Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Ming-Fong Lin

Abstract

Prostate cancer is the second leading cause of cancer-related deaths in U.S. men, primarily due to the development of castration-resistant (CR) prostate cancer (PCa), of which there are no effective treatment options. Reactive oxygen species (ROS) plays a critical role in prostate carcinogenesis, including the progression of the CR PCa phenotype. ROS regulates both cell proliferation and apoptosis; a moderate increase in ROS can promote proliferation; however, a substantial rise in ROS levels will result in apoptosis. Oxidase p66Shc is elevated in clinical PCa cells and has been associated with a metastatic phenotype of CR PCa cells, promoting PCa cell proliferation and migration in culture. However, ROS generated by p66Shc can also result in apoptosis. Our working hypothesis is that aberrant p66Shc/ROS production promotes PCa progression to the CR phenotype.

Within our studies, we have demonstrated that hydrogen peroxide treatment can promote an aggressive, AI phenotype in androgen-sensitive (AS) PCa cells. Furthermore, we attribute these ROS-mediated phenotypic and cell signaling alterations to p66Shc. In our second study, we can effectively mitigate CR PCa, neuroendocrine-like PCa and docetaxel-resistant PCa growth by exploiting this ROS balance and promoting excessive ROS production via treatments with microtubule targeting agents CIL-102 derivatives. These selective anti-cancer agents are promising new therapeutic options for not only PCa, but other taxane-resistant cancers via depolymerization of microtubules.

CIL-102 Derivatives.JPG (82 kB)
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Elsevior using article in thesis.JPG (122 kB)
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Available for download on Wednesday, April 21, 2021

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