Abstract
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.
Highlights
Lung cancer is the most common malignant cancer with high incidence and (especially non-small cell lung cancer (NSCLC)) has become the leading cause of cancer-related death[1,2]
As a serious complication of thoracic radiotherapy, radiation-induced pulmonary fibrosis (RIPF) is characterized by excessive fibroblast proliferation and massive deposition of extracellular matrix and causes severe physiologic abnormalities and chronic respiratory failure in patients[28,29]
These studies found that approximately 30–50% of murine lung fibroblasts in lung fibrosis were derived from epithelial cells that had undergone Epithelial–mesenchymal transition (EMT) as identified by genetic tagging[30,31,32]
Summary
Lung cancer is the most common malignant cancer with high incidence and (especially non-small cell lung cancer (NSCLC)) has become the leading cause of cancer-related death[1,2]. Radiotherapy, an effective treatment modality for thorax-associated neoplasms, is recommended as a mainstay in the treatment of NSCLC3,4. The risk of radiation-induced lung injury (RILI) in normal tissues hampers the efficacy of lung cancer radiotherapy. Radiation-induced pulmonary fibrosis (RIPF), the adverse late effect of RILI, limits further application of radiotherapy with increasing radiation doses[3,4,5,6]. Epithelial–mesenchymal transition (EMT) plays a critical role in pathological fibrosis in many tissues. Activated fibroblasts originating from alveolar epithelial cells through EMT produce collagen and extracellular matrix proteins in the lung interstitium, which results in lung fibrosis[11,12,13,14]. Radiation-induced EMT may play an important role in RIPF.
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