Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, Korea.
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 609-735, Korea.
Molecules. 2018 Nov 20;23(11):3030. doi: 10.3390/molecules23113030.
Maritoclax, an active constituent isolated from marine bacteria, has been known to induce Mcl-1 downregulation through proteasomal degradation. In this study, we investigated the sensitizing effect of maritoclax on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. We found that combined treatment with maritoclax and TRAIL markedly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung cancer (A549) and hepatocellular carcinoma (SK-Hep1) cells. The upregulation of death receptor 5 (DR5) and downregulation of cellular FLICE-inhibitory protein (cFLIP) were involved in maritoclax plus TRAIL-induced apoptosis. Maritoclax-induced DR5 upregulation was regulated by induction of C/EBP homologous protein (CHOP) expression. Interestingly, maritoclax induced cFLIP downregulation through the increased expression of miR-708. Ectopic expression of cFLIP prevented combined maritoclax and TRAIL-induced apoptosis. Taken together, maritoclax sensitized TRAIL-induced apoptosis through CHOP-mediated DR5 upregulation and miR-708-mediated cFLIP downregulation.
从海洋细菌中分离出来的活性成分马替考昔可通过蛋白酶体降解诱导 Mcl-1 下调。在这项研究中，我们研究了马替考昔对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的人肾癌细胞凋亡的敏化作用。我们发现，马替考昔和 TRAIL 的联合治疗显著诱导肾癌细胞（Caki、ACHN 和 A498）、肺癌细胞（A549）和肝癌细胞（SK-Hep1）凋亡。死亡受体 5（DR5）的上调和细胞 FLICE 抑制蛋白（cFLIP）的下调参与了马替考昔加 TRAIL 诱导的凋亡。马替考昔诱导的 DR5 上调受 C/EBP 同源蛋白（CHOP）表达诱导的调节。有趣的是，马替考昔通过增加 miR-708 的表达来下调 cFLIP。cFLIP 的异位表达可防止联合使用马替考昔和 TRAIL 诱导的凋亡。总之，马替考昔通过 CHOP 介导的 DR5 上调和 miR-708 介导的 cFLIP 下调来敏化 TRAIL 诱导的凋亡。
