Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxycholic acid, a colon tumor promoter, was found to bind covalently to DNA and RNA in the presence of methyl linoleate hydroperoxide and ferrous ion. This binding was shown to occur specifically with guanine residues and its covalent nature was demonstrated by analysis of hydrolysates of nucleic acid adducts. These findings are discussed in connection with the increased risk of colon cancer associated with a high fat and meat diet.
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PMID:Activation of deoxycholic acid by the lipid peroxy radical and its covalent binding to nucleic acids. 244 90

Deoxycholic acid (DCA) has long been implicated as tumour-promoting agent in the colon. Polyamines are necessary for cell proliferation, they are accumulated in high amounts in colon cancer cells, and their concentrations in the colonic lumen can reach millimolar levels. The aim of this study was to investigate the effects of physiological DCA concentrations on proliferation and polyamine content in human colon cancer cells (Caco-2) in culture. Over an initial 48 h in culture, DCA stimulated Caco-2 cell proliferation rate three-fold, reaching a maximum with 20 microM DCA. DCA-induced increases in ornithine decarboxylase (ODC) activity corresponded to peak proliferation rates, occurring only during the initial 48 h of cell proliferation. Treatment with low-dose DCA resulted in a two-fold increase in putrescine uptake, first noted after 2 days in culture, but persisting until the cells became confluent (day 5). Both basal and DCA-stimulated putrescine uptake in Caco-2 cells were saturable. Kinetic analysis of the uptake data showed that DCA-stimulated putrescine uptake was due to an increase in the capacity of the putative putrescine transporter, without changes in its affinity, therefore implying an increased number of putrescine transporters in the cell membrane, without change in their structure.
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PMID:Low-dose deoxycholic acid stimulates putrescine uptake in colon cancer cells (Caco-2). 1080 8

Deoxycholate, a bile salt present at high levels in the colonic lumen of individuals on a high-fat diet, is a promoter of colon cancer. Deoxycholate also causes DNA damage. BRCA-1 functions in repair of DNA and in induction of apoptosis. We show that, when cultured cells of colonic origin are exposed to deoxycholate at different concentrations, BRCA-1 expression is induced at a low noncytotoxic concentration (10 microM) but is strongly inhibited at higher cytotoxic concentrations ( > or =100 microM). Indication of phosphorylation of BRCA-1 by deoxycholate (100 microM) at a lower dose was seen by Western blot analysis, whereas, at a higher dose, deoxycholate (200 and 300 microM) caused a complete loss of BRCA-1 expression. We show that BRCA-1 is substantially lower in colon adenocarcinomas from five patients compared with associated non-neoplastic colon tissue from the same patients, suggesting that the loss of BRCA-1 expression contributes to the malignant phenotype. In the non-neoplastic colon tissue, BRCA-1 was localized to the nongoblet cells. Our results imply that reduced expression of BRCA-1 may be associated with carcinoma of the colon.
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PMID:Deoxycholate, an endogenous tumor promoter and DNA damaging agent, modulates BRCA-1 expression in apoptosis-sensitive epithelial cells: loss of BRCA-1 expression in colonic adenocarcinomas. 1292 8

Deoxycholic acid (DCA) has been implicated in colonic carcinogenesis through effects mediated by protein kinase C (PKC) activation. By contrast, ursodeoxycholic acid (UDCA) is reported to reduce colon cancer incidence in ulcerative colitis. The aim of this study was to investigate whether UDCA modulated DCA-induced PKC isoenzyme translocation to its site of activity. HCT116 cells were treated with DCA, UDCA alone or pre-treated with UDCA followed by DCA. Analysis of translocation of endogenous and enhanced green fluorescent protein (EGFP) constructs of PKC isoenzymes was performed. Both DCA and phorbol myristate acetate (PMA) but not UDCA caused translocation of endogenous PKC alpha, epsilon and delta and transfected PKC beta1-, epsilon- and delta-EGFP from cytosol to plasma membrane, reflecting isoenzyme activation. Furthermore, UDCA inhibited DCA-induced translocation of PKC isoenzymes. Inhibition of DCA-induced PKC translocation may be a mechanism for UDCA-mediated chemoprevention of colon carcinogenesis.
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PMID:Ursodeoxycholic acid inhibits translocation of protein kinase C in human colonic cancer cell lines. 1612 20

Apoptosis resistance, a condition favoring genomic instability, is associated with higher risk of colorectal cancer. Deoxycholate (DOC) is a hydrophobic bile salt found in high concentrations in colon cancer patients, and induces apoptosis in cultured colonic cells and ex vivo in colonic biopsies. We showed previously that the chronic exposure of colon cancer cells to increasing concentrations of DOC leads to apoptosis resistance, and the suggested mechanism involves oxidative/nitrosative stress. Nitric oxide (NO) is a key signaling molecule that regulates cell function in a variety of physiologic and pathophysiologic states. In part, NO exerts its actions by S-nitrosylation of target thiols, and several proteins are regulated through this PTM, including the caspases, the main effectors of apoptosis. Here, we performed a proteomics study in the DOC-induced apoptosis-resistant colon cell line, HCT-116RC. Its profile of S-nitrosylated proteins was compared to a control cell line not exposed to DOC. Eighteen differentially S-nitrosylated proteins were identified in the HCT-116RC cell line, 14 of these are novel targets of S-nitrosylation not previously reported. These proteins include cytoskeletal and signaling proteins, metabolic enzymes, chaperones, and redox- and differentiation-related proteins. These results broaden our knowledge of potential signal transduction pathways that may lead to the development of new biomarkers and therapy targets.
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PMID:Identification of S-nitrosylated proteins after chronic exposure of colon epithelial cells to deoxycholate. 1640 23

