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)

A functional Gly388Arg variation in the FGFR4 gene has been reported to be associated with breast and colorectal cancer prognostic parameters. To further examine the functional role of this genetic polymorphism at the population level, we assessed the presence of the Arg388 allele in 142 breast carcinoma patients, 179 colorectal carcinoma patients and 220 general population controls with respect to an association with cancer prognosis and/or risk. No significant association with cancer risk, survival or any other prognostic parameters was observed in either breast or colorectal cancer. A pooled analysis of the present and published data on nodal status by FGFR4 genotypes revealed no association in either breast cancer [odds ratio (OR), 1.0; 95% confidence interval (CI), 0.7-1.4; 702 subjects] or colorectal cancer (OR, 1.4; 95% CI, 0.6-3.4; 260 cases). Thus, the FGFR4 polymorphism may not be relevant in predicting nodal involvement of breast cancer or colon cancer patients.
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PMID:FGFR4 Gly388Arg polymorphism and prognosis of breast and colorectal cancer. 1601 24

The IGF/IGF-1R system, which includes the IGF, IGF-1R, and IGFBPs proteins, plays an important role in the development and growth of colorectal cancer. We previously reported that in the HT29 human colon cancer cell line EGCG, the major biologically active component of green tea, inhibits activation of the RTKs EGFR, HER2, and HER3, and that this is associated with inhibition of multiple downstream signaling pathways. Since IGF-1R is also a RTK, in this study we examined the effects of EGCG on the activity of IGF/IGF-1R system in human colon cancer cells. We found that the colon cancer cell lines Caco2, HT29, SW837, and SW480 express high levels of the IGF-1R receptor, and that both SW837 and SW480 cells display constitutive activation of this receptor. Treatment of SW837 cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused within 6 h a decrease in the phosphorylated (i.e., activated) form of the IGF-1R protein. At 12 h, there was a decrease in the levels of both IGF-1 protein and mRNA and within 3-6 h there was an increase in the levels of both IGFBP-3 protein and mRNA. The increased expression of the latter protein was sustained for at least 48 h. When SW837 cells were treated with EGCG for a longer time, i.e., 96 h, a very low concentration (1.0 microg/ml) of EGCG also caused inhibition of activation of IGF-1R, a decrease in the IGF-1 protein, and an increase in the IGFBP-3 protein. EGCG also caused a decrease in the levels of mRNAs that encode MMPs-7 and -9, proteins that proteolyze IGFBP-3. In addition, treatment with EGCG caused a transient increase in the expression of TGF-beta2, an inducer of IGFBP-3 expression. These findings expand the roles of EGCG as an inhibitor of critical RTKs involved in cell proliferation, providing further evidence that EGCG and related compounds may be useful in the chemoprevention or treatment of colorectal cancer.
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PMID:EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. 1605 20

With the advent of agents directed against specific molecular targets in drug discovery, it has become imperative to show a compound's cellular impact on the intended biomolecule in vivo. The objective of the present study was to determine if we could develop an assay to validate the in vivo effects of a compound. Hence, we investigated the in vivo pharmacodynamic activity of JNJ-10198409, a relatively selective inhibitor of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK), in tumor tissues after administering the compound orally in a nude mouse xenograft model of human LoVo colon cancer. We developed a novel assay to quantify the in vivo anti-PDGF-RTK activity of the inhibitor in tumor tissue by determining the phosphorylation status of phospholipase Cgamma1 (PLCgamma1), a key downstream cellular molecule in the PDGF-RTK signaling cascade. We used two antibodies, one specific for the total (phosphorylated and unphosphorylated forms) PLCgamma1 (pan-PLCgamma1) and the other, specific for phosphorylated form of PLCgamma1 (ph-PLCgamma1) to immunohistochemically detect their expression in tumor tissues. Computer-assisted image analysis was then used to directly compare the ratio of ph-PLCgamma1 to pan-PLCgamma1 immunolabeling intensities in serial sections (5 mum) of tumors obtained from vehicle- and JNJ-10198409-treated tumor-bearing mice. Our data showed statistically significant, dose-dependent differences in the ph-PLC/pan-PLC ratio among the four treatment groups (vehicle, 25, 50, and 100 mg/kg b.i.d.). These results confirmed this compound's ability to suppress PDGF-RTK downstream signaling in tumor tissues in vivo. In addition to this specific application of this in vivo validation approach to those targets that use PLCgamma as a downstream signaling partner, these methods may also benefit other drug discovery targets.
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PMID:Validation of in vivo pharmacodynamic activity of a novel PDGF receptor tyrosine kinase inhibitor using immunohistochemistry and quantitative image analysis. 1609 35

