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

Jiyeon Kim, Zeping Hu, Ling Cai, Kailong Li, Eunhee Choi, Brandon Faubert, Divya Bezwada, Jaime Rodriguez-Canales, Pamela Villalobos, Yu Fen Lin, Min Ni, Kenneth E. Huffman, Luc Girard, Lauren A. Byers, Keziban Unsal-Kacmaz, Christopher G. Peña, John V. Heymach, Els Wauters, Johan Vansteenkiste, Diego H. Castrillon & 6 others Benjamin P.C. Chen, Ignacio Wistuba, Diether Lambrechts, Jian Xu, John D. Minna, Ralph J. Deberardinis

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)168-172
Number of pages5
JournalNature
Volume546
Issue number7656
DOIs
StatePublished - Jun 1 2017

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Carbamyl Phosphate
Ligases
Lung Neoplasms
DNA
Ammonia
Non-Small Cell Lung Carcinoma
Pyrimidines
Nitrogen
DNA Damage
Neoplasms
Cell Death
AMP-Activated Protein Kinases
Metabolomics
DNA-Directed DNA Polymerase
Bicarbonates
Growth
pyrimidine
S Phase
Oncogenes
Urea

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

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

In: Nature, Vol. 546, No. 7656, 01.06.2017, p. 168-172.

Research output: Contribution to journalArticle

Kim, J, Hu, Z, Cai, L, Li, K, Choi, E, Faubert, B, Bezwada, D, Rodriguez-Canales, J, Villalobos, P, Lin, YF, Ni, M, Huffman, KE, Girard, L, Byers, LA, Unsal-Kacmaz, K, Peña, CG, Heymach, JV, Wauters, E, Vansteenkiste, J, Castrillon, DH, Chen, BPC, Wistuba, I, Lambrechts, D, Xu, J, Minna, JD & Deberardinis, RJ 2017, 'CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells', Nature, vol. 546, no. 7656, pp. 168-172. https://doi.org/10.1038/nature22359
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. / CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. In: Nature. 2017 ; Vol. 546, No. 7656. pp. 168-172.
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AU - Faubert, Brandon

AU - Bezwada, Divya

AU - Rodriguez-Canales, Jaime

AU - Villalobos, Pamela

AU - Lin, Yu Fen

AU - Ni, Min

AU - Huffman, Kenneth E.

AU - Girard, Luc

AU - Byers, Lauren A.

AU - Unsal-Kacmaz, Keziban

AU - Peña, Christopher G.

AU - Heymach, John V.

AU - Wauters, Els

AU - Vansteenkiste, Johan

AU - Castrillon, Diego H.

AU - Chen, Benjamin P.C.

AU - Wistuba, Ignacio

AU - Lambrechts, Diether

AU - Xu, Jian

AU - Minna, John D.

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