Deoxycholic acid suppresses p53 by stimulating proteasome-mediated p53 protein degradation

Bile acids, principally deoxycholic acid (DCA), have been implicated in the promotion of colon tumorigenesis in both animals and humans, Increasing ev idence suggests that bile acids may exert their tumor promoting activity by modulating intracellular signaling and altering gene expression. In this s tudy we have investigated the effect of bile acids on the tumor suppressor p53 using the human colon tumor cell line HCT116, which retains the wild-ty pe p53 gene and functional p53 signaling in response to DNA damage. We foun d that exposure of the cells to elevated concentrations of DCA suppressed a ccumulation of p53 protein as well as p53 transactivation and impaired the p53 response of the cells to DNA damaging agents, such as ionizing radiatio n. Neither ursodeoxycholic acid, a putative chemopreventive agent, nor chol ic acid, which is biologically inert, had any effect on p53 protein level a nd transactivation activity. Further examination revealed that instead of i nhibition, DCA induced p53 mRNA in a dose-dependent manner, indicating that the inhibitory effect of DCA on p53 protein is mediated by a post-transcri ptional mechanism, Both lactacystin, a specific inhibitor of the 26S protea some, and leptomycin B, a specific inhibitor of the nuclear export protein CRM1, could block the effect that DCA had on p53 protein levels, suggesting that DCA suppressed p53 by stimulating the process of proteasome-mediated degradation of p53, Significantly, blocking extracellular signal-regulated kinase (ERK) signaling, but not protein kinase C (PKC), blunted suppression by DCA of p53 protein levels and transactivation activity, suggesting that DCA suppressed p53, in part, by stimulating the ERK signaling pathway. Bot h ERK and PKC signaling have been previously demonstrated to be stimulated by DCA, These results suggest a novel signaling mechanism of bile acids tha t may play an important role in colon tumor promotion mediated by bile acid s.