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)

Wnt regulation of gene expression requires binding of LEF/T-cell factor (LEF/TCF) transcription factors to Wnt response elements (WREs) and recruitment of the activator beta-catenin. There are significant differences in the abilities of LEF/TCF family members to regulate Wnt target genes. For example, alternatively spliced isoforms of TCF-1 and TCF-4 with a C-terminal "E" tail are uniquely potent in their activation of LEF1 and CDX1. Here we report that the mechanism responsible for this unique activity is an auxiliary 30-amino-acid DNA interaction motif referred to here as the "cysteine clamp" (or C-clamp). The C-clamp contains invariant cysteine, aromatic, and basic residues, and surface plasmon resonance (SPR) studies with recombinant C-clamp protein showed that it binds double-stranded DNA but not single-stranded DNA or RNA (equilibrium dissociation constant = 16 nM). CASTing (Cyclic Amplification and Selection of Targets) experiments were used to test whether this motif influences WRE recognition. Full-length LEF-1, TCF-1E, and TCF-1E with a mutated C-clamp all bind nearly identical WREs (TYYCTTTGATSTT), showing that the C-clamp does not alter WRE specificity. However, a GC element downstream of the WRE (RCCG) is enriched in wild-type TCF-1E binding sites but not in mutant TCF-1E binding sites. We conclude that the C-clamp is a sequence-specific DNA binding motif. C-clamp mutations destroy the ability of beta-catenin to regulate the LEF1 promoter, and they severely impair the ability of TCF-1 to regulate growth in colon cancer cells. Thus, E-tail isoforms of TCFs utilize two DNA binding activities to access a subset of Wnt targets important for cell growth.
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PMID:A unique DNA binding domain converts T-cell factors into strong Wnt effectors. 1789 22

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

(-)-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

Isotope-coded affinity tag (ICAT) labeling, in combination with mass spectrometry (MS), has been widely adopted as an effective method for comparing protein abundance levels. This chapter describes the ICAT labeling procedure in search for the celecoxib-regulated proteins in a colon cancer cell line. Celecoxib, a cyclooxygenase-2 (COX-2) specific inhibitor, is used as a colorectal cancer preventative drug in clinical trials. Here, celecoxib is used to inhibit the expression of COX-2 in a colon cancer cell line HT-29. To elucidate the proteomic changes induced by celecoxib, the protein lysates from the treated and control cells are prepared. The cysteine-containing proteins are labeled with the heavy and light ICAT reagents, respectively. The labeled proteins are then combined and digested with trypsin. The ICAT-labeled peptides are subject to the purification through an avidin column and eventually the cleavage of the biotin tags. This chapter focuses on the ICAT labeling procedure itself, because sample preparation is the most critical step of an ICAT-based protein expression comparison experiment. Other related procedures such as the cation exchange high performance liquid chromatography separation of peptides and MS analysis are detailed elsewhere in this book.
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PMID:Comparison of protein expression by isotope-coded affinity tag labeling. 1828 74

As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of [Ti(4)(maltolato)(8)(mu-O)(4)], (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(3) and CO(2)CH(2)CH(3)), and three water-soluble titanocene-amino acid complexes-[Cp(2)Ti(aa)(2)]Cl(2) (aa = L: -cysteine, L: -methionine, and D: -penicillamine)-on the human colon adenocarcinoma cell line, HT-29. The capacity of [Ti(4)(maltolato)(8)(mu-O)(4)] to donate Ti(IV) to human apo-transferrin and its hydrolytic stability have been investigated and compared to the previously reported data on modified titanocenes with either hydrophilic ancillary ligands or the functionalized cyclopentadienyl ligands. Notably, the titanium-maltolato complex does not transfer Ti(VI) to human apo-transferrin at any time within the first seven days of its interaction, demonstrating the inert character of this species. Stability studies on these complexes have shown that titanocene complexes decompose at physiological pH while the [Ti(4)(maltolato)(8)(mu-O)(4)] complex is stable at this pH without any notable decomposition for a period of ten days. The antitumor activity of these complexes against colon cancer HT-29 cells was determined using an MTT cell viability assay at 72 and 96 h. The titanocene-amino acid and the (Cp-R)(2)TiCl(2)/(Cp-R)CpTiCl(2) (R = CO(2)CH(3)) complexes were not biologically active when human transferrin was absent; they also were inactive when human transferrin was present at dose-equivalent concentrations. (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(2)CH(3)) showed cytotoxic activity in HT-29 cells comparable to that which is displayed by titanocene dichloride. The titanium-maltolato complex had higher levels of cytotoxic activity than any other titanocene complex investigated. Transferrin may be important in protecting the titanium center from hydrolysis, but this may be achieved by selecting ligands that could result in hydrolytically stable, yet active, complexes.
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PMID:Structure-activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells. 1828 5

