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MAP3K7 and CHD1 are Novel Mediators of Resistance to Oncolytic Vesicular Stomatitis Virus in Prostate Cancer

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abstract
Cancers are commonly defective in antiviral signaling. The anti-tumorigenic effects of interferon create a selective pressure in cancer to inhibit antiviral defenses. This phenomenon can be exploited through the utilization of viruses as cancer treatments, termed oncolytic viral therapy. A matrix protein mutant of vesicular stomatitis virus (M51R-VSV) is a candidate oncolytic virus that replicates rapidly and induces apoptosis in cancer cells. Oncolytic viruses display tropism for cancerous cells. Viral replication in the tumor initiates an immune response that leads to remission. The application of oncolytic viral therapy is challenged by the heterogeneity of cancer. Some cancers constitutively express interferon-stimulated genes and do not suffer the anti-tumorigenic effects normally associated with antiviral defense. The mechanisms that control viral resistance in cancer are not fully understood. PC3 cells are a prostate cancer cell line that constitutively expresses interferon-stimulated genes. The work in this thesis identified two genes, MAP3K7 and CHD1, necessary for resistance to oncolytic M51R-VSV in PC3 cells. Inhibition of MAP3K7 and/or CHD1 increased viral susceptibility of PC3 cells and decreased protein levels of interferon-stimulated genes. Although mRNA expression of interferon-stimulated genes was decreased in PC3 cells inhibited for MAP3K7 and CHD1, mRNA expression was unexpectedly increased in PC3 cells inhibited only for MAP3K7. Inhibition of MAP3K7 and CHD1 in PC3 reversed tumor resistance to M51R-VSV in an animal model. These findings demonstrate that MAP3K7 and CHD1 regulate novel mechanisms of viral resistance in prostate cancer. MAP3K7 and CHD1 are commonly co-deleted in aggressive prostate cancers, and may define a population of patients that are good candidates for treatment with oncolytic virus.
subject
CHD1
Interferon
Oncolytic
Prostate Cancer
TAK1
VSV
contributor
Bayne, Robert (author)
Lyles, Douglas S (committee chair)
Alexander-Miller, Martha A (committee member)
Hollis, Thomas (committee member)
McCall, Charles E (committee member)
Ornelles, David A (committee member)
Perrino, Fred W (committee member)
Poehling, Katherine A (committee member)
date
2019-05-24T08:35:51Z (accessioned)
2019-05-24T08:35:51Z (available)
2019 (issued)
degree
Biochemistry and Molecular Biology (discipline)
identifier
http://hdl.handle.net/10339/93987 (uri)
language
en (iso)
publisher
Wake Forest University
title
MAP3K7 and CHD1 are Novel Mediators of Resistance to Oncolytic Vesicular Stomatitis Virus in Prostate Cancer
type
Dissertation

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