The toll-like receptor pathway: A novel mechanism of infection-induced carcinogenesis of prostate epithelial cells

Shilajit D. Kundu, Chung Lee, Benjamin K. Billips, Geoffrey M. Habermacher, Qiang Zhang, Victoria Liu, Larry Y. Wong, David J. Klumpp, Praveen Thumbikat*

*Corresponding author for this work

Research output: Contribution to journalArticle

104 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)223-229
Number of pages7
JournalProstate
Volume68
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • Epithelia
  • Infection
  • Proliferation
  • Prostate
  • Prostatitis

ASJC Scopus subject areas

  • Oncology
  • Urology

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