Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-kappa B activity in hepatocellular carcinoma
Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-kappa B activity in hepatocellular carcinoma
复制标题
Parkin 通过抑制肝细胞癌中 NF-κ B 活性促进蛋白酶体抑制剂诱导的细胞凋亡
DOI：
10.1038/s41419-019-1881-x
复制
发表时间：
2019
影响因子：
9
通讯作者：
Liu Jinbao
中科院分区：
文献类型：
--
作者：
Zhang Xiaolan;Lin Chun;Song Junwei;Chen Han;Chen Xuhong;Ren Liangliang;Zhou Zhongqiu;Pan Jinyuan;Yang Zhenjun;Bao Wenhao;Ke Xueping;Yang Jianan;Liang Yingying;Huang Hongbiao;Tang Daolin;Jiang Lili;Liu Jinbao
泛素-蛋白酶体系统（UPS）是细胞内蛋白质降解和周转的一种严密的稳态控制机制，与许多人类疾病有关。蛋白酶体抑制剂最初被开发为具有抑制肿瘤生长的潜在益处的抗癌剂。然而，实体瘤患者的临床试验未能证明这些蛋白酶体抑制剂具有相同的疗效。在这里，我们表明，帕金，E3泛素连接酶，是牵连在肿瘤的发生和治疗耐药的肝细胞癌（HCC），最常见的类型的原发性肝癌在成人。低水平的Parkin表达与HCC患者的低生存率相关。体外和体内异位表达Parkin增强蛋白酶体介导的HCC细胞凋亡和肿瘤抑制相比之下，帕金森蛋白表达的敲低会促进细胞凋亡抵抗和肿瘤生长。从机制上讲，Parkin促进TNF受体相关因子（TRAF）2和TRAF 6降解，从而促进核因子-κ-B（NF-κB）抑制，最终导致细胞凋亡。这些发现揭示了Parkin与NF-κB通路控制中的蛋白降解之间的直接分子联系，并可能为通过诱导凋亡治疗HCC提供新的UPS依赖性策略。
The ubiquitin–proteasome system (UPS) is a tight homeostatic control mechanism of intracellular protein degradation and turnover involved in many human diseases. Proteasome inhibitors were initially developed as anticancer agents with potential benefits in the suppression of tumor growth. However, clinical trials of patients with solid tumors fail to demonstrate the same efficacy of these proteasome inhibitors. Here, we show that Parkin, an E3 ubiquitin ligase, is implicated in tumorigenesis and therapy resistance of hepatocellular carcinoma (HCC), the most common type of primary liver cancer in adults. LowerParkinexpression correlates with poor survival in patients with HCC. EctopicParkinexpression enhances proteasome inhibitor-induced apoptosis and tumor suppression in HCC cells in vitro and in vivo. In contrast, knockdown ofParkinexpression promotes apoptosis resistance and tumor growth. Mechanistically,Parkinpromotes TNF receptor-associated factor (TRAF) 2 and TRAF6 degradation and thus facilitates nuclear factor-kappa-B (NF-κB) inhibition, which finally results in apoptosis. These findings reveal a direct molecular link between Parkin and protein degradation in the control of the NF-κB pathway and may provide a novel UPS-dependent strategy for the treatment of HCC by induction of apoptosis.