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

Abstract

Bile acids, principally deoxycholic acid (DCA), have been implicated in the promotion of colon tumorigenesis in both animals and humans. Increasing evidence suggests that bile acids may exert their tumor promoting activity by modulating intracellular signaling and altering gene expression. In this study 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-type p53 gene and functional p53 signaling in response to DNA damage. We found that exposure of the cells to elevated concentrations of DCA suppressed accumulation of p53 protein as well as p53 transactivation and impaired the p53 response of the cells to DNA damaging agents, such as ionizing radiation. Neither ursodeoxycholic acid, a putative chemopreventive agent, nor cholic acid, which is biologically inert, had any effect on p53 protein level and transactivation activity. Further examination revealed that instead of inhibition, DCA induced p53 mRNA in a dose-dependent manner, indicating that the inhibitory effect of DCA on p53 protein is mediated by a post-transcriptional mechanism. Both lactacystin, a specific inhibitor of the 26S proteasome, 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. Both ERK and PKC signaling have been previously demonstrated to be stimulated by DCA. These results suggest a novel signaling mechanism of bile acids that may play an important role in colon tumor promotion mediated by bile acids.

Taurocholic acid metabolism by gut microbes and colon cancer

“…93 In addition, DCA can activate proteosomal degradation of the tumor suppressor p53 selecting for cells resistant to apoptosis in spite of DNA damage. 94 Taken together, diets high in animal protein and fat appear to promote colon carcinogenesis by selecting for bacteria capable of converting primary host bile acids to toxic, tumor-promoting secondary bile acids. Epidemiological, animal models, in vitro cell culture studies converge on DCA in particular as a metabolite whose serum levels correlate with disease and whose membrane-perturbing and activation of cellular signaling pathways associated with cell proliferation and apoptosis provide mechanisms for long term environmental risk of neoplasia.…”

Intestinal bile acid physiology and pathophysiology

“…Thus, DCA has genotoxic effects, which are believed to be secondary to induction of oxidative stress in the cell [74] , and suppresses the p53 response to DNA damage, an action that is at least partly dependent on ERK signaling [75] . Moreover, inhibition of BRCA-1 by relatively high DCA concentrations contributes to defective DNA repair [76] .…”

Cancer Chemoprevention by Targeting Proteasomal Degradation

“…There is ample evidence that activation of the proteasome may contribute to the carcinogenic process. The bile acid deoxycholic acid is reported to stimulate proteasome-mediated degradation of p53 resulting in impaired p53 transactivation and response to DNA damage (10). Many publications deal with the inhibition of the proteasome as a cancer chemotherapeutic mechanism.…”

“…p21 and p27 (inhibitors of cell cycle progression), Rb and p53 (tumor suppressors), and inhibitor B are all substrates for the proteasome. Inhibition of the degradation of these substrates would result in the accumulation of proteins that are negative regulators of the cell cycle and cell proliferation and would induce apoptosis (10). Inhibition of the proteasome by green tea polyphenol (-)epigallocatechin-3-gallate could also result in increased levels of the tumor suppressor genes p53, pRB, p21, and Bax, any of which may inhibit cell proliferation and/or induce apoptosis, and this has also been proposed as the cancer prevention mechanism (12).…”