初步探索DIM-C-pPhOH(NR4A1拮抗剂)对胶质瘤细胞增殖、迁移及侵袭的抑制作用及作用机制  

DIM-C-pPhOH(NR4A1 antagonist)can inhibit cell proliferation,migration and invasion by inducing autophagy in glioma

作　　者：徐杨熙 黄海韬[1] 马逸[1] 王斌[1] 王全才[1] 李岩峰[1] 周建波[1] 董经宇[1] Xu Yangxi;Huang Haitao;Ma Yi;Wang Bin;Wang Quancai;Li Yanfeng;Zhou Jianbo;Dong Jingyu(Department of Neurosurgery,the People’s Hospital of Liaoning Province,Shengyang 110016,China)

机构地区：[1]辽宁省人民医院神经外科,沈阳110016

出　　处：《中华脑科疾病与康复杂志（电子版）》2020年第6期339-345,共7页Chinese Journal of Brain Diseases and Rehabilitation（Electronic Edition）

摘　　要：目的探索DIM-C-pPhOH(NR4A1拮抗剂)对胶质瘤细胞增殖、迁移、侵袭的抑制作用及其作用机制,以及对于胶质瘤小鼠模型生存期及肿瘤生长的影响。方法不同浓度DIM-C-pPhOH处理胶质瘤细胞系(GL261、U251、U118)48 h后,用CellTiter法检测细胞活性及IC50;采用划痕实验和3D-invasion实验检测DIM-C-pPhOH对U251细胞系侵袭迁移作用的影响;通过腹腔注射该化合物治疗小鼠胶质瘤模型,观察DIM-C-pPhOH对于小鼠胶质瘤生长以及生存期的影响。结果U251、GL261和U118胶质瘤细胞系经DIM-C-pPhOH处理48 h后,细胞活性随药物浓度增加显著降低,IC50分别为5.76、6.87、9.93μmol/L;U251细胞系经10μmol/L DIM-C-pPhOH处理后其迁移和侵袭能力显著下降;同时DIM-C-pPhOH可以抑制由TGF-β诱导的NR4A1出核表达;小鼠胶质瘤模型中DIM-C-pPhOH治疗组生存期延长,肿瘤生长受到抑制。蛋白免疫印迹显示DIM-C-pPhOH可以明显抑制Akt、P70S6K蛋白表达,通过抑制PI3K/Akt/mTOR/p70s6k信号通路,诱导细胞自噬发生。结论DIM-C-pPhOH可以抑制胶质瘤的迁移及侵袭能力,延长小鼠胶质瘤模型的生存期并抑制肿瘤生长,作用机制可能与DIM-C-pPhOH诱导细胞发生自噬有关。Objective To explore the inhibitory effect of DIM-C-pPhOH(NR4A1 antagonist)on proliferation,migration and invasion of glioma cells and its mechanism,as well as the effect on the survival time and tumor of glioma mouse model.Methods Cell viability of glioma cell lines(GL261,U251,U118)treated with DIM-C-pPhOH for 48 h and then detected cell viability and IC50 by CellTiter.The effect of DIM-C-pPhOH on invasion and migration of U251 cell line was studied by scratch experiment and 3D-invasion experiment.Meanwhile,DIM-C-pPhOH inhibited the TGF-β-induced nucleotide expression of NR4A1.Intraperitoneal injection of DIM-C-pPhOH in mice glioma model was used to simulate in vivo environment to observe the survival curve and its effect on tumor growth.Western blotting showed that DIM-C-pPhOH could significantly inhibit the expression of Akt and p70S6K proteins,and induce autophagy by inhibiting the PI3K/Akt/mTOR/p70S6K signaling pathway.Results After DIM-C-pPhOH treatment,the cell activity of glioma cell lines decreased significantly with the increase of drug concentration,and the IC50 of U251,GL261 and U118 gloma cell lines were 5.76,6.87,and 9.93μmol/L,respectively.The migration and invasion ability of U251 cells in glioma decreased significantly after DIM-C-pPhOH(10μmol/L)treatment.In the mouse glioma model,the survival time of the drug treatment group was prolonged and tumor growth was inhibited.Western blotting showed that DIM-C-pPhOH could significantly inhibit the expression of Akt and P70S6K,and induce autophagy by inhibiting PI3K/Akt/mTOR/p70S6K signaling pathway.Conclusion DIM-C-pPhOH can reduce the migration and invasion of glioma,prolong the survival time of mouse glioma model and inhibit tumor growth.The underlying mechanism may be related to autophagy induced by DIM-C-pPhOH.

关 键 词：NR4A1基因 胶质瘤 自噬 NR4A1拮抗剂 DIM-C-pPhOH 

分 类 号：R739.41[医药卫生—肿瘤]