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 G. Jung, Qingguo Xu, Jie Fu, Ajit G. Thomas, Takashi Tsukamoto, Justin S Hanes, Barbara Slusher, Arthur J.L. Cooper, Quy Hoa Le Thi

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
DOIs
StatePublished - Jan 1 2019

Fingerprint

glutamine-pyruvate aminotransferase
glutamine - phenylpyruvate transaminase
Glutaminase
Enzyme inhibition
Pancreatic Neoplasms
Glutamic Acid
Up-Regulation
Glutamine
Metabolism
Tumors
Neoplasms
Genetic Suppression
Metabolic Networks and Pathways
Enzymes
Carcinogenesis
Therapeutics
Clinical Trials
Pharmacology

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer. / Udupa, Sunag; Nguyen, Stephanie; Hoang, Giang; Nguyen, Tu; Quinones, Addison; Pham, Khoa; Asaka, Ryoichi; Nguyen, Kiet; Zhang, Cissy; Elgogary, Amira; Jung, Jin G.; Xu, Qingguo; Fu, Jie; Thomas, Ajit G.; Tsukamoto, Takashi; Hanes, Justin S; Slusher, Barbara; Cooper, Arthur J.L.; Le Thi, Quy Hoa.

In: Proteomics, 01.01.2019.

Research output: Contribution to journalArticle

Udupa, S, Nguyen, S, Hoang, G, Nguyen, T, Quinones, A, Pham, K, Asaka, R, Nguyen, K, Zhang, C, Elgogary, A, Jung, JG, Xu, Q, Fu, J, Thomas, AG, Tsukamoto, T, Hanes, JS, Slusher, B, Cooper, AJL & Le Thi, QH 2019, 'Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer', Proteomics. https://doi.org/10.1002/pmic.201800451
Udupa, Sunag ; Nguyen, Stephanie ; Hoang, Giang ; Nguyen, Tu ; Quinones, Addison ; Pham, Khoa ; Asaka, Ryoichi ; Nguyen, Kiet ; Zhang, Cissy ; Elgogary, Amira ; Jung, Jin G. ; Xu, Qingguo ; Fu, Jie ; Thomas, Ajit G. ; Tsukamoto, Takashi ; Hanes, Justin S ; Slusher, Barbara ; Cooper, Arthur J.L. ; Le Thi, Quy Hoa. / Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer. In: Proteomics. 2019.
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