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The toll‐like receptor pathway: A novel mechanism of infection‐induced carcinogenesis of prostate epithelial cells
Author(s) -
Kundu Shilajit D.,
Lee Chung,
Billips Benjamin K.,
Habermacher Geoffrey M.,
Zhang Qiang,
Liu Victoria,
Wong Larry Y.,
Klumpp David J.,
Thumbikat Praveen
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20710
Subject(s) - prostate cancer , transfection , cancer research , biology , apoptosis , carcinogenesis , cpg site , inflammation , prostate , lipopolysaccharide , microbiology and biotechnology , cell culture , immunology , cancer , dna methylation , gene expression , genetics , biochemistry , gene
BACKGROUND Inflammation and infection have been linked to the pathogenesis of many cancers including prostate cancer. Components of bacteria and viruses have been identified within pathological specimens of men with prostate cancer. METHODS We characterized the in vitro response of benign prostate epithelial cells to components of infectious agents as they relate to toll‐like receptors. RESULTS Primary and immortalized prostate epithelial cells (RWPE) exhibited increased proliferation in response to exposure to lipopolysaccharide (LPS) and CpG DNA. These molecules are well‐characterized surrogates for gram negative bacteria (e.g., E. coli ) and DNA viruses (e.g., HPV and HSV), which are common in the genitourinary system. Our experiments show that RWPE cells express both TLR 4 (LPS‐specific) and TLR 9 (CpG‐specific). Targeted knock down of individual TLR expression using siRNA abrogated the proliferative response of RWPE cells to LPS and CpG, respectively. In addition, compared to non‐stimulated cells, LPS and CpG up‐regulate active NF‐kB expression. Increased NF‐kB activation was confirmed using RWPE cells that were stably transfected with a NF‐kB reporter construct. Interestingly, NF‐kB activation was both concentration‐ and time‐dependent when stimulated with LPS. RWPE cells were less susceptible to TNF‐alpha induced apoptosis as measured by TUNEL staining when stimulated with CpG or LPS. High concentrations of LPS also prevented cell death as measured by LDH release. CONCLUSIONS Our study has identified a unique mechanism that describes how components of pathogens common in the urinary system may contribute to the malignant transformation of benign prostate epithelia. Prostate 68: 223–229, 2008. © 2007 Wiley‐Liss, Inc.