Punicalagin promotes autophagic degradation of human papillomavirus E6 and E7 proteins in cervical cancer through the ROS-JNK-BCL2 pathway.
Punicalagin promotes autophagic degradation of human papillomavirus E6 and E7 proteins in cervical cancer through the ROS-JNK-BCL2 pathway.
复制标题
安石榴苷通过ROS-JNK-BCL2途径促进宫颈癌中人乳头瘤病毒E6和E7蛋白的自噬降解
DOI：
10.1016/j.tranon.2022.101388
复制
发表时间：
2022-05
影响因子：
5
通讯作者：
Meng S
中科院分区：
文献类型：
--
作者：
Xie X;Hu L;Liu L;Wang J;Liu Y;Ma L;Sun G;Li C;Aisa HA;Meng S
这项研究为揭示Pingicalagin诱导的自噬导致E6和E7的降解机制提供了新的视角。因此，我们的研究结果将为HPV感染的宫颈癌的治疗提供新的策略。据报道，从石榴皮中提取的Punicalagin对多种癌症具有生长抑制作用。然而，其潜在的机制尚未阐明。人乳头瘤病毒(HPV)是一种主要的肿瘤病毒，它利用宿主的自噬机制支持其复制。在这里，Punicalagin通过自噬-溶酶体系统显著下调宫颈癌细胞中主要HPV癌蛋白E6和E7的水平。此外，Punicalagin激活了ROS-JNK途径，促进了BCL2的磷酸化，导致BCL2与BECN1的解离，并诱导了自噬。用自噬和JNK抑制剂或ROS清除剂处理减轻了Punicalagin诱导的E6和E7的降解。此外，使用簇状规则间隔回文重复/Cas 9系统敲除ATG5可减轻Punicalagin诱导的E6/E7下调。这表明Punicalagin诱导的E6和E7的降解依赖于自噬。体内研究结果表明，普尼卡拉金有效地抑制了宫颈癌的生长。综上所述，本研究阐明了Punicalagin诱导E6和E7自噬降解的机制。这将使Pucicalagin作为治疗HPV诱导的宫颈癌的未来应用成为可能。
This study provides a novel insight into the mechanism of degradation of E6 and E7 caused by punicalagin-induced autophagy. Therefore, our results will offer new strategy for treatment of HPV-infected cervical cancer. Punicalagin, which is derived from pomegranate peel, is reported to exert growth-inhibitory effects against various cancers. However, the underlying mechanisms have not been elucidated. Human papillomavirus (HPV), a major oncovirus, utilizes the host autophagic machinery to support its replication. Here, punicalagin markedly downregulated the levels of the major HPV oncoproteins E6 and E7 in cervical cancer cells through the autophagy-lysosome system. Additionally, punicalagin activated the reactive oxygen species (ROS)-JNK pathway and promoted the phosphorylation of BCL2, which led to the dissociation of BCL2 from BECN1 and the induction of autophagy. Treatment with autophagy and JNK inhibitors or ROS scavengers mitigated the punicalagin-induced degradation of E6 and E7. Moreover, the knockout of ATG5 using the clustered regularly interspaced palindrome repeat/Cas 9 system mitigated the punicalagin-induced downregulation of E6/E7. This indicated that punicalagin-induced degradation of E6 and E7 was dependent on autophagy. The results of in vivo studies demonstrated that punicalagin efficiently inhibits cervical cancer growth. In conclusion, this study elucidated a mechanism of punicalagin-induced autophagic degradation of E6 and E7. It will enable the future applications of punicalagin as a therapeutic for HPV-induced cervical cancer.
登录
查看更多内容
影响因子：
51.1
作者：
de Sanjose, Silvia;Quint, Wim G. V.;Xavier Bosch, F.
通讯作者：
Xavier Bosch, F.
影响因子：
7.6
作者：
Liu C;Cai D;Zhang L;Tang W;Yan R;Guo H;Chen X
通讯作者：
Chen X
影响因子：
3.6
作者：
Fang, Le;Wang, Hong;Fang, Xiaolei
通讯作者：
Fang, Xiaolei
影响因子：
28.2
作者：
Lock R;Kenific CM;Leidal AM;Salas E;Debnath J
通讯作者：
Debnath J
影响因子：
9.7
作者：
Hu, Wei;Chen, Sang-Sang;Zhou, Hui-Jun
通讯作者：
Zhou, Hui-Jun