Functional analysis of human Beta Defensin-1: Novel insight into its role in prostate cancer

• Main Author: Bullard, Rebecca S
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2008
• Subjects: Molecular biology
• ISBN: 9780549557845; 0549557849

Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. The molecular pathogenesis of this disease includes genetic alterations, infection, and exposure to inflammatory or dietary oxidants. Recently, research has focused on the role of host defense peptides in tumor immunity. Defensins, a highly conserved multigene family of proteins that possess antimicrobial and antiviral properties, play an essential role in innate and adaptive immunity. These peptides are categorized into alpha- and beta-defensins based upon the spacing and connection between the six conserved cysteine residues of the mature peptide. Human Beta Defensin-1 (hBD-1), an important component of the innate immune system, is lost at high frequencies in malignant prostatic tissue, while expression is maintained in adjacent benign regions. Several studies indicate there may be multiple tumor suppressor genes present within the 8p22-23 region in prostate carcinoma, an area where frequent genetic alterations occur. The high incidence of loss of hBD-1 expression in prostate cancer, along with its chromosomal location of 8p23.2, raised the possibility that it may play a role in tumor suppression. Our studies demonstrated that induction of hBD-1 expression results in significant changes in cell morphology and membrane permeability, as well as the activation of caspase-mediated apoptosis in DU145 and PC3 cell lines. However, no effect was observed following the induction of hBD-1 in LNCaP. To gain insight into the caspase-mediated cell death, we analyzed the activation of specific caspases within the intrinsic and extrinsic pathway following the induction of hBD-1 expression. In DU145 and PC3 prostate cancer cell lines the activation of both apoptotic pathways was observed, specifically the activation of caspases 3, 8 and 9. However, no caspase activation was observed in the LNCaP prostate cancer cell line. Although our studies suggest that within our expression system and employed methodologies, hBD-1 does not exhibit a 'bystander effect' on neighboring cells, the results indicate a possible upward trend suggesting that hBD-1 may exhibit a 'bystander effect' under different conditions than those used in this study. Collectively, this data indicates the loss of hBD-1 in the area surrounding prostate cancer cells may create an environment that promotes the progression of prostate cancer.