Ursodeoxycholic acid inhibits interleukin beta 1 and deoxycholic acid-induced activation of NF-[kappa]B and AP-1 in human colon cancer cells

Deoxycholic acid (DCA) has been implicated in colorectal carcinogenesis in humans with effects on proliferation and apoptosis, mediated at least in part by activation of transcription factors nuclear factor kappa B (NF-jB), activator protein 1 (AP-1) and protein kinase C (PKC) enzymes. Ursodeoxycholic acid (UDCA) is reported to reduce the frequency of colonic carcinogenesis in ulcerative colitis patients. Hence, we postulated that it might differ from DCA in its regulation of these transcription factors. The aim of the study was to determine effects of DCA and UDCA on NFjB and AP-1 activation and explore its relationship to PKC. Human colonic tumour cell lines HCT116 were treated with DCA, UDCA, alone or pretreated with UDCA followed by DCA or IL1b. In other experiments, cells were pretreated with PKC inhibitors and then stimulated with DCA and IL-1b or PMA. Gel shift assays were performed on nuclear extracts of the cells for NF-jB and AP-1 analysis. Western blot analyses and immunofluorescence were performed for Rel A (p65) and IjB-a levels on the treated cells. DCA increased NF-jB and AP-1 DNA binding. UDCA did not increase DNA binding of NF-jB and AP-1 and UDCA pretreatment inhibited DCA-induced NF-jB and AP-1 DNA binding. PKC inhibitors blocked DCA-induced NF-jB and AP-1 activation. These results were validated by Western blot analysis for RelA and IjB-a. In conclusion, UDCA did not induce NF-jB and AP-1 DNA binding but also blocked DCA-induced NF-jB and AP-1 activation. These findings suggest a possible mechanistic role for UDCA in blocking pathways thought to be involved in colon carcinogenesis. ' 2005 Wiley-Liss, Inc.