Asparagine Plays a Critical Role in Regulating Cellular Adaptation to Glutamine Depletion
Open accessAbstract
Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.
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Asparagine can rescue cancer cells from glutamine deprivation-induced apoptosis.
“Interestingly, asparagine was reported to be able to rescue cancer cells from glutamine deprivation-induced apoptosis43.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [43]
Asparagine supplementation does not restore levels of other NEAAs (alanine, proline, and glutamate) or any TCA cycle intermediates (α-KG, malate, and fumarate).
“This finding is surprising because asparagine supplementation does not restore the levels of other NEAAs (alanine, proline, and glutamate) or any TCA cycle intermediates (α-KG, malate, and fumarate).”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [43]
Glutamate supplementation during glutamine deprivation cannot rescue impaired cell growth or mitochondrial respiration, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.
“Although glutamate is the major downstream product of glutamine, glutamate supplementation during glutamine deprivation cannot rescue the impaired cell growth or mitochondrial respiration16,43–45, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [43]
Asparagine plays a crucial regulatory role in conditions of glutamine deprivation.
“Yet despite this, asparagine plays a crucial regulatory role in conditions of glutamine deprivation (Zhang et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Zhang et al., 2014
ASNS is frequently upregulated in tumors and associated with poor prognosis.
“ASNS is frequently upregulated in tumors and is associated with poor prognosis (Sircar et al., 2012; Zhang et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Zhang et al., 2014
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- Authors
- Zhang, J., Fan, J., Venneti, S., Cross, J. R., Takagi, T., Bhinder, B., Djaballah, H., Kanai, M., Cheng, E. H., Judkins, A. R., Pawel, B., Baggs, J., Cherry, S., Rabinowitz, J. D., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Princeton University (US)
- University of Southern California (US)
- University of Pennsylvania (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 56
- Issue
- 2
- Pages
- 205-218
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4224619
- OpenAlex
- W2007725129
- Cited by
- 439
- References
- 33
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 42 · 2023: 34 · 2022: 52 · 2021: 43 · 2020: 50 · 2019: 37 · 2018: 31 · 2017: 33 · 2016: 24 · 2015: 27 · 2014: 1
- FWCI
- 12.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (K08CA181475, R01CA125562, R01CA105463, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- asparagine, glutamine deprivation, citrate synthase, TCA cycle anaplerosis, apoptosis, asparagine synthetase, oxaloacetate, non-essential amino acids, aspartic acid, cancer metabolism, L-asparaginase, pediatric leukemia, cancer prognosis
- MeSH terms
- Asparagine, Aspartate-Ammonia Ligase, Aspartic Acid, Cell Survival, Citrate (si)-Synthase, Citric Acid Cycle, Glutamine, Humans, Apoptosis, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Activating Transcription Factor 4, Oxaloacetic Acid
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