Role of Smad proteins in the regulation of NF-κB by TGF-β in colon cancer cells

Nuclear factor kappa B (NF-kappa B) has been implicated in cancer cell survival. We explored the role of the TGF-beta pathway in the regulation of NF-kappa B in colon cancer cells. TGF-beta-1 treatment of the colon adenocarcinoma cell line FET-1, results in ail early increase in I kappa B-alpha phosphorylation that precedes NF-kappa B nuclear translocation and DNA binding activity. Activation of the TGF-beta type I receptor is required for the TGF-beta-mediated activation of NF-kappa B. No activation of NF-kappa B is observed in a Smad4 null cell line, SW480, even though TGF-beta does result in I kappa B-alpha. phosphorylation in these cells. Smad4 restores the TGF-beta-1-mediatcd NF-kappa B activation in SW480 cells. TGF-beta-1 treatment fails to activate NF-kappa B or phosphorylate I kappa B-alpha in FET-1 cells expressing the inhibitory Smad, Smad7. Taken together, these results suggest a role for Smad4 in the transcriptional activation of NF-kappa B, and a direct effect of Smad7 inhibiting I kappa B-alpha phosphorylation rather than through the well-established inhibition of Smad2/3 phosphorylation with subsequent inhibition of the TGF-beta pathway. (c) 2005 Elsevier Inc. All rights reserved.