mTORC1 inhibitor RAD001 (everolimus) enhances non-small cell lung cancer cell radiosensitivity in vitro via suppressing epithelial-mesenchymal transition
mTORC1 inhibitor RAD001 (everolimus) enhances non-small cell lung cancer cell radiosensitivity in vitro via suppressing epithelial-mesenchymal transition
复制标题
mTORC1 抑制剂 RAD001（依维莫司）通过抑制上皮间质转化增强体外非小细胞肺癌细胞放射敏感性
DOI：
10.1038/s41401-019-0215-y
复制
发表时间：
2019-08-01
影响因子：
8.2
通讯作者：
Chen, Yuan
中科院分区：
文献类型：
--
作者：
Chen, Yu;Li, Wen-wen;Chen, Yuan
对放疗的抵抗会导致非小细胞肺癌（NSCLC）治疗失败，并伴有局部复发和转移。因此，了解 NSCLC 细胞的放射敏感性对于开发新疗法和改善预后至关重要。 mTORC1已被证明可以调节肿瘤细胞的放射敏感性，但其潜在机制尚不清楚。此外，mTORC1 还调节对转移和复发很重要的上皮间质转化 (EMT)。在这项研究中，我们探讨了 mTORC1 是否通过改变 EMT 来调节 NSCLC 细胞的放射敏感性。我们对 50 名 NSCLC 患者的肿瘤、癌旁组织和正常组织进行了免疫组织化学分析，证实 NSCLC 组织中 mTOR 蛋白表达显着升高。然后我们使用NCI-H460和NCI-H661细胞系检测mTORC1抑制剂RAD001（依维莫司）对体外放射敏感性、蛋白表达和剂量生存曲线的影响。 RAD001 (10 nmol/L) 显着抑制两种细胞系中的 mTORC1 通路。 RAD001（0.1 nmol/L）预处理增强了具有野生型PIK3CA和KRAS的NCI-H661细胞的放射敏感性，但没有增强具有突变型PIK3CA和KRAS的NCI-H460细胞的放射敏感性；两种 NSCLC 细胞系的敏感性增强比分别为 1.40 和 1.03。此外，RAD001 (0.1 nmol/L) 预处理显着降低了受辐射的 NCI-H661 细胞的迁移和侵袭，并改变了几种 EMT 相关蛋白的表达（显着增加了 E-cadherin 并降低了波形蛋白表达）。公开的表达数据证实，辐射影响 NSCLC 细胞转录水平的 mTOR 和 EMT 相关基因。这些结果表明，mTORC1 抑制通过影响 EMT 来增强具有野生型 PIK3CA 和 KRAS 的 NSCLC 细胞的体外放射敏感性。我们的临床前数据可能为 NSCLC 治疗提供潜在的新策略。
Resistance to radiotherapy causes non-small cell lung cancer (NSCLC) treatment failure associated with local recurrence and metastasis. Thus, understanding the radiosensitization of NSCLC cells is crucial for developing new treatments and improving prognostics. mTORC1 has been shown to regulate tumor cell radiosensitivity, but the underlying mechanisms are unclear. Moreover, mTORC1 also regulates epithelial-mesenchymal transition (EMT) that is important to metastasis and recurrence. In this study we explored whether mTORC1 regulated NSCLC cell radiosensitivity by altering EMT. We performed immunohistichemical analysis using tumor, adjacent and normal tissues from 50 NSCLC patients, which confirmed significantly elevated mTOR protein expression in NSCLC tissue. Then we used NCI-H460 and NCI-H661 cell lines to examine the effects of the mTORC1 inhibitor RAD001 (everolimus) on in vitro radiosensitivity, protein expression and dose-survival curves. RAD001 (10 nmol/L) significantly inhibited the mTORC1 pathway in both the cell lines. Pretreatment with RAD001 (0.1 nmol/L) enhanced the radiosensitivity in NCI-H661 cells with wild-type PIK3CA and KRAS but not in NCI-H460 cells with mutant PIK3CA and KRAS; the sensitivity enhancement ratios in the two NSCLC cell lines were 1.40 and 1.03, respectively. Furthermore, pretreatment with RAD001 (0.1 nmol/L) significantly decreased the migration and invasion with altered expression of several EMT-associated proteins (significantly increased E-cadherin and decreased vimentin expression) in irradiated NCI-H661 cells. Publicly available expression data confirmed that irradiation affected mTOR and EMT-associated genes at the transcript level in NSCLC cells. These results suggest that mTORC1 inhibition enhances the in vitro radiosensitivity of NSCLC cells with wild-type PIK3CA and KRAS by affecting EMT. Our preclinical data may provide a potential new strategy for NSCLC treatment.