AZD5153 enhances the oncolytic adenovirus effect by affecting the STING in cervical cancer

Abstract

Abstract Background: Oncolytic viruses (OVs) are potential cancer treatment therapy. However, the therapeutic efficacy of OVs was limited due to coxsackie and adenovirus receptor expression levels and antivirus immune response. In this study, we explored the effect of AZD5153, a BRD4 inhibitor, on the regulation ADV5/dE1A oncolytic effect in cervical cancer models. Methods: The effect of AZD5153 on ADV5/dE1A infection was evaluated by using GFP-reporter assays and immunofluorescence. The effect of BRD4 inhibition was further examined by flow cytometry analysis, CCK8, ELISA Kit, RNA sequencing, vitro viral replication assays and cytopathic effect assay. The expression of STING/TBK1/IRF3/NF-KB and IFN-stimulated genes were detected by qRT-PCR and western blot. The cervical cancer xenograft mice models were used to further observe the effect of combination therapy in vivo. Results: GFP-reporter assays showed that GFP positive cells of the AZD5153 and Adv5/dE1A group increased from 21.9% to 46.3% in Hela cells. For Caski cells, the infection rate of GFP positive cells in combination group increased from 22.7% to 34.9%. Moreover, AZD5153 caused sustained tumor regression and enhanced adenovirus E1A expression compared with Adv5/dE1A only group. Low-does AZD5153 did not induce DNA damage response, cell cycle and apoptosis. AZD5153 inhibited the expression level of IFN-stimulated genes. And BRD4 bond to the promoter of STING and regulated STING/TBK1/IRF3/NF-KB expression. Conclusion: In summary, BRD4 inhibitor enhanced ADV5/dE1A oncolytic effect via regulating STING/TBK1/IRF3/NF-KB pathway and IFN-stimulated genes in cervical cancer.