Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase
Open accessAbstract
KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation. Inhibition of AKT suppressed ASNS expression and, combined with depletion of extracellular asparagine, decreased tumor growth. Therefore, KRAS is important for the cellular response to nutrient stress, and ASNS represents a promising therapeutic target in KRAS mutant NSCLC.
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K-Ras sensitizes cells to glutamine deprivation, and K-Ras knockdown rescues cells from apoptosis induced by low glutamine.
“Consistent with this observation, K-Ras sensitizes cells to glutamine deprivation, and K-Ras knockdown rescues cells from apoptosis induced by low glutamine levels187.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [187]
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References 60 · Cited by 230
- Authors
- Gwinn, D. M., Lee, A. G., Briones-Martin-del-Campo, M., Conn, C. S., Simpson, D. R., Scott, A. I., Le, A., Cowan, T. M., Ruggero, D., & Sweet-Cordero, E. A.
- Affiliations
- University of California, San Francisco (US)
- Stanford University (US)
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 33
- Issue
- 1
- Pages
- 91-107.e6
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5761662
- OpenAlex
- W2783383798
- Cited by
- 230
- References
- 60
- Citations by year
- 2026: 16 · 2025: 32 · 2024: 30 · 2023: 24 · 2022: 25 · 2021: 38 · 2020: 29 · 2019: 29 · 2018: 7
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Cancer Society (PF-12-189-01)
- National Cancer Institute (4R01CA129562, CA09302)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- KRAS, asparagine biosynthesis, asparagine synthetase, ATF4, amino acid homeostasis, nutrient stress response, non-small cell lung cancer, Keap1, Akt, Nrf2, mTORC1, therapeutic target
- MeSH terms
- Animals, Asparaginase, Aspartate-Ammonia Ligase, Carcinoma, Non-Small-Cell Lung, Homeostasis, Humans, Lung Neoplasms, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Mice, Activating Transcription Factor 4
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