Deoxycholic acid (DCA) is an endogenous secondary bile acid implicated in numerous pathological conditions including colon cancer formation and progression and cholestatic liver disease. DCA involvement in these disease processes results partly from its ability to modulate signaling cascades within the cell, presumably through both direct receptor activation and general detergent mediated membrane changes. To further explore DCA induced changes in cell signaling, we completed a total synthesis of enantiomeric deoxycholic acid (ent-DCA) from achiral 2-methyl-1,3-cyclopentanedione. Using a modified method of the synthesis of ent-testosterone that proceeds through the (R)-(-)-Hajos-Parrish ketone, we have completed the successful synthesis of ent-DCA in 25 steps with a yield of 0.3% with all stereochemical assignments of the product confirmed by X-ray crystallography. Our studies toward this synthesis also uncovered the methodology for the development of a novel A,B-cis steroidal skeleton system containing a C3-C9 single bond as well as conditions to selectively ketalize the typically less reactive 12-carbonyl in poly-keto A,B-cis androgens. The critical micelle concentration (cmc) of ent-DCA, determined by a dye solubilization method, was identical to the cmc of natural DCA. Toxicity studies toward HT-29 and HCT-116 human colon cancer cell lines demonstrated that ent-DCA had similar effects on proliferation, yet showed a markedly decreased ability to induce apoptosis as compared to natural DCA.
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PMID:Enantiomeric deoxycholic acid: total synthesis, characterization, and preliminary toxicity toward colon cancer cell lines. 1795 46

Deoxycholic acid (DCA) is a secondary bile acid that modulates signalling pathways in epithelial cells. DCA has been implicated in pathogenesis of colon carcinoma, particularly by activation of the protein kinase C (PKC) pathway. Ursodeoxycholic acid (UDCA), a tertiary bile acid, has been observed to have chemopreventive effects. The aim of this study was to investigate the effect of DCA and UDCA on the subcellular localization and activity of PKCeta and its downstream effects on Golgi structure in a colon cancer cell model. PKCeta expression was localized to the Golgi in HCT116 colon cancer cells. DCA induced fragmentation of the Golgi in these cells following activation of PKCeta and its downstream effector protein kinase D (PKD). Pretreatment of cells with UDCA or a glucocorticoid, dexamethasone, inhibited DCA-induced PKCeta/PKD activation and Golgi fragmentation. Knockdown of glucocorticoid receptor (GR) expression using small interfering RNA or inhibition using the GR antagonist mifepristone attenuated the inhibitory effect of UDCA on Golgi fragmentation. Elevated serum and faecal levels of DCA have been previously reported in patients with ulcerative colitis (UC) and colon cancer. Analysis of Golgi architecture in vivo using tissue microarrays revealed Golgi fragmentation in UC and colorectal cancer tissue. We have demonstrated that DCA can disrupt the structure of the Golgi, an organelle critical for normal cell function. Inhibition of this DCA-induced Golgi fragmentation by UDCA was mediated via the GR. This represents a potential mechanism of observed chemopreventive effects of UDCA in benign and malignant disease of the colon.
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PMID:Bile acids modulate the Golgi membrane fission process via a protein kinase Ceta and protein kinase D-dependent pathway in colonic epithelial cells. 2009 83

Bile acids have secretory, motility and antimicrobial effects in the intestine. In patients with bile acid malabsorption the amount of primary bile acids in the colon is increased compared to healthy controls. Deoxycholic acid is affecting the intestinal smooth muscle activity. Chenodeoxycholic acid has the highest potency to affect intestinal secretion. Litocholic acid has little effect in the lumen of intestine compared to both deoxycholic acid and chenodeoxycholic acid. There is no firm evidence that clinically relevant concentrations of bile acids induce colon cancer. Alterations in bile acid metabolism may be involved in the pathophysiology of constipation.
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PMID:Bile acids: short and long term effects in the intestine. 2033 75

We synthesized four cationic bile acid based facial amphiphiles featuring trimethyl ammonium head groups. We evaluated the role of these amphiphiles for cytotoxic activities against colon cancer cells and their membrane interactions by varying charge, hydration and hydrophobicity. The singly charged cationic Lithocholic acid based amphiphile (LCA-TMA1) is most cytotoxic, whereas the triply charged cationic Cholic acid based amphiphile (CA-TMA3) is least cytotoxic. Light microscopy and Annexin-FITC assay revealed that these facial amphiphiles caused late apoptosis. In addition, we studied the interactions of these amphiphiles with model membrane systems by Prodan-based hydration, DPH-based anisotropy, and differential scanning calorimetry. LCA-TMA1 is most hydrophobic with a hard charge causing efficient dehydration and maximum perturbations of membranes thereby facilitating translocation and high cytotoxicity against colon cancer cells. In contrast, the highly hydrated and multiple charged CA-TMA3 caused least membrane perturbations leading to low translocation and less cytotoxicity. As expected, Chenodeoxycholic acid and Deoxycholic acid based amphiphiles (CDCA-TMA2, DCA-TMA2) featuring two charged head groups showed intermediate behavior. Thus, we deciphered that charge, hydration, and hydrophobicity of these amphiphiles govern membrane interactions, translocation, and resulting cytoxicity against colon cancer cells.
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PMID:Deciphering the role of charge, hydration, and hydrophobicity for cytotoxic activities and membrane interactions of bile acid based facial amphiphiles. 2359 Sep 96