title: Nuclear factor-kappaB/p65 (Rel A) is constitutively activated in human prostate adenocarcinoma and correlates with disease progression.
abstract: Aberrant nuclear factor-kappaB (NF-kappaB) activation has been implicated in the pathogenesis of several human malignancies. In this study, we determined whether NF-kappaB is constitutively activated in human prostate adenocarcinoma, and, if so, whether increased NF-kappaB activation and its binding to DNA influence tumor progression. Using tissue samples obtained during transurethral prostatic resection and paraffin-embedded sections of benign and cancer specimens, we determined the nuclear expression of NF-kappaB/p65 and NF-kappaB/p50, cytoplasmic expression of IkappaBalpha, its phosphorylation, and expression of NF-kappaB-regulated genes, specifically Bcl2, cyclin D1, matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF). A progressive increase in the expression of NF-kappaB/p65 (but not of p50) was observed in cancer specimens compared to benign tissue, which correlated with increasing levels of IkappaBalpha and its phosphorylation. NF-kappaB DNA-binding activity increased with increasing tumor grade and the binding complex mainly consisted of NF-kappaB/p65-p50 heterodimers. Immunohistochemical analysis showed enhanced nuclear staining for NF-kappaB/p65 in both high-grade (P <.0001) and low-grade (P <.003) cancer specimens, compared to benign tissue. The nuclear levels of NF-kappaB/p65 correlated with concurrent increase in cytosolic levels of IkappaBalpha along with NF-kappaB-dependent expression of Bcl2, cyclin D1, MMP-9, and VEGF. These results demonstrate that NF-kappaB/p65 is constitutively activated in human prostate adenocarcinoma and is related to tumor progression due to transcriptional regulation of NF-kappaB-responsive genes.
authors.affiliation: Department of Urology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Shukla
authors.forename: Gregory T
authors.initials: GT
authors.lastname: MacLennan
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Jigar
authors.initials: J
authors.lastname: Patel
authors.forename: Susan R
authors.initials: SR
authors.lastname: Marengo
authors.forename: Martin I
authors.initials: MI
authors.lastname: Resnick
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D019938:Cyclin D1 / Q000235:genetics; D017931:DNA Primers; D019281:Dimerization; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051996:Transcription Factor RelA; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; D020780:Matrix Metalloproteinase 9