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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Ammonia / metabolism
  • Animals
  • Bicarbonates / metabolism
  • Carbamoyl-Phosphate Synthase (Ammonia) / deficiency
  • Carbamoyl-Phosphate Synthase (Ammonia) / genetics
  • Carbamoyl-Phosphate Synthase (Ammonia) / metabolism*
  • Carbamyl Phosphate / metabolism
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Death
  • Cell Proliferation
  • DNA / biosynthesis*
  • DNA Damage / drug effects
  • DNA Replication
  • DNA-Directed DNA Polymerase / metabolism
  • Female
  • Gene Silencing
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Male
  • Metabolomics
  • Mice
  • Mitochondria / metabolism
  • Nitrogen / metabolism
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Purines / metabolism
  • Pyrimidines / metabolism*
  • Pyrimidines / pharmacology
  • S Phase
  • Transcription, Genetic
  • Xenograft Model Antitumor Assays

Substances

  • Bicarbonates
  • KRAS protein, human
  • Purines
  • Pyrimidines
  • Carbamyl Phosphate
  • Ammonia
  • DNA
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • DNA-Directed DNA Polymerase
  • Proto-Oncogene Proteins p21(ras)
  • Carbamoyl-Phosphate Synthase (Ammonia)
  • pyrimidine
  • Nitrogen
  • purine