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

Autor: Yongbo Cheng, Dandan Lin, Yu Deng, Zou Wang, Xinglou Yang, Shizhe Xie, Hao Guo, Wei Yang, Bo Zhong, Peng Wang, Hong-Peng Dong, Yu-Yao Guo, Hu Gan
Rok vydání: 2021
Předmět:
non‐small cell lung cancer
Programmed cell death
Lung Neoplasms
Science
General Chemical Engineering
General Physics and Astronomy
Medicine (miscellaneous)
Oxidative phosphorylation
Tumor initiation
medicine.disease_cause
Biochemistry
Genetics and Molecular Biology (miscellaneous)
Mice
chemistry.chemical_compound
Carcinoma
Non-Small-Cell Lung
medicine
Animals
Homeostasis
Humans
oxidative stress
General Materials Science
Research Articles
reactive oxygen species
chemistry.chemical_classification
Reactive oxygen species
Cell Death
IL‐36γ
IL‐36Ra
General Engineering
Receptors
Interleukin-1
glutathione metabolism
Glutathione
respiratory tract diseases
Mice
Inbred C57BL
Disease Models
Animal
chemistry
Disease Progression
Cancer research
Carcinogenesis
Oxidative stress
Research Article
Interleukin-1
Zdroj: Advanced Science, Vol 8, Iss 19, Pp n/a-n/a (2021)
Advanced Science
ISSN: 2198-3844
DOI: 10.1002/advs.202101501
Popis: 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 Kras LSL‐G12D/+ Tp53 fl/fl and Kras LSL‐G12D/+ Lkb1 fl/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.
The homeostasis of redox critically regulates tumor initiation and progression. Here, it is shown that IL‐36γ and IL‐36Ra reciprocally regulate non‐small cell lung cancer (NSCLC) progression by modulating glutathione metabolism, reactive oxygen species, and oxidative stress‐induced cell death. These findings highlight essential roles of IL‐36 family cytokines in redox for tumorigenesis and potential therapeutic strategy for NSCLC.
Databáze: OpenAIRE
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