• bile acids
• colorectal cancer
• high-fat diet
• intestinal flora
• tumorigenesis

• Bile acids
• Gastric cancer
• Gastric juice
• Gut microbiome
• Histidine decarboxylase
• LC-MS/MS

• Bile Acids and Salts/analysis
• Bile Acids and Salts/metabolism
• Chromatography, Liquid/methods
• Disease Progression
• Gastric Juice/metabolism
• Histamine/analysis
• Histamine/metabolism
• Histidine/analysis
• Histidine/metabolism
• Humans
• Metaplasia/metabolism
• Metaplasia/pathology
• Precancerous Conditions/metabolism
• Precancerous Conditions/pathology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Tandem Mass Spectrometry/methods

• DUBs
• USP2
• cell-cycle arrest
• colorectal carcinoma
• cyclin D1
• lithocholic acid
• non-competitive inhibitor
• ubiquitin-specific peptidase

• Catalytic Domain
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Cyclin D1/antagonists & inhibitors
• Cyclin D1/genetics
• Cyclin D1/metabolism
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• Cyclin-Dependent Kinase Inhibitor p27/metabolism
• Cycloheximide/chemistry
• Cycloheximide/pharmacology
• Down-Regulation/drug effects
• Endopeptidases/chemistry
• Endopeptidases/genetics
• Endopeptidases/metabolism
• G1 Phase Cell Cycle Checkpoints/drug effects
• Glycogen Synthase Kinase 3 beta/metabolism
• HCT116 Cells
• Humans
• Lithocholic Acid/analogs & derivatives
• Lithocholic Acid/pharmacology
• MCF-7 Cells
• Proto-Oncogene Proteins c-akt/metabolism
• RNA Interference
• Signal Transduction/drug effects
• Tumor Suppressor Protein p53/deficiency
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Ubiquitin Thiolesterase

• MC_UP_A500_1020 Medical Research Council
• MC_UU_12016/5 Medical Research Council

Bile acids are cholesterol-derived bioactive lipids that play essential roles in the maintenance of a heathy lifespan. These amphipathic molecules with detergent-like properties display numerous beneficial effects on various longevity- and healthspan-promoting processes in evolutionarily distant organisms. Recent studies revealed that lithocholic bile acid not only causes a considerable lifespan extension in yeast, but also exhibits a substantial cytotoxic effect in cultured cancer cells derived from different tissues and organisms. The molecular and cellular mechanisms underlying the robust anti-aging and anti-tumor effects of lithocholic acid have emerged. This review summarizes the current knowledge of these mechanisms, outlines the most important unanswered questions and suggests directions for future research.

• Apoptosis/drug effects
• Apoptosis/physiology
• Bile Acids and Salts/pharmacology
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• HCT116 Cells
• Humans
• Intracellular Fluid/metabolism
• Membrane Glycoproteins/genetics
• Membrane Glycoproteins/metabolism
• Taurocholic Acid/pharmacology

• Dietary lipids
• Emulsifying agents
• Filtration
• Gastric lipase
• In vitro digestion
• Micellarization
• Transfer of carotenoids to mixed micelles

• Apoptosis
• Bile acids
• Cell death
• Chemotherapy
• Cytotoxicity
• Extracellular
• In vitro
• Lithocholic acid
• Mitochondrial membrane permeability
• Prostate cancer

• Animal Feed
• Animals
• Bile Acids and Salts/metabolism
• Cholesterol/metabolism
• Gene Expression Regulation
• Glycogen/metabolism
• Hydroxymethylglutaryl CoA Reductases/metabolism
• Inflammation
• Intestinal Mucosa/metabolism
• Lipid Metabolism
• Protein Isoforms/metabolism
• RNA, Messenger/metabolism
• Real-Time Polymerase Chain Reaction
• Salmo salar
• Glycine max/metabolism
• Time Factors
• Transcription, Genetic
• Transcriptome
• Up-Regulation

Aging is one of the major risk factors of cancer. The onset of cancer can be postponed by pharmacological and dietary anti-aging interventions. We recently found in yeast cellular models of aging that lithocholic acid (LCA) extends longevity. Here we show that, at concentrations that are not cytotoxic to primary cultures of human neurons, LCA kills the neuroblastoma (NB) cell lines BE(2)-m17, SK-n-SH, SK-n-MCIXC and Lan-1. In BE(2)-m17, SK-n-SH and SK-n-MCIXC cells, the LCA anti-tumor effect is due to apoptotic cell death. In contrast, the LCA-triggered death of Lan-1 cells is not caused by apoptosis. While low concentrations of LCA sensitize BE(2)-m17 and SK-n-MCIXC cells to hydrogen peroxide-induced apoptotic cell death controlled by mitochondria, these LCA concentrations make primary cultures of human neurons resistant to such a form of cell death. LCA kills BE(2)-m17 and SK-n-MCIXC cell lines by triggering not only the intrinsic (mitochondrial) apoptotic cell death pathway driven by mitochondrial outer membrane permeabilization and initiator caspase-9 activation, but also the extrinsic (death receptor) pathway of apoptosis involving activation of the initiator caspase-8. Based on these data, we propose a mechanism underlying a potent and selective anti-tumor effect of LCA in cultured human NB cells. Moreover, our finding that LCA kills cultured human breast cancer and rat glioma cells implies that it has a broad anti-tumor effect on cancer cells derived from different tissues and organisms.

Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.

• Bile acids
• Cancer
• Adenocarcinoma
• Esophagus
• Stomach
• Small intestine
• Pancreas
• Colon
• Apoptosis
• DNA damage

Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.

• bile acids
• colon cancer
• genomic instability

At physiologic concentration in serum, the bile acid sodium deoxycholate (DC) induces survival and migration of breast cancer cells. Here we provide evidence of a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells.

Murine mammacarcinoma 4T1 cells were used in vitro to determine apoptosis and alteration of sphingolipid metabolism by DC, and in vivo to quantify the effect of DC on metastasis.

We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. The metastatic nodes contained slowly dividing cancer cells in immediate vicinity of newly formed blood vessels. These cells were positive for CD44, a marker that has been suggested to be expressed on breast cancer stem cells. In culture, a subpopulation (3 ± 1%) of slowly dividing, CD44⁺ cells gave rise to rapidly dividing, CD44^- cells. DC promoted survival of CD44⁺ cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. Z-guggulsterone, an antagonist of the farnesoid-X-receptor, obliterated this anti-apoptotic effect, indicating that DC increased cell survival via farnesoid-X-receptor. DC also increased the gene expression of the vascular endothelial growth factor receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. The Flk-1 antagonist SU5416 obliterated the reduction of ceramide and apoptosis by DC, indicating that enhanced cell survival is due to Flk-1-induced reduction in ceramide.

Our findings show, for the first time, that DC is a natural tumor promoter by elevating Flk-1 and decreasing ceramide-mediated apoptosis of breast cancer progenitor cells. Reducing the level or effect of serum DC and elevating ceramide in breast cancer progenitor cells by treatment with Z-guggulsterone and/or vascular endothelial growth factor receptor 2/Flk-1 antagonists may thus be a promising strategy to reduce breast cancer metastasis.

Bile acids (BAs) have a long established role in fat digestion in the intestine by acting as tensioactives, due to their amphipathic characteristics. BAs are reabsorbed very efficiently by the intestinal epithelium and recycled back to the liver via transport mechanisms that have been largely elucidated. The transport and synthesis of BAs are tightly regulated in part by specific plasma membrane receptors and nuclear receptors. In addition to their primary effect, BAs have been claimed to play a role in gastrointestinal cancer, intestinal inflammation and intestinal ionic transport. BAs are not equivalent in any of these biological activities, and structural requirements have been generally identified. In particular, some BAs may be useful for cancer chemoprevention and perhaps in inflammatory bowel disease, although further research is necessary in this field. This review covers the most recent developments in these aspects of BA intestinal biology.

• Colitis
• Bile acid absorption
• Colon cancer

• cholestasis
• liver fibrogenesis
• lipid peroxidation
• oxldl
• oxidative stress

• Animals
• Antioxidants
• Cholestasis/metabolism
• Cholestasis/pathology
• Disease Models, Animal
• Jaundice, Obstructive/metabolism
• Jaundice, Obstructive/pathology
• Lipid Peroxidation/physiology
• Lipoproteins, LDL/metabolism
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Male
• Malondialdehyde/analysis
• Oxidative Stress/physiology
• Random Allocation
• Rats
• Superoxide Dismutase/analysis
• Time Factors

• Actins/metabolism
• Bone and Bones/chemistry
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Movement/physiology
• Cell Survival
• Culture Media, Conditioned
• DNA-Binding Proteins/metabolism
• Deoxycholic Acid/chemistry
• Deoxycholic Acid/metabolism
• Female
• Humans
• Lipids/isolation & purification
• Receptors, Cytoplasmic and Nuclear/metabolism
• Transcription Factors/metabolism
• Urokinase-Type Plasminogen Activator/metabolism

• R01 NS-046835 NINDS NIH HHS

• Adenocarcinoma/genetics
• Apoptosis/genetics
• Biomarkers, Tumor/analysis
• Cell Transformation, Neoplastic
• Colonic Neoplasms/genetics
• Electron Transport Complex IV/biosynthesis
• Electron Transport Complex IV/genetics
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Intestinal Mucosa/pathology
• Risk Assessment

• CA23074 NCI NIH HHS
• CA72008 NCI NIH HHS
• P50CA95060-01 NCI NIH HHS

AIM: To investigate the effect of six bile salts: glycocholate (GC), glycochenodeoxycholate (GCDC), glycodeoxycholate (GDC), taurocholate (TC), taurochenodeoxycholate (TCDC), taurodeoxycholate (TDC), and their mixture on cultured human normal esophageal mucosal epithelial cells.

