UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) is a highly reactive free radical that modulates tumorigenesis through its ability to regulate cell proliferation, cell death, migration and angiogenesis. Although the role of NO has been well studied in inflammatory cells, much less is known about the regulation of NO production in epithelial cells. We demonstrated that in intestinal epithelial cells the expression of inducible NO synthase (iNOS), the critical enzyme in the synthesis of NO, is synergistically stimulated by bacterial lipopolysaccharide (LPS) and interferon gamma (IFNgamma) or by the combination of tumor necrosis factor (TNF) and IFNgamma at the transcriptional level. Expression of iNOS and the production of NO in response to LPS/IFNgamma were significantly increased upon induction of oncogenic K-Ras, underlying frequently elevated expression of iNOS in colon cancer. Silencing of STAT1, a major transcription factor involved in signaling by IFNgamma, or pharmacological inhibition of JAKs, kinases that phosphorylate STATs, prevented the induction of iNOS and the production of NO in response to stimulation of cells with LPS/IFNgamma or TNF/IFNgamma, underscoring the importance of the intact JAK/STAT signaling in the regulation of iNOS expression in intestinal epithelial cells. Butyrate, a histone deacetylase (HDAC) inhibitor and a dietary chemopreventive agent, decreased NO production in macrophages and in intestinal myofibroblasts, consistent with its anti-inflammatory activity. In contrast, in intestinal epithelial cells, butyrate significantly enhanced the expression of iNOS and the production of NO in response to treatment with LPS/IFNgamma. Despite the fact that, like butyrate, three structurally unrelated inhibitors of HDAC activity, trichostatin A, suberoylanilide hydroxamic acid, and apicidin, induced acetylation of H3 and H4 in epithelial cells, they failed to increase the production of NO, demonstrating that butyrate regulates NO production in epithelial cells in an HDAC-independent manner. The ability of butyrate to regulate the production of NO in a variety of cell types is likely to underlie its potent chemopreventive and anti-inflammatory activity.
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PMID:Essential role of the JAK/STAT1 signaling pathway in the expression of inducible nitric-oxide synthase in intestinal epithelial cells and its regulation by butyrate. 1725 Nov 86

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables such as broccoli. This anticarcinogen was first identified as a potent inducer of Phase 2 enzymes, but evidence is mounting that SFN acts through other cancer chemopreventive mechanisms. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells and prostate epithelial cells, namely the inhibition of histone deacetylase (HDAC). In the present investigation, we sought to test whether SFN also might inhibit HDAC activity in vivo. When consumed in the diet at an average daily dose of 7.5 mumol per animal for 21 days, SFN suppressed the growth of human PC-3 prostate cancer cells by 40% in male nude mice. There was a significant decrease in HDAC activity in the xenografts, as well as in the prostates and mononuclear blood cells (MBC), of mice treated with SFN, compared to controls. There also was a trend towards increased global histone acetylation in the xenografts, prostates, and MBC. In human subjects, a single dose of 68 g BroccoSprouts inhibited HDAC activity significantly in peripheral blood mononuclear cells (PBMC) 3 and 6 hrs following consumption. These findings provide evidence that one mechanism through which SFN acts as a cancer chemopreventive agent in vivo is through the inhibition of HDAC activity. Moreover, the data suggest that HDAC activity in PBMC may be used as a biomarker for assessing exposure to novel dietary HDAC inhibitors in human subjects.
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PMID:Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. 1725 30

The short fatty acid, butyrate, which is produced by intestinal anaerobic bacteria in the colon, has inhibitory activity on histone deacetylases (HDACs). Treatment of the human colon cancer cell line, LS174T, with 1-2 mM sodium butyrate stimulated MUC2 mucin production, as determined by histological PAS staining of carbohydrate chains of mucin, and confirmed at the protein and mRNA levels by immunoblotting with anti-MUC2 antibody and real-time RT-PCR, respectively. Increases in acetylated histone H3 in the LS174T cells treated with butyrate suggest inhibition of HDACs in these cells. Butyrate-stimulated MUC2 production in the LS174T cells was inhibited by the MEK inhibitor, U0126, implicating the involvement of extracellular signal-regulated kinase (ERK) cascades in this process. Proliferation of the LS174T cells was inhibited by butyrate treatment. Although apoptotic nuclear DNA fragmentation could not be detected, cell-cycle arrest at the G0/G1 phase in the butyrate-treated cells was demonstrated by flow cytometry. Thus butyrate, an HDAC inhibitor, inhibits proliferation of LS174T cells but stimulates MUC2 production in individual cells.
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PMID:The short chain fatty acid, butyrate, stimulates MUC2 mucin production in the human colon cancer cell line, LS174T. 1737 66

