期刊文献+

mTOR抑制剂通过mTOR通路介导胰腺癌顺铂耐药的机制研究 被引量:1

Mechanism of mTOR inhibitors in cisplatin resistance in pancreatic cancer by mediating the mTOR pathway
在线阅读 下载PDF
收藏 分享 导出
摘要 目的 研究哺乳动物雷帕霉素靶体蛋白(mTOR)抑制剂雷帕霉素(RAPA)通过mTOR通路介导胰腺癌(PC)顺铂(DDP)耐药的机制,探索逆转该耐药性的可行性方案。方法 用含10%胎牛血清的达尔伯克必需培养基DMEM(PANC-1)或RPMI-1640(BxPC-3、SW1990)于37℃、5%CO2培养箱中培养,取对数期细胞进行实验:用划痕修复实验检测细胞的迁移能力;用迁移(Transwell)实验检测细胞的侵袭能力;用四甲基偶氮唑盐(MTT)实验检测加入0、5、10、20μmol/L的RAPA后,DDP对PANC-1、BxPC-3、SW1990耐药株的半数抑制浓度(IC50)的变化;用Western blot实验检测0、5、10、20μmol/L的RAPA抑制mTOR信号通路相关蛋白磷脂酰肌醇3激酶(PI3K)、磷酸化的PI3K(p-PI3K)、蛋白激酶B(AKT)、磷酸化的AKT(p-AKT)、mTOR、磷酸化的mTOR(p-mTOR)的表达。结果 PANC-1、BxPC-3、SW1990 3种PC细胞株均对DDP耐药,单用DDP时,3种细胞株均具有很强的细胞迁移能力和侵袭能力,其IC50较高;联用RAPA后,3种细胞株的迁移能力和侵袭能力显著下降(P<0.01);加入不同浓度的RAPA后,3种细胞株的生存率均明显降低,其IC50显著下降(P<0.01)。Western blot实验显示:RAPA可明显下调PANC-1及BxPC-3细胞中PI3K、AKT、mTOR蛋白的表达,抑制PI3K、AKT、mTOR被磷酸化,对SW1990的mTOR蛋白表达的影响较弱,但降低p-mTOR蛋白表达。结论 RAPA可降低PC细胞迁移能力、侵袭能力,提高PC对DDP的敏感性,逆转DDP耐药性,该过程是通过抑制mTOR信号通路相关蛋白的表达及磷酸化来实现的。 Objective To investigate the mechanism of mTOR inhibitors in cis-dichlorodiamine platinum(DDP)resistance in pancreatic cancer by mediating the mTOR pathway,and to explore the feasibility of reversing the drug resistance.Methods PANC-1,BxPC-3 and SW1990 were cultured in 10%fetal bovine serum and RPMI-1640 in an incubator with 5%CO2 and temperature 37℃.Then the cells in logarithmic growth phase received the various detections:wound healing assay for migration ability;Transwell for invasion ability;MTT for half maximal inhibitory concentration(IC50)after adding rapamycin(0,5,10,20μmol/L);Western blot for the expression levels of PI3 K,p-PI3 K,AKT,p-AKT,mTOR,and p-mTOR.Results The PANC-1,BxPC-3 and SW1990 were all resistant to cisplatin,which also had strong cell migration and invasion ability when DDP was used,and the IC50 was at high level.After the application of DDP combined with rapamycin,the migration ability and invasive ability of the three cell lines decreased significantly(P<0.01),moreover,the survival rate of the three cell lines was decreased significantly,so did the IC50(P<0.01).Western blot showed that rapamycin significantly down-regulated the expression of PI3 K,AKT and mT OR proteins in PANC-1 and BxPC-3 cells,inhibited the phosphorylation of PI3 K,AKT and mT OR,decreased p-mTOR protein expression,but its effect on the expression of mT OR protein in SW1990 was weaker.Conclusion Rapamycin can reduce the migration and invasion of pancreatic cancer cells,increase the sensitivity of pancreatic cancer to cisplatin,and reverse the resistance of cisplatin.This process is achieved by inhibiting the expression and phosphorylation of mT OR signaling pathway related proteins.
作者 朱小长 陶连元 杜瀛瀛 时云 Zhu Xiaozhang;Tao Lianyuan;Du Yingying(Dept of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei 230022;Dept of Oncology,Lujiang Hospital of Traditional Chinese Medicine,Hefei 231500;Dept of Hepatobiliary and Pancreatic Surgery,Henan Provincial People's Hospital,Zhengzhou 450003)
出处 《安徽医科大学学报》 CAS 北大核心 2019年第8期1205-1210,共6页 Acta Universitatis Medicinalis Anhui
基金 安徽省重点研究计划和开发计划项目(编号:1704a0802163).
关键词 MTOR抑制剂 胰腺癌 MTOR信号通路 耐药性 mTOR inhibitors pancreatic cancer mTOR pathway resistance
  • 相关文献

参考文献9

二级参考文献181

  • 1Law BK.Rapamycin:an anti-cancer inmunosuppressant? Crit Rev Oncol Hematol,2005,56:47-60. 被引量:1
  • 2Shaw RJ,Bardeesy N,Manning BD,et al.The LKB1 tumor suppressor negatively regulates mTOR signaling.Cancer Cell,2004,6:91-89. 被引量:1
  • 3Inoki K,Corradetti MN,Guan KL.Dysregulation of the TSC-mTOR pathway in human disease.Nat Genet,2005,37:19-24. 被引量:1
  • 4Chan S.Targeting the mammalian target of rapamycin (mTOR):a new approach to treating cancer.Br J Cancer,2004,91:1420-1424. 被引量:1
  • 5Mohi MG,Boulton C,Gu TL,et al.Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs.Proc Natl Acad Sci USA,2004,101:3130-3135. 被引量:1
  • 6Akcakanat A,Sahin A,Shaye AN,et al.Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases.Cancer,2008,112:2352-2358. 被引量:1
  • 7Yan J,Kuroyanagi H,Tomemori T,et al.Mouse ULK2,a novel member of the UNC-51-like protein kinases:unique features of functional domains.Oncogene,1999,18:5850-5859. 被引量:1
  • 8Chan EY,Longatti A,McKnight NC,et al.Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism.Mol Cell Biol,2009,29:157-171. 被引量:1
  • 9Soroceanu L,Kharbanda S,Chen R,et al.Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma.Proc Natl Acad Sci USA,2007,104:3466-3471. 被引量:1
  • 10Zhang L,Huang J,Yang N,et al.Integrative genomic analysis of phosphatidylinositol 3'-kinase family identifies PIK3R3 as a potential therapeutic target in epithelial ovarian cancer.Clin Cancer Res,2007,13:5314-5321. 被引量:1

共引文献63

同被引文献1

引证文献1

论文智能改写系统
维普数据出版直通车
投稿分析
职称考试

相关作者

内容加载中请稍等...

相关机构

内容加载中请稍等...

相关主题

内容加载中请稍等...

浏览历史

内容加载中请稍等...
;
使用帮助 返回顶部 意见反馈