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Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth

Jiang-Sha Zhao1,2, Shuo Shi3, Hai-Yan Qu4

  • 1Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. zhaojsh@zju.edu.cn.

Nature Metabolism
|February 11, 2022
PubMed

Insights

Glutamine synthetase (GS) drives cancer cell proliferation by regulating mitosis, independent of its metabolic role. Depleting GS halts cancer growth and enhances chemotherapy, revealing a novel therapeutic target.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Metabolic enzymes are reprogrammed in tumors.
  • Key metabolic enzymes have not been known to directly regulate cell mitosis.
  • Glutamine synthetase (GS) is an essential metabolic enzyme.

Purpose of the Study:

  • To investigate the non-metabolic functions of glutamine synthetase (GS).
  • To determine if GS directly regulates cell mitosis and cancer proliferation.
  • To explore GS as a potential therapeutic target in non-small cell lung cancer.

Main Methods:

  • Depletion of GS in cancer cell lines, organoids, and xenografts.
  • Assessing mitotic progression and cell cycle regulation.
  • Investigating the interaction between GS, NUP88, and CDC20.
  • Evaluating tumor growth and chemotherapy efficacy in mouse models.

Main Results:

  • GS depletion, not enzymatic inhibition, caused mitotic arrest and multinucleation.
  • GS directly interacts with NUP88, preventing its binding to CDC20.
  • This interaction is crucial for the metaphase-to-anaphase transition.
  • GS is overexpressed in non-small cell lung cancer, and its depletion reduced tumor growth and improved chemotherapy response.

Conclusions:

  • Glutamine synthetase (GS) possesses a moonlighting function in governing cell mitosis.
  • GS promotes cancer cell proliferation and tumor development beyond its metabolic role.
  • Targeting GS offers a novel strategy for cancer therapy, particularly in combination with microtubule-targeting agents.

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