title: Relationship between IL-6/ERK and NF-κB: a study in normal and pathological human prostate gland.
abstract: BACKGROUND
  There is growing evidence that inflammation is a causal factor in cancer, where pro-inflammatory cytokines such as IL-6, IL-1 or TNF-α could induce cellular proliferation by activation of NF-κB. This study focuses on the IL-6/ERK transduction pathway, its relationship with NF-κB, and the consequences of dysregulation in the development of prostate pathologies such as benign prostate hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and prostate cancer (PC).
  
  
  METHODS
  Immunohistochemical and Western blot analyses for IL-6, gp-130, Raf-1, MEK-1, ERK-1, p-MEK, ERK-2, p-ERK, NF-κB/p-50 and NF-κB/p-65 were carried out in 20 samples of normal prostate glands, 35 samples of BPH, 27 samples with a diagnosis of PIN (low-grade PIN or high-grade PIN), and 95 samples of PC (23 with low, 51 with medium and 21 with high Gleason scores).
  
  
  RESULTS
  Immunoreaction to IL-6, gp-130, ERK-1, ERK-2, p-ERK and NF-κB/p50 was found in the cytoplasm of epithelial cells in normal prostate samples; p-MEK was found in the nucleus of epithelial cells; but not expression to Raf-1, MEK-1 and NF-κB/p65. In BPH, all of these proteins were immunoexpressed, while there was increased immunoexpression of IL-6, gp-130, p-MEK, ERK-1, ERK-2 and NF-κB/p50 (cytoplasm). In PC, immunoexpression of IL-6 and gp-130 were similar to that found in BPH; while immunoexpression of Raf-1, MEK-1, p-MEK, ERK-1, ERK-2, p-ERK, NF-κB/p50 (nucleus and cytoplasm), and NF-κB/p65 (nucleus and cytoplasm) was higher than in BPH.
  
  
  CONCLUSIONS
  Translocation of NF-κB to the nucleus in PC and high-grade PIN could be stimulated by the IL-6/ERK transduction pathway, but might also be stimulated by other transduction pathways, such as TNF-α/NIK, TNF/p38, IL-1/NIK or IL-1/p38. Activation of NF-κB in PC could regulate IL-6 expression. These transduction pathways are also related to activation of other transcription factors such as Elk-1, ATF-2 or c-myc (also involved in cell proliferation and survival). PC is a heterogeneous disease, where multiple transduction pathways might alter the apoptosis/proliferation balance. Significant attention should be give to the combination of novel agents directed towards inactivation of pro-inflammatory cytokines than can disrupt tumour cell growth.
authors.affiliation: Department of Cell Biology and Genetics. University of Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Rodríguez-Berriguete
authors.forename: Angela
authors.initials: A
authors.lastname: Prieto
authors.forename: Benito
authors.initials: B
authors.lastname: Fraile
authors.forename: Yosra
authors.initials: Y
authors.lastname: Bouraoui
authors.forename: Fermín R
authors.initials: FR
authors.lastname: de Bethencourt
authors.forename: Pilar
authors.initials: P
authors.lastname: Martínez-Onsurbe
authors.forename: Gabriel
authors.initials: G
authors.lastname: Olmedilla
authors.forename: Ricardo
authors.initials: R
authors.lastname: Paniagua
authors.forename: Mar
authors.initials: M
authors.lastname: Royuela
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011467:Prostate / Q000201:enzymology* / Q000473:pathology*; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; C096335:B59 protein, human; D017027:Protein Tyrosine Phosphatases