Doxorubicin sensitizes cancer cells to Smac mimetic via synergistic activation of the CYLD/RIPK1/FADD/caspase-8-dependent apoptosis
Doxorubicin sensitizes cancer cells to Smac mimetic via synergistic activation of the CYLD/RIPK1/FADD/caspase-8-dependent apoptosis
复制标题
阿霉素通过协同激活 CYLD/RIPK1/FADD/caspase-8 依赖性细胞凋亡使癌细胞对 Smac 模拟物敏感
DOI：
10.1007/s10495-020-01604-6
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发表时间：
2020-05-16
期刊：
影响因子：
7.2
通讯作者：
He, Sudan
中科院分区：
文献类型：
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作者：
Yang, Chengkui;Ran, Qiao;He, Sudan
Smac/Diablo是一种促凋亡蛋白，通过与凋亡蛋白抑制剂（IAP）相互作用来缓解其对半胱天冬酶的抑制。Smac模拟化合物（也称为IAP的拮抗剂）模拟Smac/Diablo的功能并使癌细胞对TNF诱导的细胞凋亡敏感。然而，大多数癌细胞对单独的Smac模拟物具有抗性。多柔比星是一种广泛应用的化疗药物，在许多患者中引起心脏毒性的不良反应。因此，寻找联合化疗的策略，提高化疗敏感性，减少毒副作用，具有重要意义。在这里，我们报告说，阿霉素协同Smac模拟触发肿瘤坏死因子介导的细胞凋亡，这是从阿霉素诱导的细胞死亡的机制不同。阿霉素使癌细胞（包括人胰腺癌和结肠直肠癌细胞）对Smac模拟物治疗敏感。联合治疗通过激活NF-κ B和c-Jun信号传导途径协同诱导TNF α启动细胞凋亡。敲除caspase-8或敲除FADD显著阻断Smac模拟物和阿霉素协同诱导的细胞凋亡，但对单独阿霉素引起的细胞死亡没有影响。此外，Smac模拟物和阿霉素诱导的细胞凋亡需要受体相互作用蛋白激酶1（RIPK 1）及其去泛素化酶圆柱瘤病（CYLD），而不是A20。这些体外发现表明，Smac模拟物和阿霉素的组合通过TNF/CYLD/RIPK 1/FADD/半胱天冬酶-8信号传导途径协同触发细胞凋亡。重要的是，联合治疗在异种移植肿瘤模型中诱导体内协同抗肿瘤作用。因此，使用Smac模拟物和多柔比星的联合治疗呈现出有希望的肿瘤诱导策略，具有开发抗肿瘤治疗的巨大潜力。
Smac/Diablo is a pro-apoptotic protein via interaction with inhibitors of apoptosis proteins (IAPs) to relieve their inhibition of caspases. Smac mimetic compounds (also known as antagonists of IAPs) mimic the function of Smac/Diablo and sensitize cancer cells to TNF-induced apoptosis. However, the majority of cancer cells are resistant to Smac mimetic alone. Doxorubicin is a widely used chemotherapeutic drug and causes adverse effect of cardiotoxicity in many patients. Therefore, it is important to find strategies of combined chemotherapy to increase chemosensitivity and reduce the adverse effects. Here, we report that doxorubicin synergizes with Smac mimetic to trigger TNF-mediated apoptosis, which is mechanistically distinct from doxorubicin-induced cell death. Doxorubicin sensitizes cancer cells including human pancreatic and colorectal cancer cells to Smac mimetic treatment. The combined treatment leads to synergistic induction of TNF alpha to initiate apoptosis through activating NF-kappa B and c-Jun signaling pathways. Knockdown of caspase-8 or knockout of FADD significantly blocked apoptosis synergistically induced by Smac mimetic and doxorubicin, but had no effect on cell death caused by doxorubicin alone. Moreover, Smac mimetic and doxorubicin-induced apoptosis requires receptor-interacting protein kinase 1 (RIPK1) and its deubiquitinating enzyme cylindromatosis (CYLD), not A20. These in vitro findings demonstrate that combination of Smac mimetic and doxorubicin synergistically triggers apoptosis through the TNF/CYLD/RIPK1/FADD/caspase-8 signaling pathway. Importantly, the combined treatment induced in vivo synergistic anti-tumor effects in the xenograft tumor model. Thus, the combined therapy using Smac mimetic and doxorubicin presents a promising apoptosis-inducing strategy with great potential for the development of anti-cancer therapy.