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)

The h-prune protein is a member of the DHH protein superfamily, and its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and degree of lymph-node metastasis. Taken together with the observation that h-prune is highly expressed in metastatic breast cancer, this suggests that h-prune can be used as a marker for the identification of subsets of cancer patients with highly aggressive tumours. H-prune possesses a phosphodiesterase (cAMP-PDE) activity, and inhibition of PDE activity with dipyridamole suppresses cell motility. H-prune interacts with nm23-H1, GSK-3beta and gelsolin. Although a correlation between an h-prune PDE activity and cellular motility has been shown, GSK-3beta does not affect the PDE activity of h-prune. Inhibition of the interactions between h-prune and GSK-3beta and nm23-H1 additively suppresses the migration of colon cancer and breast cancer cells, thus suggesting that h-prune regulates cell motility by two different means of action: through its PDE activity and in its interactions with protein partners. Therefore, the identification of highly specific inhibitors of h-prune should be useful in the development of drugs to treat cancer metastasis.
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PMID:Understanding h-prune biology in the fight against cancer. 1795 13

Recent studies indicate that secondary bile acids promote colon cancer cell proliferation but their role in maintaining cell survival has not been explored. We found that deoxycholyltaurine (DCT) markedly attenuated both unstimulated and TNF-alpha-stimulated programmed cell death in colon cancer cells by a phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. To examine the role of bile acids and PI3K signaling in maintaining colon cancer cell survival, we explored the role of signaling downstream of bile acid-induced activation of the epidermal growth factor receptor (EGFR) in regulating both apoptosis and proliferation of HT-29 and H508 human colon cancer cells. DCT caused dose- and time-dependent Akt (Ser(473)) phosphorylation, a commonly used marker of activated PI3K/Akt signaling. Both EGFR kinase and PI3K inhibitors attenuated DCT-induced Akt phosphorylation and Akt activation, as demonstrated by reduced phosphorylation of a GSK-3-paramyosin substrate. Transfection of HT-29 cells with kinase-dead EGFR (K721M) reduced DCT-induced Akt phosphorylation. In HT-29 cells, EGFR and PI3K inhibitors as well as transfection with dominant negative AKT attenuated DCT-induced cell proliferation. DCT-induced PI3K/Akt activation resulted in downstream phosphorylation of GSK-3 (Ser(21/9)) and BAD (Ser(136)), and nuclear translocation (activation) of NF-kappaB, thereby confirming that DCT-induced activation of PI3K/Akt signaling regulates both proproliferative and prosurvival signals. Collectively, these results indicate that DCT-induced activation of post-EGFR PI3K/Akt signaling stimulates both colon cancer cell survival and proliferation.
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PMID:Deoxycholyltaurine rescues human colon cancer cells from apoptosis by activating EGFR-dependent PI3K/Akt signaling. 1806 5

Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.
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PMID:(-)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. 1913 73

Wnt/beta-catenin signaling plays an essential role in colon carcinogenesis. Galectin-3, a beta-galactoside-binding protein, has been implicated in Wnt signaling, but the precise mechanisms by which galectin-3 modulates the Wnt pathway are unknown. In the present study, we determined the effects of galectin-3 on the Wnt/beta-catenin pathway in colon cancer cells, as well as the mechanisms involved. Galectin-3 levels were manipulated in human colon cancer cells by stable transfection of galectin-3 antisense, short hairpin RNA, or full-length galectin-3 cDNA, and effects on beta-catenin levels, subcellular distribution, and Wnt signaling were determined. Galectin-3 levels correlated with beta-catenin levels in a variety of colon cancer cell lines. Down-regulation of galectin-3 resulted in decreased beta-catenin protein levels but no change in beta-catenin mRNA levels, suggesting that galectin-3 modulates beta-catenin by another mechanism. Reduction of galectin-3 led to reduced nuclear beta-catenin with a concomitant decrease in TCF4 transcriptional activity and expression of its target genes. Conversely, transfection of galectin-3 cDNA into colon cancer cells increased beta-catenin expression and TCF4 transcriptional activity. Down-regulation of galectin-3 resulted in AKT and glycogen synthase kinase-3beta (GSK-3beta) dephosphorylation and increased GSK activity, increasing beta-catenin phosphorylation and degradation. Ly294002, an inhibitor of phosphatidylinositol 3-kinase, and dominant-negative AKT, suppressed TCF4 transcriptional activity induced by galectin-3 whereas LiCl, a GSK-3beta inhibitor, increased TCF4 activity, mimicking the effects of galectin-3. These results suggest that galectin-3 mediates Wnt signaling, at least in part, by regulating GSK-3beta phosphorylation and activity via the phosphatidylinositol 3-kinase/AKT pathway, and, thus, the degradation of beta-catenin in colon cancer cells.
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PMID:Galectin-3 mediates nuclear beta-catenin accumulation and Wnt signaling in human colon cancer cells by regulation of glycogen synthase kinase-3beta activity. 1919 Mar 23

