Carbamoyl phosphate synthetase 1 (CPS1), a rate-limiting enzyme in the urea cycle, catalyzes the conversion of ammonia and bicarbonate to carbamoyl phosphate in mitochondria. Non-small cell lung carcinoma (NSCLC) cells with oncogenic KRAS and loss of the tumor suppressor LKB1 express CPS1 and depend on this enzyme for growth. CPS1 maintains pyrimidine/purine balance in these cancer cells. Silencing CPS1 reduces the pyrimidine to purine ratio and stalls DNA synthesis, leading to DNA damage and cancer cell death. In addition, the tumor suppressor p53 represses the expression of urea cycle enzymes CPS1, OTC, and ARG1 and, therefore, causes the accumulation of ammonia, suppressing cancer growth. Furthermore, research studies suggest that hypermethylation-mediated downregulation of CPS1 expression may contribute to the progression of normal hepatocytes to hepatocellular carcinoma (HCC).
