Glycochenodeoxycholic acid promotes proliferation of intestinal epithelia via reduction of cyclic AMP and increase in H2AX phosphorylation after exposure to γ-rays.
Bile acids (BAs) are considered to be promotive factors in colorectal carcinogenesis. We investigated whether BAs in the cellular environment influence proliferation of intestinal epithelial cell lines. Some BAs induced proliferation in several epithelial cell lines. In the proliferation assay, significant increases in IEC-6 cell proliferation were observed in response to glycodeoxycholic acid or glycochenodeoxycholic acid (GCDCA). Among the glycine-conjugated derivatives of BAs, especially GCDCA reduced cAMP production in IEC-6 cells. Pertussis toxin completely inhibited the GCDCA-induced increase in IEC-6 proliferation, suggesting GCDCA-induced proliferation required Gαi activation and cAMP reduction. Treatment with 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, also suppressed GCDCA-induced IEC-6 proliferation. We confirmed an increase in MEK1/2 phosphorylation in GCDCA-treated IEC-6 cells, and inhibition of MEK1/2 by U0126 clearly suppressed GCDCA-induced IEC-6 cell proliferation. A significant increase was observed in the phosphorylation of histone H2AX in GCDCA-treated IEC-6 cells after exposure to γ-rays. Cell cycle analysis revealed that GCDCA increased the proportion of cells in S phase only after γ-ray exposure. These results indicate that glycine-conjugated BAs in the cellular environment are potent inducers of cell proliferation accompanied by genomic instability in intestinal epithelia.
Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan. zuka@chem.agr.hokudai.ac.jp
Satoshi
S
Ishizuka
Maiko
M
Shiwaku
Masahito
M
Hagio
Takuya
T
Suzuki
Tohru
T
Hira
Hiroshi
H
Hara
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D005720:Gamma Rays / Q000009:adverse effects; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D000242:Cyclic AMP; D005999:Glycochenodeoxycholic Acid; D006657:Histones; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated