Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
Int J Mol Sci. 2023 Jul 24;24(14):11840. doi: 10.3390/ijms241411840.
Tubeimoside-1 (TBMS-1), a traditional Chinese medicinal herb, is commonly used as an anti-cancer agent. In this study, we aimed to investigate its effect on the sensitization of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Our results revealed that even though monotherapy using TBMS-1 or TRAIL at sublethal concentrations did not affect cancer cell death, combination therapy using TBMS-1 and TRAIL increased apoptotic cell death. Mechanistically, TBMS-1 destabilized c-FLIP expression by downregulating STAMBPL1, a deubiquitinase (DUB). Specifically, when STAMBPL1 and c-FLIP bound together, STAMBPL1 deubiquitylated c-FLIP. Moreover, STAMBPL1 knockdown markedly increased sensitivity to TRAIL by destabilizing c-FLIP. These findings were further confirmed in vivo using a xenograft model based on the observation that combined treatment with TBMS-1 and TRAIL decreased tumor volume and downregulated STAMBPL1 and c-FLIP expression levels. Overall, our study revealed that STAMBPL1 is essential for c-FLIP stabilization, and that STAMBPL1 depletion enhances TRAIL-mediated apoptosis via c-FLIP downregulation.
标题：Tubeimoside-1 通过降解 c-FLIP 增强 TRAIL 诱导的肿瘤细胞凋亡
摘要：作为一种传统的中药，冬凌草甲素（TBMS-1）常用于癌症治疗。本研究旨在探讨 TBMS-1 对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的肿瘤细胞凋亡的影响。结果表明，TBMS-1 或 TRAIL 的亚致死浓度单药治疗并不影响癌细胞死亡，但 TBMS-1 和 TRAIL 的联合治疗增加了凋亡细胞死亡。机制上，TBMS-1 通过下调去泛素化酶 STAMBPL1 来降低 c-FLIP 的表达。具体来说，当 STAMBPL1 和 c-FLIP 结合时，STAMBPL1 去泛素化 c-FLIP。此外，STAMBPL1 的敲低通过降低 c-FLIP 的稳定性显著增加了 TRAIL 的敏感性。在基于观察联合治疗 TBMS-1 和 TRAIL 降低肿瘤体积和下调 STAMBPL1 和 c-FLIP 表达水平的异种移植模型中进一步证实了这些发现。总之，我们的研究表明 STAMBPL1 对于 c-FLIP 的稳定至关重要，并且 STAMBPL1 的耗竭通过降低 c-FLIP 表达增强了 TRAIL 诱导的细胞凋亡。
