# Glutamine synthetase in cancer cell metabolism and oncogenesis

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $451,360

## Abstract

SUMMARY
Dysregulated metabolism has long been recognized as a key hallmark of neoplastic disease. One of the major
metabolic changes in tumor cells is increased glutamine (Gln) usage via glutaminolysis: Gln is deaminated by
glutaminase (GLS) to glutamate (glutamic acid, Glu), which is converted by glutamate dehydrogenase (GLUD)
to α-ketoglutarate (aKG) to enter the tricarboxylic acid (TCA) cycle for anaplerosis (replenishment of metabolic
intermediates for energy production or biosynthesis). It is well recognized that oncogenic c-Myc (hereafter
referred to as Myc) enhances Gln usage by directly transactivating the expression of Gln transporters SLC1A5
and SLC7A5/SLC3A2, and by increasing GLS1 expression via transcriptional suppression of the GLS1
repressor micro RNAs (miR)-23a/b. Pharmacologically targeting GLS1 is being actively pursued as an anti-
cancer approach, although thus far with little success. On the other hand, several recent studies, including
those from our laboratory, point to the importance of Gln synthesis, at least in certain cell/tissue types. Gln is
synthesized de novo by condensation of Glu and ammonia, catalyzed by the enzyme Gln synthetase (GS, also
known as glutamate ammonia ligase, GLUL). Using stable isotope-based metabolite tracing, we recently
reported that this synthesized Gln is not used via glutaminolysis to fuel the TCA cycle; rather it is used for
several TCA-independent anabolic processes including biosynthesis of nucleotides and transport of essential
amino acids. Importantly, elevated expression of GS promoted cell survival under Gln limitation; inhibition of
GS led to decreased cell proliferation and increased cell death upon Gln limitation, and slowed xenograft tumor
growth. Moreover, we recently reported that Myc can induce the expression of GS in a number of cancer cell
lines. We also found a positive correlation between Myc activation and GS expression several mouse models
and in human patient samples. These findings lead us to propose the following hypothesis: oncogenic Myc,
at least in certain cell/tissue types, upregulates GS expression to promote Gln production and its
anabolic usage (away from the TCA cycle), thereby facilitating oncogenesis. We propose two Specific
Aims to study this hypothesis: 1) Study the metabolic and cell biological consequences, and the regulation of
increased GS expression in the context of Myc activation; and 2) Determine the in vivo role of GS in Myc-
driven metabolic reprogramming and oncogenesis. If accomplished, this study will provide a novel dimension
to understanding the functions of dysregulated Myc in cancer cells and a potential new target for treatment of
Myc-driven tumors.

## Key facts

- **NIH application ID:** 9981701
- **Project number:** 5R01CA224550-03
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Wei-Xing Zong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,360
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981701

## Citation

> US National Institutes of Health, RePORTER application 9981701, Glutamine synthetase in cancer cell metabolism and oncogenesis (5R01CA224550-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981701. Licensed CC0.

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