Determining the mechanism of double-stranded RNA-induced cell death in ovarian cancer.

Ovarian cancer is the most lethal of all gynecological cancers. Current ovarian cancer drug regimens, including taxanes and platinum-based agents, are susceptible to chemoresistance necessitating the development of novel chemotherapeutics. Within tumors pathogen-derived ligands, such as dsRNA, can activate pattern recognition receptors (PRRs) that are capable of inducing apoptosis. In this dissertation we have found that in ovarian cancer cell lines (DOV-13, SKOV-3, CAOV-3, and OVCAR-3), dsRNA treatment alters cell survival. When treated with dsRNA, ovarian cancer cell lines and patient samples could be divided into two categories, responsive which undergo significant levels of apoptosis (CAOV-3 and OVCAR-3) or non-responsive which are unaffected (DOV-13 and SKOV-3). Following dsRNA treatment, dsRNA receptor expression levels increase in responsive cell lines and patient samples only. This suggests a potential role for dsRNA receptors as biomarkers to identify dsRNA-responsive patients. Detailed investigation of the mechanism by which cell lines succumb to or avoid dsRNA-induced cell death showed that in responsive cell lines, NF-kappaB, IFN-beta and caspase 3 activation occurred. Cell death was caspase and IFN-dependent. In non-responsive cell lines, increased c-IAP2 levels and RIP1 kinase ubiquitination occurred, as well as, an increase in basal level autophagy with dsRNA stimulation. However, individual blockade of these pathways did not restore dsRNA-induced apoptosis. In a non-responsive cell line, dsRNA enhanced the action of paclitaxel, carboplatin, and vorinostat through an as yet undetermined mechanism. In a responsive cell line, dsRNA produced a synergistic effect when combined with these drugs. These novel dual therapies, innate immune ligand plus cytotoxic agent, may find application in chemoresistant ovarian cancers.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Year dc:date.available

2011

Author dc:creator

• Van, Danielle

Contributors dc:contributor

• Jessica Bell

• Biochemistry, Biophysics, and Structural Biology
• Life Sciences

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/265

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-1264