Metformin-sensitized NSCLC cells to osimertinib via AMPK-dependent autophagy inhibition
Metformin-sensitized NSCLC cells to osimertinib via AMPK-dependent autophagy inhibition
复制标题
二甲双胍通过 AMPK 依赖性自噬抑制对奥希替尼敏感的 NSCLC 细胞
DOI：
10.1111/crj.13091
复制
发表时间：
2019-12-01
影响因子：
1.7
通讯作者：
He, Yong
中科院分区：
文献类型：
--
作者：
Chen, Hengyi;Lin, Caiyu;He, Yong
第三代表皮生长因子受体（EGFR）抑制剂奥希替尼是晚期非小细胞肺癌（NSCLC）患者二线或一线治疗中很有前景的治疗选择，因为它可以选择性地抑制EGFR T790M和EGFR-酪氨酸激酶抑制剂致敏突变。然而，与奥希替尼治疗相关的自噬激活可能在奥希替尼诱导的NSCLC细胞损伤中发挥保护作用。本研究旨在研究奥希替尼诱导的非小细胞肺癌细胞自噬的影响，以及二甲双胍是否能调节自噬并增强奥希替尼的敏感性。方法采用MTT法、BrdUrd掺入法、菌落形成法、侵袭法、流式细胞术、western blot法和siRNA技术检测二甲双胍对奥希替尼体外和体内敏感性的增强作用。结果在本研究中，我们证实了奥希替尼在H1975和PC-9GR细胞中诱导了促生存自噬，二甲双胍通过抑制自噬进一步使H1975和PC-9GR细胞对奥希替尼致敏。其潜在机制是二甲双胍诱导AMPK持续激活，以时间依赖性的方式抑制自噬。结论二甲双胍通过诱导AMPK的激活，以时间依赖性的方式抑制细胞自噬并增强奥希替尼的敏感性。
Introduction The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib is a promising therapeutic option for patients with advanced non-small-cell lung cancer (NSCLC) in second-line or first-line treatment because of its applications in selectively inhibiting EGFR T790M and EGFR-tyrosine kinase inhibitor sensitizing mutations. However, the activation of autophagy associated with osimertinib treatment may play a protective role in NSCLC cells injury induced by osimertinib. Objectives The aim of the present study was to study the effects of the osimertinib-induced autophagy in NSCLC cells and whether metformin modulates the autophagy and enhances osimertinib sensitivity. Methods The effect of metformin on enhancing osimertinib sensitivity was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, colony formation assay, invasion assay, flow cytometry analysis, western blot analysis and siRNA technique. Results In the present study, we confirmed that osimertinib induced pro-survival autophagy in H1975 and PC-9GR cells, and metformin further sensitized H1975 and PC-9GR cells to osimertinib via inhibiting autophagy. The potential mechanism was that the continual activation of AMPK induced by metformin could inhibit autophagy in a time-dependent manner. Conclusion Metformin inhibited autophagy and enhanced osimertinib sensitivity via inducing AMPK activation in a time-dependent manner.