Abstract

Prostate cancer (PCa) is the second most diagnosed cancer in males. This disease disproportionately affects African American men, with a higher incidence and mortality compared to other ethnic/racial groups. An aging male population and the complexity of addressing the health disparities associated with this disease puts PCa into the spotlight due to its serious public health implications and the imminent fiscal challenge over the next decades. Chronic prostate inflammation resulting in activation of stress and prosurvival pathways contribute to disease progression and the development of chemoresistance. Lens epithelium-derived growth factor p75 (LEDGF/p75) is a stressresponse protein that promotes cellular survival against environmental stressors, including oxidative stress, radiation, and cytotoxic drugs. It is overexpressed in PCa and other cancers and has been associated with features of tumor aggressiveness, including resistance to cell death and chemotherapy. This research work shows that the endogenous levels of LEDGF/p75 are upregulated in metastatic castration resistant prostate cancer (mCRPC) cells selected for resistance to the taxane drug docetaxel (DTX). These cells also showed resistance to the taxanes cabazitaxel (CBZ) and paclitaxel (PTX), but not to the classical inducer of apoptosis TRAIL. Silencing LEDGF/p75 effectively sensitized taxane-resistant PC3 and DU145 cells to DTX and CBZ, as evidenced by a significant decrease in their clonogenic potential. While TRAIL induced apoptotic blebbing, caspase-3 processing, and apoptotic LEDGF/p75 cleavage, which leads to its inactivation, in both taxane- resistant and -sensitive PC3 and DU145 cells, treatment with DTX and CBZ failed to robustly induce these signature apoptotic events. Also, pretreatment with caspase inhibitor zVAD partially rescued the cells from TRAIL-induced cell death. These observations suggested that taxanes induce both caspase-dependent and -independent cell death in mCRPC cells, and that maintaining the structural integrity of LEDGF/p75 is critical for its role in promoting drug-resistance. We also report the initial screening and selection of candidate small molecule inhibitors (SMIs) to target this protein and sensitize taxane-resistant cells to chemotherapy.

LLU Discipline

Biochemistry

Department

Basic Sciences

School

School of Medicine

First Advisor

Buchholz, John

Second Advisor

Brantley, Eileen

Third Advisor

Casiano, Carlos A.

Fourth Advisor

De León, Daisy

Fifth Advisor

Neamati, Nouri

Sixth Advisor

Payne, Kimberly J.

Seventh Advisor

Zhang, Lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2017

Date (Title Page)

6-2017

Language

English

Library of Congress/MESH Subject Headings

Prostatic Neoplasms; African Americans; Chemotherapy; Drug therapy; Inhibitor of Apoptosis Proteins

Subject - Local

Chemoresistance; Lens epithelium-derived growth factor; Stress-response protein

Type

Dissertation

Page Count

172

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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