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  • Title: [Thioridazine Sensitizes Apoptotic Effect of TRAIL in Human Lung Cancer PC9 Cells Through ER Stress Mediated Up-regulation of DR5].
    Author: Li J, Wang Y, Liu L, Yuan Y, Bao Y.
    Journal: Zhongguo Fei Ai Za Zhi; 2017 Feb 20; 20(2):80-87. PubMed ID: 28228218.
    Abstract:
    BACKGROUND: Tumor necrosis factor-related apoptosis-inducting ligand (TRAIL) can induce 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 endoplasmic 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 measured 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 combination 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. CONCLUSIONS: Thioridazine enhanced proliferation inhibition effect of TRAIL in PC9 cells may be facilitated through ER stress mediated upregulation of DR5.
. 背景与目的 肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducting ligand, TRAIL）可诱导肿瘤细胞发生凋亡，然而相当数量的肿瘤细胞可耐受TRAIL诱导的凋亡而得以存活。本实验观察硫利达嗪（thioridazine, THZ）通过诱导内质网应激（endoplasmic reticulum stress, ER stress）介导的死亡受体5（death receptor 5, DR5）表达上调，继而增敏TRAIL对肺腺癌细胞PC9的生长抑制及凋亡诱导效应，探讨其机制。方法 不同浓度硫利达嗪及TRAIL单独或联合处理PC9细胞，MTT法检测细胞活性变化，流式细胞术检测细胞表面DR5表达及细胞凋亡率，Western blotting检测内质网应激相关蛋白GRP78 （glucose regulated protein 78）、C/EBP环磷酸腺苷反应元件结合转录因子同源蛋白（C/EBP homologous protein, CHOP）、p-PERK（PKR-like ER kinase）、p-eIF2α（eukaryotic initiation factor-2α, eIF2α）、ATF4（activating transcription factor 4, ATF4）及凋亡相关蛋白Caspase-3、Caspase-9、Caspase-8、PARP、DR5表达变化。结果 硫利达嗪对PC9细胞的增殖抑制效应呈浓度依赖性（P<0.05），硫利达嗪可增加TRAIL对PC9细胞的抑制作用及凋亡诱导作用且可上调PC9细胞表面DR5表达水平，流式细胞术结果显示：TRAIL联合硫利达嗪组细胞凋亡率较单独TRAIL组显著增加（P<0.05），Western blotting结果显示：TRAIL联合硫利达嗪组细胞Cleaved-caspase-8、Cleaved-PARP、DR5表达水平较单独TRAIL组明显上调。DR5表达上调及促凋亡效应是通过诱导内质网应激发生，并伴随着GRP78及CHOP表达上调发生的，且该效应可被4-苯基丁酸（4-phenylbutyric acid, 4-PBA）可抑制（P<0.05）。结论 硫利达嗪增敏TRAIL对PC9细胞的增殖抑制效应显著，其机制可能与硫利达嗪内质网应激介导的DR5上调有关。.
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