A classical PKA inhibitor increases the oncolytic effect of M1 virus via activation of exchange protein directly activated by cAMP 1.

Kai Li,Jiankai Liang,Jun Hu,Xiao Xiao,Wenbo Zhu,Fan Xing,Jing Cai,Yaqian Tan,Guangmei Yan,Haipeng Zhang,Yuan Lin

doi:10.18632/oncotarget.10305

Kai Li, Jiankai Liang + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.10305

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Abstract

Oncolytic virotherapy is an emerging and promising treatment modality that uses replicating viruses as selective antitumor agents. Here, we report that a classical protein kinase A (PKA) inhibitor, H89, synergizes with oncolytic virus M1 in various cancer cells through activation of Epac1 (exchange protein directly activated by cAMP 1). H89 substantially increases viral replication in refractory cancer cells, leading to unresolvable Endoplasmic Reticulum stress, and cell apoptosis. Microarray analysis indicates that H89 blunts antiviral response in refractory cancer cells through retarding the nuclear translocation of NF-κB. Importantly, in vivo studies show significant antitumor effects during M1/H89 combination treatment. Overall, this study reveals a previously unappreciated role for H89 and demonstrates that activation of the Epac1 activity can improve the responsiveness of biotherapeutic agents for cancer.

Highlights

Oncolytic viruses (OVs) are therapeutically useful viruses that selectively infect and damage cancerous tissues without causing harm to normal tissues [1, 2]
Irrespective of protein kinase A (PKA) activator db-cyclic adenosine monophosphate (cAMP), we find that PKA inhibitor H89 increases M1 induced cytopathic effects in colorectal cancer cell line HCT-116 (Figure 1A)
We observed that db-cAMP treatment activates PKA pathway through detection of phosphorylated CREB and H89 almost totally blocks the phosphorylation of CREB (Figure 1B and 1C)

Summary

Introduction

Oncolytic viruses (OVs) are therapeutically useful viruses that selectively infect and damage cancerous tissues without causing harm to normal tissues [1, 2]. An increasing number of viruses including measles virus, adenovirus, poxvirus, vesicular stomatitis virus, and herpes simplex virus can be adapted to cancer therapies for their restricted replication in cancer cells before or after engineering and some of them have advanced deeply into clinical trials [3,4,5,6,7,8,9]. Talimogene laherparepvec (T-VEC), a herpes simplex virus type 1–derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colonystimulating factor (GM-CSF) to enhance antitumor immune response, is the first approved oncolytic immunotherapy by the US Food and Drug Administration (FDA) demonstrated therapeutic benefit against melanoma [10,11,12]. We previously have identified that alphavirus M1 as a potential and promising antitumor agent that selectively targets various cancer cells in vitro, in vivo and ex vivo [13, 14]. Two central apoptotic pathways are activated: the Jun N-terminal kinase (JNK) pathway, and the Caspase-12 pathway, but not another C/EBP-homologous protein (CHOP) pathway [13]

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