Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea.
Int J Mol Sci. 2018 Oct 22;19(10):3280. doi: 10.3390/ijms19103280.
Cepharanthine (CEP) is a natural plant alkaloid, and has anti-inflammatory, antineoplastic, antioxidative and anticancer properties. In this study, we investigated whether CEP could sensitize renal carcinoma Caki cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. CEP alone and TRAIL alone had no effect on apoptosis. However, combined CEP and TRAIL treatment markedly enhanced apoptotic cell death in cancer cells, but not in normal cells. CEP induced downregulation of survivin and cellular-FLICE inhibitory protein (c-FLIP) expression at post-translational levels. Ectopic expression of survivin blocked apoptosis by combined treatment with CEP plus TRAIL, but not in c-FLIP overexpression. Interestingly, CEP induced survivin downregulation through downregulation of deubiquitin protein of STAM-binding protein-like 1 (STAMBPL1). Overexpression of STAMBPL1 markedly recovered CEP-mediated survivin downregulation. Taken together, our study suggests that CEP sensitizes TRAIL-mediated apoptosis through downregulation of survivin expression at the post-translational levels in renal carcinoma cells.
石蒜裂碱（CEP）是一种天然植物生物碱，具有抗炎、抗肿瘤、抗氧化和抗癌作用。在本研究中，我们研究了 CEP 是否能增强肾癌细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡的敏感性。CEP 单独和 TRAIL 单独对细胞凋亡没有影响。然而，CEP 和 TRAIL 的联合治疗显著增强了癌细胞而非正常细胞的凋亡细胞死亡。CEP 诱导生存素和细胞-FLICE 抑制蛋白（c-FLIP）表达在翻译后水平下调。生存素的异位表达阻断了 CEP 加 TRAIL 联合治疗的凋亡，但不能阻断 c-FLIP 的过表达。有趣的是，CEP 通过下调 STAM 结合蛋白样 1（STAMBPL1）的去泛素化蛋白诱导生存素下调。STAMBPL1 的过表达显著恢复了 CEP 介导的生存素下调。总之，我们的研究表明，CEP 通过下调肾癌细胞中生存素的翻译后水平，增强 TRAIL 介导的凋亡。
