title: The chemopreventive agent ursodeoxycholic acid inhibits proliferation of colon carcinoma cells by suppressing c-Myc expression.
abstract: Ursodeoxycholic acid (UDCA) can prevent chemical and colitis-associated colon carcinogenesis by unknown mechanism(s). One of the processes underlying the chemopreventive action could be the inhibition of proliferation by UDCA. To clarify the antiproliferative mechanism of UDCA, we used p53 wt colon carcinoma cell lines HCT8 and HCT116. UDCA-induced inhibition of proliferation was reversible and was associated with a decrease of the S-phase and an increase of G1 phase population, but not with apoptosis or senescence. The treatment suppressed the expression of c-Myc protein and, as a consequence, of several cell cycle regulatory molecules, including CDK4 and CDK6. Using the HCT8 cell line as a model, we show that UDCA suppresses c-Myc at the protein level. The suppression of c-Myc alone or a simultaneous suppression of CDK4 and of CDK6 kinase is sufficient to inhibit cell proliferation. In sum, we identified c-Myc as a primary UDCA target in colon carcinoma cells. The degradation of c-Myc protein decreases the expression of the cell cycle regulators CDK4 and CDK6, which reversibly slows down the cell cycle. The suppression of these proproliferatory molecules is the likely initial mechanism of antiproliferatory action of UDCA on colon cancer cells.
authors.affiliation: Department of Gastroenterology, Charité Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Roser
authors.initials: R
authors.lastname: Peiró-Jordán
authors.forename: Santosh
authors.initials: S
authors.lastname: Krishna-Subramanian
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Hanski
authors.forename: Juliane
authors.initials: J
authors.lastname: Lüscher-Firzlaff
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Christoph
authors.initials: C
authors.lastname: Hanski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D045325:HCT116 Cells; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D014580:Ursodeoxycholic Acid