Thioridazine Sensitizes Apoptotic Effect of TRAIL in Human Lung Cancer PC9 Cells Through ER Stress Mediated Up-regulation of DR5
10.3779/j.issn.1009-3419.2017.02.02
- VernacularTitle:硫利达嗪通过内质网应激介导DR5表达上调增敏TRAIL对肺癌PC9细胞的促凋亡效应
- Author:
LI JUAN
1
;
WANG YI
;
LIU LIU
;
YUAN YUAN
;
BAO YANGYI
Author Information
1. 安徽医科大学第三附属医院(合肥市第一人民医院)肿瘤科
- Keywords:
Lung neoplasms;
Thioridazine;
TRAIL;
Endoplasmic reticulum stress;
DR5
- From:
Chinese Journal of Lung Cancer
2017;20(2):80-87
- CountryChina
- Language:Chinese
-
Abstract:
Background and objective Tumor necrosis factor-related apoptosis-inducting ligand (TRAIL) can in-duce apoptosis of tumor cells, however, various of tumor cells may survive because of resistance to TRAIL-mediated apoptosis. This study is to observe the proliferation inhibition effect of TRAIL sensitized by thioridazine on PC9 cells through endoplas-mic reticulum (ER) stress mediated up-regulation of death receptor 5 (DR5) and investigate its mechanism.Methods PC9 cells were treated with different concentrations of thioridazine and TRAIL alone or in combination. Cell proliferation was mea-sured by MTT assay, and cell apoptosis and cell-surface DR5 were detected by flow cytometry. Western blotting was utilized to measure the expressions of ER stress-related proteins glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), p-PKR-like ER kinase (PERK), p-eukaryotic initiation factor-2α (eIF2α), activating transcription factor 4 (ATF4) and apoptosis-related proteins caspase-3, caspase-9, caspase-8, PARP, DR5.Results Thioridazine inhibited the proliferation of PC9 cells in a dose-dependent manner (P<0.05). Thioridazine increased the inhibition and apoptosis of PC9 cells and up-regulated the expression of cell-surface DR5 induced by TRAIL. Flow cytometry showed that compared with TRAIL group,combination group of TRAIL and thioridazine increased cell apoptotic rates significantly (P<0.05). Western blotting indicated that compared with TRAIL group, expressions of Cleaved-caspase-8, Cleaved-PARP and DR5 increased significantly in combi-nation group of TRAIL and thioridazine. The induction of DR5 and pro-apoptotic effect were mediated through activation of ER stress accompanying by increased synthesis of GRP78 and CHOP, which can be blocked by adding of ER stress inhibitor 4-PBA.Conclusion Thioridazine enhanced proliferation inhibition effect of TRAIL in PC9 cells may be facilitated through ER stress mediated upregulation of DR5.
