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

Area of Science:

• Gastroenterology
• Molecular Biology
• Cancer Research

Background:

• Ursodeoxycholic acid (UDCA) is known to attenuate colon carcinogenesis, but its precise mechanism remains elusive.
• Understanding UDCA's effects on normal intestinal epithelium is crucial for identifying its chemopreventive potential.

Purpose of the Study:

• To investigate the in vivo and in vitro effects of UDCA on normal intestinal epithelial cells.
• To elucidate the molecular mechanisms underlying UDCA's antiproliferative and potential chemopreventive actions.

Main Methods:

• Mice were fed UDCA, and intestinal cell proliferation and gene expression were analyzed.
• The rat intestinal cell line IEC-6 was used as an in vitro model to study UDCA's effects on proliferation and signaling pathways.
• ERK1/ERK2 kinase activity and Insulin Receptor Substrate 1 (Irs-1) gene expression were assessed.

Main Results:

• UDCA feeding reduced mouse intestinal cell proliferation by 50% and suppressed proproliferatory genes, including Irs-1.
• In vitro, UDCA inhibited IEC-6 cell proliferation by inducing sustained ERK1/ERK2 hyperphosphorylation, which blocked EGF and IGF-1 effects.
• This ERK hyperphosphorylation led to Irs-1 transcriptional suppression, both sufficient to inhibit cell proliferation; ERK inhibition abrogated UDCA's effects.

Conclusions:

• UDCA inhibits normal intestinal epithelial cell proliferation via sustained ERK1 kinase hyperphosphorylation, slowing the cell cycle and reducing Irs-1 expression.
• These findings provide new insights into the physiological and chemopreventive roles of UDCA.
• The study identifies novel targets for chemoprevention strategies involving UDCA.