UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation

Ursodeoxycholic acid (UDCA) attenuates colon carcinogenesis in humans and in animal models by an unknown mechanism. We investigated UDCA effects on normal intestinal epithelium in vivo and in vitro to identify the potential chemopreventive mechanism. Feeding of mice with 0.4% UDCA reduced cell proliferation to 50% and suppressed several potential proproliferatory genes including insulin receptor substrate 1 (Irs-1). A similar transcriptional response was observed in the rat intestinal cell line IEC-6 which was then used as an in vitro model. UDCA slowed down the proliferation of IEC-6 cells and induced sustained hyperphosphorylation of ERK1/ERK2 kinases which completely inhibited the proproliferatory effects of EGF and IGF-1. The hyperphosphorylation of ERK1 led to a transcriptional suppression of the Irs-1 gene. Both, the hyperphosphorylation of ERK as well as the suppression of Irs-1 were sufficient to inhibit proliferation of IEC-6 cells. ERK1/ERK2 inhibition in vitro or ERK1 elimination in vitro or in vivo abrogated the antiproliferatory effects of UDCA. We show that UDCA inhibits proliferation of nontransformed intestinal epithelial cells by inducing a sustained hyperphosphorylation of ERK1 kinase which slows down the cell cycle and reduces expression of Irs-1 protein. These data extend our understanding of the physiological and potentially chemopreventive effects of UDCA and identify new targets for chemoprevention.