Journal
CELL REPORTS
Volume 27, Issue 2, Pages 491-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.03.036
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Funding
- NIH [R01-CA193895, R01-CA112314, 1S10OD025226-01, UL1 TR 001079]
- Hopkins-Allegheny Health Network Cancer Research Fund
- Doris M. Weinstein Pancreatic Cancer Research Fund
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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-acetylaspartate (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 thatNAAGserves 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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