UMLS:C0699790 - FACTA Search

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

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

Alterations in genes encoding transforming growth factor-beta-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-beta signaling molecule, Smad3, develop colon cancer, but only after a bacterial trigger occurs, resulting in chronic inflammation. To determine whether Smad3-null lymphocytes contribute to increased cancer susceptibility, we crossed Smad3-null mice with mice deficient in both B and T lymphocytes (Rag2(-/-) mice). Helicobacter-infected Smad3/Rag2-double knockout (DKO) mice had more diffuse inflammation and increased incidence of adenocarcinoma compared with Helicobacter-infected Smad3(-/-) or Rag2(-/-) mice alone. Adoptive transfer of WT CD4(+)CD25(+) T-regulatory cells provided significant protection of Smad3/Rag2-DKO from bacterial-induced typhlocolitis, dysplasia, and tumor development, whereas Smad3(-/-) T-regulatory cells provided no protection. Immunohistochemistry, real-time reverse transcriptase-polymerase chain reaction, and Western blot analyses of colonic tissues from Smad3/Rag2-DKO mice 1 week after Helicobacter infection revealed an influx of macrophages, enhanced nuclear factor-kappaB activation, increased Bcl(XL)/Bcl-2 expression, increased c-Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-gamma, IL-1alpha, TNF-alpha, IL-1beta, and IL-6 transcription levels. These results suggest that the loss of Smad3 increases susceptibility to colon cancer by at least two mechanisms: deficient T-regulatory cell function, which leads to excessive inflammation after a bacterial trigger; and increased expression of proinflammatory cytokines, enhanced nuclear factor-kappaB activation, and increased expression of both pro-oncogenic and anti-apoptotic proteins that result in increased cell proliferation/survival of epithelial cells in colonic tissues.
...
PMID:Bacterial infection of Smad3/Rag2 double-null mice with transforming growth factor-beta dysregulation as a model for studying inflammation-associated colon cancer. 1911 84

p21(Waf1) (p21) was described as a cyclin-dependent kinase inhibitor, but other p21 activities have subsequently been described, including its ability to inhibit apoptosis in some models. Comparative work on the human colon cancer isogenic cell lines HCT116 and HCT116p21(-/-) led to the proposal that p21 protects colon cancer cells against apoptosis by genotoxic drugs. We asked whether p21 also protected from cell death induced by non-genotoxic drugs, such as tyrosine kinase inhibitors. We found that p21-deficient cells were dramatically more sensitive towards imatinib and gefitinib than parental cells. Interestingly, HCT116p21(-/-) also showed higher basal activity of protein kinases as c-Abl, c-Src, and Akt. We generated HCT116p21(-/-) sublines with inducible p21 expression and found that p21 did not rescue the hypersensitivity to imatinib. Moreover, down-regulation of p21 by enforced c-Myc expression or by p21 siRNA did not sensitize parental HCT116 cells. We found that, in HCT116p21(-/-) cells, p53 showed higher stability, higher transcriptional activity and phosphorylation in serines associated with p53 activity. Furthermore, silencing of p53 with siRNA and inactivation of p53 with a dominant negative mutant rescued the hypersensitive response to kinases inhibitors, 5-fluorouracil and adriamycin in HCT116p21(-/-) cells. Consistently, HCT116p53(-/-) cells are more resistant to imatinib than parental cells, suggesting that imatinib activity is partly dependent on p53 in colon cancer cells. We conclude that high p53 activity, rather than p21 deficiency, is the mechanism responsible for hypersensitivity to drugs of HCT116p21(-/-) cells. Therefore the role of p21 on apoptosis of HCT116 colon cancer cells should be re-evaluated.
...
PMID:HCT116 cells deficient in p21(Waf1) are hypersensitive to tyrosine kinase inhibitors and adriamycin through a mechanism unrelated to p21 and dependent on p53. 1915 Feb 57