The histone deacetylase (HDAC) inhibitors are an exciting new class of drugs that are targeted as anti-cancer agents. These compounds can induce growth arrest, apoptosis, and/or terminal differentiation in a variety of cancers. The inhibition of HDACs shifts toward hyper-acetylation, thereby driving transcriptional activation. In present study, HDAC inhibitor apicidin was used to elucidate the effect on expression of cell cycle related proteins and the molecular mechanism for transcriptional regulation of cyclin D3 in response to HDAC inhibitors in human colon cancer cells. We found that apicidin increases the transcriptional activity of cyclin D3 gene, which results in accumulation of cyclin D3 mRNA and protein. Apicidin-induced cyclin D3 expression is mediated by Sp1 sites within the cyclin D3 promoter. Apicidin-mediated cyclin D3 expression is attenuated by rottlerin, a specific protein kinase C-delta (PKC-delta) inhibitor, but not mitogen-activated protein kinases (MAPKs) inhibitors. Furthermore, suppression of PKC-delta expression by transfection with its siRNA prominently attenuated apicidin-induced cyclin D3 expression. These results indicate that the cyclin D3 induction caused by apicidin was associated with PKC-delta signaling pathway not MAPKs signaling pathways. Taken together, these results suggest that the activation of cyclin D3 transcription by HDAC inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of PKC-delta.
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PMID:Expression of cyclin D3 through Sp1 sites by histone deacetylase inhibitors is mediated with protein kinase C-delta (PKC-delta) signal pathway. 1740 53

The MAP kinase pathway inhibitor U0126 in combination with butyrate promotes differentiation in some colon cancer cell lines. We examined several inhibitors of histone deacetylase (HDAC) in combination with U0126 and other protein kinase inhibitors to see if these effects are general properties of HDAC inhibitors or butyrate alone. Alkaline phosphatase and peptidase activities were examined as markers for cellular differentiation in the human colon cancer cell lines Caco-2 and HT29 and the minimally transformed NCM460. Several HDAC inhibitors caused greater increases of alkaline phosphatase in the cancer cells than in NCM460, in which butyrate was the only HDAC inhibitor that caused a consistent increase. Unlike the JNK and PKC inhibitors examined, the MEK 1/2 inhibitor U0126 induced alkaline phosphatase activity in Caco-2 as a single agent and caused additive effects with HDAC inhibitors. The PI-3 kinase inhibitor LY294002 had little effect alone but enhanced the response of most HDAC inhibitors as did the raf inhibitor GW5074. In addition to butyrate, several HDAC inhibitors can induce differentiation in colon cancer cells and the responses may be enhanced by U0126, GW5074 and LY294002.
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PMID:Induction of differentiation of colon cancer cells by combined inhibition of kinases and histone deacetylase. 1746 97

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumab-induced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21(+/+) cells but not in the HCT116 p21(-/-) cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab.
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PMID:Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels. 1763 11

Hedgehog-interacting protein (HHIP) was identified as a putative antagonist of the Hh pathway and as a target of Hh signalling. Our aim was to clarify the expression profiles and epigenetic alterations of the HHIP gene in gastrointestinal cancer. The expression and promoter epigenetic status of HHIP in cancer cell lines and freshly resected gastrointestinal cancer tissues were examined using RT-PCR, tissue microarray analysis, methylation-specific PCR, and chromatin immunoprecipitation assay. Cells were treated with the demethylating agent 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor trichostatin A. WST-8 assays and in vitro invasion assays after treatment with HHIP-specific siRNA were performed. HHIP expression levels were reduced in most of the gastrointestinal cancer cell lines and in a certain subset of cancer tissues, and these were correlated with promoter hypermethylation. A heterochromatic structure characterized by neither acetylated H3 nor acetylated H4, and histone H3 lysine 9 hypermethylation and histone H3 lysine 4 hypomethylation was observed in cancer cells in which the HHIP gene was aberrantly silenced. On the other hand, overexpression of the HHIP gene was also found in some cancer tissues and there were significant correlations between protein expression levels of HHIP and those of Sonic hedgehog (Shh), Indian hedgehog, Patched, and glioma-associated oncogene homologue-1. An association was found between lymph node metastasis and HHIP silencing in colorectal cancer tissues with strong Shh expression and between advanced TNM stage and HHIP silencing in diffuse-type gastric cancer tissues with strong Shh expression. Down-regulation of HHIP expression by siRNA resulted in a significant increase in colon cancer cell growth and invasion in vitro. Silencing of the HHIP gene due to hypermethylation and chromatin remodelling appears to be frequently involved in gastrointestinal tumourigenesis.
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PMID:Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer. 1772 92

