Association Between Activation Of Atypical Nf-Kappa B1 P105 Signaling Pathway And Nuclear Beta-Catenin Accumulation In Colorectal Carcinoma

Recent studies have demonstrated that increased expression of coding region determinant-binding protein (CRD-BP) in response to beta-catenin signaling leads to the stabilization of beta-TrCP1, a substrate-specific component of SCF E3 ubiquitin ligase complex, resulting in an accelerated degradation of I kappa B alpha and activation of canonical nuclear factor-kappa B (NF-kappa B) pathway. Here, we show that the noncanonical NF-kappa B1 p105 pathway is constitutively activated in colorectal carcinoma specimens, being particularly associated with beta-catenin-mediated increased expression of CRD-BP and beta-TrCP1. In the carcinoma tissues exhibiting high levels of nuclear beta-catenin the phospho-p105 levels were increased and total p105 amounts were decreased in comparison to that of normal tissue indicating an activation of this NF-kappa B pathway. Knockdown of CRD-BP in colorectal cancer cell line SW620 resulted in significantly higher basal levels of both NF-kappa B inhibitory proteins, p105 and I kappa B alpha. Furthermore decreased NF-kappa B binding activity was observed in CRD-BP siRNA-transfected SW620 cells as compared with those transfected with control siRNA. Altogether, our findings suggest that activation of NF-kappa B1 p105 signaling in colorectal carcinoma might be attributed to beta-catenin-mediated induction of CRD-BP and beta-TrCP1. (C) 2009 Wiley-Liss, Inc.