2'-Hydroxycinnamaldehyde (HCA) inhibits cell growth of several human cancer cells with unknown mechanisms. We investigated the inhibitory effect of HCA on TNF-alpha-induced cell growth and possible signal pathway in SW620 colon cancer cells. HCA inhibited TNF-alpha-induced SW620 colon cell growth in time- and dose-dependent manner through induction of apoptotic cell death. Parallel with inhibitory effect on cell growth, HCA dose dependency inhibited TNF-alpha-induced activation of NF-kappaB accompanied with inhibition of the translocation of p50. HCA also induced expression of caspase-3 and Bax, but decreased Bcl-2. HCA furthermore activated ERK pathway, and ERK inhibitor reversed inhibitory effect of HCA on cell growth and transcriptional activation of NF-kappaB. These results demonstrate that HCA inhibits cell growth through induction of apoptotic cell death by ERK pathway-dependent NF-kappaB inactivation.
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PMID:Induction of apoptotic cell death by 2'-hydroxycinnamaldehyde is involved with ERK-dependent inactivation of NF-kappaB in TNF-alpha-treated SW620 colon cancer cells. 1614 16

Development of cutaneous metastases from colon cancer is a rare event, usually occurring in the setting of diffusely-disseminated disease and commonly carrying a dismal prognosis. Cutaneous and subcutaneous metastases in surgical scars occur extremely rarely, with only a few cases reported. We describe two cases of cutaneous metastases from colon cancer. A 62-year-old woman developed an 11-cm midline abdominal mass that slowly grew on the skin surface. The mass occurred at the scar site of her previous surgery performed 5 years prior for resection of a colon adenocarcinoma. A 46-year-old male presented with a subcutaneous 4.5-cm nodule in midline-abdominal scar, 3 years after resection of the primary colon cancer. These cases illustrate the pathological features and natural history of cutaneous metastases observed until the tumors have reached a very large size. Particular features of cutaneous scar metastases from colon cancer observed in our cases are a superficial pattern of spread, strong positivity for EGFR, low serum carcinoembrionic antigen, and long survival of the patients, possibly contributed to by the use of chemotherapy.
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PMID:Unusually large colon cancer cutaneous and subcutaneous metastases occurring in resection scars. 1615 Feb 30

Glycine-extended gastrin (G-Gly) is an end product of processing of the progastrin precursor peptide that has a different spectrum of activity to amidated gastrin. G-Gly promotes cell proliferation in normal and malignant colonic epithelium but the mechanisms responsible are poorly understood. Prostaglandins produced by the cyclo-oxygenase (COX) enzymes have been implicated as downstream mediators of several growth factors, and COX inhibitors such as non-steroidal anti-inflammatory drugs inhibit the proliferation and invasiveness of colonic cancer and reduce the incidence of colon cancer. We have examined the mechanisms of the actions of G-Gly in HT-29 colon cancer cells. G-Gly induced a dose-dependent increase in cell proliferation that was insensitive to inhibition of either COX-1 or COX-2, but was abolished by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. G-Gly did not increase prostaglandin E2 production. Celecoxib induced apoptosis and reduced viable cell numbers in a COX-independent manner. G-Gly significantly reduced serum-starvation and celecoxib-induced apoptosis and this effect was also blocked by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. Stimulation of HT-29 cells with G-Gly led to a rapid increase in ERK and p38 MAP kinase phosphorylation and increased nuclear translocation of active NF-kappaB. Activation of NF-kappaB was independent of ERK and p38 MAP kinase. G-Gly stimulates proliferation and inhibits apoptosis in colon cancer cells via COX-independent and ERK-, p38 MAP kinase-, and NF-kappaB-dependant pathways. Locally and systemically produced G-Gly may be important in reducing the beneficial effects of chemopreventative agents in colon cancer.
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PMID:Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways. 1616 10

High expression of epidermal growth factor receptor (EGFR) is found in a variety of solid tumors, including colorectal cancer. EGFR has been identified as a rational target for anticancer therapy. Curcumin, the yellow pigment of turmeric in curry, has received attention as a promising dietary supplement for cancer prevention and treatment. We recently reported that curcumin inhibited the growth of human colon cancer-derived Moser cells by suppressing gene expression of cyclinD1 and EGFR. The aim of the present study was to explore the molecular mechanisms underlying curcumin inhibition of gene expression of EGFR in colon cancer cells. The generality of the inhibitory effect of curcumin on gene expression of EGFR was verified in other human colon cancer-derived cell lines, including Caco-2 and HT-29 cells. Promoter deletion assays and site-directed mutageneses identified a binding site for the transcription factor early growth response-1 (Egr-1) in egfr promoter as a putative curcumin response element in regulating the promoter activity of the gene in Moser cells. Electrophoretic mobility shift assays demonstrated that curcumin significantly reduced the DNA-binding activity of the transcription factor Egr-1 to the curcumin response element. In addition, curcumin reduced the trans-activation activity of Egr-1 by suppressing egr-1 gene expression, which required interruption of the ERK signal pathway and reduction of the level of phosphorylation of Elk-1 and its activity. Taken together, our results demonstrated that curcumin inhibited human colon cancer cell growth by suppressing gene expression of EGFR through reducing the trans-activation activity of Egr-1. These results provided novel insights into the mechanisms of curcumin inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.
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PMID:Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. 1617 Mar 59

