The Potential Role of LEDGF/p75 in Prostate Cancer

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Year

2004

Author dc:creator

• Daniels, Tracy Ruth

Contributors dc:contributor

• Carlos Casiano
• Daisy DeLeon
• Penelope Duerken-Hughes
• Michael Lilly
• Thomas Linkhart

• Amino Acids, Peptides, and Proteins
• Immunopathology
• Laboratory and Basic Science Research
• Microbiology
• Molecular Genetics
• Neoplasms
• Prostatic Neoplasms -- genetics; Prostatic Neoplasms -- microbiology; Antigens, Tumor-Associated, Carbohydrate; Serologic Tests; Prognosis -- methods.

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/1485

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-2262