Chemically synthesized cinobufagin suppresses nasopharyngeal carcinoma metastasis ENKUR to stabilize
Chemically synthesized cinobufagin suppresses nasopharyngeal carcinoma metastasis ENKUR to stabilize
复制标题
化学合成华蟾素通过诱导ENKUR稳定p53表达抑制鼻咽癌转移
DOI：
10.1016/j.canlet.2022.01.025
复制
发表时间：
2022-02-13
期刊：
影响因子：
9.7
通讯作者：
Fang, Weiyi
中科院分区：
文献类型：
--
作者：
Hou, Rentao;Liu, Xiong;Fang, Weiyi
在临床上，肿瘤细胞的转移是导致肿瘤患者死亡的关键因素。在这项研究中，我们使用转移性鼻咽癌（NPC）模型来探索一种新的化学物质，cinobufagin （CB）联合顺铂（DDP）的效果。我们观察到化学合成的CB能显著降低鼻咽癌的转移。此外，CB联合DDP治疗效果更好。分子分析显示，CB通过去调控PI3K/AKT通路和抑制c-Jun（一种与ENKUR启动子结合并负向调节其在鼻咽癌中的表达的致癌转录因子）诱导ENKUR表达。ENKUR作为肿瘤抑制因子与MYH9结合，通过enkurin结构域募集β -catenin来抑制MYH9的核积累，从而抑制c- jun诱导的MYH9表达。随后，下调的MYH9减少了E3连接酶UBE3A的参与，从而降低了UBE3A介导的p53的泛素化降解，而p53是抑制上皮间质转化（EMT）的关键肿瘤抑制因子。临床样本分析显示ENKUR在鼻咽癌组织中的表达水平显著降低。其表达的降低大大促进了鼻咽癌患者的临床进展，反映了鼻咽癌患者预后不良。本研究表明，CB诱导ENKUR抑制β -catenin/c-Jun/MYH9信号，从而降低ube3a介导的p53泛素化降解。结果，EMT信号被灭活以抑制鼻咽癌转移。
Clinically, the metastasis of tumor cells is the key factor of death in patients with cancer. In this study, we used a model of metastatic nasopharyngeal carcinoma (NPC) to explore the effects of a new chemical, cinobufagin (CB), combined with cisplatin (DDP). We observed that chemically synthesized CB strongly decreased the metastasis of NPC. Furthermore, a better therapeutic effect was shown when CB was combined with DDP. Molecular analysis revealed that CB induced ENKUR expression by deregulating the PI3K/AKT pathway and suppressing c-Jun, an oncogenic transcriptional factor that binds to the ENKUR promoter and negatively modulated its expression in NPC. ENKUR as a tumor suppressor binds to MYH9 and decreases its expression by recruiting beta-catenin via its enkurin domain to prevent its nuclear accumulation, which therefore suppresses c-Jun-induced MYH9 expression. Subsequently, downregulated MYH9 reduces the enlistment of E3 ligase UBE3A and thus decreases the UBE3A-mediated ubiquitination degradation of p53, a key tumor suppressor that decreases epithelialmesenchymal transition (EMT). Clinical sample analysis demonstrated that the ENKUR expression level was significantly reduced in NPC tissues. Its decreased expression substantially promoted clinical progression and reflected poor prognosis for patients with NPC. This study demonstrated that CB induced ENKUR to repress the beta-catenin/c-Jun/MYH9 signal and thus decreased UBE3A-mediated p53 ubiquitination degradation. As a result, the EMT signal was inactivated to suppress NPC metastasis.