文章摘要
多硫代二酮哌嗪类化合物1004体外对MDA-MB-231细胞转移能力的影响及机制研究
Effect of epipolythiodiketopiperazine 1004 on the metastatic-ability of MDA-MB-231 cells in vitro and related mechanism study
投稿时间:2018-12-17  修订日期:2019-03-20
DOI:
中文关键词: MDA-MB-231  转移  信号通路  AKT  ERK
英文关键词: MDA-MB-231  Metastasis  Signaling pathway  AKT  ERK
基金项目:国家自然科学基金项目(面上项目,重点项目,重大项目)
作者单位E-mail
陈奥 中国海洋大学 chenao@stu.ouc.edu.cn 
甘琪 中国海洋大学  
戚欣 中国海洋大学  
顾谦群 中国海洋大学  
李静 中国海洋大学 ljlilac@163.com 
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中文摘要:
      摘要:目的 检测多硫代二酮哌嗪类化合物1004体外对三阴性乳腺癌MDA-MB-231细胞转移能力的影响,并初步研究其作用机制。方法 利用磺酰罗丹明染色法(SRB)检测1004作用于MDA-MB-231细胞24和72 h的细胞毒活性;细胞粘附实验检测1004对MDA-MB-231细胞外基质粘附的影响;划痕实验和Transwell侵袭实验,分别检测1004对MDA-MB-231细胞迁移和侵袭的影响;明胶酶谱法检测1004对MDA-MB-231细胞基质金属蛋白酶MMP9活性的影响;Western Blot检测1004对MDA-MB-231细胞N-cadherin、Snail、c-Myc和FGFR1的蛋白表达的影响,检测AKT和ERK表达和活化水平。结果 1004作用于MDA-MB-231细胞72 h的IC50为(6.28±1.25)μmol?L-1,而1004作用于MDA-MB-231细胞24 h的IC50超过100 μmol?L-1。1004作用于MDA-MB-231细胞可增加细胞粘附,并抑制细胞的迁移和侵袭。1004可以显著降低N-cadherin、c-Myc 及Snail 的表达水平,并抑制MMP9 的活性。1004 作用于MDA-MB-231细胞可以浓度依赖性地引起FGFR1的表达下调,并抑制下游ERK和AKT 的活化。结论 1004体外对MDA-MB-231细胞具有转移抑制活性,其机制可能与下调FGFR1的蛋白水平并抑制FGFR信号通路有关。
英文摘要:
      Abstract: Objective To investigate the effect of epipolythiodiketopiperazine (ETP) 1004 on the metastatic ability of MDA-MB-231 cells in vitro and its related mechanism. Methods The cytotoxic activities of 1004 on MDA-MB-231 cells at 24 h and 72 h were detected by sulforhodamine staining (SRB). The effect of 1004 on the adhesion of MDA-MB-231 cells was detected by cell adhesion assay. Wound healing assay and transwell invasion assay were used to detect the effects of 1004 on MDA-MB-231 cell migration and invasion; Zymography was used to detect the effect of 1004 on MDA-MB-231 cell matrix metalloproteinase MMP9 activity; Western Blot assay was used to detect the effects of 1004 on protein expressions of N-cadherin, Snail, c-Myc and FGFR1 in MDA-MB-231 cells, expression and activation levels of AKT and ERK. Results The IC50 of 1004 on MDA-MB-231 cells was(6.28±1.25)μmol?L-1 for 72 h, while the IC50 of 1004 on MDA-MB-231 cells for 24 h was over 100 μmol?L-1, 1004 increased the adhesion and inhibited migration and invasion of MDA-MB-231. 1004 significantly reduced the expression levels of N-cadherin, c-myc and snail, and inhibited the activity of MMP9. Furthermore, the mechanism study showed that the level of FGFR1 was down-regulated in a concentration-dependent manner accompanied by inactivation of ERK and AKT after 1004 treatment. Conclusion 1004 exhibits metastasis inhibitory activity on MDA-MB-231 cells in vitro, which may be related to down-regulation of FGFR1 signaling pathway.
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