A classical PKA inhibitor increases the oncolytic effect of M1 virus via activation of exchange protein directly activated by cAMP 1.
A classical PKA inhibitor increases the oncolytic effect of M1 virus via activation of exchange protein directly activated by cAMP 1.
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经典的 PKA 抑制剂通过激活由 cAMP 1 直接激活的交换蛋白来增强 M1 病毒的溶瘤作用
DOI：
10.18632/oncotarget.10305
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Yan G
中科院分区：
文献类型：
--
作者：
Li K;Liang J;Lin Y;Zhang H;Xiao X;Tan Y;Cai J;Zhu W;Xing F;Hu J;Yan G
溶瘤病毒疗法是一种新兴且有前途的治疗方式，它使用复制病毒作为选择性抗肿瘤药物。在此，我们报道了经典蛋白激酶 A (PKA) 抑制剂 H89 通过激活 Epac1（由 cAMP 1 直接激活的交换蛋白）与多种癌细胞中的溶瘤病毒 M1 协同作用。 H89 显着增加难治性癌细胞中的病毒复制，导致无法解决的内质网应激和细胞凋亡。微阵列分析表明，H89 通过延迟 NF-κB 的核转位来减弱难治性癌细胞的抗病毒反应。重要的是，体内研究显示 M1/H89 联合治疗期间具有显着的抗肿瘤作用。总的来说，这项研究揭示了 H89 以前未被认识到的作用，并证明 Epac1 活性的激活可以提高癌症生物治疗药物的反应性。
Oncolytic virotherapy is an emerging and promising treatment modality that uses replicating viruses as selective antitumor agents. Here, we report that a classical protein kinase A (PKA) inhibitor, H89, synergizes with oncolytic virus M1 in various cancer cells through activation of Epac1 (exchange protein directly activated by cAMP 1). H89 substantially increases viral replication in refractory cancer cells, leading to unresolvable Endoplasmic Reticulum stress, and cell apoptosis. Microarray analysis indicates that H89 blunts antiviral response in refractory cancer cells through retarding the nuclear translocation of NF-κB. Importantly, in vivo studies show significant antitumor effects during M1/H89 combination treatment. Overall, this study reveals a previously unappreciated role for H89 and demonstrates that activation of the Epac1 activity can improve the responsiveness of biotherapeutic agents for cancer.