Cited by 333Biochemical and Molecular ResearchCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

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CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells

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Kim, Jiyeon, Hu, Zeping, Cai, Ling, Li, Kailong, Choi, Eunhee, Faubert, Brandon, Bezwada, Divya, Rodriguez-Canales, Jaime, Villalobos, Pamela, Lin, Yu-Fen, Ni, Min, Huffman, Kenneth E., Girard, Luc, Byers, Lauren A., Unsal-Kacmaz, Keziban, Peña, Christopher G., Heymach, John V., Wauters, Els, Vansteenkiste, Johan, Castrillon, Diego H., Chen, Benjamin P. C., Wistuba, Ignacio, Lambrechts, Diether, Xu, Jian, Minna, John D., DeBerardinis, Ralph J.·2017·Nature

DOI 10.1038/nature22359PMC PMC5472349

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Abstract

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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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: Kim, Jiyeon
Hu, Zeping
Cai, Ling
Li, Kailong
Choi, Eunhee
Faubert, Brandon
Bezwada, Divya
Lin, Yu-Fen
Ni, Min
Girard, Luc
Byers, Lauren A.
Heymach, John V.
Wauters, Els
Vansteenkiste, Johan
Chen, Benjamin P. C.
Wistuba, Ignacio
Lambrechts, Diether
Xu, Jian
Minna, John D.
DeBerardinis, Ralph J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-05-24
Volume: 546
Issue: 7656
Pages: 168-172
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature22359
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells

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