Blocking TBK1 alleviated radiation-induced pulmonary fibrosis and epithelial-mesenchymal transition through Akt-Erk inactivation
Blocking TBK1 alleviated radiation-induced pulmonary fibrosis and epithelial-mesenchymal transition through Akt-Erk inactivation
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阻断 TBK1 通过 Akt-Erk 失活减轻辐射诱导的肺纤维化和上皮间质转化
DOI：
10.1038/s12276-019-0240-4
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发表时间：
2019-04-15
影响因子：
12.8
通讯作者：
Cai, Jianming
中科院分区：
文献类型：
--
作者：
Qu, Hongjin;Liu, Lei;Cai, Jianming
放射性肺纤维化（RIPF）是胸部放疗常见的严重并发症，严重限制了放射治疗。上皮-间质转化（EMT）是纤维形成过程中成纤维细胞库的直接贡献者，预防EMT被认为是抑制组织纤维化的有效策略。我们以前的研究表明，TANK结合激酶1（TBK 1）调节肺癌细胞的EMT。在本研究中，我们旨在研究靶向TBK 1预防RIPF和EMT进展的治疗潜力。我们发现在正常肺泡上皮细胞和肺组织中存在辐射诱导的EMT和肺纤维化。TBK 1敲低或抑制显著逆转体内和体外EMT，并减轻肺纤维化和胶原沉积。此外，我们观察到TBK 1在辐射中以时间和剂量依赖性方式升高。同时，辐射还诱导AKT和ERK的激活，其抑制剂抑制辐射诱导的EMT。有趣的是，用shRNA沉默TBK 1也阻断了辐射诱导的AKT和ERK信号转导的激活。ERK抑制剂对TBK 1和磷酸化AKT的表达无明显影响，而AKT抑制剂抑制ERK的活化，但不改变TBK 1的表达。最后，我们发现TBK 1抑制剂在RIPF模型中抑制炎性细胞因子的表达，氨来赞保护正常细胞和小鼠免受电离辐射。总之，我们的研究结果表明，TBK 1-AKT-ERK信号通路调节正常肺泡上皮细胞辐射诱导的EMT，表明TBK 1是癌症放疗期间预防肺纤维化的潜在靶点。
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 radiationinduced 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.