Survivin, a member of the apoptosis inhibitor family, shows increased expression in human cancers of various origins. It has been demonstrated that survivin inhibits apoptosis via caspase inhibition and promotes mitosis via aurora-B kinase activation. We recently reported that survivin enhances the expression of human telomerase reverse transcriptase (hTERT), a major determinant of telomerase activity in colon cancer cells. Survivin up-regulates hTERT expression by promoting the expression of specificity protein-1 (Sp1)- and c-Myc-mediated gene transcription via enhancing the phosphorylation of these transcriptional factors. However, the mechanism by which survivin regulates the phosphorylation of Sp1 and c-Myc is not well defined. In the present study, we hypothesized that survivin promotes the phosphorylation of Sp1 and c-Myc by activating aurora-B kinase. Inhibition of this enzyme by introducing small inhibitory RNA attenuated the phosphorylation of Sp1 and c-Myc and resulted in the abolition of the survivin effect on hTERT expression. In addition, blocking survivin phosphorylation at a threonine residue by inhibiting cyclin-dependent kinase 1 caused the dissociation of aurora-B kinase from survivin and attenuated the up-regulation of hTERT expression by survivin. Taken together, these results suggest that the interaction between survivin and aurora-B kinase may be essential for survivin to increase hTERT expression.
...
PMID:Interaction between survivin and aurora-B kinase plays an important role in survivin-mediated up-regulation of human telomerase reverse transcriptase expression. 1928 63

The mitogen-activated protein kinase (MAPK) cascade is one of the most ubiquitous signal transduction systems and is rapidly activated by various stimuli, such as cellular stress and death. The Caco-2 cell line is an in vitro model for colon cancer studies. We investigated the activation status of the ERK1/2, p38, JNK1/2, and ERK5 kinases and their respective upstream intracellular activators in Caco-2 cells induced to proliferate by 10% fetal bovine serum (FBS). The states of phosphorylation of the above MAPKs and their upstream kinases, MEK1/2, MKK3/6, MKK4, and MKK7, respectively, were studied by Western blot analysis. Phosphorylation was barely detectable before serum stimulation, and the stimulation of cell proliferation by the addition of FBS increased MEK1/2 and ERK1/2 phosphorylation 2 to 3 fold after 3 min. FBS stimulated p38 and MKK3/6 to the same extent within 2 min of treatment and JNK1/2 and its upstream kinases MKK4 and MKK7 5-fold (3 min). Addition of FBS also rapidly phosphorylated ERK5 (2 to 3.5-fold between 2 and 5 min) and the transcription factor CREB. Incubation of Caco-2 cells with FBS was followed by a rapid induction of c-Fos and c-Myc expression. Studies with ERK1/2 specific inhibitor PD98059, p38 MAPK inhibitor SB203580, or JNK inhibitor SP600125 showed that FBS regulates Caco-2 cell proliferation via the three MAPK pathways.
...
PMID:MAP kinases in proliferating human colon cancer Caco-2 cells. 1930 Oct 97

The cyclopentenone prostaglandin 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) has been shown to possess antineoplastic activity in human cancers of various origins. However, the mechanism of the antineoplastic activity of 15d-PGJ2 remains to be completely elucidated. It has been reported that inhibiting the expression of human telomerase reverse transcriptase (hTERT), a major determinant of telomerase activity, induces rapid apoptosis in cancer cells. In this study, we investigated the effect of 15d-PGJ2 on hTERT expression. Treatment with 30 microM 15d-PGJ2 for 72 h induced apoptosis in the colon cancer cells LS180. 15d-PGJ2 treatment decreased hTERT protein expression in a dose-dependent manner. Down-regulation of hTERT expression by hTERT-specific small inhibitory RNA induced apoptosis. These results indicate that the down-regulation of hTERT expression by 15d-PGJ2 plays an important role in its proapoptotic properties. Since 15d-PGJ2 reduced hTERT mRNA expression, we examined the effect of 15d-PGJ2 on the DNA-binding activity of c-Myc, specificity protein 1 (Sp1) and estrogen receptor (ER) to the hTERT gene promoter using an electrophoretic mobility shift assay. 15d-PGJ2 attenuated the DNA-binding of all three transcriptional factors. Further, we observed that 15d-PGJ2 inhibited the DNA binding of these factors by different mechanisms; suppressed c-Myc mRNA expression, enhanced Sp1 protein degradation via the ubiquitin-proteasome pathway and inhibited ERbeta phosphorylation at serine residues. We conclude that hTERT down-regulation by 15d-PGJ2 plays an important role in its proapoptotic properties. Furthermore, 15d-PGJ2 inhibits the transcriptional activity of c-Myc, Sp1 and ER by three different mechanisms and results in the transcriptional repression of the hTERT gene.
...
PMID:Down-regulation of hTERT expression plays an important role in 15-deoxy-Delta12,14-prostaglandin J2-induced apoptosis in cancer cells. 1936 Mar 48

