Enhanced oncolytic activity of E4orf6-deficient adenovirus by facilitating nuclear export of HuR.
Enhanced oncolytic activity of E4orf6-deficient adenovirus by facilitating nuclear export of HuR.
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DOI：
10.1016/j.bbrc.2020.04.147
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发表时间：
2020-08
影响因子：
3.1
通讯作者：
Ishraque Ahmed;M. T. Alam;Aya Yanagawa-Matsuda;Elora Hossain;T. Kitamura;K. Minowa;F. Higashino
中科院分区：
文献类型：
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作者：
Ishraque Ahmed;M. T. Alam;Aya Yanagawa-Matsuda;Elora Hossain;T. Kitamura;K. Minowa;F. Higashino
一种富含AU的元素(ARE)是一种RNA元素，它能促进mRNA的快速衰退。RNA结合蛋白Hur通过将ARE-mRNA输出到细胞质来稳定它。在大多数癌细胞中，HUR被输出到细胞质，ARE-mRNA稳定。此外，病毒基因产物E4orf6输出Hur以稳定腺病毒感染细胞中的ARE-mRNA，这种稳定是病毒完全复制所必需的。以前我们展示了E4orf6缺失腺病毒dl355的溶瘤活性，它可以在ARE-mRNA稳定的癌细胞中复制。在这项研究中，我们研究了进一步增强HUR输出是否可以刺激d1355的复制和溶瘤活性。我们发现乙醇处理促进了Hur在癌细胞中的胞浆再定位。此外，dl355在乙醇处理的细胞中的复制效率提高，作为回应，该病毒在体内的体外杀伤活性也增加。乙醇介导的感染细胞中裂解PARP水平的上调表明乙醇激活了dl355诱导的细胞凋亡。乙醇处理使腺病毒转录本中唯一的ARE-mRNA IVa2mRNA表达增强。这些数据表明，乙醇处理导致的ARE-mRNA稳定性的增强上调了d1355的溶瘤活性，并提示联合使用溶瘤腺病毒和乙醇治疗可能是一种良好的癌症治疗策略。
An AU-rich element (ARE) is RNA element that enhances the rapid decay of mRNA. The RNA binding protein HuR stabilizes ARE-mRNA by exporting it to the cytoplasm. In most of cancer cells, HuR is exported to the cytoplasm and ARE-mRNA is stabilized. In addition, the viral gene product E4orf6 exports HuR to stabilize ARE-mRNA in adenovirus-infected cells and the stabilization is required for full virus replication. Previously we showed the oncolytic activity of E4orf6-deleted adenovirus dl355, which can replicate in cancer cells where ARE-mRNA is stabilized. In this study, we examined whether the further enhancement of HuR export can stimulate the replication and the oncolytic activity of dl355. We found that ethanol treatment promoted the cytoplasmic relocalization of HuR in cancer cells. In addition, the replication efficiency of dl355 increased in ethanol-treated cells, and in response, the cytolytic activity of the virus also increasedin vitroandin vivo. Upregulation of a cleaved-PARP level in infected cells mediated by ethanol is suggesting that ethanol activated the apoptosis induced by dl355. IVa2 mRNA, the only ARE-mRNA among transcripts of adenovirus was augmented by ethanol treatment. These data indicate that the enhancement of ARE-mRNA stabilization as a result of ethanol treatment upregulates the oncolytic activity of dl355 and suggests that the combined use of an oncolytic adenovirus and ethanol treatment may be a good strategy for cancer therapy.