Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer
Biochemistry and Molecular Biology
The targeting of glutamine metabolism specifically via pharmacological inhibition of glutaminase 1 (GLS1) has been translated into clinical trials as a novel therapy for several cancers. The results, though encouraging, show room for improvement in terms of tumor reduction. Here, we demonstrate that pancreatic tumors upregulate the production of glutamate from glutamine via the glutaminase II pathway upon GLS1 inhibition. Moreover, genetic suppression of glutamine transaminase K (GTK), a key enzyme of the glutaminase II pathway, leads to complete inhibition of pancreatic tumorigenesis in vivo unveiling GTK as a new metabolic target for cancer therapy. These results suggest that current trials using GLS1 inhibition as a therapeutic approach targeting glutamine metabolism in cancer should take into account the upregulation of other metabolic pathways that can lead to glutamate production, one such pathway is the glutaminase II pathway via GTK. This article is protected by copyright. All rights reserved.
Udupa, S., Nguyen, S., Hoang, G., Nguyen, T., Quinones, A., Pham, K., Asaka, R., Nguyen, K., Elgogary, A., Jung, J., Xu, Q., Fu, J., Thomas, A., Tsukamoto, T., Hanes, J., Slusher, B., Cooper, A., & Le, A. (2019). Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer. Proteomics, 19 (21-22), e1800451. https://doi.org/10.1002/pmic.201800451