瑞戈菲尼通过活化ROS/ER stress通路上调Noxa表达诱导食管癌细胞凋亡的实验研究  

Regorafenib Induces Apoptosis in Esophageal Cancer Cells by Up-regulating Noxa Through Activating ROS/ER Stress Signaling Pathway:An Experimental Study

作　　者：赵群 张安杰 龚运来 吴婧轶 付力维 赵明慧 李婷婷[3] 余贤军 ZHAO Qun;ZHANG An-jie;GONG Yun-lai;WU Jingyi;FU Li-wei;ZHAO Ming-hui;LI Ting-ting;YU Xian-jun(School of Basic Medical Sciences,Hubei University of Medicine,Shiyan,Hubei 442000,China;The Second Clinical School,Hubei University of Medicine,Shiyan,Hubei 442000,China;School of Biomedical Engineering,Hubei University of Medicine,Shiyan,Hubei 442000,China)

机构地区：[1]湖北医药学院基础医学院,湖北十堰442000 [2]湖北医药学院第二临床学院,湖北十堰442000 [3]湖北医药学院生物工程学院,湖北十堰442000

出　　处：《湖北医药学院学报》2025年第1期1-8,共8页Journal of Hubei University of Medicine

基　　金：湖北省自然科学基金(2022CFB481);武当特色重要研究湖北省重点实验室开放课题项目(WDCM2023007);湖北省高校中青年创新团队(T2022021);大学生创新创业训练计划项目(S202413249007,202410929010)。

摘　　要：目的:探讨瑞戈菲尼(Regorafenib,Reg)通过激活活性氧/内质网应激(ROS/ER stress)通路诱导食管癌细胞凋亡的作用及分子机制。方法:通过CCK-8及克隆形成方法检测Reg对食管癌细胞ECA109和KYSE150增殖能力的影响;通过流式细胞术和Western blot检测Reg处理后ECA109和KYSE150细胞的凋亡情况;通过Noxa敲除稳定细胞株明确Noxa在Reg诱导ECA109和KYSE150细胞凋亡中的作用;通过通路抑制剂明确ROS/ER stress信号通路对Noxa表达、凋亡诱导的影响。裸鼠皮下荷瘤模型评估Reg体内抗癌作用。结果:Reg显著抑制ECA109和KYSE150细胞生长并促进细胞凋亡;Reg通过上调Noxa表达促进细胞凋亡;Reg激活ROS/ER stress信号,从而促进Noxa诱导的细胞凋亡;Reg显著抑制裸鼠皮下荷瘤的生长。结论:Reg通过激活ROS/ER stress信号通路诱导Noxa表达,促进食管癌细胞凋亡,进而抑制肿瘤生长。Objctive To explore the effect and molecular mechanism of regorafenib(Reg)in inducing apoptosis in esopha⁃geal cancer cells via activating the ROS/ER stress pathway.Methods The effects of Reg on the proliferation of ECA109 and KYSE150 cells were detected by the CCK-8 assay and colony formation assay,and the apoptosis was evaluated by flow cy⁃tometry and Western blot.The role of Noxa in Reg-induced apoptosis in ECA109 and KYSE150 cells was demonstrated u⁃sing Noxa-knockout stable cell lines.The influence of the ROS/ER stress signaling pathway on Noxa expression and apop⁃tosis induction was clarified with signaling pathway inhibitors.The anti-cancer effect of Reg in vivo was assessed in nude mice bearing subcutaneous ECA109 tumors.Results Reg significantly inhibited the growth of ECA109 and KYSE150 cells and induced apoptosis by up-regulating Noxa.It activated the ROS/ER stress signaling pathway,thereby promoting Noxainduced cell apoptosis.Additionally,Reg inhibited the growth of subcutaneous tumors in nude mice.Conclusion Reg pro⁃motes apoptosis in esophageal cancer cells and inhibits tumor growth by up-regulating Noxa through activating the ROS/ER stress signaling pathway.

关 键 词：瑞戈菲尼 食管癌 凋亡 NOXA ROS/ER stress通路 

分 类 号：R735.1[医药卫生—肿瘤]