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 behaviour1,2. 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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We thank A. Jaffe and members of the DeBerardinis laboratory for critiquing the manuscript and J. Kozlitina for statistical expertise. R.J.D. is supported by grants from the NIH (R01CA157996), Cancer Prevention and Research Institute of Texas (CPRIT RP130272), Robert A. Welch Foundation (I1733) and H.H.M.I. (Faculty Scholars Program). J.K. is supported by an American Lung Association Senior Research Training Fellowship (RT-306212). D.H.C. is supported by NIH grant (1R01CA196912). J.D.M., J.R.C., P.V. and I.W. are supported by the University of Texas Lung Specialized Programs of Research Excellence (SPORE) grant (P50CA70907). J.D.M. is also supported by NIH grant CA176284 and CPRIT grants RP120732 and RP110708.
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Differentially Expressed Mitochondrial Proteins in Human MCF7 Breast Cancer Cells Resistant to Paclitaxel
International Journal of Molecular Sciences (2019)