Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer and Key Laboratory of Tumour Microbiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Department of Hepatobiliary Surgery, Affiliated Putian Hospital of Putian College, Fujian, China.
Cell Signal. 2020 Aug;72:109654. doi: 10.1016/j.cellsig.2020.109654. Epub 2020 Apr 22.
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.
胆囊癌恶性程度高，晚期肿瘤患者尚无有效治疗手段。第二线粒体衍生的半胱天冬酶激活剂（Smac）是凋亡蛋白抑制剂的拮抗剂。Smac 模拟物是一类正在进行临床试验的有效的肿瘤靶向药物。然而，关于 Smac 模拟物对胆囊癌的作用研究尚不多见。本研究发现 Smac 模拟物可促进肿瘤坏死因子-α（TNF-α）抑制胆囊癌细胞的增殖并激活凋亡途径，从而促进受体相互作用蛋白激酶-1（RIPK1）上 Lys48 的泛素化，并导致蛋白酶体降解，导致 RIPK1 蛋白完整性受损。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）的形成受到抑制。然后，未泛素化的 RIPK1 与 Fas 相关死亡域和半胱天冬酶-8 结合形成复合物 II，并促进凋亡受体途径的凋亡。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并诱导移植瘤细胞的凋亡。本研究为胆囊癌的靶向治疗提供了新的方向。
