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

Abstract

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 β-catenin led to decreased urea cycle and elevated ammonia waste burden. While β-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.

A pan-cancer analysis of the oncogenic role of ATP binding cassette subfamily E member 1 (ABCE1) in human tumors: An observational study

“…[12,14,22] In various cancers, metabolic profile changes dramatically, and the phosphatidylinositol 3-kinase (PI3K)/ AKT/mTOR pathway is highly responsive to these changes, promoting the translation of MYC. [23][24][25][26] Therefore, the different expression patterns of ABCE1 in cancers might be related with these upstream factors.…”

Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma

“…recently provided evidence of GS’s tumour suppressor role in β-catenin-activated HCCs. 109 The authors used an in vivo approach in mice similar to that described above. They delivered c-Met and the constitutively active mutant of β-catenin (ΔN90-β-catenin) into livers, either wild-type or harbouring hepatocyte-specific ablation of GS (GS KO ).…”

Spatial metabolomics and its application in the liver

“…The impact of Wnt/β-catenin-induced metabolic changes on liver carcinogenesis has recently been thoroughly explored. [18][19][20] Other pathways have also been implicated in liver zonation mostly by counteracting Wnt/β-catenin signaling. Hedgehog signaling, although presenting low activity in healthy mature hepatocytes, is higher in the periportal region and hypothetically implicated in the regulation of zone 1 hepatocytes.…”

“…More importantly, compelling studies have demonstrated that conditional liver-specific β-catenin knockouts, 14,15 inducible liver-specific adenomatous polyposis coli knockouts, 16 and Lrp5/6 knockouts 17 loosen zonation patterns, supporting Wnt/β-catenin as the gatekeeper of liver metabolic zonation. The impact of Wnt/β-catenin–induced metabolic changes on liver carcinogenesis has recently been thoroughly explored 18–20 …”