Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Department of Osteoporosis, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
Asia Pac J Clin Oncol. 2024 Apr;20(2):210-219. doi: 10.1111/ajco.13926. Epub 2023 Jan 19.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells but has no significant effect on normal cells. However, the use of TRAIL is limited for resistance by more than 50% of the tumor cell lines. It's very important to develop a more efficient form of TRAIL for cancer treatment.
The N-terminal in soluble fragments (114-281aa) of TRAIL was redesigned to construct a novel TRAIL mutant-MuR5S4-TR. The Cell Counting Kit-8 method to explore the antitumor effects. The potential mechanisms were also explored.
Novel TRAIL mutant with cell-penetrating peptides (CPP) like and Second mitochondria-derived activator of caspases (Smac) like structure-MuR5S4-TR was successfully constructed. The prokaryotic expression system was successfully built, and the MuR5S4-TR was purified and reconfirmed by western blot. MuR5S4-TR could enhance the antitumor effects of TRAIL in most of the cancer cell lines significantly, NCI-H460 lung cancer cell line, for instance. After MuR5S4-TR treatment, the expressions of death receptor 4 (DR4), DR5, Caspase-8, and cleaved Caspase-3 were remarkably increased, however, there was no significant difference in X-linked inhibitor of apoptosis expression.
We constructed a novel TRAIL mutant with CPP-like and Smac-like structure-MuR5S4-TR. The MuR5S4-TR showed significantly stronger antitumor effects than TRAIL in many tumor cell lines. The MuR5S4-TR showed strong antitumor effects both in vitro and in vivo. This preliminary study implies that MuR5S4-TR may be a more efficient form of TRAIL for cancer therapy.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可以选择性地杀死肿瘤细胞，但对正常细胞没有明显影响。然而，超过 50%的肿瘤细胞系对 TRAIL 的耐药性限制了其应用。因此，开发更有效的 TRAIL 形式用于癌症治疗非常重要。
设计 TRAIL 的可溶性片段（114-281aa）的 N 端，构建一种新型 TRAIL 突变体-MuR5S4-TR。使用细胞计数试剂盒-8 法来探索其抗肿瘤作用。还探讨了潜在的机制。
成功构建了具有细胞穿透肽（CPP）样和第二线粒体衍生的半胱天冬酶激活剂（Smac）样结构的新型 TRAIL 突变体-MuR5S4-TR。成功构建了原核表达系统，并通过 Western blot 对 MuR5S4-TR 进行了纯化和重新确认。MuR5S4-TR 可显著增强大多数癌细胞系（例如 NCI-H460 肺癌细胞系）中 TRAIL 的抗肿瘤作用。在 MuR5S4-TR 处理后，死亡受体 4（DR4）、DR5、Caspase-8 和裂解 Caspase-3 的表达显著增加，而凋亡抑制因子 X 连锁（XIAP）的表达没有明显差异。
我们构建了一种具有 CPP 样和 Smac 样结构的新型 TRAIL 突变体-MuR5S4-TR。与 TRAIL 相比，MuR5S4-TR 在许多肿瘤细胞系中表现出更强的抗肿瘤作用。MuR5S4-TR 在体内外均表现出较强的抗肿瘤作用。这项初步研究表明，MuR5S4-TR 可能是一种更有效的 TRAIL 形式，用于癌症治疗。
