Study of TRAIL apoptosis signaling regulated by Helicobacter pylori in activation of mitochondria pathway
Date Issued
2005
Date
2005
Author(s)
Lee, Yao-Jen
DOI
en-US
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family of ligands capable of initiating apoptosis through engagement of its death receptors. TRAIL selectively induces apoptosis of a variety of tumor cells and transformed cells, but not most normal cells. Previous studies in our laboratory have demonstrated that human gastric epithelial cells are resistant to TRAIL. However, Helicobacter pylori can confer human gastric epithelium cells to TRAIL sensitivity. The enhanced TRAIL sensitivity by H. pylori is via activation of caspase-8 downstream pathway to activate mitochondria signaling pathway, leading to breaking apoptosis resistance. The alteration of H. pylori-sensitized TRAIL sensitivity is at the level of caspase-8 downstream pathway and upstream of Bid cleavage.
In this study, our results demonstrated that caspase-2 was activated by TRAIL in human gastric epithelial cells only in the presence of H. pylori. Pre-treatment with caspase-2 inhibitor, z-VDVAD-fmk, could block H. pylori-sensitized TRAIL-mediated apoptosis in human gastric epithelium cells. This suggested that caspase-2 is required for H pylori- induced TRAIL apoptosis signaling.
To further explore the regulatory mechanism of caspase-2 in TRAIL-mediated apoptosis, we investigated Bid cleavage by pretreatment with z-VDVAD-fmk. Our results showed that in the presence of H. pylori, TRAIL induced Bid cleavage and truncated Bid (t-Bid) formation in gastric epithelial cells. This phenomenon was blocked by z-VDVAD-fmk. Therefore, caspase-2 could function upstream of Bid cleavage in H. pylori-induced TRAIL apoptosis signaling. Moreover, pretreatment with caspase-8 inhibitor, z-IETD-fmk, inhibit caspase-2 processing but pretreatment with caspase-2 inhibitor, z-VDVAD-fmk have no effect on caspase-8 processing. These results suggest that caspase-2 is in the downstream pathway of caspase-8 in TRAIL apoptosis signaling. In addition, TRAIL induced Bax translocation in the presence of H. pylori, indicating that t-Bid activated Bax to promote cytochrome c release from mitochondria during H pylori-induced TRAIL apoptosis signaling. Taken together, these results show that caspase-2 can play a regulatory role on Bid cleavage and activation of mitochondria pathway via BAX translocation in H. pylori-induced TRAIL apoptosis signaling.
Subjects
細胞凋亡
粒線體
胃幽門螺旋桿菌
apoptosis
mitochondria
Helicobactor pylori
Type
other
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