Alk(en)yl sulfides are characteristic flavor components of garlic. Several lines of epidemiological study indicate that the risk of a certain cancer can be prevented by consumption of garlic. In this manuscript, we examined the anticancer property of garlic-derived alk(en)yl sulfides, and the molecular basis especially for diallyl trisulfide which is a major constituent of the garlic oil. Alk(en)yl sulfides with different numbers of sulfur atom (i.e., mono-, di-, and trisulfide) were synthesized and purified (>99%). The anticancer activity of the alk(en)yl sulfides was primarily examined using human colon cancer cells HCT-15 and DLD-1. The growth of the cells was significantly suppressed by diallyl trisulfide, but neither diallyl monosulfide nor diallyl disulfide showed such an effect. The number of cells arrested at G2/M phase, the cells with a sub-G1 DNA content, and the cells with caspase-3 activity were dramatically increased by diallyl trisulfide treatment. Diallyl trisulfide disrupted microtubule network formation of the cells, and microtubule fragments could be seen at the interphase. There was a specific oxidative modification of cysteine residues Cys12 beta and Cys354 beta, forming S-allylmercaptocysteines in the tubulin molecule. These results suggest that diallyl trisulfide is responsible, at least in part, for the epidemiologically proven anticancer effect for garlic eaters.
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PMID:Anticancer effects of diallyl trisulfide derived from garlic. 1829 48

Our laboratory has been investigating the use of compounds which disrupt beta-catenin/T cell factor (TCF) binding to treat human colon cancer. There are several cysteine residues on the surface of beta-catenin where it binds to TCF. Some bis[2-(acylamino)phenyl] disulfides might have the ability to form a disulfide bond with the cysteine residues of beta-catenin, leading to inhibition of the growth of human colon cells. Bis[2-(acylamino)phenyl] disulfides were screened to inhibit the growth of cancer cells. Among them, bis[2-(2,2-dimethylpropanoylamino)phenyl] disulfide (1) had promising inhibitory effects (HCT116, IC50: 9.7 microM; DLD-1, IC50: 6.9 microM) on cell proliferation, and did not show any cytotoxicity among normal human fibroblast CCD-1059SK cells even at 200 microM. This derivative reduced the beta-catenin/TCF4 association in the HCT116 cells to ca. 50% at 150 microM. Furthermore, it activated markedly the phosphorylation of c-Jun N-terminal kinase (JNK) connected to stress-activated apoptosis at a lower concentration (30 microM). In view of cell cycle analyses, Hoechst staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin Nick end-labeling (TUNEL) assays along with the above results, it is likely that 1 inhibited the growth of HCT116 cells through pathways including the JNK-mediated apoptosis.
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PMID:Growth inhibition of human colon cancer cell line HCT116 by bis[2-(acylamino)phenyl] disulfide and its action mechanism. 1845 18

