Abstract
Oncolytic viruses represent an emerging approach to cancer therapy. However, better understanding of their interaction with the host cancer cell and approaches to enhance their efficacy are needed. Here, we investigate the effect of chemically induced endoplasmic reticulum (ER) stress on the activity of the chimeric group B adenovirus Enadenotucirev, its closely related parental virus Ad11p, and the archetypal group C oncolytic adenovirus Ad5. We show that treatment of colorectal and ovarian cancer cell lines with thapsigargin or ionomycin caused an influx of Ca2+, leading to an upregulation in E1A transcript and protein levels. Increased E1A protein levels, in turn, increased levels of expression of the E2B viral DNA polymerase, genome replication, late viral protein expression, infectious virus particle production, and cell killing during Enadenotucirev and Ad11p, but not Ad5, infection. This effect was not due to the induction of ER stress, but rather the influx of extracellular Ca2+ and consequent increase in protein kinase C activity. These results underscore the importance of Ca2+ homeostasis during adenoviral infection, indicate a signaling pathway between protein kinase C and E1A, and raise the possibility of using Ca2+ flux-modulating agents in the manufacture and potentiation of oncolytic virotherapies.
Highlights
There is increasing interest in the deployment of oncolytic viruses (OVs) in the treatment of cancer, many offering powerful cancerkilling properties.[1]
Enhances Viral Protein Production We examined the effect of three common endoplasmic reticulum (ER) stress inducers, Tg, Im, and tunicamycin (Tm), on the rate of viral protein production following infection of either SK-OV-3 ovarian or DLD-1 colorectal cancer cells with EnAd or adenovirus serotype 5 (Ad5)
In SK-OV-3 ovarian cancer cells, Tg and Im treatment drastically increased the percentage of cells expressing EnAd-encoded GFP, as measured 3 days post-infection (p.i.)
Summary
There is increasing interest in the deployment of oncolytic viruses (OVs) in the treatment of cancer, many offering powerful cancerkilling properties.[1]. Lysis of infected cells can contribute toward an inflammatory and immune response in the tumor, further enhancing cell killing.[3,4,5] OVs may be engineered to express immune-modulatory transgenes within tumor cells, allowing for a high local concentration of an immunotherapeutic in the cancer microenvironment and avoiding off-target. The adenovirus serotype that has historically been used as a model for adenoviral research and is most commonly used as both a vector in gene therapy and as an oncolytic agent is the group C adenovirus serotype 5 (Ad5).[23] Within the fields of oncolytic virotherapy and gene therapy, adenoviruses are widely used[24] for a variety of reasons, including their high stability, large capacity for encoding transgenes, and ease of production.
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