2. Academic Validation
  3. Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth

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

  • Nat Metab. 2022 Feb;4(2):239-253. doi: 10.1038/s42255-021-00524-2.
Jiang-Sha Zhao 1 2,  Shuo Shi 3,  Hai-Yan Qu 4,  Zuzana Keckesova 5,  Zi-Jian Cao 6,  Li-Xian Yang 6,  Xiaofu Yu 7,  Limin Feng 4,  Zhong Shi 8,  Joanna Krakowiak 9,  Ruo-Ying Mao 4,  Yi-Tong Shen 6,  Yu-Meng Fan 6,  Tian-Min Fu 10,  Cunqi Ye 11,  Daqian Xu 4 12,  Xiaofei Gao 13,  Jia You 13,  Wenbo Li 9 14,  Tingbo Liang 15 16,  Zhimin Lu 17 18,  Yu-Xiong Feng 19 20
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 2 Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  • 3 Shanghai Advanced Institute of Immunochemical Studies, ShanghaiTech University, Shanghai, China.
  • 4 Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • 6 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Thoracic Radiotherapy, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
  • 8 Department of Medical Oncology, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
  • 9 Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center Houston, Houston, TX, USA.
  • 10 Department of Biological Chemistry and Pharmacology, College of Medicine, The Ohio State University, Ohio, OH, USA.
  • 11 Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 12 Cancer Center, Zhejiang University, Hangzhou, China.
  • 13 School of Life Sciences, Westlake University, Hangzhou, China.
  • 14 MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, TX, USA.
  • 15 Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 16 Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  • 17 Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 18 Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  • 19 Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 20 Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
PMID: 35145325 DOI: 10.1038/s42255-021-00524-2
Abstract

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver Cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung Cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic Enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

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