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Abstract：
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.
摘要：
土贝莫塞德-1(TBMS-1),一种传统的中草药，通常用作抗癌剂。在这项研究中,我们旨在研究其对肿瘤坏死因子相关凋亡诱导配体(TRAIL)致敏作用.我们的结果表明，即使使用亚致死浓度的TBMS-1或TRAIL的单一疗法也不会影响癌细胞死亡，使用TBMS-1和TRAIL的联合治疗增加了凋亡性细胞死亡。机械上,TBMS-1通过下调STAMBPL1(一种去泛素酶(DUB))使c-FLIP表达不稳定。具体来说,当STAMBPL1和c-FLIP绑定在一起时，STAMBPL1去泛素化c-FLIP。此外，STAMBPL1敲低通过使c-FLIP不稳定而显着增加对TRAIL的敏感性。基于用TBMS-1和TRAIL组合治疗减少肿瘤体积并下调STAMBPL1和c-FLIP表达水平的观察,使用异种移植模型在体内进一步证实了这些发现。总的来说,我们的研究表明，STAMBPL1对c-FLIP稳定至关重要，并且STAMBPL1耗竭通过c-FLIP下调增强TRAIL介导的细胞凋亡。