An immunohistochemical analysis of human colorectal adenocarcinomas showed that cancer cells express widely varying levels of HDAC3. The SW480 colon cancer cell line was found to express high levels of HDAC3 compared to other colon cancer cell lines. p21 was poorly induced in SW480 cells relative to the lower HDAC3-expressing HT-29 cells. RNAi-induced reduction of HDAC3 in SW480 cells increased their constitutive, butyrate-, TSA-, and TNF-alpha-induced expression of p21, but did not cause all the gene expression changes induced upon general histone deacetylase (HDAC) inhibition. SW480 cells with lower HDAC3 expression appeared to be poised for gene expression responses with increased histone H4-K12 acetylation, but not K5, K8, or K16 acetylation. Even though p21 was readily activated in HT29 cells, HDAC3 siRNA nonetheless stimulated p21 expression in these cells to a greater degree than HDAC1 and HDAC2 siRNA. SW480 cells with lower HDAC3 levels displayed an enhanced cell cycle arrest and growth inhibition by butyrate, but without changes in apoptosis or sensitivity to chemotherapeutic agents. As reported for other colon cancer cell lines, butyrate induced the rapid downregulation of the secretory cell differentiation markers mucin 2 and intestinal trefoil factor in SW480 cells. Interestingly, selective HDAC3 inhibition was sufficient to downregulate these genes. Our data support a central role for HDAC3 in regulating the cell proliferation and differentiation of colon cancer cells and suggest a potential mechanism by which colon cancers may become resistant to luminal butyrate.
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PMID:HDAC3 overexpression and colon cancer cell proliferation and differentiation. 1784 19

COLO 205 colon adenocarcinoma cells are highly resistant to extrinsic apoptosis induced by immunomodulatory cytokines. One of the antiapoptotic mechanisms is the expression of cFLIP protein, which inhibits TNF-alpha-induced cell death. The use of metabolic inhibitors, such as sodium butyrate (NaBt), the potent repressor of histone deacetylase, sensitizes tumor cells to TNF-alpha-mediated apoptosis. The Western-blot analysis revealed that in COLO 205 cells the susceptibility to apoptogenic stimuli results from time-dependent reduction in cFLIP(L) protein assembled with DISC complex. At the same time, the level of transmembrane TNF-alpha receptor 1 (TNF-R1) was elevated which is consistent with the exaggerated rate of cell death. Since preincubation of COLO 205 cells with N-acetyl-L-cysteine (NAC), or sodium ascorbate (ASC) did not protect cells from combined NaBt- and TNF-alpha-induced apoptosis, we concluded that deletion of cancer cells is not evoked by oxidative stress. Our results suggest that the combination of TNF-alpha with NaBt targets antiapoptotic protein(s) and may provide efficient and non-toxic treatment of colon cancer.
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PMID:Sodium butyrate-dependent sensitization of human colon adenocarcinoma COLO 205 cells to TNF-alpha-induced apoptosis. 1790 92

Colon cancer remains a significant global health concern. The impact of specific dietary components on colon tissue likely depends on a host of genomic processes that influence the growth, development, and differentiation of the epithelial cells at the colon crypt surface, where the balance between proliferation and differentiation is maintained possibly through the Wnt (beta-catenin/T-cell factor) signaling pathway. A loss of balance caused by either genetic mutations or environmental factors such as dietary habits can modulate the risk for the formation of aberrant crypt foci and ultimately the development of colon cancer. Evidence exists that butyrate reduces the number and the size of aberrant crypt foci in the colon. Butyrate is a natural histone deacetylase inhibitor as well as a molecule involved with enhanced TGF-beta-induced SMAD3 phosphorylation, increased IFN-gamma-mediated apoptosis, and altered expression of the intestinal muc2 gene that is responsible for mucin synthesis. Other dietary components, such as vitamin D and (n-3) fatty acids, may regulate proliferative properties of colon progenitor cells as well as the differentiation of subcellular lineages. Although these findings are intriguing, there are uncertainties that remain to be resolved including the optimal exposure needed to bring about an effect, the appropriate timing of administration, and if nutrient-nutrient and nutrient-gene interactions determine the overall response. The expanded use of high-throughput technologies, knowledge about the expression of genes and protein fingerprints, and metabolomic profiling will assist in addressing these issues and ultimately in determining the physiological significance of bioactive food components as cancer protectants.
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PMID:Dietary modulation of colon cancer risk. 1795 6

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