Abstract

The serum autoantibody repertoire from cancer patients is currently being exploited for the identification of tumor associated antigens (TAA) and the design of TAA arrays. Such arrays would facilitate autoantibody profiling and potentially aid in the serological diagnosis and prognosis of tumors. The goal of this study was to identify and characterize prostate-specific TAA. We observed that while the general frequency and titers of autoantibodies in PCa patients were relatively similar to those in matched controls, significant differences could be detected between the two groups in the autoantibody response to the lens epithelial-derived growth factor p75 (LEDGF/p75). LEDGF/p75 is a survival protein that confers resistance to stress-induced cell death. Autoantibodies targeting LEDGF/p75 were detected in 18.4% (38/206) of prostate cancer sera, as opposed to only 4.5% (9/199) in sera from matched controls. This immune response suggested that the protein might be aberrantly expressed in prostate tumors. To explore this hypothesis the expression of LEDGF/p75 in prostate tissue was analyzed using the Human prostate cancer Histo™-Array (Imgenex). The 3 normal prostate tissues on the array showed negative staining. Of the 54 cancer specimens, 33 (61%) showed strong staining, 17 of 54 (31%) showed weak staining, and 3 of 54 (6%) were negative. LEDGF/p75 is known to be upregulated by oxidative stress. There is increasing evidence that oxidative stress plays an important role in the development of prostate cancer. To investigate the biological impact of LEDGF/p75 overexpression in prostate tumors, RWPE-2 prostate cancer cells stably overexpressing LEDGF/p75 were developed. Overexpression of LEDGF/p75 in RWPE-2 cells conferred resistance to caspase-independent cell death induced by the pro-oxidants t-butyl hydroperoxide (TBHP) or Taxotere® but not to cell death induced by classical apoptotic stimuli such as staurosporine and TRAIL. RWPE-2 cells overexpressing LEDGF/p75 showed decreased levels of reactive oxygen species and the upregulation of the endoplasmic reticulum protein 57 (ERp57), a thiol-dependent reductase. Taken together, these results suggest that overexpression of LEDGF/p75, which may be triggered by the oxidative stress environment in the prostate, might provide a growth advantage to prostate cells through the upregulation of ERp57 contributing to the development and progression of prostate cancer.

LLU Discipline

Microbiology and Molecular Genetics

Department

Microbiology

School

Graduate School

First Advisor

Carlos Casiano

Second Advisor

Daisy DeLeon

Third Advisor

Penelope Duerken-Hughes

Fourth Advisor

Michael Lilly

Fifth Advisor

Thomas Linkhart

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2004

Date (Title Page)

12-2004

Language

English

Library of Congress/MESH Subject Headings

Prostatic Neoplasms -- genetics; Prostatic Neoplasms -- microbiology; Antigens, Tumor-Associated, Carbohydrate; Serologic Tests; Prognosis -- methods.

Type

Dissertation

Page Count

xvii; 200

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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