Novel gene expression profiles and cellular functions modulated in Caco-2 cells in response to the dietary polyphenol, ellagic acid (EA), and its colonic metabolites, urolithin-A (3,8-dihydroxy-6H-dibenzo[b,d] pyran-6-one) and urolithin-B (3-hydroxy-6H-dibenzo[b,d] pyran-6-one) have been identified. Exposure of cells to EA and urolithins arrested cell growth at the S- and G(2)/M-phases. Transcriptional profiling using microarray and functional analysis revealed changes in the expression levels of MAPK signalling genes such as, growth factor receptors (FGFR2, EGFR), oncogenes (K-Ras, c-Myc), and tumour suppressors (DUSP6, Fos) and of genes involved in cell cycle (CCNB1, CCNB1IP1). Results suggest that EA and urolithin-A and -B, at concentrations achievable in the lumen from the diet, might contribute to colon cancer prevention by modulating the expression of multiple genes in epithelial cells lining the colon. Some of these genes are involved in key cellular processes associated with cancer development and are currently being investigated as potential chemopreventive targets.
...
PMID:Gene expression, cell cycle arrest and MAPK signalling regulation in Caco-2 cells exposed to ellagic acid and its metabolites, urolithins. 1943 80

Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands in mice. The aims of this study were to evaluate the effect of embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), an antagonist of XIAP, on colon cancer, with a particular focus on whether PPARgamma is required for embelin to exert its effect. A dominant-negative PPARgamma was used to antagonize endogenous PPARgamma in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-kappaB (NF-kappaB) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPARgamma(+/+) and PPARgamma(+/-) mice. Mice were fed embelin daily for 10 days before DMH injection, and continued for 30 more weeks. Embelin inhibited proliferation and induced apoptosis in HCT116 cells with marked up-regulation of PPARgamma. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPARgamma. PPARgamma(+/-) mice were more susceptible to DMH-induced colon carcinogenesis than PPARgamma(+/+) mice, and embelin significantly reduced the incidence of colon cancer in PPARgamma(+/+) mice but not in PPARgamma(+/-) mice. Embelin inhibited NF-kappaB activity in PPARgamma(+/+) mice but marginally so in PPARgamma(+/-) mice. Thus, reduced expression of PPARgamma significantly sensitizes colonic tissues to the carcinogenic effect of DMH. Embelin inhibits chemical carcinogen-induced colon carcinogenesis, but this effect is partially dependent on the presence of functional PPARgamma, indicating that PPARgamma is a necessary signaling pathway involved in the antitumor activity of normal organisms.
...
PMID:Peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of Embelin on colon carcinogenesis. 1945 67

