IL-10 knockdown with siRNA enhances the efficacy of Doxorubicin chemotherapy in EBV-positive tumors by inducing lytic cycle via PI3K/p38 MAPK/NF-kB pathway

通过 PI3K/p38 MAPK/NF-kB 通路诱导溶解循环,利用 siRNA 敲低 IL-10 可增强阿霉素化疗对 EBV 阳性肿瘤的疗效

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作者:Li Gao, Haige Han, Honglei Wang, Li Cao, Wen-Hai Feng

Abstract

High levels of IL-10 expression in Epstein-Barr virus (EBV) associated tumors have been reported and it is likely to be important for maintaining EBV latency and EBV-associated tumors. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. Here, we found that knockdown of IL-10 induced EBV lytic replication. Subsequently, we demonstrated that IL-10 knockdown activated BZLF1 promoter through PI3K-p38 MAPK-NF-κB signaling pathway. Interestingly, we verified that VEGF-A was required for IL-10 knockdown to activate PI3K signaling and the accompanying EBV lytic induction. Exogenous recombinant human VEGF-A induced PI3K activation and EBV lytic infection, and inhibition of VEGF-A signaling prevented the PI3K/AKT phosphorylation and EBV reactivation responded to IL-10 knockdown. Most importantly, IL-10 knockdown synergized with chemotherapeutic agent Doxorubicin to kill EBV associated tumor cells in vitro and repress EBV-positive tumor growth in vivo. Our results suggest that inhibition of IL-10 has the potential to serve as a new supplemental strategy for the treatment of EBV-associated tumors.

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