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)

When SW620 colon cancer-derived metastatic cells were exposed to nanomolar concentrations of Taxol, colchicine or (Z)-3,5,4'-trimethoxystilbene (R3), huge aneuploid, polynuclear cells survived the treatment. These cells released considerable amounts of the matrix metalloproteinase matrilysin (MMP-7), and tissue-type plasminogen activator (tPA) into the surrounding culture medium. MMP-7, and other proteolytic enzymes were highly expressed by these cells. In spite of their enormous size, the polyploid cells exhibited a considerable migratory capacity, as was demonstrated by their migration through an artificial basement membrane. While colchicine and R3-treated cells showed an inverse relationship between drug concentration and invasiveness, treatment with Taxol increased the capacity of the SW620 cells to penetrate through the membrane. The invasive capacity was not correlated with the induction and release of proteolytic enzymes. The idea that expression and release of proteolytic enzymes is a fundamental prerequisite of tumour cell invasiveness is generally accepted. The ability of the cells to respond to chemotactic signalling, and the filamentous structures of the cells, together with several cell adhesion factors, which are the basis of cell migration, are prerequisites of invasiveness. These factors are presumably different in the aneuploid cells produced by Taxol, colchicine and R3, and await scrutiny.
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PMID:Polyploidisation of metastatic colon carcinoma cells by microtubule and tubulin interacting drugs: effect on proteolytic activity and invasiveness. 1537 54

It is now becoming clear that matrix metalloproteinases (MMPs) play a key role in tumor development and growth. MMPs are overexpressed in a variety of premalignant tumor tissues, including colorectal adenoma. Little is known about the mechanisms underlying the overexpression of MMPs in adenoma tissues. E1AF, an Ets family transcriptional factor, has been shown to play an important role in the expression of MMPs and cyclooxygenase-2 (COX-2) in advanced colorectal cancers. The aim of this study was to examine the E1AF expression and determine whether it is correlated with the expression of MMPs, COX-2 and inducible nitric oxide synthase (iNOS) in human colorectal adenoma and submucosal cancer (pT1). Using the semi-quantitative RT-PCR, 90 colorectal tumors, including 63 adenomas and 27 cancers (pT1), were analyzed for the expression of E1AF, MMPs, COX-2 and iNOS. Immunohistochemical analysis and in vitro transfection assays were also performed. E1AF mRNA was detected in 43 (47.8%) of the 90 colorectal tumors. E1AF overexpression was significantly correlated with histopathology. E1AF expression was correlated significantly with the expression of MMP-1 and MMP-7. Overexpression of COX-2 and iNOS mRNA expression was observed in 42.2% and 66.7% of the 90 colorectal tumors, respectively. COX-2 was correlated significantly with size, gender, histopathology and E1AF. iNOS was correlated significantly with size, histopathology, E1AF and COX-2. The correlation of E1AF expression with COX-2 and iNOS expression was also demonstrated by immunohistochemistry. Northern blot analysis of transfectants showed the effect of E1AF on COX-2 expression as well as iNOS on E1AF/COX-2 expression in colon cancer cell lines. The results suggest that E1AF, in conjunction with the expression of MMP-1, MMP-7, COX-2 and iNOS, plays an important role in the early stage of colorectal carcinogenesis.
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PMID:Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis. 1569 37

Curcumin (diferuloylmethane) is a chemical derived from several Curcuma species (turmeric), possessing anti-inflammatory and antioxidant properties and which, thus, may be a potential anticancer drug. However, its mechanism of action is not fully understood. Our previous studies had shown that curcumin induced cytotoxicity, cell cycle arrest and apoptosis in human colon cancer colo 205 cells. In this study, curcumin affected the levels of NF-kappaB/ p65 in a time-dependent manner but did not affect NF-kappaB/ p50, based on Western blotting methods. In vitro experiments revealed that curcumin inhibited Cox-2 levels, but promoted those of Cox-1 in colo 205 cells. Curcumin also inhibited MMP-2 levels and promoted MMP-9 levels, but did not affect MMP-7 levels, based on Western blotting assays. These effects were also confirmed by cDNA microarray. Remarkably, curcumin not only exerted its effect on the protein levels of NF-kappaB, Cox-1 and -2, MMP-2 and -7, but also directly inhibited their mRNA levels. Curcumin was also found to significantly repress the in vitro invasion of colo 205 cells.
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PMID:Curcumin inhibits cell migration of human colon cancer colo 205 cells through the inhibition of nuclear factor kappa B /p65 and down-regulates cyclooxygenase-2 and matrix metalloproteinase-2 expressions. 1661 35

