title: Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation.
abstract: Consumption of a high-fat diet causes an increase in bile acid deoxycholic acid (DCA) in colon lumen and colon cancer risk, while butyrate, an intestinal microbiota metabolite of dietary fiber, has been shown to exhibit colon cancer-preventive effects. To distinguish these opposing effects of DCA and butyrate (two major metabolites in colon lumen), we examined the effects of physiologically relevant doses of butyrate (0.5-2 mmol/l) and DCA (0.05-0.3 mmol/l) on colon cell proliferation. We hypothesize that butyrate and DCA each modulates the cell cycle and apoptosis via common and distinct cellular signaling targets. In this study, we demonstrated that both butyrate and DCA inhibited cell proliferation by up to 89% and 92% and increased cell apoptosis rate by up to 3.1- and 4.5-fold, respectively. Cell cycle analyses revealed that butyrate led to an increase in G1 and G2 fractions with a concomitant drop in the S-phase fraction, but DCA induced an increase in only G1 fraction with a concomitant drop in the S-phase fraction when compared with the untreated cells. The examination of early cellular signaling revealed that DCA but not butyrate increased intracellular reactive oxygen species, genomic DNA breakage, the activation of ERK1/2, caspase-3 and PARP. In contrast, DCA decreased activated Rb protein level, and butyrate but not DCA increased p21 expression. Collectively, although both butyrate and DCA inhibit colonic cell proliferation, butyrate increases tumor suppressor gene expression, whereas DCA decreases tumor suppressor activation in cell cycle and apoptosis pathways.
authors.affiliation: Agricultural Research Service, Grand Forks Human Nutrition Research Center, United States Department of Agriculture, Grand Forks, ND 58203, USA. Electronic address: huawei.zeng@ars.usda.gov.
authors.forename: Huawei
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Agricultural Research Service, Grand Forks Human Nutrition Research Center, United States Department of Agriculture, Grand Forks, ND 58203, USA.
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Claycombe
authors.affiliation: Department of Biological Sciences, North Dakota State University, Fargo, ND 58108, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Reindl
mesh_terms: D017209:Apoptosis; D002087:Butyrates / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology*; D003840:Deoxycholic Acid / Q000008:administration & dosage*; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D015398:Signal Transduction
chemical_list: D002087:Butyrates; D003840:Deoxycholic Acid
keywords: Apoptosis; Butyrate; Cell cycle; Colon cancer; Deoxycholic acid