Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer

Sunag Udupa, Stephanie Nguyen, Giang Hoang, Tu Nguyen, Addison Quinones, Khoa Pham, Ryoichi Asaka, Kiet Nguyen, Cissy Zhang, Amira Elgogary, Jin Gyoung Jung, Qingguo Xu, Jie Fu, Ajit G. Thomas, Takashi Tsukamoto, Justin Hanes, Barbara S. Slusher, Arthur J.L. Cooper, Anne Le

Research output: Contribution to journalArticle

Abstract

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. In this study, the glutaminase II pathway is found to be upregulated for glutamate production upon GLS1 inhibition in pancreatic tumors. Moreover, genetic suppression of glutamine transaminase K (GTK), a key enzyme of the glutaminase II pathway, leads to the 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.

Original languageEnglish (US)
Article number1800451
JournalProteomics
Volume19
Issue number21-22
DOIs
StatePublished - Nov 1 2019

Keywords

  • glutaminase 1 inhibition
  • glutaminase II pathway
  • glutamine transaminase K

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Fingerprint Dive into the research topics of 'Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer'. Together they form a unique fingerprint.

  • Cite this

    Udupa, S., Nguyen, S., Hoang, G., Nguyen, T., Quinones, A., Pham, K., Asaka, R., Nguyen, K., Zhang, C., Elgogary, A., Jung, J. G., Xu, Q., Fu, J., Thomas, A. G., Tsukamoto, T., Hanes, J., Slusher, B. S., Cooper, A. J. L., & Le, A. (2019). Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer. Proteomics, 19(21-22), [1800451]. https://doi.org/10.1002/pmic.201800451