Abstract

Prostate Cancer (PCa) progression leads to an advanced stage called metastatic castration resistant PCa (mCRPC), for which currently there is no cure in spite of advances in treatment with new generation anti-androgen drugs and chemotherapy with taxanes such as docetaxel (DTX). Our laboratory demonstrated previously that the stress oncoprotein Lens Epithelium Derived Growth Factor of 75 kD (LEDGF/p75) is upregulated in clinical prostate tumors and contributes to DTX-resistance in mCRPC cells. However, little is known about the molecular mechanisms by which LEDGF/p75 promotes taxane resistance. The C-terminus of LEDGF/p75 contains a domain called the Integrase Binding Domain (IBD), which in T cells is responsible for tethering the HIV-integrase complex to transcriptionally active chromatin. In non-PCa cells, the LEDGF/p75 IBD interacts with transcription complexes, such as Menin-MLL and the c-MYC binding protein JPO2, to promote cell survival. However, the relevance of these and others protein-protein interactions in the context of PCa chemoresistance has never been explored. The overall hypothesis of this study is that LEDGF/p75 interacts with JPO2-cMYC and Menin-MLL as part of a transcription complex that contributes to DTX-resistance in PCa, and that targeting these interactions will abrogate this resistance. This dissertation sought to characterize the interactions between LEDGF/p75 and its IBD-interacting partners (ie. JPO2-cMYC, Menin-MLL, among others) in DTX-resistant mCRPC cells and their contribution to chemoresistance. Our results revealed a significant co-upregulation of LEDGF/p75 and its IBD-interacting partners in the DTX-resistant PC3-DR and DU145-DR cell lines, compared to the parental, drug sensitive cells. We also observed nuclear co-localization of these proteins by confocal microscopy. Additionally, using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners in the DTX-resistant PCa cell lines. Silencing of LEDGF/p75, Menin, JPO2 and HRP2 robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of DTX-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance, and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.

LLU Discipline

Pharmacology

Department

Pharmacology

School

School of Medicine

First Advisor

John Buchholz

Second Advisor

Eileen Brantley

Third Advisor

Carlos A. Casiano

Fourth Advisor

Juli Unternaehrer

Fifth Advisor

Sourav Roy

Sixth Advisor

Ubaldo Soto

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2022

Date (Title Page)

10-2021

Language

English

Library of Congress/MESH Subject Headings

lens epithelium-derived growth factor; Prostatic Neoplasms, Castration-Resistant; Drug Resistance, Neoplasm

Type

Dissertation

Page Count

xvii, 236 p.

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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