Targeting LEDGF/p75 to Sensitize Chemoresistant Prostate Cancer Cells to Taxanes

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Basic Sciences

Year

2017

Author dc:creator

• Rios-Colón, Leslimar

Contributors dc:contributor

• Buchholz, John
• Brantley, Eileen
• Casiano, Carlos A.
• De León, Daisy
• Neamati, Nouri
• Payne, Kimberly J.
• Zhang, Lubo

• Medical Biochemistry
• Medical Pharmacology
• Medicine and Health Sciences
• Neoplasms
• Oncology
• Race and Ethnicity
• Prostatic Neoplasms; African Americans; Chemotherapy; Drug therapy; Inhibitor of Apoptosis Proteins
• Chemoresistance
• Lens epithelium-derived growth factor
• Stress-response protein

Statement dc: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.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/459

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1459