Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs
Open accessAbstract
Cancer cells undergo a metabolic transformation that allows for increased anabolic demands, wherein glycolytic and tricarboxylic acid (TCA) cycle intermediates are shunted away for the synthesis of biological molecules required for cell growth and division. One of the key shunts is the exit of citrate from the mitochondria and the TCA cycle for the generation of cytosolic acetyl-coenzyme A that can be used for fatty acid and cholesterol biosynthesis. With the loss of mitochondrial citrate, cancer cells rely on the 'conditionally essential' amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates. Although Q deprivation causes G1 cell cycle arrest in non-transformed cells, its impact on the cancer cell cycle is not well characterized. We report here a correlation between bypass of the Q-dependent G1 checkpoint and cancer cells harboring K-Ras mutations. Instead of arresting in G1 in response to Q-deprivation, K-Ras-driven cancer cells arrest in either S- or G2/M-phase. Inhibition of K-Ras effector pathways was able to revert cells to G1 arrest upon Q deprivation. Blocking anaplerotic utilization of Q mimicked Q deprivation--causing S- and G2/M-phase arrest in K-Ras mutant cancer cells. Significantly, Q deprivation or suppression of anaplerotic Q utilization created synthetic lethality to the cell cycle phase-specific cytotoxic drugs, capecitabine and paclitaxel. These data suggest that disabling of the G1 Q checkpoint could represent a novel vulnerability of cancer cells harboring K-Ras and possibly other mutations that disable the Q-dependent checkpoint.
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Limiting glutamine use combined with chemotherapy halts pancreatic tumor growth in preclinical mouse models and is not toxic to normal cells.
“Limiting glutamine use combined with chemotherapy is a viable means to halt pancreatic tumor growth in preclinical mouse models and is not toxic to normal cells58,60,65.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [65]
Activation of K-Ras in cancer cells results in bypass of the late G1 glutamine-dependent checkpoint; glutamine deprivation causes growth arrest in S or G2/M instead of G1.
“Importantly, activation of K-Ras in cancer cells results in bypass of the late G1 glutamine-dependent checkpoint. Specifically, glutamine deprivation in K-Ras-driven cancer cells leads to growth arrest in S or G2/M phase instead of in G1 phase.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [185]
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NF1 deficiency drives metabolic reprogramming in ER+ breast cancerPreprint
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- Authors
- Saqcena, M., Mukhopadhyay, S., Hosny, C., Alhamed, A., Chatterjee, A., & Foster, D. A.
- Affiliations
- Hunter College (US)
- Corresponding author
- Foster, D A
- Venue
- Oncogene
- Published
- 2014-07-14
- Volume
- 34
- Issue
- 20
- Pages
- 2672-2680
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC4418945
- OpenAlex
- W1980502224
- Cited by
- 67
- References
- 42
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 12 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 9 · 2014: 1
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (RP-03037)
- National Cancer Institute (R01CA046677, R01CA179542)
- National Center for Research Resources
- National Institute on Minority Health and Health Disparities (G12MD007599)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glutamine, TCA cycle, KRAS mutation, anaplerosis, G1 cell cycle checkpoint, synthetic lethality, capecitabine, paclitaxel, cancer metabolism, cell cycle arrest
- MeSH terms
- Capecitabine, Antimetabolites, Antineoplastic, Antineoplastic Agents, Phytogenic, Citric Acid Cycle, Cytotoxins, Deoxycytidine, Fluorouracil, Glutamine, Humans, Mutation, Neoplasms, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Paclitaxel, ras Proteins, Cell Line, Tumor, Cell Cycle Checkpoints
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