title: The toll-like receptor pathway: a novel mechanism of infection-induced carcinogenesis of prostate epithelial cells.
abstract: 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.
authors: Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors: Shilajit D
authors: SD
authors: Kundu
authors: Chung
authors: C
authors: Lee
authors: Benjamin K
authors: BK
authors: Billips
authors: Geoffrey M
authors: GM
authors: Habermacher
authors: Qiang
authors: Q
authors: Zhang
authors: Victoria
authors: V
authors: Liu
authors: Larry Y
authors: LY
authors: Wong
authors: David J
authors: DJ
authors: Klumpp
authors: Praveen
authors: P
authors: Thumbikat
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018899:CpG Islands / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D027383:Papillomaviridae / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology / Q000821:virology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D018139:Simplexvirus / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D007770:L-Lactate Dehydrogenase