NDRG (N-Myc downstream-regulated gene)-2 is a member of the NDRG family. Although it has been suggested that NDRG2 is involved in cellular differentiation and tumor suppression, its intracellular signal and regulatory mechanism are not well known. Here, we show the differential expression of NDRG2 in human colon carcinoma cell lines and tissues by reverse transcription-polymerase chain reaction and immunohistochemical analyses with monoclonal antibody against NDRG2. NDRG2 was strongly expressed in normal colonic mucosa and colonic adenomatous tissues (25 of 25) but not in all invasive cancer tissues [44 of 99 (44%)]. Most distinctive results indicated that the high expression level of NDRG2 has a positive correlation with tumor differentiation and inverse correlation with tumor invasion depth and Dukes' stage of colon adenocarcinoma. To investigate the roles of NDRG2 in tumorigenesis, we used in vitro cell culture system. SW620 colon cancer cell line with a low level of intrinsic NDRG2 protein was transfected with NDRG2-expressing plasmid. TOPflash luciferase reporter assay showed that the transcriptional activity of T-cell factor (TCF)/lymphoid enhancer factor (LEF) was reduced by NDRG2 introduction, but not by the introduction of mutant NDRG2 generated by deletion or site-directed mutagenesis. Intracellular beta-catenin levels were slightly reduced in the NDRG2-transfected SW620 cells and this regulation of beta-catenin stability and TCF/LEF activity were mediated through the modulation of glycogen synthase kinase-3beta activity by NDRG2 function. Our results suggest that NDRG2 might play a pivotal role as a potent tumor suppressor by the attenuation of TCF/beta-catenin signaling for the maintenance of healthy colon tissues.
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PMID:NDRG2 expression decreases with tumor stages and regulates TCF/beta-catenin signaling in human colon carcinoma. 1923 7

Colon cancer is the third most common cancer and third most common cause of cancer-related death in the USA according to 2008 American Cancer Society statistics. The carcinogenesis of colon cancer has been associated with both genetics and environmental factors. It has been found that several signal pathways, including K-ras, Src/PI3K/Akt, beta-catenin, TGFbeta and p53 play critical roles in its pathogenesis. The 5 y survival rate of metastatic colon cancer is below 10%. Thus, it is necessary to further understand its biology and search for effective therapy. Azoxymethane (AOM) is a common model for colon cancer. It can specifically induce colon cancer similar to the pathogenesis of human sporadic colon cancer. Thus, it has been extensively used in the study of the molecular biology, prevention and treatment of colon cancer. After administration, AOM is metabolised into methylazoxymethanol by CYP2E1, which causes DNA mutations. Mutation of K-ras activates this pathway and its downstream PI3K/Akt pathway and MAPK pathway. Mutation of beta-catenin also prevents it from being degraded by GSK-3 and accumulation of beta-catenin leads to cell proliferation. TGFbeta, a pro-apoptotic protein, is inhibited. All of these changes form the basis of AOM carcinogenesis. This model has been used in the study of the genetic deficiencies of colon cancer and in the prevention and treatment of the disease. For example, TGF-betaR2 and adiponectin knockout mice are more susceptible to AOM, while high amylose cornstarch, green tea and artemisia have protective effects.
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PMID:The signal pathways in azoxymethane-induced colon cancer and preventive implications. 1950 80

PHLPP1 belongs to a novel family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating Akt signaling. Our recent studies have demonstrated that loss of PHLPP expression occurs at high frequency in colorectal cancer. In this study, we identified PHLPP1 as a proteolytic target of a beta-TrCP-containing Skp-Cullin 1-F-box protein (SCF) complex (SCF(beta-TrCP)) E3 ubiquitin ligase in a phosphorylation-dependent manner. Overexpression of wild-type but not DeltaF-box mutant beta-TrCP leads to decreased expression and increased ubiquitination of PHLPP1, whereas knockdown of endogenous beta-TrCP has the opposite effect. In addition, we show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity. Furthermore, expression of a degradation-deficient PHLPP1 mutant in colon cancer cells results in a more effective dephosphorylation of Akt and inhibition of cell growth. Taken together, our findings demonstrate a key role for beta-TrCP in controlling the level of PHLPP1, and activation of Akt negatively regulates this degradation process.
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PMID:beta-TrCP-mediated ubiquitination and degradation of PHLPP1 are negatively regulated by Akt. 1979 85

