Aspartate Rescues S-phase Arrest Caused by Suppression of Glutamine Utilization in KRas-driven Cancer Cells
Open accessAbstract
During G1-phase of the cell cycle, normal cells respond first to growth factors that indicate that it is appropriate to divide and then later in G1 to the presence of nutrients that indicate sufficient raw material to generate two daughter cells. Dividing cells rely on the "conditionally essential" amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates and as a nitrogen source for nucleotide biosynthesis. We previously reported that while non-transformed cells arrest in the latter portion of G1 upon Q deprivation, mutant KRas-driven cancer cells bypass the G1 checkpoint, and instead, arrest in S-phase. In this study, we report that the arrest of KRas-driven cancer cells in S-phase upon Q deprivation is due to the lack of deoxynucleotides needed for DNA synthesis. The lack of deoxynucleotides causes replicative stress leading to activation of the ataxia telangiectasia and Rad3-related protein (ATR)-mediated DNA damage pathway, which arrests cells in S-phase. The key metabolite generated from Q utilization was aspartate, which is generated from a transaminase reaction whereby Q-derived glutamate is converted to α-ketoglutarate with the concomitant conversion of oxaloacetate to aspartate. Aspartate is a critical metabolite for both purine and pyrimidine nucleotide biosynthesis. This study identifies the molecular basis for the S-phase arrest caused by Q deprivation in KRas-driven cancer cells that arrest in S-phase in response to Q deprivation. Given that arresting cells in S-phase sensitizes cells to apoptotic insult, this study suggests novel therapeutic approaches to KRas-driven cancers.
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Exogenous aspartate can restore cell cycle arrest caused by glutamine deprivation.
“Thus, exogenous aspartate can restore cell cycle arrest caused by glutamine deprivation33.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [33]
Enhanced transamination and aspartate synthesis in K-Ras-driven cancer cells are important for nucleotide biosynthesis and redox balance.
“Significantly, enhanced transamination and aspartate synthesis in K-Ras-driven cancer cells are important in the promotion of nucleotide biosynthesis184 and maintenance of redox balance29.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [184]
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An engineered biosensor enables dynamic aspartate measurements in living cellsPreprint
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An engineered biosensor enables dynamic aspartate measurements in living cellsPreprint
Davidsen, K., Marvin, J. S., Aggarwal, A., Brown, T. A., & Sullivan, L. B. (2024) · eLife · doi:10.7554/elife.90024.2
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- Authors
- Patel, D., Menon, D., Bernfeld, E., Mroz, V., Kalan, S., Loayza, D., & Foster, D. A.
- Affiliations
- The Graduate Center, CUNY (US)
- City University of New York (US)
- Corresponding author
- Foster, David A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 291
- Issue
- 17
- Pages
- 9322-9329
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4861495
- OpenAlex
- W2277073486
- Cited by
- 86
- References
- 26
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 13 · 2023: 6 · 2022: 9 · 2021: 6 · 2020: 11 · 2019: 10 · 2018: 8 · 2017: 6 · 2016: 3 · 2014: 1
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01-CA046677, R01-CA179542)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glutamine deprivation, aspartic acid, S phase arrest, KRAS-driven cancers, replicative stress, nucleotide synthesis, TCA cycle anaplerosis, purine and pyrimidine biosynthesis, transamination, oxaloacetate, alpha-ketoglutarate, glutamate
- MeSH terms
- Aspartic Acid, Citric Acid Cycle, Humans, Purine Nucleotides, Pyrimidine Nucleotides, Proto-Oncogene Proteins p21(ras), Glutamic Acid, G1 Phase Cell Cycle Checkpoints, S Phase Cell Cycle Checkpoints, MCF-7 Cells, Ataxia Telangiectasia Mutated Proteins
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