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Nature. 2017 Jun 1;546(7656):168-172. doi: 10.1038/nature22359. Epub 2017 May 24.

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

Author information

1
Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
3
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, Texas 77030, USA.
4
Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
5
Hamon Center for Therapeutic Oncology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
6
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, Texas 77030, USA.
7
Oncology Research Unit, Pfizer, 401 North Middletown Road, Pearl River, New York 10965, USA.
8
Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
9
Respiratory Division, University of Gasthuisberg, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
10
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, O&N 4 Herestraat 49 - box 912, 3000 Leuven, Belgium.
11
VIB Center for Cancer Biology, KU Leuven, O&N 4 Herestraat 49 - box 912, 3000 Leuven, Belgium.
12
Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
13
McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA.

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.

PMID:
28538732
PMCID:
PMC5472349
DOI:
10.1038/nature22359
[Indexed for MEDLINE]
Free PMC Article

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