Cisplatin Relocalizes RNA Binding Protein HuR and Enhances the Oncolytic Activity of E4orf6 Deleted Adenovirus
Cisplatin Relocalizes RNA Binding Protein HuR and Enhances the Oncolytic Activity of E4orf6 Deleted Adenovirus
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DOI：
10.3390/cancers12040809
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发表时间：
2020-04-01
期刊：
影响因子：
5.2
通讯作者：
Higashino, Fumihiro
中科院分区：
文献类型：
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作者：
Habiba, Umma;Hossain, Elora;Higashino, Fumihiro
腺病毒与化疗药物的联合应用是一种新的肿瘤治疗方法。腺病毒和化疗药物之间的细致分析可以帮助设计有效的抗癌疗法。人类抗原R（HuR）是一种RNA结合蛋白，其结合特定mRNA的富含AU的元件（ARE），并参与ARE-mRNA的输出和稳定。我们最近的报道揭示了E4 orf 6基因缺失的溶瘤腺病毒（dl 355）在某些类型的癌症中复制，其中ARE-mRNA是稳定的。本研究旨在研究dl 355和顺二氨二氯铂（CDDP）的联合治疗是否对癌细胞具有协同细胞杀伤作用。我们证实了CDDP在核质HuR穿梭中的作用。体外和体内实验表明，通过细胞凋亡诱导增强癌细胞死亡，并且在联合治疗后显著减少肿瘤生长。这些结果表明，联合治疗通过上调CDDP诱导的细胞质HuR发挥协同抗肿瘤活性，这导致ARE mRNA稳定和增加病毒增殖。此外，增强的细胞杀伤作用是由于激活了内源性凋亡途径。因此，CDDP和dl 355的联合治疗可以代表癌症治疗的合理方法。
The combination of adenoviruses and chemotherapy agents is a novel approach for human cancer therapeutics. A meticulous analysis between adenovirus and chemotherapeutic agents can help to design an effective anticancer therapy. Human antigen R (HuR) is an RNA binding protein that binds to the AU-rich element (ARE) of specific mRNA and is involved in the export and stabilization of ARE-mRNA. Our recent report unveiled that the E4orf6 gene deleted oncolytic adenovirus (dl355) replicated for certain types of cancers where ARE-mRNA is stabilized. This study aimed to investigate whether a combined treatment of dl355 and Cis-diamminedichloroplatinum (CDDP) can have a synergistic cell-killing effect on cancer cells. We confirmed the effect of CDDP in nucleocytoplasmic HuR shuttling. In vitro and in vivo experiments showed the enhancement of cancer cell death by apoptosis induction and a significant reduction in tumor growth following combination treatment. These results suggested that combination therapy exerted a synergistic antitumor activity by upregulation of CDDP induced cytoplasmic HuR, which led to ARE mRNA stabilization and increased virus proliferation. Besides, the enhanced cell-killing effect was due to the activation of the intrinsic apoptotic pathway. Therefore, the combined treatment of CDDP and dl355 could represent a rational approach for cancer therapy.