Previously we reported that auraptene was a potent suppressant for matrix metalloproteinase (MMP)-7 expression in HT-29 human colon cancer cells. In the present study, we examined the effects of auraptene on MMP-2, -7, and -9 expression in colonic mucosa from dextran sulfate sodium (DSS)-induced ulcerative colitis mice. Auraptene remarkably suppressed the DSS-induced gelatinolytic activity of MMP-7 as well as the expression of MMP-2 and -9, suggesting that it might be useful in anti-metastatic therapies via the targeting of MMPs.
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PMID:Auraptene decreases the activity of matrix metalloproteinases in dextran sulfate sodium-induced ulcerative colitis in ICR mice. 1715 46

n-3 Polyunsaturated fatty acids have been shown to powerfully inhibit the growth of colon cancer cells, mainly acting as pro-apoptotic agents through inhibition of cycloxygenase-2 (COX-2) expression. Since dysregulation of beta-catenin expression is frequently found at early stage of colorectal carcinogenesis, we analyzed whether docosahexaenoic acid (DHA) may modify the expression of beta-catenin in colon cancer cells (SW480 and HCT116) over-expressing this protein, but lacking COX-2. Futhermore, we investigated if alterations in beta-catenin expression may be associated with apoptosis induction. Treatment of cells with increasing concentrations of DHA induced a dose- and time-dependent inhibition of beta-catenin protein expression which, however, was not accompanied by modifications in beta-catenin transcription. Conversely, the proteasomal inhibitors MG132 and lactacystin prevented DHA-induced beta-catenin decrease, suggesting that DHA may regulate the proteasomal degradation of beta-catenin. The reduced levels of beta-catenin were accompanied by decreased translocation of beta-catenin into the nucleus, where it acts as a transcription factor in concert with T-Cell Factor (TCF). DHA, at the same range of concentrations, was also able to induce apoptosis by a caspase-3-dependent mechanism and to cause a dose- and time-dependent decrease of survivin, an apoptosis inhibitor undetectable in normal tissues and expressed in colorectal cancer through TCF-beta-catenin stimulation. Several other proteins regulated by the TCF-beta-catenin pathway and involved in regulation of tumor growth were down-regulated by DHA, including peroxisome proliferator-activated receptor-delta, membrane type 1 (MT1)-matrix metalloproteinase (MMP), MMP-7 and vascular endothelial growth factor. The present study, thus, raises the possibility that DHA may exert pro-apoptotic and antitumoral effects through proteasomal regulation of beta-catenin levels and alterations in the expression of TCF-beta-catenin target genes.
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PMID:Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. 1718 61

Prior evidence indicates that bile acids stimulate colon cancer cell proliferation by muscarinic receptor-induced transactivation of epidermal growth factor receptors (EGFR). To explore further the mechanism underlying this action, we tested the hypothesis that bile acids activate a matrix metalloproteinase (MMP) that catalyzes release of an EGFR ligand. Initial studies showed that non-selective MMP inhibitors blocked the actions of deoxycholyltaurine (DCT), thereby indicating a role for MMP-catalyzed release of an EGFR ligand. DCT-induced cell proliferation was reduced by increasing concentrations of EGFR kinase inhibitors, by antibodies to the ligand binding domain of EGFR, by neutralizing antibodies to heparin binding-EGF-like growth factor (HB-EGF) and by CRM197, an inhibitor of HB-EGF release. These findings and our observations with more selective MMP inhibitors suggested that MMP-7, an enzyme known to release HB-EGF, plays a key role in mediating bile acid-induced H508 colon cancer cell proliferation. We observed that recombinant HB-EGF and MMP-7 mimicked both the signaling and proliferative actions of bile acids. Strikingly, reducing MMP-7 expression with either neutralizing antibody or small interfering RNA attenuated the actions of DCT. MMP-7 expression in H508 cells was confirmed using quantitative reverse transcription PCR. DCT stimulated a greater than 10-fold increase in MMP-7 gene transcription. Co-localization of pro-MMP-7 and pro-HB-EGF at the cell surface (immunofluorescence microscopy) was demonstrated, indicating proximity of the enzyme to its substrate. These findings provide strong evidence that in H508 human colon cancer cells, DCT-induced transactivation of EGFR is mediated by MMP-7-catalyzed release of the EGFR ligand HB-EGF.
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PMID:Matrix metalloproteinase-7-catalyzed release of HB-EGF mediates deoxycholyltaurine-induced proliferation of a human colon cancer cell line. 1722 8

Many growth factors and cytokines are immobilized on the extracellular matrix (ECM) by binding to glycosaminoglycans and are stored in an inactive form in the cellular microenvironment. However, the mechanisms of ECM-bound growth factor or cytokine activation have not been well documented. We showed that the insulin-like growth factor type-1 receptor (IGF-1R) was rapidly phosphorylated after the addition of matrix metalloproteinase (MMP)-7 to a serum-starved human colon cancer cell line (HT29) and that phosphorylation was completely inhibited by an IGF-II neutralizing antibody. In the ECM of this cell line, IGF-II and IGF binding protein (BP)-2 coexisted, but IGFBP-2 disappeared from the ECM fraction after treatment with MMP-7 or heparinase III. On the other hand, in a cell line in which IGF-1R was overexpressed, IGF-1R was phosphorylated by supernatant from the MMP-7-treated ECM fraction of HT29 but not by that from a heparinase-III-treated ECM fraction. We also demonstrated that MMP-7 degrades IGFBP-2 in vitro at three cleavage sites (peptide bonds E(151)-L(152), G(175)-L(176) and K(181)-L(182)), which have not been documented previously. Taken together, these results demonstrate that MMP-7 generates bioactive IGF-II by degrading the IGF-II/IGFBP-2 complex binding to heparan sulfate proteoglycan in the ECM, resulting in IGF-II-induced signal transduction. This evidence indicates that some ECM-associated growth factors enhance their ability to bind to their receptors by some proteases in the tumor microenvironment. This mechanism of action ('protease-triggered matricrine') represents an attractive model for understanding ECM-tumor interactions.
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PMID:Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix. 1735 88

