Defense Date

2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biochemistry

First Advisor

Jessica Bell

Abstract

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.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

August 2011

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