
對外發佈Yes

指紋

Glutamate Carboxypeptidase II
Glutamic Acid
Glutaminase
Neoplasms
Neurotransmitter Agents
N-acetyl-1-aspartylglutamic acid
Cells
Pharmacology
Peptides
Enzymes
Growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

引用此文

Nguyen, T., Kirsch, B. J., Asaka, R., Nabi, K., Quinones, A., Tan, J., ... 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

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer. / Nguyen, Tu; Kirsch, Brian James; Asaka, Ryoichi; Nabi, Karim; Quinones, Addison; Tan, Jessica; Antonio, Marjorie Justine; Camelo, Felipe; Li, Ting; Nguyen, Stephanie; Hoang, Giang; Nguyen, Kiet; Udupa, Sunag; Sazeides, Christos; Shen, Yao-An; Elgogary, Amira; Reyes, Juvenal; Zhao, Liang; Kleensang, Andre; Chaichana, Kaisorn Lee; Hartung, Thomas; Betenbaugh, Michael J; Marie, Suely K; Jung, Jin G; Wang, Tian-Li; Gabrielson, Edward; Le, Anne.

於: Cell Reports, 卷 27, 編號 2, 09.04.2019, p. 491-501.e6.

研究成果: 雜誌貢獻文章

Nguyen, T, Kirsch, BJ, Asaka, R, Nabi, K, Quinones, A, Tan, J, Antonio, MJ, 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, Chaichana, KL, Hartung, T, Betenbaugh, MJ, Marie, SK, Jung, JG, Wang, T-L, Gabrielson, E & Le, A 2019, 'Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer', Cell Reports, 卷 27, 編號 2, 頁 491-501.e6. https://doi.org/10.1016/j.celrep.2019.03.036
Nguyen T, Kirsch BJ, Asaka R, Nabi K, Quinones A, Tan J 等. Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer. Cell Reports. 2019 4月 9;27(2):491-501.e6. https://doi.org/10.1016/j.celrep.2019.03.036
Nguyen, Tu ; Kirsch, Brian James ; Asaka, Ryoichi ; Nabi, Karim ; Quinones, Addison ; Tan, Jessica ; Antonio, Marjorie Justine ; Camelo, Felipe ; Li, Ting ; Nguyen, Stephanie ; Hoang, Giang ; Nguyen, Kiet ; Udupa, Sunag ; Sazeides, Christos ; Shen, Yao-An ; Elgogary, Amira ; Reyes, Juvenal ; Zhao, Liang ; Kleensang, Andre ; Chaichana, Kaisorn Lee ; Hartung, Thomas ; Betenbaugh, Michael J ; Marie, Suely K ; Jung, Jin G ; Wang, Tian-Li ; Gabrielson, Edward ; Le, Anne. / Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer. 於: Cell Reports. 2019 ; 卷 27, 編號 2. 頁 491-501.e6.
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AU - Quinones, Addison

AU - Tan, Jessica

AU - Antonio, Marjorie Justine

AU - Camelo, Felipe

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AU - Nguyen, Stephanie

AU - Hoang, Giang

AU - Nguyen, Kiet

AU - Udupa, Sunag

AU - Sazeides, Christos

AU - Shen, Yao-An

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AU - Zhao, Liang

AU - Kleensang, Andre

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AU - Betenbaugh, Michael J

AU - Marie, Suely K

AU - Jung, Jin G

AU - Wang, Tian-Li

AU - Gabrielson, Edward

AU - Le, Anne

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N2 - 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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