Dissertation/Thesis Abstract

Molecular interactions between galectin-3 and prostate specific antigen: Relevance to prostate cancer
by Gilbride, Rebecca Jane, Ph.D., University of Arkansas for Medical Sciences, 2012, 243; 3551925
Abstract (Summary)

Prostate cancer is the most frequently diagnosed cancer, excluding skin cancer and the second leading cause of cancer-related mortality among men in the United States. Detection of the disease before it escapes the prostate greatly improves survival rate, and thus emphasis has been placed on screening and surveillance methods, particularly the use of prostate specific antigen (PSA) serum concentration as a biomarker for prostate cancer. While the mortality rate from prostate cancer has decreased by 30% since the advent of PSA screening, the role of PSA testing in the decreased mortality and the effectiveness of PSA as a prostate cancer biomarker remains controversial. In the described dissertation research, PSA was studied in concert with the Beta-galactoside binding protein galectin-3. Galectin-3 has been implicated in a variety of cellular processes including cellular crosslinking and adhesion and has been shown to play a role in cell adhesion with the extracellular matrix. PSA has been shown to have several functions in prostate cancer including proteolytic degradation of the basement membrane of the prostatic secretory duct, activation of transforming growth factor-Beta; which leads to cell detachment and tumor spread, and participate in the release of insulin-like growth factor 1 which acts as a mitogen for prostate cells. A novel purification scheme using continuous elution electrophoresis and thiophilic-gel chromatography was developed to obtain a native source of human seminal plasma PSA, and the resulting purified PSA was shown to be enzymatically active against galectin-3. PSA purified using this method was shown to contain fewer contaminants than PSA available commercially. This purification method was used to purify PSA from the LNCaP and C4-2 prostate cancer cell lines. Significantly, PSA purified from these cell lines was shown to proteolytically process galectin-3 from its full-length form to its truncated carbohydrate recognition domain (CRD) form in an in vitro cleavage assay using biotinylated recombinant galectin-3. Galectin-3 lectin blot analysis of PSA from LNCaP and C4-2 cells demonstrated interaction of the galectin-3 CRD with the PSA N-glycan; however, this interaction was not detected with PSA from human seminal plasma. These findings suggest that the interaction between the PSA N-glycan and the galectin-3 CRD may be exploited as a potential diagnostic tool to discriminate between PSA from benign versus cancer cell types. An in vitro invasion assay demonstrated inhibition of prostate cancer cell invasiveness with the addition of full-length galectin-3, suggesting a potential protective effect of galectin-3 on tumor cell invasion. Furthermore, immunohistochemistry experiments performed on serial sections of prostate tumors demonstrated that PSA and cleaved galectin-3 CRD co-localize with increasing prostate tumor progression. Collectively, these results indicate that PSA and galectin-3 interact both as enzyme/substrate and as lectin/glycoconjugate ligand and have significant implications for prostate cancer disease progression. Cleavage of full-length galectin-3 by PSA may lead to local progression of prostate cancer. Additionally, alterations on the PSA N-glycan allow for galectin-3 to bind to prostate cancer PSA and implicate the interaction as a potential biomarker for prostate cancer. This research will potentially impact the understanding of prostate cancer and influence the prevention, diagnosis, prognosis and treatment of the disease.

Indexing (document details)
Advisor: Diekman, Alan
Commitee: Davidson, Mari K., Higuchi, Masahiro, Kelly, Thomas, Raney, Kevin
School: University of Arkansas for Medical Sciences
Department: Biochemistry and Molecular Biology
School Location: United States -- Arkansas
Source: DAI-B 74/06(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Biochemistry, Oncology
Keywords: Galectin-3, Prostate cancer, Prostate specific antigen, Psa
Publication Number: 3551925
ISBN: 9781267900746
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