2. Academic Validation
  3. IL-36γ and IL-36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress-Induced Cell Death

IL-36γ and IL-36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress-Induced Cell Death

  • Adv Sci (Weinh). 2021 Oct;8(19):e2101501. doi: 10.1002/advs.202101501.
Peng Wang 1 2 3 4,  Wei Yang 1 2 3,  Hao Guo 1 2 3,  Hong-Peng Dong 1 2 3,  Yu-Yao Guo 1 2 3,  Hu Gan 1 2 3,  Zou Wang 5,  Yongbo Cheng 6,  Yu Deng 7,  Shizhe Xie 8 9,  Xinglou Yang 8 9,  Dandan Lin 10,  Bo Zhong 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, College of Life Sciences, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 3 Department of Immunology, Medical Research Institute and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
  • 4 Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, 430071, China.
  • 5 Wuhan Biobank Co., Ltd, Wuhan, Wuhan, 430075, China.
  • 6 Elem Biotech Co., Ltd, Wuhan, 430075, China.
  • 7 Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 8 CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 9 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 10 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
PMID: 34369094 DOI: 10.1002/advs.202101501
Abstract

The balance between Antioxidants and Reactive Oxygen Species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36γ and IL-36RA reciprocally regulate the progression of non-small cell lung Cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36γ significantly inhibits NSCLC progression and prolongs survival of the KrasLSL-G12D/+ Tp53fl/fl and KrasLSL-G12D/+ Lkb1fl/fl mice after tumor induction, whereas knockout of IL-36RA exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36γ directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36RA or IL-36γ neutralizing antibody. Consistently, IL-36γ staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.

Keywords

IL-36γ; IL-36Ra; glutathione metabolism; non-small cell lung cancer; oxidative stress; reactive oxygen species.

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