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胰腺癌细胞中凋亡调控基因的多重协同失调

Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells.

作者信息

Trauzold A, Schmiedel S, Röder C, Tams C, Christgen M, Oestern S, Arlt A, Westphal S, Kapischke M, Ungefroren H, Kalthoff H

机构信息

Molecular Oncology, Clinic for General Surgery, UK-SH, Camus Kiel, Germany.

出版信息

Br J Cancer. 2003 Nov 3;89(9):1714-21. doi: 10.1038/sj.bjc.6601330.

Abstract

Inability to die by apoptosis is one of the reasons for the deregulated growth of tumour cells and the frequently observed failure of chemotherapy. In this study we thought to identify the common and functionally important characteristics responsible for the apoptosis resistance of pancreatic tumour cells. We analysed cell surface expression level of death receptors CD95 and TRAIL-R1-4 as well as the expression profile of sixteen apoptosis-relevant proteins in five pancreatic carcinoma cell lines Capan1, Colo357, PancTuI, Panc89 and Panc1. These data were evaluated in the context of sensitivity towards anti-CD95 and TRAIL-mediated apoptosis. Here we report that except for resistant Panc1 cells, which only marginally expressed CD95, all other cell lines showed comparable levels of CD95 and TRAIL receptors irrespectively of their apoptotic phenotype. Interestingly, we found that the elevated expression of FLIP, Bcl-x(L) and IAP in parallel with a downregulation of FADD and Bid was common for the resistant cell lines. Consequently, stable overexpression of XIAP, Bcl-x(L) or dominant negative FADD in sensitive cells significantly reduced the death receptor mediated apoptosis while the overexpression of Bid rendered the resistant cells sensitive.

摘要

无法通过凋亡死亡是肿瘤细胞生长失控以及化疗常出现失败的原因之一。在本研究中,我们试图确定导致胰腺肿瘤细胞抗凋亡的共同且具有功能重要性的特征。我们分析了死亡受体CD95和TRAIL-R1 - 4的细胞表面表达水平,以及五种胰腺癌细胞系Capan1、Colo357、PancTuI、Panc89和Panc1中十六种凋亡相关蛋白的表达谱。这些数据在对抗CD95和TRAIL介导的凋亡敏感性的背景下进行评估。在此我们报告,除了仅微量表达CD95的耐药Panc1细胞外,所有其他细胞系无论其凋亡表型如何,均显示出相当水平的CD95和TRAIL受体。有趣的是,我们发现耐药细胞系中FLIP、Bcl-x(L)和IAP的表达升高,同时FADD和Bid下调是常见现象。因此,在敏感细胞中稳定过表达XIAP、Bcl-x(L)或显性负性FADD可显著降低死亡受体介导的凋亡,而过表达Bid则使耐药细胞变得敏感。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/551d/2394395/1387ba4e2557/89-6601330f1.jpg

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