Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) shows little or no toxicity in most normal cells and preferentially induces apoptosis in a variety of malignant cells. However, patients develop resistance to TRAIL, therefore, sensitizing agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are necessary. In this study, we investigated the effect of 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), an useful flavonoid, to overcome the TRAIL-resistant triple negative breast cancer (TNBC) cells. We found that CSC-3436 potentiated TRAIL-induced apoptosis in TRAIL-resistant TNBC cells and this correlated with the upregulation of death receptors (DR)-5 and down-regulation of decreased decoy receptor (DcR)-1 expression. When examined for its mechanism, we found that the decreased expression of anti-apoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, Survivin, and XIAP. CSC-3436 would increase the expression of Bax and promoted the cleavage of bid. In addition, the induction of DR5 by CSC-3436 was found to be dependent on the modulation of reactive oxygen species (ROS)/p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results indicated that CSC-3436 could potentiate the apoptotic effects of TRAIL through down-regulation of cell survival proteins and upregulation of DR5 via the ROS-mediated upregulation of CHOP protein.

中文翻译：

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CSC-3436 通过 ROS 介导的 p38/CHOP/死亡受体 5 信号通路使三阴性乳腺癌细胞对 TRAIL 诱导的细胞凋亡敏感

肿瘤坏死因子相关的凋亡诱导配体 (TRAIL) 在大多数正常细胞中几乎没有或没有毒性，并且优先诱导多种恶性细胞的凋亡。然而，患者对 TRAIL 产生耐药性，因此，可以使肿瘤细胞对 TRAIL 介导的细胞凋亡敏感的敏化剂是必要的。在这项研究中，我们研究了 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436)（一种有用的黄酮类化合物）对克服 TRAIL 抗性三阴性乳腺癌 (TNBC) 细胞的作用。我们发现 CSC-3436 在 TRAIL 抗性 TNBC 细胞中增强了 TRAIL 诱导的细胞凋亡，这与死亡受体 (DR)-5 的上调和诱饵受体 (DcR)-1 表达的下调有关。当检查其机制时，我们发现抗凋亡蛋白 c-FLIPS/L、Bcl-Xl、Bcl-2、Survivin 和 XIAP 的表达降低。CSC-3436会增加Bax的表达并促进bid的裂解。此外，发现 CSC-3436 对 DR5 的诱导依赖于活性氧 (ROS)/p38/C/EBP 同源蛋白 (CHOP) 信号通路的调节。总体而言，我们的结果表明，CSC-3436 可以通过下调细胞存活蛋白和通过 ROS 介导的 CHOP 蛋白上调上调 DR5 来增强 TRAIL 的凋亡作用。发现 CSC-3436 对 DR5 的诱导依赖于活性氧 (ROS)/p38/C/EBP 同源蛋白 (CHOP) 信号通路的调节。总体而言，我们的结果表明，CSC-3436 可以通过下调细胞存活蛋白和通过 ROS 介导的 CHOP 蛋白上调上调 DR5 来增强 TRAIL 的凋亡作用。发现 CSC-3436 对 DR5 的诱导依赖于活性氧 (ROS)/p38/C/EBP 同源蛋白 (CHOP) 信号通路的调节。总体而言，我们的结果表明，CSC-3436 可以通过下调细胞存活蛋白和通过 ROS 介导的 CHOP 蛋白上调上调 DR5 来增强 TRAIL 的凋亡作用。