# Glutamine synthetase in beta-catenin driven hepatocellular carcinoma

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $492,130

## Abstract

PROJECT SUMMARY
Glutamine (Gln) is a multifaceted amino acid that serves as important carbon and nitrogen sources. In a
situation where circulatory supply of Gln is limited, such as in poorly vascularized tumors, cell autonomous Gln
synthesis is turned on to assimilate the inorganic ammonia into Gln to support the nitrogen anabolic processes.
In mammals, Gln synthesis is catalyzed by glutamine synthetase (GS) that condenses ammonium with
glutamate to produce Gln. GS has been shown to enhance cell survival/growth/repairs in various cancers by
promoting de novo glutamine synthesis and subsequent nitrogen anabolism. In the liver, where blood supply of
Gln is abundant, GS-mediated Gln synthesis serves as a mechanism for ammonia detoxification next to the
urea cycle. Interestingly, in hepatocellular carcinoma (HCC), the major histological subtype of liver malignancy,
GS expression is frequently elevated whereas urea cycle enzymes (UCEs) down-regulated. Both elevated GS
and decreased UCEs correlate well with -catenin activation, a prevalent oncogenic driving event in HCC.
While this seems to be consistent with the common thought that GS promotes tumor growth, surprisingly, using
the Glulflox/flox mouse, we recently reported that genetic ablation of hepatic GS accelerated tumor growth in
several HCC models that involve -catenin6. Echoing the scenario in clinic, oncogenic -catenin suppressed
the expression of the UCEs while induced the expression of GS. It was then speculated that the suppression of
UCEs led to defective ammonia clearance, and GS was upregulated to help alleviate the hyperammonemia
situation. GS ablation exacerbated the ammonia burden and facilitated the production of Glu-derived non-
essential amino acids (NEAAs) that subsequently stimulated mTORC1. These findings prompt us to form the
hypothesis that GS-mediated ammonia clearance functions to suppress tumor growth in -catenin-driven HCC.
We propose two Specific Aims: 1) Study the theory that defective ammonia clearance promotes HCC. We will
first determine whether GS suppresses HCC growth in a cell-intrinsic fashion, study how hyperammonemia
promotes HCC, and take unbiased approach to uncover other mechanisms that may be responsible for
enhanced HCC growth resulting from hyperammonemia. 2) Study how -catenin regulates GS expression in
the liver. GS transcription is activated by Wnt/-catenin during liver zonal development and upon oncogenic
transformation of hepatocytes. However, the underlying mechanism remains elusive. Our preliminary data
suggest that GS expression is regulated by a liver-specific cis-acting distal enhancer. We will identify and
characterize the liver-specific distal enhancer and study the underlying mechanism for GS expression
regulated by the novel transcription factors that are associated with the enhancer. Accomplishing these Aims
will help establish a novel theory that GS-mediated ammonia clearance is a tumor-suppressing mechanism in
HCC, and will uncover ...

## Key facts

- **NIH application ID:** 10980780
- **Project number:** 2R01CA224550-06A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Wei-Xing Zong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $492,130
- **Award type:** 2
- **Project period:** 2018-09-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980780

## Citation

> US National Institutes of Health, RePORTER application 10980780, Glutamine synthetase in beta-catenin driven hepatocellular carcinoma (2R01CA224550-06A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10980780. Licensed CC0.

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