The present study investigated the role of calcineurin (CaN) in the proliferation of human colorectal cancers. CaN activity and protein expression were increased in human colorectal cancers. Nuclear transcription factor NFAT, a physiological substrate for CaN, was activated in human colon cancer specimen as well as in the human colon cancer cell lines. CaN inhibitor cyclosporine A (CsA) reduced cell growth in these cell lines. CsA decreased the expressions of c-Myc and the proliferating cell nuclear antigen (PCNA) but also increased p21(WAF1/CIP1) expression. Our results suggest that CaN promotes colorectal cancer proliferation probably by regulating levels of c-Myc, p21(WAF1/CIP1), and PCNA.
...
PMID:Cyclosporine A inhibits colorectal cancer proliferation probably by regulating expression levels of c-Myc, p21(WAF1/CIP1) and proliferating cell nuclear antigen. 1948 39

Oxidative/nitrosative stress and generation of proinflammatory cytokines are hallmarks of inflammation. Because chronic inflammation is implicated in several pathologic conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. Stilbenes, such as resveratrol, have diverse pharmacologic activities, which include anti-inflammation, cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span. We previously showed that pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene), a structural analogue of resveratrol, is present in blueberries and that pterostilbene inhibited expression of certain inflammation-related genes in the colon and suppressed aberrant crypt foci formation in rats. Here, we examined molecular mechanisms of the action of pterostilbene in colon cancer. Pterostilbene reduced cell proliferation, down-regulated the expression of c-Myc and cyclin D1, and increased the level of cleaved poly(ADP-ribose) polymerase. A combination of cytokines (tumor necrosis factor-alpha, IFN-gamma, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase and cyclooxygenase-2, which was significantly suppressed by treatment with pterostilbene. We further identified upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene by investigating multiple signaling pathways, including nuclear factor-kappaB, Janus-activated kinase-signal transducer and activator of transcription, extracellular signal-regulated kinase, p38, c-Jun NH(2)-terminal kinase, and phosphatidylinositol 3-kinase. Cytokine induction of the p38-activating transcription factor 2 pathway was markedly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38 alpha isoform, there was significant reduction in cytokine induction of inducible nitric oxide synthase and cyclooxygenase-2. Our data suggest that the p38 mitogen-activated protein kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured HT-29 colon cancer cells.
...
PMID:Anti-inflammatory action of pterostilbene is mediated through the p38 mitogen-activated protein kinase pathway in colon cancer cells. 1954 98

Estrogen receptor beta (ERbeta) is the predominant ER in the colorectal epithelium. Compared with normal colon tissue, ERbeta expression is reduced in colorectal cancer. Our hypothesis is that ERbeta inhibits proliferation of colon cancer cells. Hence, the aim of this study has been to investigate the molecular function of ERbeta in colon cancer cells, focusing on cell cycle regulation. SW480 colon cancer cells have been lentivirus transduced with ERbeta expression construct with or without mutated DNA-binding domain or an empty control vector. Expression of ERbeta resulted in inhibition of proliferation and G(1) phase cell cycle arrest and this effect was dependent on a functional DNA-binding region. c-Myc is overexpressed in an overwhelming majority of colorectal tumors. By Western blot and real-time PCR, we found c-Myc to be down-regulated in the ERbeta-expressing cells. Furthermore, the c-Myc target gene p21((Waf1/Cip1)) was induced and Cdc25A was reduced by ERbeta at the transcriptional level. The second cdk2-inhibitor, p27(Kip1), was induced by ERbeta, but this regulation occurred at the posttranscriptional level, probably through ERbeta-mediated repression of the F-box protein p45(Skp2). Expression of the ERbeta-variant with mutated DNA binding domain resulted in completely different cell cycle gene regulation. We performed in vivo studies with SW480 cells +/- ERbeta transplanted into severe combined immunodeficient/beige mice; after three weeks of ERbeta-expression, a 70% reduction of tumor volume was seen. Our results show that ERbeta inhibits proliferation as well as colon cancer xenograft growth, probably as a consequence of ERbeta-mediated inhibition of cell-cycle pathways. Furthermore, this ERbeta-mediated cell cycle repression is dependent on functional ERE binding.
...
PMID:Tumor repressive functions of estrogen receptor beta in SW480 colon cancer cells. 1960 91

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>