Abstract
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.
Highlights
Oncolytic adenoviruses are being developed as novel antitumor therapeutics
We previously demonstrated the role of Human antigen R (HuR) in AU-rich element (ARE) mRNA stabilization that lead to dl355 propagation [22]
The functions of different genes in the E4 region was evaluated and found that dl355 showed impaired virus DNA replication, accumulation of late viral mRNAs, and shutoff of host cell mRNAs compared to wild type adenovirus type 5 [2]
Summary
Oncolytic adenoviruses are being developed as novel antitumor therapeutics. The E4 region encoding proteins such as E4orf, E4orf, and E4or, are known to have oncogenic activities that are required for DNA replication, late gene expression, and host cell shutoff [2,3,4,5,6,7]. E4orf and E4orf proteins of adenovirus type 5 (subgroup C) have the potentials to transform cells in cooperation with E1A and E1B and intensify the growth of tumors transplanted in nude mice [5,6,7]. We confirmed that in cells transfected with adenovirus type 5, E4orf associated with cellular pp protein and AU-rich element (ARE)-containing mRNAs were exported to the cytoplasm in a chromosome region maintenance 1 (CRM1)-independent manner [9]. The exported ARE-mRNAs were stabilized and acquired the potential to transform cells [10,11]
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