Decitabine enhances the tumoricidal potential of TRAIL via the epigenetic regulation of death receptor 4 in gastric cancer.
Decitabine enhances the tumoricidal potential of TRAIL via the epigenetic regulation of death receptor 4 in gastric cancer.
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DOI：
10.21037/jgo-22-928
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发表时间：
2022-12
影响因子：
2.1
通讯作者：
Yang, Guibin
中科院分区：
文献类型：
--
作者：
Li, Lin;Niu, Qian;Zhu, Yuanmin;Fan, Biao;Yang, Guibin
关键词：
脱氧核糖核酸 (DNA) 甲基转移酶抑制剂，例如地西他滨，作为组合药物在癌症治疗中取得了巨大进展。肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有明显的抗肿瘤作用；然而，一些胃癌（GC）细胞对 TRAIL 诱导的细胞死亡具有抵抗力。本研究旨在探讨TRAIL和地西他滨的协同抗肿瘤作用及其潜在的协同机制。通过 IncuCyte ZOOM 活细胞分析系统监测细胞生长抑制效果，并通过 Cell Counting Kit-8 测定法测定细胞活力。通过膜联蛋白V/碘化丙啶双染色检测细胞凋亡。通过核糖核酸（RNA）干扰敲低死亡受体4（DR4），并分析DR4缺失对TRAIL敏感性的影响。应用甲基化特异性聚合酶链反应（PCR）来确定 DR4 的甲基化状态。通过定量实时聚合酶链反应（qRT-PCR）和蛋白质印迹检测信使RNA（mRNA）和蛋白质表达水平。通过流式细胞术分析细胞膜表面DR的表达。地西他滨和 TRAIL 联合使用可协同抑制 2 种 TRAIL 耐药细胞系的细胞生长。此外，地西他滨以半胱天冬酶依赖性方式增强 TRAIL 诱导的细胞凋亡。地西他滨和 TRAIL 的共同应用促进了 caspase-7、-8、-9 和聚 ADP-核糖聚合酶 (PARP) 的激活。值得注意的是，地西他滨在转录和转录后水平上增加了 DR4 的表达。暴露于地西他滨后，细胞膜表面的 DR4 表达也上调。特异性抑制剂对 DR4 的消耗减弱了 TRAIL 诱导的细胞凋亡，并削弱了地西他滨和 TRAIL 的协同作用。此外，DR4基因在SNU-1细胞中呈现甲基化状态。在SNU-1细胞中也检测到DR4的低mRNA和蛋白表达。地西他滨通过抑制GC细胞的生长并诱导其凋亡来增强TRAIL的作用。这是通过地西他滨的表观遗传修饰实现的，它上调 DR4。地西他滨可能充当 TRAIL 的敏化剂。地西他滨与TRAIL联合使用可能为GC治疗提供新思路。
Deoxyribonucleic acid (DNA) methyltransferase inhibitors, such as decitabine, have made great advances in cancer therapy as combinational drugs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has an obvious anti-tumor effect; however, some gastric cancer (GC) cells are resistant to TRAIL-induced cell death. This study sought to explore the synergistic anti-tumor effect of TRAIL and decitabine, and the potential synergetic mechanism. The cell growth inhibition effect was monitored by the IncuCyte ZOOM Live-Cell Analysis System, and cell viability was determined by Cell Counting Kit-8 assays. Apoptosis was detected by Annexin V/Propidium Iodide double staining. Death receptor 4 (DR4) was knocked down by ribonucleic acid (RNA) interference, and the effect of DR4 deletion on TRAIL sensitivity was analyzed. Methylation-specific polymerase chain reaction (PCR) was applied to determine the methylation status of DR4. The messenger RNA (mRNA) and protein expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The expression of the DRs on the cell membrane surfaces was analyzed by flow cytometry. The combined use of decitabine and TRAIL synergistically inhibited cell growth in 2 TRAIL-resistant cell lines. Further, decitabine augmented TRAIL-induced apoptosis in a caspase-dependent manner. The co-application of decitabine and TRAIL facilitated the activation of caspase-7, -8, -9, and poly ADP-ribose polymerase (PARP). Notably, decitabine increased the expression of DR4 at the transcriptional and post-transcriptional levels. DR4 expression on the cell membrane surfaces was also upregulated after decitabine exposure. The depletion of DR4 by specific inhibitors attenuated TRAIL-induced apoptosis and weakened the synergistic effects of decitabine and TRAIL. In addition, DR4 gene presented methylation status in SNU-1 cells. The low mRNA and protein expression of DR4 were also detected in SNU-1 cells. Decitabine enhances the effect of TRAIL by inhibiting the growth and inducing the apoptosis of GC cells. This is achieved by the epigenetic modification of decitabine, which upregulates DR4. Decitabine may act as a sensitizing agent of TRAIL. The combined use of decitabine and TRAIL may provide a novel idea for GC treatment.
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