Functional analysis of the host defense peptide Human Beta Defensin-1: New insight into its potential role in cancer

Abstract

Although it is known that innate immunity is key for protecting the body against foreign agents such as bacteria, little is known about elements of the innate immune system that have anti-tumor activity. Human Beta Defensin-1 (hBD-1), an important component of the innate immune response, is lost at high frequencies in malignant prostatic tissue, while high levels of expression are maintained in adjacent benign regions. In prostate carcinoma, frequent genetic alterations occur in the 8p22-23 region and several studies indicate there may be multiple tumor suppressor genes present within this region. 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. To gain insight as to its function in prostate cancer, hBD-1 was cloned and ectopically expressed in four prostate cancer cell lines. Induction of hBD-1 expression resulted in a decrease in cellular growth in DU145 and PC3 cells. However, hBD-1 has no effect on the growth of androgen receptor (AR) positive LNCaP prostate cancer cells, but was again growth suppressive to PC3 cells with ectopic AR expression (PC3/AR+). hBD-1 also caused rapid induction of cytolysis and caspase-mediated apoptosis in DU145 and PC3 prostate cancer cells. Although the regulation of hBD-1 was not addressed in this study, our preliminary data demonstrated that the pathways involoved may include cMYC and/or PAX2. Data presented here are the first to provide evidence of its potential role in prostate cancer cell death.

Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients

“…However, further significant differences in alterations were seen including more frequent losses of chromosome 17p13 carrying the TP53 gene in EGFR-wt tumors and losses in chromosome 8p23 in EGFRmut tumors. Earlier data suggested that the high allelic loss frequencies seen at 8p23 loci could be the result of activation of one or more specific suppressor genes [34] possibly such as host defence peptide Human Beta Defensin-1 [35].…”

Alarmins: awaiting a clinical response

“…Dying tumor cells following chemotherapy and radiotherapy release HMGB1, which can induce the maturation of DCs via TLR2 and TLR4 to promote a cytotoxic T lymphocyte response through cross-presentation of tumor antigens (94)(95)(96). Various defensins have been found to have tumor suppressor properties (97)(98)(99) and are significantly downregulated in various carcinomas, including DEFB1 in renal cell and prostate carcinomas and DEFB4A and α-defensin HNP-2 in cervical squamous cell carcinomas. Furthermore, although data on the role of α-defensins in cancer biology are currently lacking, they may be antiangiogenic, acting by disrupting fibronectin signaling via the α5β1 integrin (100).…”

β-Defensins: Multifunctional Modulators of Infection, Inflammation and More?

“…This study showed that growth of an OSCC cancer cell line decreased after the addition of hBD1, but increased after treatment with hBD2 or hBD3. Similarly, in prostate cancer cells, hBD1 was shown to decrease the growth rate [104]. Expression of hBD1 in late-stage prostate cancer cell lines (PC3 and DU145) caused rapid cell death.…”