Caveolin is a major component of caveolae which is a plasma membrane microdomain. The emerging role of caveolin in tumorigenesis was based mainly on in vitro experiments with cancer cell lines. We performed semi-quantitative RT-PCR for caveolin, Akt and EGFR to understand the role of caveolins in colorectal tumor biology. Cancer tissue samples and the neighboring normal colon mucosa were obtained from 95 colorectal cancer patients who underwent operations at Ewha Womans University Mokdong Hospital. With these fresh tissues, semi-quantitative RT-PCR was performed by coamplification of the gene for caveolin-1, EGFR and Akt-1 with beta-actin. The average age was 60.21+/-13.33 years old, and sex ratio was 1.44:1. Caveolin-1 is more expressed in tumors than normal mucosa (P=0.025). The expression of caveolin-1 and Akt-1 had a definitive positive relationship (P=0.002). But, the expression of caveolin-1 and EGFR was not significantly related. We could not find correlations between caveolin-1 expression and clinical factors. In conclusion, caveolin-1 is more expressed in cancer tissues than normal colon and related with Akt-1, not with EGFR expression in colorectal cancer tissues, which suggests that signaling for caveolin-1 affects Akt-1 activation, but this reaction is not initiated by EGFR stimulation in colon cancer.
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PMID:Expression of caveolin-1 is correlated with Akt-1 in colorectal cancer tissues. 1620 96

Transmembrane proteins with extracellular Frizzled domain, such as ROR1, ROR2, MUSK, MFRP, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9 and FZD10, are key molecules for WNT signaling network. Here, comparative integromics analyses on ROR1 and ROR2 orthologs were performed by using bioinformatics. Zebrafish ror2 gene, consisting of nine exons, was identified within CR-450684.3 genome sequence. CV490605.1 EST corresponded to the 5'-end of zebrafish ror2 mRNA, and BM533602.1 EST corresponded to the 3'-end. Zebrafish ror2 gene was found to encode a 939-aa transmembrane protein, showing 71.7% and 56.2% total amino-acid identity with human ROR2 and ROR1, respectively. Immunoglobulin-like domain, Frizzled domain, Kringle domain within the extracellular region, tyrosine kinase domain, Ror homology C-terminal (RORHC) domain and juxta-C-terminal LLGD motif within the cytoplasmic region were conserved among vertebrate ROR1 and ROR2 orthologs. SH2 binding site within the RORHC domain was conserved among vertebrate ROR2 orthologs, but not among vertebrate ROR1 orthologs. ROR1 mRNA was expressed in embryonic stem (ES) cells, infant brain, renal cancer, and colon cancer. ROR2 mRNA was expressed in parathyroid, testis, uterus, and also in diffuse type gastric cancer with signet ring cell features. ROR2 promoter rather than ROR1 promoter was more evolutionarily conserved. WNT5A and ROR family receptors, co-expressed in ES cells and gastric cancer, are implicated in the planar cell polarity (PCP) pathway. ROR1 and ROR2 are the pharmacogenomics targets in the fields of stem cell biology and oncology.
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PMID:Comparative genomics on ROR1 and ROR2 orthologs. 1621 13

The DNA-interactive drug, echinomycin, is a potent antitumor agent, which is able to induce apoptosis in a multitude of cancer cell lines. Previously, we showed that echinomycin strongly inhibited the growth of a variety of cancer cell lines, and the activation of mitogen-activated protein kinases (MAPK) in human colon cancer cells (HT-29). However, little information currently exists regarding the details of intracellular signaling pathways such as the MAPK, mitochondrial, and caspase pathways. In order to clarify this issue, we verified the plausible molecular signaling cascade by performing an immunobiochemical apoptosis experiment involving the mitochondrial and caspase pathways. The apoptotic process of HT-29 cells was accompanied by the activation of procaspase-9, -3 and cytochrome c release. Both caspase and MAPK inhibitors were used in the determination of the specific roles of MAPK and caspase in echinomycin-induced apoptosis. ERK (PD98059) or caspase-3-specific (Z-DEVD-FMK) inhibitors were discovered to significantly attenuate echinomycin-induced apoptosis. PD98059 treatment or overexpression of kinase-inactive ERK did not alter the echinomycin-induced cytochrome c release into the cytosol, but did diminish the activation of procaspase-3. Also, Z-DEVD-FMK was found to have no effect on either cytochrome c release or ERK activation. Taken together, these results indicate that cytochrome c release, and the activation of ERK and caspase-3 in the final apoptosis pathway are all relevant factors in echinomycin-induced apoptosis. To our knowledge, this study is the first to delineate the echinomycin's direct detrimental effects on colon cancer cells.
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PMID:Molecular signaling cascade in DNA bisintercalator, echinomycin-induced apoptosis of HT-29 cells: evidence of the apoptotic process via activation of the cytochrome c-ERK-caspase-3 pathway. 1621 85


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