Blocking TBK1 alleviated radiation-induced pulmonary fibrosis and epithelial-mesenchymal transition through Akt-Erk inactivation

Autor: Zebin Liao, Lei Liu, Bailong Li, Qu Hongjin, Liu Zhe, Fu Gao, Yanyong Yang, Jianming Cai, Penglin Xia, Hongran Qin
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
MAPK/ERK pathway
Epithelial-Mesenchymal Transition
Pulmonary Fibrosis
Blotting
Western
Clinical Biochemistry
Fluorescent Antibody Technique
lcsh:Medicine
Apoptosis
Enzyme-Linked Immunosorbent Assay
Protein Serine-Threonine Kinases
Biochemistry
Article
lcsh:Biochemistry
Mice
03 medical and health sciences
0302 clinical medicine
Pulmonary fibrosis
medicine
Animals
Gene silencing
lcsh:QD415-436
Epithelial–mesenchymal transition
Extracellular Signal-Regulated MAP Kinases
Lung cancer
Molecular Biology
Protein kinase B
Cell Proliferation
Lung
business.industry
lcsh:R
medicine.disease
Rats
Mice
Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Female
Signal transduction
business
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Experimental and Molecular Medicine, Vol 51, Iss 4, Pp 1-17 (2019)
Experimental & Molecular Medicine
ISSN: 2092-6413
1226-3613
Popis: As a common serious complication of thoracic radiotherapy, radiation-induced pulmonary fibrosis (RIPF) severely limits radiation therapy approaches. Epithelial–mesenchymal transition (EMT) is a direct contributor to the fibroblast pool during fibrogenesis, and prevention of EMT is considered an effective strategy to inhibit tissue fibrosis. Our previous study revealed that TANK-binding kinase 1 (TBK1) regulates EMT in lung cancer cells. In the present study, we aimed to investigate the therapeutic potential of targeting TBK1 to prevent RIPF and EMT progression. We found radiation-induced EMT and pulmonary fibrosis in normal alveolar epithelial cells and lung tissues. TBK1 knockdown or inhibition significantly reversed EMT in vivo and in vitro and attenuated pulmonary fibrosis and collagen deposition. Moreover, we observed that TBK1 was elevated in a time- and dose-dependent manner by radiation. Meanwhile, radiation also induced time- and dose-dependent activation of AKT and ERK, each of whose inhibitors suppressed radiation-induced EMT. Intriguingly, silencing of TBK1 with shRNA also blocked the radiation-induced activation of AKT and ERK signaling. The ERK inhibitor did not obviously affect the expression of TBK1 or phosphorylated AKT, while AKT inhibition suppressed activation of ERK without changing the expression of TBK1. Finally, we found that a TBK1 inhibitor inhibited inflammatory cytokine expression in a RIPF model and Amlexanox protected normal cells and mice from ionizing radiation. In conclusion, our results indicate that the TBK1–AKT–ERK signaling pathway regulates radiation-induced EMT in normal alveolar epithelial cells, suggesting that TBK1 is a potential target for pulmonary fibrosis prevention during cancer radiotherapy.
Lung cancer: Suppressing fibrosis during radiotherapy The risk of scarred tissues and respiratory distress during radiation treatment of lung cancer could be reduced by targeting an enzyme that alters healthy cells. Lung cancer radiotherapy often causes pulmonary fibrosis, excessive growth of fibrous tissues in the lungs, involving the transition of normal epithelial cells into an invasive form of multipotent stem cells. The development of pulmonary fibrosis limits the clinical application of radiotherapy. Hongjin Qu and co-workers at the Second Military University in Shanghai, China, previously demonstrated that the TANK-binding kinase 1 (TBK1) enzyme regulates this transition. Now, the team have shown that levels of TBK1 itself increased during radiation treatment, together with two proteins that would normally suppress alterations in healthy cells. Inhibiting TBK1, both in cell cultures and mouse models, reversed the cell transitions and prevented pulmonary fibrosis.
Databáze: OpenAIRE
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