The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism
Open accessAbstract
Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose deprivation led to a marked reduction in glutamine uptake and progressive cellular atrophy in multiple mammalian cell types. Despite the continuous presence of growth factor and an abundant supply of extracellular glutamine, interleukin-3 (IL-3)-dependent cells were unable to maintain TCA cycle metabolite pools or receptor-dependent signal transduction when deprived of glucose. This was due at least in part to down-regulation of IL-3 receptor α (IL-3Rα) surface expression in the absence of glucose. Treatment of glucose-starved cells with N-acetylglucosamine (GlcNAc) to maintain hexosamine biosynthesis restored mitochondrial metabolism and cell growth by promoting IL-3-dependent glutamine uptake and metabolism. Thus, glucose metabolism through the hexosamine biosynthetic pathway is required to sustain sufficient growth factor signaling and glutamine uptake to support cell growth and survival.
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Glucose carbon is important to be metabolized through other branches of glycolytic metabolism, including serine synthesis and the hexosamine pathway.
“It would also fit with the importance of glucose carbon to be metabolized through other branches of glycolytic metabolism, including serine synthesis (as discussed above) and the hexosamine pathway (Wellen et al., 2010).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Wellen et al., 2010
Glucose and glutamine collaborate in the hexosamine pathway to modify nutrient transporters and growth factor receptors, enabling their expression on the cell membrane.
“But they also collaborate in another biochemical pathway to produce hexosamines, which modify nutrient transporters and growth factor receptors, enabling their expression on the cell membrane (Figure 2).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Wellen et al., 2010
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- Authors
- Wellen, K. E., Lu, C., Mancuso, A., Lemons, J. M. S., Ryczko, M., Dennis, J. W., Rabinowitz, J. D., Coller, H. A., & Thompson, C. B.
- Affiliations
- University of Pennsylvania (US)
- Princeton University (US)
- Mount Sinai Hospital (CA)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-11-24
- Volume
- 24
- Issue
- 24
- Pages
- 2784-2799
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3003197
- OpenAlex
- W2034586537
- Cited by
- 377
- References
- 55
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 14 · 2023: 15 · 2022: 29 · 2021: 25 · 2020: 17 · 2019: 24 · 2018: 36 · 2017: 24 · 2016: 28 · 2015: 29 · 2014: 34 · 2013: 26 · 2012: 35
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- National Cancer Institute (P01CA104838, R01CA105463)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- hexosamine biosynthetic pathway, glutamine uptake, glucose metabolism, interleukin-3, CD123, N-acetylglucosamine, TCA cycle, mitochondrial metabolism, glucose deprivation, cell growth, growth factor signaling, receptor down-regulation
- MeSH terms
- Acetylglucosamine, Animals, Atrophy, Biological Transport, Cell Survival, Citric Acid Cycle, Glucose, Glutamine, Hexosamines, Interleukin-3, Signal Transduction, Intercellular Signaling Peptides and Proteins, Mice, Metabolic Networks and Pathways
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