Oncolytic Bovine Herpesvirus 1 Inhibits Human Lung Adenocarcinoma A549 Cell Proliferation and Tumor Growth by Inducing DNA Damage.

Wencai Qiu,Liqian Zhu,Shitao Li,Xiuyan Ding,Yongming He

doi:10.3390/ijms22168582

Abstract

Bovine herpesvirus 1 (BoHV-1) is a promising oncolytic virus with broad antitumor spectrum; however, its oncolytic effects on human lung adenocarcinoma in vivo have not been reported. In this study, we report that BoHV-1 can be used as an oncolytic virus for human lung adenocarcinoma, and elucidate the underlying mechanism of how BoHV-1 suppresses tumor cell proliferation and growth. First, we examined the oncolytic activities of BoHV-1 in human lung adenocarcinoma A549 cells. BoHV-1 infection reduced the protein levels of histone deacetylases (HDACs), including HDAC1-4 that are promising anti-tumor drug targets. Furthermore, the HDAC inhibitor Trichostatin A (TSA) promoted BoHV-1 infection and exacerbated DNA damage and cytopathology, suggesting a synergy between BoHV-1 and TSA. In the A549 tumor xenograft mouse model, we, for the first time, showed that BoHV-1 can infect tumor and suppressed tumor growth with a similar high efficacy as the treatment of TSA, and HDACs have potential effects on the virus replication. Taken together, our study demonstrates that BoHV-1 has oncolytic effects against human lung adenocarcinoma in vivo.

Highlights

Bovine herpesvirus type 1 (BoHV-1) is an important viral pathogen of cattle that can induce severe respiratory lesions, conjunctivitis, abortion, vulvovaginitis, balanopostitis and systemic infection in neonate calves [1]
There was an additional upper band detected by the HDAC2 antibody in cells after infection for 24 and 36 h (Figure 1B). It suggests that viral infection might lead to post-translational modifications of HDAC2, which will be investigated in the future
Since the virus infection led to protein depletion of HDAC1, 2, 3 and 4, we examined the roles of histone acetylation in BoHV-1 infection by using two chemical inhibitor Trichostatin A (TSA) and Anacardic acids (AA)

Summary

Introduction

Bovine herpesvirus type 1 (BoHV-1) is an important viral pathogen of cattle that can induce severe respiratory lesions, conjunctivitis, abortion, vulvovaginitis, balanopostitis and systemic infection in neonate calves [1]. Diverse HSV-1 strains have been developed as cancer therapeutic reagents by deletion of viral genes essential for replication in normal tissue but not in cancerous cells [3]. Human CD155 that belongs to the nectin-like molecule family has been identified as an entry receptor for BoHV-1 [11,12]. CD155 is overexpressed widely in multiple tumor tissues, including the human lung adenocarcinoma [13]. The patients of lung cancer with programmed death-ligand 1(PD-L1) and CD155 expressed at high levels normally have the shortest survival rate [14].

Methods

Results

Discussion

Conclusion