Alk(en)yl trisulfides (R-SSS-R') are organosulfur compounds produced by crushed garlic and other Allium vegetables. We found that these compounds exhibit potent anticancer effects through the reaction with microtubules, causing cell cycle arrest. Nine alk(en)yl trisulfides including dimethyl trisulfide, diethyl trisulfide, dipropyl trisulfide (DPTS), dibutyl trisulfide, dipentyl trisulfide, diallyl trisulfide (DATS), dibutenyl trisulfide, dipentenyl trisulfide and allyl methyl trisulfide were synthesized and added to cultures of HT-29 human colon cancer cells at a concentration of 10 muM. The trisulfides with alkenyl groups such as DATS, but not those with alkyl groups, induced rapid microtubule disassembly at 30-60 min as well as cell cycle arrest during the mitotic phase approximately at 4 h after the treatment. Both DATS-induced microtubule disassembly and the cell cycle arrest were cancelled by the simultaneous treatment of the cancer cells with 2 mM L-cysteine, glutathione (GSH) or N-acetyl-L-cysteine. Reciprocally, L-buthionine-(S,R)-sulfoximine (500 muM), an inhibitor of GSH synthesis, enhanced the power of DATS in inducing the cell cycle arrest. These results indicate that alk(en)yl trisulfide react with sulfhydryl groups in cysteine residues of cellular proteins such as microtubule proteins. Thus, the present study provides evidence that trisulfides with alkenyl groups have potent anticancer activities, at least in part, directed toward microtubules. These findings suggest that alkenyl trisulfides and their structurally related compounds may provide novel and effective anticancer agents.
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PMID:Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells. 1851 80

The role of nonsteroidal anti-inflammatory drugs (NSAIDs) was studied on the antioxidant defense system and nitric oxide-derived damage in a 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Early precancerous lesions were established in the proximal and distal regions of the colon by morphological and histopathological examinations that were greatly regressed by the simultaneous treatment of the three NSAIDs, such as aspirin, celecoxib, and etoricoxib, along with the procarcinogen DMH. The intestinal brush border membrane (BBM) was isolated from the two regions and the colon-specific marker enzyme cysteine-sensitive alkaline phosphatase was assayed, which showed considerable elevation by DMH but reverted back to normal level by all the three NSAIDs. DMH also caused a higher level of lipid peroxidation as measured by malonyldialdehyde production, which was also found to be corrected by the NSAIDs, in both the region of the colonic tissue. The antioxidant activities were further established by a higher level of superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase in the NSAID treatment as compared to the DMH. The nonenzyme tripeptide, glutathione content was also recovered similarly as an antioxidant defense mechanism. To elucidate whether nitric oxide (NO) also plays an important role in the pathophysiology of colon cancer, the NO and citrulline levels were measured. The results show that the NO was lowered in DMH treatment and elevated by the administration of the NSAIDs while the citrulline level could not be recovered back. The findings of the present investigation indicate the chemopreventive modalities of the NSAIDs, particularly the COX-2 inhibitors.
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PMID:Antioxidative effects of nonsteroidal anti-inflammatory drugs during the initiation stages of experimental colon carcinogenesis in rats. 1854 Aug 45

The geldanamycin derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) are promising chemotherapeutic drugs that inhibit heat shock protein 90 (HSP90) function. Previous studies have shown that 17-AAG/DMAG treatment induces the degradation of mutant BRAF (V600E) and inhibits the activation of mitogen-activated protein/extracellular signal-regulated kinase 1/2 (MEK1/2). We have found, however, that HSP90 inhibition alone is not sufficient for efficient BRAF(V600E) degradation in some cells. HSP90 inhibitors structurally unrelated to geldanamycin, radicicol and novobiocin, while inducing the degradation of the HSP90 client protein RAF-1 fail to induce BRAF(V600E) degradation or inhibit MEK1/2 activation in HT29 human colon cancer cells. Moreover, after treatment with 17-DMAG, the kinase activity of residual, undegraded BRAF(V600E) was also lost. Incubation of cells with a reactive oxygen species (ROS) scavenger, N-acetyl cysteine, partially restored kinase activity and also partially prevented BRAF(V600E) degradation due to 17-DMAG treatment. Conversely, treatment with the ROS producing drug menadione clearly inhibited MEK1/2 and reduced BRAF(V600E). These results suggest that in addition to direct inhibition of HSP90, the antitumor effect of geldanamycin and its derivatives is also mediated though the production of ROS, which may directly inactivate tumorigenic mutant BRAF(V600E).
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PMID:Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives. 1867 57


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