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Glutamine synthetase facilitates cancer cells to recover from irradiation-induced G2/M arrest

Authors
  • Peng, Yanni1
  • Fu, Shujun1, 2
  • Hu, Wenfeng1, 2
  • Qiu, Yanfang1
  • Zhang, Lu1, 2
  • Tan, Rong1, 2, 3
  • Sun, Lun-Quan1, 2, 3, 4
  • 1 Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, China , (China)
  • 2 Key Laboratory of MolecularRadiation Oncology Hunan Province, China , (China)
  • 3 Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, China , (China)
  • 4 National Clinical Research Center for Gerontology, China , (China)
Type
Published Article
Journal
Cancer Biology & Therapy
Publisher
Landes Bioscience
Publication Date
Sep 17, 2019
Volume
21
Issue
1
Pages
43–51
Identifiers
DOI: 10.1080/15384047.2019.1665394
PMID: 31526079
PMCID: PMC7012188
Source
PubMed Central
Keywords
License
Unknown

Abstract

Resistance to radiation of cancer cells can be either intrinsic or acquired, leading to treatment failure. In response to DNA damage caused by IR, cancer cells are arrested in cell cycle showing limited proliferation and increased apoptosis. However, radiation-resistant cells are able to overcome the cell cycle block and proceed to proliferation, for which the detailed mechanism remains to be elucidated. In the present study, we showed that radioresistant cells exhibited a recoverable G2/M phase during prolonged cell cycle and manifested lower apoptosis rate and more colony formation. RNA-seq analysis revealed that glutamine synthetase (GS, GLUL) gene was highly expressed in radioresistant cancer cells in comparison with the parental cells, which was in accordance with the G2/M arrest after ionizing radiation. Knocking out of GS in radioresistant cells resulted in a delayed G2/M recovery and lowered proliferation rate after ionizing radiation treatment, which was accompanied with increased inhibitory phosphorylation of CDK1 at Y15 and downregulated Cdc25B, a dual specific phosphatase of CDK1. Moreover, there was an enhanced complex formation of CDK1 and Cyclin B1 when the cells were rescued by re-introducing GS. In vivo, knocking down of GS significantly sensitized CNE2-R xenografts to RT in mice. In this study, we demonstrate a novel role of glutamine synthetase independent of metabolic function in promoting recovery from G2/M arrest caused by ionizing radiation, thus, causing cancer cell resistance to radiotherapy.

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