Bcl-XL protects pancreatic adenocarcinoma cells against CD95-and TRAIL-receptor-mediated apoptosis
Bcl-XL protects pancreatic adenocarcinoma cells against CD95-and TRAIL-receptor-mediated apoptosis
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DOI：
10.1038/sj.onc.1203936
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发表时间：
2000-11-16
期刊：
影响因子：
8
通讯作者：
Ungefroren, H
中科院分区：
文献类型：
--
作者：
Hinz, S;Trauzold, A;Ungefroren, H
在这项研究中，我们试图阐明胰腺癌细胞中凋亡相关配体TRAIL（APO-2L）和CD 95受体所引起的死亡途径中线粒体促凋亡潜能的作用。我们集中于Bcl-2家族成员Bcl-X-L的作用，使用三种胰腺癌细胞系作为模型系统，其中两种具有高（Panc-1，PancTuI）和一种具有低（Colo 357）Bcl-X-L表达。在这些细胞系中，Bcl-X-L的表达与对TRAIL或抗CD 95诱导的凋亡的敏感性相关。流式细胞术分析显示TRAIL-Ri和TRAIL-R2在PancTuI和Colo 357上的细胞表面表达，以及TRAIL-R2在Panc-1细胞上的细胞表面表达。在用Bcl-X-L逆转录病毒转导的Colo 357细胞中，响应于用TRAIL或抗CD 95抗体处理的caspase-8活化与亲本细胞和EGFP转染的对照没有不同，然而，通过线粒体跨膜电位Δ Psim、caspase-3活性和细胞凋亡的抑制，（PARP裂解）和DNA片段化，Bax过表达或Bcl-X-L mRNA反义寡核苷酸抑制Bcl-X-L功能，导致Panc-1细胞对TRAIL敏感，PancTuI细胞对抗TRAIL敏感。CD 95抗体诱导的细胞死亡。结果表明，Bcl-X-L可以保护胰腺癌细胞免于CD 95和TRAIL介导的凋亡。因此，在这些上皮肿瘤细胞中，胰腺介导的“II型”凋亡诱导途径不仅对CD 95系统有效，而且对TRAIL系统也有效。
In this study we sought to clarify the role of the proapoptotic potential of mitochondria in the death pathway emanating from the TRAIL (APO-2L) and CD95 receptors in pancreatic carcinoma cells. We focused on the role of the Bcl-2 family member Bcl-X-L, using three pancreatic carcinoma cell lines as a model system, two of which have high (Panc-1, PancTuI) and one has low (Colo357) Bcl-X-L expression. In these cell lines, the expression of Bcl-X-L correlated with sensitivity to apoptosis induced by TRAIL or anti-CD95. Flow cytometric analysis revealed cell surface expression of TRAIL-Ri and TRAIL-R2 on PancTuI and Colo357, and TRAIL-R2 on Panc-1 cells. In Colo357 cells retrovirally transduced with Bcl-X-L, caspase-8 activation in response to treatment with TRAIL or anti-CD95 antibody was not different from parental cells and EGFP-transfected controls, however, apoptosis was completely suppressed as measured by the mitochondrial transmembrane potential Delta Psim, caspase-3 activity (PARP cleavage) and DNA-fragmentation, Inhibition of Bcl-X-L function by overexpression of Bax or administration of antisense oligonucleotides against Bcl-X-L mRNA resulted in sensitization of Panc-1 cells to TRAIL and PancTuI cells to anti-CD95 antibody-induced cell death. The results show that Bcl-X-L can protect pancreatic cancer cells from CD95- and TRAIL-mediated apoptosis, Thus, in these epithelial tumour cells the mitochondrially mediated 'type II' pathway of apoptosis induction is not only operative regarding the CD95 system but also regarding the TRAIL system.