Gallbladder carcinoma has a high degree of malignancy. No effective treatment exists for patients with advanced tumors. The second mitochondria-derived activator of caspases (Smac) is the antagonist of the inhibitors of apoptosis protein. Smac mimetics are a class of effective tumor-targeted drugs undergoing clinical trials. However, studies on the effect of Smac mimetics on gallbladder cancer are unavailable. In this study, Smac mimetics can promote tumor necrosis factor-α (TNF-α) to inhibit the proliferation of gallbladder cancer cells and activate the apoptotic pathway, thereby promoting the ubiquitination of Lys48 on Receptor interacting protein kinase-1 (RIPK1) and leading to proteasomal degradation that causes damage to RIPK1 protein integrity. The formation of complex I (RIPK1, tumor necrosis factor 1-associated death domain protein, and TNF receptor-associated factor 2) is inhibited. Then, nonubiquitinated RIPK1 binds with the Fas-associated death domain and caspase-8 to form complex II and promotes the death receptor pathway of apoptosis. Animal experiments further verify that TNF-α combined with Smac mimetics can inhibit the growth of transplanted tumors and induce the apoptosis of transplanted tumor cells. This research provides a new direction for the targeted therapy of gallbladder cancer.

中文翻译：

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Smac 模拟物促进 TNF-α 诱导胆囊癌细胞凋亡。

胆囊癌的恶性程度很高。晚期肿瘤患者没有有效的治疗方法。第二种线粒体衍生的半胱天冬酶激活剂 (Smac) 是细胞凋亡蛋白抑制剂的拮抗剂。Smac mimetics 是一类有效的肿瘤靶向药物，正在进行临床试验。然而，尚无关于 Smac 模拟物对胆囊癌影响的研究。本研究中，Smac mimetics可促进肿瘤坏死因子-α（TNF-α）抑制胆囊癌细胞增殖并激活凋亡通路，从而促进Lys48在受体相互作用蛋白激酶-1（RIPK1）上的泛素化并导致蛋白酶体降解导致 RIPK1 蛋白质完整性受损。复合物 I（RIPK1，肿瘤坏死因子 1 相关死亡域蛋白，和 TNF 受体相关因子 2) 被抑制。然后，非泛素化的 RIPK1 与 Fas 相关死亡域和 caspase-8 结合形成复合物 II 并促进细胞凋亡的死亡受体途径。动物实验进一步验证了TNF-α联合Smac模拟物可以抑制移植瘤的生长，诱导移植瘤细胞的凋亡。该研究为胆囊癌的靶向治疗提供了新的方向。