Modulation of p53 expression in cultured colonic adenoma cell lines by the naturally occurring lumenal factors butyrate and deoxycholate.

Abstract

The high incidence of colorectal cancer in Western society is believed to be strongly related to diet. Mutation of the p53 gene is a late event in colorectal carcinogenesis, and thus, the majority of pre-malignant adenomas express wild-type p53. As loss of p53 protein function is an important step in colorectal carcinogenesis, we investigated whether naturally occurring lumenal factors can modulate the expression of p53 in non-tumorigenic human colonic adenoma cell lines. Levels of p53 protein and mRNA were measured in adherent cells which had been incubated with growth-inhibitory concentrations of sodium butyrate (a by-product of dietary fibre fermentation) or sodium deoxycholate (a bile acid) for up to 48 hr. We report that both butyrate and deoxycholate can down-regulate the expression of wild-type and mutant p53. In contrast, incubation for 48 hr with the endogenous inhibitory growth factor TGFbeta1 did not alter p53 protein expression. Thus, in addition to cellular mechanisms which regulate p53 function, such as post-translational stabilisation, nuclear exclusion, negative feedback inhibition of p53 mRNA translation or binding of p53 by cellular proteins, p53 protein levels also may be regulated by changes in the level of p53 gene transcription. Furthermore, we show that lumenal factors are able to affect directly the expression of p53 protein in colonic epithelial cells.