Molecular lesions in Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) occur frequently during the development of colon cancer. To identify small molecules that suppress CRT, we screened natural compounds in a cell-based assay for detection of TOPFalsh reporter activity. Murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa, antagonized CRT that was stimulated by Wnt3a-conditioned medium (Wnt3a-CM) or LiCl, an inhibitor of glycogen synthase kinase-3beta (GSK-3beta), and promoted the degradation of intracellular beta-catenin without altering its N-terminal phosphorylation at the Ser33/37 residues, marking it for proteasomal degradation, or the expression of Siah-1, an E3 ubiquitin ligase. Murrayafoline A repressed the expression of cyclin D1 and c-myc, which is known beta-catenin/T cell factor (TCF)-dependent genes and thus inhibited the proliferation of various colon cancer cells. These findings indicate that murrayafoline A may be a potential chemotherapeutic agent for use in the treatment of colon cancer.
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PMID:Murrayafoline A attenuates the Wnt/beta-catenin pathway by promoting the degradation of intracellular beta-catenin proteins. 1996 66

PURPOSE: The Wnt/beta-catenin (beta-cat) signaling cascade is a key regulator of development, and dysregulation of Wnt/beta-cat contributes to selected cancers, such as colorectal, breast, and hepatocellular carcinoma, through abnormal activation of Wnt target genes. To identify novel modulators of the Wnt/beta-cat pathway that may emerge as therapeutic targets, we did an unbiased high-throughput RNA interference screen. EXPERIMENTAL DESIGN: A synthetic oligonucleotide small interfering RNA library targeting 691 known and predicted human kinases was screened in Wnt3a-stimulated human cells in a live cell luciferase assay for modulation of Wnt/beta-cat-dependent transcription. Follow-up studies of a selected high-confidence "hit" were conducted. RESULTS: A robust quartile-based statistical analysis and secondary screen yielded several kinases worthy of further investigation, including Cdc2L1, Lmtk3, Pank2, ErbB3, and, of note, vascular endothelial growth factor receptor (VEGFR)1/Flt1, a receptor tyrosine kinase (TK) with putative weak kinase activity conventionally believed to be a negative regulator of angiogenesis. A series of loss-of-function, genetic null, and VEGFR TK inhibitor assays further revealed that VEGFR1 is a positive regulator of Wnt signaling that functions in a glycogen synthase kinase-3beta (GSK3beta)-independent manner as a potential synthetic lethal target in Wnt/beta-cat-addicted colon carcinoma cells. CONCLUSIONS: This unanticipated non-endothelial link between VEGFR1 TK activity and Wnt/beta-cat signaling may refine our understanding of aberrant Wnt signaling in colon carcinoma and points to new combinatorial therapeutics targeted to the tumor cell compartment, rather than angiogenesis, in the context of colon cancer. (Clin Cancer Res 2009;15(24):7529-37).
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PMID:Vascular Endothelial Growth Factor Receptor-1 Is Synthetic Lethal to Aberrant {beta}-Catenin Activation in Colon Cancer. 2000 53

It has been reported that Rho and Rho-kinase are involved in actin cytoskeleton organization and associated with carcinogenesis and progression of human cancers. However, the mechanism how the Rho/Rho-kinase pathway is involved in cell cycle progression has not been precisely characterized. In this study, we investigated the role of Rho-kinase in epidermal growth factor (EGF) signaling in SW480 colon cancer cells. We found that Y27632, a Rho-kinase inhibitor, dose-dependently induced cell proliferation in these cells. The blockade of EGF stimulation utilizing anti-EGF receptor neutralizing antibodies significantly suppressed cell growth, suggesting that EGF stimulation plays an important role in cell proliferation in SW480 cells. We also found that EGF induced Rho-kinase activation. Interestingly, EGF-induced phosphorylation of both Akt and glycogen synthase kinase-3beta (GSK-3beta), but not p44/p42 mitogen-activated protein (MAP) kinase, were dose-dependently enhanced when the cells were pretreated with Y27632 or fasudil, another Rho-kinase inhibitor. Moreover, whereas EGF increased the phosphorylation of retinoblastoma tumor suppressor protein as well as cyclin D1 protein expression level, pretreatment with Y27632 accelerated them. Taken together, our results suggest that Rho-kinase regulates negatively EGF-induced cell proliferation upstream of Akt/GSK-3beta in colon cancer cells.
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PMID:Rho-kinase regulates negatively the epidermal growth factor-stimulated colon cancer cell proliferation. 2012 78

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