CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells
Open accessAbstract
Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.
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KRAS/LKB1-null lung cancer cells are more reliant on CPS1 for pyrimidine biosynthesis, independent of mTOR signaling.
“KRAS/LKB1-null lung cancer cells are more reliant on the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1) for pyrimidine biosynthesis, although this dependency is independent of mTOR signaling (Kim et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Kim et al., 2017
The first step in de novo pyrimidine biosynthesis mediated by CPSs occurs mainly in mitochondria via CPS1 in K-Ras/LKB1-mutant lung cancer cells.
“Interestingly, the first step in de novo pyrimidine biosynthesis mediated by CPSs occurs mainly in mitochondria via CPS1 in K-Ras/LKB1-mutant lung cancer cells32 (Fig. 2).”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [32]
CPS1 is a major rate-limiting enzyme in pyrimidine biosynthesis using nitrogen released via mitochondrial glutaminolysis.
“Although cytosolic CPS2 can produce a cytosolic pool of carbamoyl phosphate, CPS1 is a major rate-limiting enzyme in pyrimidine biosynthesis using nitrogen released via mitochondrial glutaminolysis32.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [32]
KL NSCLC cells exhibit increased dependence on dTTP synthesis and rely on an unorthodox pathway of pyrimidine biosynthesis that utilizes mitochondrially generated carbamoyl phosphate.
“Furthermore, KL NSCLC cells exhibit increased dependence on dTTP synthesis and rely on an unorthodox pathway of pyrimidine biosynthesis that utilizes mitochondrially generated carbamoyl phosphate88, 89.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [89]
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- Authors
- Kim, J., Hu, Z., Cai, L., Li, K., Choi, E., Faubert, B., Bezwada, D., Rodriguez-Canales, J., Villalobos, P., Lin, Y.-F., Ni, M., Huffman, K. E., Girard, L., Byers, L. A., Unsal-Kacmaz, K., Peña, C. G., Heymach, J. V., Wauters, E., Vansteenkiste, J., Castrillon, D. H., Chen, B. P. C., Wistuba, I., Lambrechts, D., Xu, J., Minna, J. D., & DeBerardinis, R. J.
- Affiliations
- Children's Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- KU Leuven (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Corresponding author
- DeBerardinis, Ralph J.
- ORCID
- Venue
- Nature
- Published
- 2017-05-24
- Volume
- 546
- Issue
- 7656
- Pages
- 168-172
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5472349
- OpenAlex
- W2619620886
- Cited by
- 325
- References
- 30
- Citations by year
- 2026: 39 · 2025: 40 · 2024: 26 · 2023: 42 · 2022: 38 · 2021: 45 · 2020: 38 · 2019: 26 · 2018: 27 · 2017: 4
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-05-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- National Cancer Institute (P50CA070907, U01CA176284, R01CA196912, R01CA157996)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK093543, R01DK111430)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- CPS1, LKB1, KRAS mutation, non-small cell lung cancer, lung adenocarcinoma, pyrimidine metabolism, urea cycle, nitrogen metabolism, DNA synthesis, DNA damage, AMPK, tumor metabolic reprogramming, S phase progression, tumor suppressor loss
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Ammonia, Animals, Bicarbonates, Carbamyl Phosphate, Carbamoyl-Phosphate Synthase (Ammonia), Carcinoma, Non-Small-Cell Lung, DNA, DNA Damage, DNA-Directed DNA Polymerase, DNA Replication, Female, Humans, Lung Neoplasms, Male, Mitochondria, Nitrogen, Purines, Pyrimidines, Transcription, Genetic, S Phase, Proto-Oncogene Proteins p21(ras), Cell Death, Protein Serine-Threonine Kinases, Gene Silencing, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, AMP-Activated Protein Kinases, Metabolomics
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