Adenoviruses induce autophagy to promote virus replication and oncolysis

Abstract

Adenoviruses with deletion of E1b have been used in clinical trials to treat cancers that are resistant to conventional therapies. The efficacy of viral replication within cancer cells determines the results of oncolytic therapy, which remains poorly understood and requires further improvement. In this report, we show that adenoviruses induce autophagy by increasing the conversion of LC3-I to LC3-II and the formation of the Atg12-Atg5 complex. Inhibition of autophagy with 3-methyladenine (3MA) resulted in a decreased synthesis of adenovirus structural proteins, and thereby a poor viral replication; promotion of autophagy with rapamycin increased adenovirus yield. This study indicates that adenovirus-induced autophagy correlates positively with virus replication and oncolytic cell death, and that autophagy may generate nutrients that can be used for building viral progeny particles. These results further suggest that chemotherapeutic agents that increase cancer cell autophagy may improve the efficacy of oncolytic virotherapy.

Porcine Circovirus Type 2 Induces Autophagy via the AMPK/ERK/TSC2/mTOR Signaling Pathway in PK-15 Cells

“…Viruses could regulate autophagy in infected cells, but detailed mechanisms are elusive and may vary with virus types (8,28,44,67,68). Tobacco mosaic virus and hepatitis C virus (HCV) can induce autophagosome formation by inducing endoplasmic reticulum stress (29,53).…”

Indole-3-carbinol (I3C) increases apoptosis, represses growth of cancer cells, and enhances adenovirus-mediated oncolysis

“…We have previously shown that autophagy increases adenovirus replication by degrading intracellular components for building progeny virus particles. 39 Therefore, autophagy is unlikely to play an important role in I3C-reduced Ad replication.…”

The effectiveness of the oncolytic activity induced by Ad5/F35 adenoviral vector is dependent on the cumulative cellular conditions of survival and autophagy

“…Another possible explanation of the relatively low transduction efficiency of Ad5/F35 may be due to the longer stay at endosomal/lysosomal compartments without endosomal escape for nuclear import, resulting in less efficient Ad5/F35-mediated gene transfer compared to that of Ad5 (41). We therefore investigated other means of enhancing Ad5/F35 transduction efficiency, on the basis that the CD46 receptor-promoted autophagy would result in the promotion of viral replication and oncolysis (23). The chimeric Ad5/F35 adenoviral vector exerted a more significant oncolytic effect on cancer cells with a higher survival potential under autophagic conditions generated by pre-treatment with rapamycin (an mTOR inhibitor) as an autophagy inducer (Figs.…”

“…To confirm that the transduction efficiency of Ad5/F35 and the levels of CD46 were not the main factors responsible for optimal gene transfer, we investigated the possibility that autophagy facilitates a faster induction of Ad5/F35 viral particle production compared to Ad5. According to recent studies, adenovirus has the ability to induce autophagy (36-39); therefore, autophagy may be used to facilitate the release of viral progeny, promote adenovirus replication and improve oncolysis (23,39).…”

“…However, Yu et al (21,22) demonstrated that the transduction efficiency of Ad5/F35 did not directly correlate with the expression level of CD46. In addition to the distinct cell entry pathways of Ad35, another advantage is the ability of the vector to induce autophagy through the CD46-Cyt-1̸GOPC pathway, via the autophagosome formation complex, Vps34̸Beclin-1 (18), which ultimately leads to viral replication and oncolysis (23). Autophagy is a regulated process for the degradation of cellular components, that has been well-conserved in eukaryotic cells.…”