Abstract

The Parainfluenza virus 5 (PIV5) mutant P/V-CPI- is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burden in mouse model systems. Here we show that P/V-CPI- infection of human laryngeal cancer HEp-2 cells resulted in the majority of the cells dying, but unexpectedly, a population of cells emerged as P/V-CPI- persistently infected (PI) cells. P/V-CPI- PI cells had elevated levels of basal caspase activation, and viability was highly dependent on activity of cellular inhibitors of apoptosis, such as Survivin. In challenge experiments with external inducers of apoptosis, the PI cells were highly sensitive to cisplatin-induced DNA damage and cell death. This increased cisplatin sensitivity correlated with defects in the phosphorylation cascade controlling DNA damage signaling pathways, as well as translocation of damage-specific DNA binding protein 1 (DDB1) to the nucleus. Similar sensitivity to cisplatin was seen with cells during acute infection with P/V-CPI-, as well as acute infections with WT PIV5. Based on this finding, we tested the hypothesis that histone deacetylase (HDAC) inhibitors would also act with P/V-CPI- infection to enhance cancer cell killing. Using human lung and laryngeal cancer cell lines, 10 HDAC inhibitors were tested for their effect on viability of P/V-CPI- infected cells. HDAC inhibitors such as scriptaid enhanced caspase-3/7, -8 and -9 activity induced by P/V-CPI- and overall cell toxicity. Scriptaid treatment also enhanced the spread of P/V-CPI- through a population of cancer cells and suppressed interferon-beta induction through blocking phosphorylation and nuclear translocation of Interferon Regulatory Factor 3 (IRF-3). These results support a therapeutic approach of combining parainfluenza infection and chemotherapy, but also raise questions on the mechanism by which a cytoplasmic-replicating RNA virus can alter cellular DNA damage responses.

Notes

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Graduation Date

2019

Semester

Fall

Advisor

Parks, Griffith

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Biomedical Sciences

Degree Program

Biomedical Sciences

Format

application/pdf

Identifier

CFE0007803

URL

http://purl.fcla.edu/fcla/etd/CFE0007803

Language

English

Release Date

December 2024

Length of Campus-only Access

5 years

Access Status

Doctoral Dissertation (Campus-only Access)

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