Retinol inhibits the growth of all-trans-retinoic acid (ATRA)-resistant human colon cancer cell lines through a retinoic acid receptor (RAR)-independent mechanism. The objectives of the current study were to determine if retinol inhibited the invasion of ATRA-resistant colon cancer cells independent of RAR and the effects of retinol on matrix metalloproteinases (MMPs). Retinol inhibited the migration and invasion of two ATRA-resistant colon cancer cell lines, HCT-116 and SW620, in a dose-dependent manner. To determine if transcription, particularly RAR-mediated transcription, or translation of new genes was required for retinol to inhibit cell invasion, cells were treated with retinol and cycloheximide, actinomycin D, or an RAR pan-antagonist. Treatment of cells with retinol and cycloheximide, actinomycin D, or an RAR pan-antagonist did not block the ability of retinol to inhibit cell invasion. In addition, retinol decreased MMP-1 mRNA levels in both cell lines, MMP-2 mRNA levels in the SW620 cell line, and MMP-7 and -9 mRNA levels in the HCT-116 cell line. Retinol also decreased the activity of MMP-2 and -9 and MMP-9 protein levels while increasing tissue inhibitor of MMP-1 media levels. In conclusion, retinol reduces the metastatic potential of ATRA-resistant colon cancer cells via a novel RAR-independent mechanism that may involve decreased MMP mRNA levels and activity.
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PMID:Retinol inhibits the invasion of retinoic acid-resistant colon cancer cells in vitro and decreases matrix metalloproteinase mRNA, protein, and activity levels. 1751 64

Tumor progress depends on the proliferation of cancer cells, their interactions with stroma and the proteolytic action of enzymes. Colon cancer is c-kit positive and responsive to the specific tyrosine kinase inhibitor imatinib. We investigated the effect of imatinib on the proliferation of a panel of epithelial colon cancer cell lines in presence and absence of the antimetabolite 5-FU, and the effect of conditioned media (CM) derived from colon stromal fibroblasts with and without previous exposure to imatinib. The effects of imatinib on gene expression of MMPs and TIMPs were also studied. Imatinib effectively inhibited the proliferation of all cell lines, showing IC(50) from 0.3 to 3 microM. Its combination with 5-FU significantly enhances the growth inhibition of the highly tumourigenic HT-29 cells. CM derived from stromal fibroblasts induced the proliferation of the HT-29 cells; this stimulatory effect was abolished upon treatment with CM obtained after exposure of fibroblasts to imatinib. Gene expression of MT1-, MT2-MMP and MMP-7 was also inhibited depending on the cell line, whereas that of TIMP-2 was not affected. CM stimulated MT1-MMP protein expression by HT-29; this stimulatory effect was suppressed in the presence of imatinib. Activation of pro-MMP2 to MMP2 in culture medium of HT-29 treated with CM was increased and this activity was inhibited in presence of imatinib. The obtained data showed that imatinib is a powerful inhibitor of human colon cancer cell growth and effectively suppresses the stromal-induced stimulation of cancer cell growth and activation of proMMP2. Further studies are warranted to evaluate the in vivo effects.
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PMID:Imatinib inhibits colorectal cancer cell growth and suppresses stromal-induced growth stimulation, MT1-MMP expression and pro-MMP2 activation. 1772 19

(-)-Epigallocatechin-3-gallate (EGCG), one of the main constituents of green tea, has been reported to function as an antioxidant with chemopreventive potential. In contrast, we have recently reported that EGCG enhanced pro-matrix metalloproteinase (MMP)-7 in HT-29 human colon cancer cells via spontaneous superoxide generation. In the present study, we examined the effects of dietary antioxidants on both spontaneous and EGCG-upregulated proMMP-7 production in HT-29 cells. Benzyl isothiocyanate (BITC), curcumin (CUR), gallic acid (GA), and N-acetyl-L-cysteine (NAC) reduced that production, while each alone did not have any effect on spontaneous production. None of the dietary factors suppressed EGCG-induced hydrogen peroxide generation in the media tested, whereas BITC, GA, and NAC inhibited the EGCG-enhanced activator protein (AP)-1 transcription activity by 126%, 77%, and 97%, respectively. Although CUR abolished the EGCG-upregulated MMP-7 mRNA expression, it unexpectedly enhanced the AP-1 activity by 502%, suggesting that this factor may disrupt the MMP-7 mRNA stabilization process. Together, our results indicate that dietary antioxidants modulate EGCG-induced MMP-7 production through different mechanisms.
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PMID:Modifying effects of dietary factors on (-)-epigallocatechin-3-gallate-induced pro-matrix metalloproteinase-7 production in HT-29 human colorectal cancer cells. 1792 19


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