Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Histone deacetylase (HDAC) inhibitors are showing promise as treatment for a variety of human cancers, but their precise mechanism of action has not been elucidated. We examined the effects of the HDAC inhibitor butyrate on colon cancer cells, focusing on its effect on the cell cycle promoter cyclin B(1). In HT-29 cells, sodium butyrate-mediated growth inhibition is associated with a marked decrease in cyclin B(1) mRNA levels. The decrease in cyclin B(1) occurred in a delayed fashion (at 24 h), is completely blocked by concomitant treatment with protein synthesis inhibitors, and appears to be dependent on changes in transcription. Cyclin B(1) repression is linked to the differentiation process in colon cancer cells, not merely with growth arrest. The mechanism of cyclin B(1) repression by butyrate requires prolonged histone hyperacetylation and is at least partly dependent on p21 expression. In fact, p21/WAF-1 appears to directly repress a minimal cyclin B(1) promoter (-90 bp), a process that can be mediated by the amino-terminal portion of the p21 protein. These findings highlight key molecular mechanisms by which HDAC inhibitors mediate their beneficial effects on human cancer cells.
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PMID:The histone deacetylase inhibitor butyrate downregulates cyclin B1 gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells. 1616 80

Bone morphogenetic proteins (BMPs) regulate cell differentiation, proliferation, and apoptosis through a canonical SMAD signaling cascade. Absence of BMP signaling causes the formation of intestinal juvenile polyps in the colon cancer-prone syndrome familial juvenile polyposis. As sporadic colon cancers appear to have intact BMP signaling, we evaluated if K-RAS, driving a mitogenic pathway frequently activated in colon cancer, negatively affects BMP growth suppression. We treated non-tumorigenic but activated RAS/ERK FET cells with BMP2, and in combination with pharmacological or genetic inhibition of RAS/ERK, examined BMP-SMAD signaling, transcriptional activity, and cell growth, and also assessed p21(WAF1) mRNA, transcriptional activation, and protein levels. BMP2 increased nuclear phospho-SMAD1 2-fold, which increased another 2-3 fold when RAS/ERK was inhibited. BMP2 increased BMP-specific SMAD transcriptional activity 2-fold over control and decreased cell growth, but inhibition of RAS/ERK further enhanced BMP-specific transcriptional activity by an additional 1.5-2 fold and enhanced growth suppression by 20%. BMP-induced growth suppression is mediated in part by p21(WAF1), not by transcriptional upregulation but by improved p21 protein stability, which is inhibited by RAS/ERK. In colon cancer cells, BMP-SMAD signaling and growth suppression is facilitated by p21(WAF1) but modulated by oncogenic K-RAS to reduce the growth suppression directed by this pathway.
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PMID:BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK. 1731 1

The potential chemopreventive properties of the crude extract of Onopordum cynarocephalum were evaluated. Growth inhibition was investigated in FHs74Int human normal intestinal cells and ModeK mouse normal intestinal cell line and in two human colon cancer cells HCT-116 (p53+/+) and HT-29 (p53+/-). The extract was not cytotoxic to FHs74Int cells at concentrations 2-fold higher than the IC50 of HCT-116 cells. The extract inhibited dose-dependently the growth of HCT-116 cells (IC50=0.18 mg/ml) to a greater extent than HT-29 cells (IC50=1.8 mg/ml). The p53 wild-type HCT-116 cells were more sensitive than p53 mutant HT-29 cells to the pro-apoptotic effects of the plant extract; five times lower concentrations were needed to induce apoptosis in HCT-116 cells. Apoptosis induction by the extract was associated with an increase in the expression of pro-apoptotic proteins such as p53 and Bax, and a significant inhibition of the anti-apoptotic protein Bcl-2. Significant decrease in cyclin D1 protein and increase in p21 protein was observed in extract-treated HCT-116 cells. In vivo, the crude extract injected intra-peritoneally reduced the number of tumors by 64% (p<0.0001) and decreased the mean size of aberrant crypt foci in the DMH model of colon cancer. These data collectively suggest that O. cynarocephalum has potential anti-colon cancer effects.
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PMID:Onopordum cynarocephalum induces apoptosis and protects against 1,2 dimethylhydrazine-induced colon cancer. 1748 13

Sulindac has been reported to be effective in suppressing tumor growth through the induction of p21WAF1/cip1 in human, animal models of colon cancer and colon cancer cells. In this study, we treated human breast cancer cell line MCF-7 and lung cancer cell line A549 as well as colon cancer cell line SW620 with sulindac to observe the effects of sulindac in other tissue sites. In all cell lines, proliferation was significantly inhibited by sulindac after 24 and 72 h of treatment. Apoptosis was induced by sulindac in both lung cancer cells and colon cancer cells but was not induced in breast cancer cells. Western blots showed that p21 protein level were induced by sulindac in lung cancer cells and colon cancer cells, but not in breast cancer cells. However, the suppression of beta-catenin, a key mediator of Wnt signaling pathway, was seen in all three cell lines with sulindac administration. Further studies revealed that transcriptional activities of beta-catenin were significantly inhibited by sulindac and that the inhibition was sulindac dosage-dependent. The transcriptional targets of beta-catenin, c-myc, cyclin D1 and cdk 4 were also dramatically downregulated. In conclusion, our data demonstrated that the efficacy of sulindac in the inhibition of cell proliferation (rather than the induction of apoptosis) might be through the suppression of beta-catenin pathway in human cancer cells.
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PMID:Sulindac suppresses beta-catenin expression in human cancer cells. 1829 62

The antitumor activity of extracts of Centaurea ainetensis (C. ainetensis), a plant endemic to Lebanon, was investigated in human colon carcinoma cells. At concentrations that were non-cytotoxic to normal human intestinal epithelial cells, the crude extract inhibited the proliferation of a host of colon-derived cancer cells. The crude extract effect was then investigated in HCT-116 (p53+/+) cells, most sensitive to treatment and was found to cause apoptosis, increase the Bax/Bcl-2 ratio, p53 and p21 protein levels and reduce cyclin B1 proteins. In vivo, the crude extract injected intraperitoneally before the subcutaneous injection of the carcinogen 1,2-dimethylhydrazine, drastically reduced the number of tumors and decreased the mean size of aberrant crypt foci. Further bioassay-guided fractionation of the crude extract resulted in the identification of the bioactive molecule Salograviolide A, a Sesquiterpene Lactone, to which the growth inhibition in colon cancer was linked. Salograviolide A, at non-cytotoxic concentrations to normal human intestinal cells, reduced the growth of colon cancer cell lines. Salograviolide A induced growth inhibition and resulted in an increased preG1 phase and presumably apoptosis induction which was further confirmed by TUNEL. These data support the testing of the C. ainetensis extract and its bioactive molecule, Salograviolide A, in colon cancer treatment.
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PMID:Anti-colon cancer effects of Salograviolide A isolated from Centaurea ainetensis. 1835 73

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active metabolite of vitamin D3, has significant antitumor activity in a broad range of preclinical models of cancer. In this study, we show that the Iroquois homeobox gene 5 (Irx5) is down-regulated by 1,25(OH)2D3 in human prostate cancer samples from patients randomly assigned to receive weekly high-dose 1,25(OH)2D3 or placebo before radical prostatectomy. Down-regulation of Irx5 by 1,25(OH)2D3 was also shown in the human androgen-sensitive prostate cancer cell line LNCaP and in estrogen-sensitive MCF-7 breast cancer cells. Knockdown of Irx5 by RNA interference showed a significant reduction in LNCaP cell viability, which was accompanied by an increase in p21 protein expression, G2-M arrest, and an increase in apoptosis. The induced apoptosis was partially mediated by p53, and p53 protein expression was increased as a result of Irx5 knockdown. Cell survival was similarly reduced by Irx5 knockdown in the colon cancer cell line HCT 116 and in MCF-7 breast cancer cells, each being derived from clinical tumor types that seem to be inhibited by 1,25(OH)2D3. Overexpression of Irx5 led to a reduction of p21 and p53 expression. This is the first report that Irx5 is regulated by 1,25(OH)2D3 in humans and the first report to show that Irx5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells. Irx5 may be a promising new therapeutic target in cancer treatment.
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PMID:The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells. 1851 90

