TY - JOUR
T1 - CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells
AU - Kim, Jiyeon
AU - Hu, Zeping
AU - Cai, Ling
AU - Li, Kailong
AU - Choi, Eunhee
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.
AU - Deberardinis, Ralph J.
N1 - Funding Information:
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.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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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U2 - 10.1038/nature22359
DO - 10.1038/nature22359
M3 - Article
C2 - 28538732
AN - SCOPUS:85020182527
SN - 0028-0836
VL - 546
SP - 168
EP - 172
JO - Nature
JF - Nature
IS - 7656
ER -