METHODS: Human normal esophageal mucosal epithelial cells were cultured with serum-free keratinocyte medium. 3-[4,5-Dimethylthiaolyl]-2,5-diphenyl-tetrazolium bromide assay was applied to the detection of cell proliferation. Apoptotic morphology was observed by phase-contrast video microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Sub-G1 DNA fragmentations and early apoptotic cells were assayed by flow cytometry (FCM) with propidium iodide (PI) staining and annexin V-FITC conjugated with PI staining. Apoptotic DNA ladders on agarose gel electrophoresis were observed.

RESULTS: Except for GC, GCDC, GDC, TC, TCDC, TDC and their mixture could initiate growth inhibition of esophageal mucosal epithelial cells in a dose- and time-dependent manner. TUNEL and FCM assays demonstrated that the bile salts at 500 μmol/L and their mixture at 1 500 μmol/L induced apoptosis except for GC. The percentage of sub-G1 detected by FCM with PI staining was 83.5% in cells treated with 500 μmol/L TC for 2 h, and 19.8%, 20.4%, 25.6%, 13.5%, and 75.8% in cells treated with 500 μmol/L GCDC, TCDC, GDC, TDC, and 1 500 μmol/L mixture for 24 h, respectively, which were higher than that of the control (1.5%). The percentage was 1.4% in cells with 500 μmol/L GC for 24 h. DNA ladders on agarose gel electrophoresis were seen in cells treated with 500 μmol/L TC for 2 h and 1 500 μmol/L mixture for 24 h.

CONCLUSION: All GCDC, GDC, TC, TCDC, TDC and their mixture can inhibit growth and induce apoptosis of cultured human normal esophageal mucosal epithelial cells, but GC is well tolerated by the cells.

• Bile salts
• Duodenogastroesophageal reflux
• Esophageal mucosal epithelial cells
• Apoptosis

• Apoptosis/drug effects
• Bile Acids and Salts/pharmacology
• Cell Division/drug effects
• Cells, Cultured
• Epithelial Cells/cytology
• Epithelial Cells/drug effects
• Esophagus/cytology
• Humans
• Mucous Membrane/cytology

• Apoptosis/physiology
• Caspase 9
• Caspases/metabolism
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Cytochromes c/metabolism
• Deoxycholic Acid/antagonists & inhibitors
• Deoxycholic Acid/physiology
• HCT116 Cells
• Humans
• Hydrophobic and Hydrophilic Interactions
• Mitochondria/metabolism
• Ursodeoxycholic Acid/pharmacology

AIM: To explore the effect of six bile salts, including glycoc-holate (GC), glycochenodeoxycholate (GCDC), glycodeoxy-cholate (GDC), taurocholate (TC), taurochenodeoxycholate (TCDC), taurodeoxycholate (TDC), and two bile acids including cholic acid (CA) and deoxycholic acid (DCA) on esophageal cancer Eca109 cell line.

METHODS: Eca109 cells were exposed to six bile salts, two bile acids and the mixed bile salts at different concentrations for 24-72 h. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to detect the cell proliferation. Apoptotic morphology was observed by phase-contrast video microscopy and deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Sub-G1 DNA fragmentations and early apoptosis cells were assayed by flow cytometry (FCM) with propidium iodide (PI) staining and annexin V-FITC conjugated with PI staining. Apoptosis DNA ladders on agarose were observed. Activation of caspase-3 was assayed by FCM with FITC-conjugated monoclonal rabbit anti-active caspase-3 antibody and expressions of Bcl-2 and Bax proteins were examined immunocytochemically in 500 μmol/L-TC-induced apoptosis cells.

RESULTS: Five bile salts except for GC, and two bile acids and the mixed bile salts could initiate growth inhibition of Eca109 cells in a dose- and time-dependent manner. TUNEL, FCM, and DNA ladder assays all demonstrated apoptosis induced by bile salts and bile acids at 500 μmol/L, except for GC. Early apoptosis cell percentages in Eca109 cells treated with GCDC, GDC, TC, TCDC, TDC, CA at 500 μmol/L for 12 h, DCA at 500 μmol/L for 6 h, and mixed bile salts at 1 000 μmol/L for 12 h were 7.5%, 8.7%, 14.8%, 8.9%, 7.8%, 9.3%, 22.6% and 12.5%, respectively, all were significantly higher than that in control (1.9%). About 22% of the cell population treated with TC at 500 μmol/L for 24 h had detectable active caspase-3, and were higher than that in the control (1%). Immunocytochemical assay suggested that TC down-regulated Bcl-2 protein level and up-regulated Bax protein level.

CONCLUSION: GCDC, GDC, TC, TCDC, TDC, CA and DCA, except for GC, can inhibit growth and induce apoptosis of esophageal cancer Eca109 cells. Activation of caspase-3, decreased Bcl-2 protein and increased Bax protein are involved in TC-induced apoptosis of Eca109 cells.

• Bile salts
• Esophageal cancer cells
• Proliferation
• Apoptosis

• Apoptosis/drug effects
• Bile Acids and Salts/pharmacology
• Caspase 3
• Caspases/metabolism
• Cell Division/drug effects
• Cell Line, Tumor
• Enzyme Activation
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/physiopathology
• Humans
• Proto-Oncogene Proteins c-bcl-2/metabolism