Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism
Open accessAbstract
Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of Kras G12D -driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.
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GLS inhibition was ineffective in pancreatic tumor models through remodeling of compensatory metabolic pathways, despite potent growth inhibition in short-term PDAC cell proliferation assays.
“despite showing potent growth inhibitory effects in short-term PDAC cell proliferation assays, GLS inhibition was found to be ineffective in pancreatic tumor models through remodeling of compensatory metabolic pathways199”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [199]
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- Authors
- Bott, A. J., Shen, J., Tonelli, C., Zhan, L., Sivaram, N., Jiang, Y.-P., Yu, X., Bhatt, V., Chiles, E., Zhong, H., Maimouni, S., Dai, W., Velasquez, S., Pan, J.-A., Muthalagu, N., Morton, J., Anthony, T. G., Feng, H., Lamers, W. H., Murphy, D. J., Guo, J. Y., Jin, J., Crawford, H. C., Zhang, L., White, E., Lin, R. Z., Su, X., Tuveson, D. A., & Zong, W.-X.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Cold Spring Harbor Laboratory (US)
- Rutgers Cancer Institute (US)
- Northport VA Medical Center (US)
- Tisch Cancer Institute (US)
- Cancer Research UK Scotland Institute (GB)
- Boston University (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Michigan (US)
- Corresponding author
- Zong, Wei-Xing
- ORCID
- Bott, Alex J.
- Tonelli, Claudia
- Yu, Xufen
- Bhatt, Vrushank
- Chiles, Eric
- Zhong, Hua
- Maimouni, Sara
- Velasquez, Stephani
- Pan, Ji-An
- Muthalagu, Nathiya
- Morton, Jennifer
- Anthony, Tracy G.
- Feng, Hui
- Lamers, Wouter H.
- Murphy, Daniel J.
- Guo, Jessie Yanxiang
- Jin, Jian
- Crawford, Howard C.
- Zhang, Lanjing
- White, Eileen
- Lin, Richard Z.
- Su, Xiaoyang
- Tuveson, David A.
- Zong, Wei-Xing
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 29
- Issue
- 5
- Pages
- 1287-1298.e6
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6886125
- OpenAlex
- W2982569993
- Cited by
- 185
- References
- 47
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 35 · 2023: 36 · 2022: 33 · 2021: 23 · 2020: 10
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Lung Cancer Research Foundation
- Lustgarten Foundation
- American-Italian Cancer Foundation
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- glutamine, glutamine synthesis, glutaminolysis, alpha-ketoglutarate, TCA cycle, nitrogen metabolism, carbon-nitrogen coupling, pancreatic ductal adenocarcinoma, glutamine deprivation, KRAS G12D, cancer metabolism
- MeSH terms
- Animals, Carbon, Female, Glutamine, Glutamate-Ammonia Ligase, Humans, Ketoglutaric Acids, Male, Mice, Inbred C57BL, Nitrogen, Pancreatic Neoplasms, Gene Deletion, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Proliferation
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