Activation of Cyclic Adenosine Monophosphate Pathway Increases the Sensitivity of Cancer Cells to the Oncolytic Virus M1
Activation of Cyclic Adenosine Monophosphate Pathway Increases the Sensitivity of Cancer Cells to the Oncolytic Virus M1
复制标题
环磷酸腺苷途径的激活增加癌细胞对溶瘤病毒 M1 的敏感性
DOI：
10.1038/mt.2015.172
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发表时间：
2016-01-01
影响因子：
12.4
通讯作者：
Yan, Guangmei
中科院分区：
文献类型：
--
作者：
Li, Kai;Zhang, Haipeng;Yan, Guangmei
溶瘤病毒疗法是一种新型的和新兴的治疗方式，其使用具有复制能力的病毒来破坏癌细胞。尽管不同的癌细胞类型对溶瘤病毒敏感，但溶瘤病毒疗法的主要挑战之一是对溶瘤的敏感性在不同的癌细胞类型之间变化。此外，根本的作用机制尚未完全了解。在这里，我们报告说，激活环磷酸腺苷（cAMP）信号显着敏感难治性癌细胞甲病毒M1在体外，体内，和体内。我们发现cAMP信号通路的激活抑制M1诱导的抗病毒因子在难治性癌细胞中的表达，导致长期和严重的内质网（ER）应激和细胞凋亡。我们还表明，M1介导的溶瘤，这是由cAMP信号增强，涉及的因素，交换蛋白直接激活cAMP 1（Epac 1），但不是经典的cAMP依赖性蛋白激酶A（PKA）。总之，cAMP/Epac 1信号通路激活抑制抗病毒因子，并提高难治性癌细胞对M1介导的病毒疗法的反应性。
Oncolytic virotherapy is a novel and emerging treatment modality that uses replication-competent viruses to destroy cancer cells. Although diverse cancer cell types are sensitive to oncolytic viruses, one of the major challenges of oncolytic virotherapy is that the sensitivity to oncolysis ranges among different cancer cell types. Furthermore, the underlying mechanism of action is not fully understood. Here, we report that activation of cyclic adenosine monophosphate (cAMP) signaling significantly sensitizes refractory cancer cells to alphavirus M1in vitro,in vivo,andex vivo. We find that activation of the cAMP signaling pathway inhibits M1-induced expression of antiviral factors in refractory cancer cells, leading to prolonged and severe endoplasmic reticulum (ER) stress, and cell apoptosis. We also demonstrate that M1-mediated oncolysis, which is enhanced by cAMP signaling, involves the factor, exchange protein directly activated by cAMP 1 (Epac1), but not the classical cAMP-dependent protein kinase A (PKA). Taken together, cAMP/Epac1 signaling pathway activation inhibits antiviral factors and improves responsiveness of refractory cancer cells to M1-mediated virotherapy.