Glutamine synthetase limits b-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.

Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As dysregulated urea cycle is implicated in cancer development, the impact of GS' ammonia clearance function has not been explored in cancer. Here we show that, oncogenic activation of beta-catenin led to decreased urea cycle and elevated ammonia waste burden. While beta-catenin induced the expression of GS, which is thought to be cancer-promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived non-essential amino acids (NEAAs), which subsequently stimulated mTORC1. Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While HCC patients, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.