We previously performed a high-throughput screen using real-time noninvasive bioluminescence imaging of p53 transcriptional activity and identified a group of small molecules that trigger p53-like transcriptional responses in p53-deficient tumor cells. Here we further examined the anti-tumor effects of selected compounds in vitro and showed that NSC176327, a derivative of the cytotoxic plant alkaloid ellipticine, exhibited strong anti-neoplastic effect sin wild-type p53, p53-mutant or p53-deficient human colon cancer cells. NSC176327 was more potent at inhibiting tumor cell growth as compared to chemotherapeutic drugs and other ellipticine derivatives and induced cell cycle arrest and apoptosis. Surprisingly, unlike what is observed with the parent compound ellipticine, a DNA damage signaling response was not observed with NSC176327 as evidenced by lack of phosphorylated histone H2AX foci in NSC176327-treated tumor cells. NSC176327 treatment caused a significant increase in p53-activated reporter signal in HCT116, SW620 and HCT116 p53-/- cells and upregulated DR5 and p21 protein expression. NSC176327 treatment also resulted in increased p73 protein expression and knockdown of transactivating isoforms of p73 in HCT116 p53-/- cells showed significant resistance to drug treatment. These results demonstrate an important role of p73 in the anti-tumor effects of NSC176327,and suggest that a close analogue of ellipticine may act by a non-genotoxic mechanism targeting the p53/p73 pathway as compared to the original parent compound that targets the same pathway.
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PMID:Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73. 1910 35

Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention.
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PMID:Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds. 1919 85

The relationship between sphingosine kinase (SPHK), cellular ceramide concentration and chemosensitivity was investigated in human colon cancer cell lines. Among nine colon cancer cell lines, SPHK1 and SPHK2 activity and protein expression was highest in RKO cells and lowest in HCT116 cells. A viability assay revealed that HCT116 cells were sensitive to the effects of oxaliplatin (l-OHP), whereas RKO cells were resistant to those of l-OHP. Treatment with 5microg/ml l-OHP induced a marked time-dependent increase in various ceramides (C16, C24, C24:1) in HCT116 cells but not in RKO cells, as indicated by liquid chromatography/mass spectrometry. The increase in ceramide and caspase activation induced by l-OHP in the sensitive HCT116 cells was abolished by pretreatment with a neutral sphingomyelinase inhibitor, suggesting that the ceramide formation was due to the activation of neutral, rather than acid, sphingomyelinase. In contrast, in l-OHP-resistant RKO cells, treatment with an SPHK inhibitor or SPHK1 and SPHK2 silencing by RNA interference suppressed cell viability and increased caspase activity and cellular ceramide formation after l-OHP treatment. The elevated ceramide formation induced by SPHK inhibition and l-OHP was inhibited by fumonisin B1 but not myriocin, suggesting that ceramide formation was through the salvage pathway. Endogenous phosphorylated Akt levels were much higher in the resistant RKO cells than in the sensitive HCT116 cells. Either SPHK1 or SPHK2 silencing in RKO cells decreased phosphorylated Akt levels and increased p53 and p21 protein levels as well as poly(ADP-ribose) polymerase cleavage in response to l-OHP treatment. These findings indicate that SPHK isoforms and neutral sphingomyelinase contribute to the regulation of chemosensitivity by controlling ceramide formation and the downstream Akt pathway in human colon cancer cells.
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PMID:Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation. 1924 26

DIXDC1 is the human homolog of Ccd1, a recently identified DIX domain containing protein in zebrafish. It is a positive regulator in the Wnt signaling pathway functioning downstream of Wnt and upstream of Axin. Since Wnt pathway activation is correlated with human colon cancer formation and progression, the biological role of DIXDC1 in human colon cancer was examined. In the current study, up-regulation of DIXDC1 protein was detected in human colorectal adenocarcinoma tissues and was found to be correlated well with high cell proliferation index. Ectopic over-expression of DIXDC1 resulted in increased cell proliferation in vitro and accelerated tumorigenesis on nude mice in vivo. We also showed that DIXDC1 promoted G0/G1 to S phase transition concomitantly with up-regulation of cyclin D1 and down-regulation of p21 protein. DIXDC1 over-expression cells showed activation of the PI3K/AKT pathway. Both siRNA knockdown of DIXDC1 and blocking the PI3K pathway using a specific inhibitor caused G1/S phase arrest, as well as down-regulation of cyclin D1 and up-regulation of p21 in DIXDC1 over-expression colon cancer cells. Collectively, this study demonstrates that over-expression of DIXDC1 might target p21 and cyclin D1 to promote colon cancer cell proliferation and tumorigenesis at least partially through activation of the PI3K/Akt pathway.
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PMID:DIXDC1 targets p21 and cyclin D1 via PI3K pathway activation to promote colon cancer cell proliferation. 1957 78


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