Glutamine deprivation triggers NAGK-dependent hexosamine salvage
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Abstract
Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the HBP as a promising therapeutic target in pancreatic ductal adenocarcinoma (PDA). The HBP requires both glucose and glutamine for its initiation. The PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how nutrient limitation impacts hexosamine synthesis. Here, we identify that glutamine limitation in PDA cells suppresses de novo hexosamine synthesis but results in increased free GlcNAc abundance. GlcNAc salvage via N-acetylglucosamine kinase (NAGK) is engaged to feed UDP-GlcNAc pools. NAGK expression is elevated in human PDA, and NAGK deletion from PDA cells impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.
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PDAC programs CAFs to engage a BCAT1-driven metabolic program, leading to CAF production of branched-chain α-ketoacid precursors that are reciprocally exchanged to fuel PDAC metabolism.
“PDAC program CAFs to engage a BCAT1-driven metabolic program, leading to CAF production of branched-chain α-ketoacid precursors reciprocally exchanged to fuel PDAC metabolism255.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [255]
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Pancreatic cancer: Advances and challenges
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- Authors
- Campbell, S., Mesaros, C., Izzo, L., Affronti, H., Noji, M., Schaffer, B. E., Tsang, T., Sun, K., Trefely, S., Kruijning, S., Blenis, J., Blair, I. A., & Wellen, K. E.
- Affiliations
- University of Pennsylvania (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Wellen, Kathryn E
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-11-30
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8631944
- OpenAlex
- W3215354274
- Cited by
- 58
- References
- 52
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 17 · 2023: 13 · 2022: 11 · 2021: 3
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R01CA174761, R01CA228339, P30CA016520, R01CA046595, T32CA115299, F31CA217070, K00CA212455, F31CA243294)
- Pennsylvania Department of Health
- National Institute for Environmental Studies (P30ES013508)
- National Institute of General Medical Sciences (T32GM07229)
- American Diabetes Association (1-18-PDF-144)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- glutamine deprivation, N-acetylglucosamine kinase, hexosamine biosynthetic pathway, UDP-GlcNAc, N-acetylglucosamine, pancreatic ductal adenocarcinoma, tumor microenvironment, nutrient limitation, tumor growth, aberrant glycosylation, cancer metabolism
- MeSH terms
- Animals, Cell Line, Glutamine, Hexosamines, Humans, Mice, Nude, Pancreatic Neoplasms, Phosphotransferases (Alcohol Group Acceptor), Carcinoma, Pancreatic Ductal, Mice
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