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)

We have found previously that human plasma-membrane-associated sialidase (NEU3), a key glycosidase for ganglioside degradation, was markedly up-regulated in human colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to fibronectin and collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (focal adhesion kinase) and ERK (extracellular-signal-regulated kinase), whereas there was no activation on fibronectin. NEU3 markedly enhanced tyrosine phosphorylation of integrin beta4 with recruitment of Shc and Grb-2 only on laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin beta4) antibody, suggesting that association of NEU3 with integrin beta4 might facilitate promotion of the integrin-derived signalling on laminin-5. In addition, the promotion of phosphorylation of integrin beta1 and ILK (integrin-linked kinase) was also observed on laminins. G(M3) depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on fibronectin - NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in carcinogenesis, which may cause an acceleration of the malignant phenotype in cancer cells.
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PMID:Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling. 1624 5

The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/beta-catenin. Premalignant lesions of the colon express high levels of EPHB2 but the expression of this kinase is reduced or lost in most colorectal carcinomas. In addition, inactivation of EPHB2 has been shown to accelerate tumorigenesis initiated by APC mutation in the colon and rectum. In this study, we investigated the molecular mechanisms responsible for the inactivation of EPHB2 in colorectal tumors. We show here the presence of mutations in repetitive sequences in exon 17 of EPHB2 in 6 of 29 adenomas with microsatellite instability (MSI), and 101 of 246 MSI carcinomas (21% and 41%, respectively). Moreover, we found EPHB2 promoter hypermethylation in 54 of the 101 colorectal tumors studied (53%). Importantly, EPHB2 expression was restored after treatment of EPHB2-methylated colon cancer cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. In conclusion, in this study, we elucidate the molecular mechanisms of inactivation of EPHB2 and show for the first time the high incidence of frameshift mutations in MSI colorectal tumors and aberrant methylation of the regulatory sequences of this important tumor suppressor gene.
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PMID:Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. 1628 1

The present study was designed to investigate the effects of two main constituents of green tea, (-)-epigallocatechin-3-gallate (EGCG) and caffeine, on intestinal tumorigenesis in Apc(min/+) mice, a recognized mouse model for human intestinal cancer, and to elucidate possible mechanisms involved in the inhibitory action of the active constituent. We found that p.o. administration of EGCG at doses of 0.08% or 0.16% in drinking fluid significantly decreased small intestinal tumor formation by 37% or 47%, respectively, whereas caffeine at a dose of 0.044% in drinking fluid had no inhibitory activity against intestinal tumorigenesis. In another experiment, small intestinal tumorigenesis was inhibited in a dose-dependent manner by p.o. administration of EGCG in a dose range of 0.02% to 0.32%. P.o. administration of EGCG resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, phospho-Akt, and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) in small intestinal tumors. Treatment of HT29 human colon cancer cells with EGCG (12.5 or 20 micromol/L at different times) also increased protein levels of E-cadherin by 27% to 58%, induced the translocation of beta-catenin from nucleus to cytoplasm and plasma membrane, and decreased c-Myc and cyclin D1 (20 micromol/L EGCG for 24 hours). These results indicate that EGCG effectively inhibited intestinal tumorigenesis in Apc(min/+) mice, possibly through the attenuation of the carcinogenic events, which include aberrant nuclear beta-catenin and activated Akt and ERK signaling.
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PMID:Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea. 1628 56

The gene that encodes the alpha-isoform of phosphatidylinositol 3-kinase (PIK3Ca) is frequently mutated in human cancers. We profiled the mutation status of the PIK3Ca gene in the National Cancer Institute (NCI)-60 panel of human cancer cell lines maintained by the Developmental Therapeutics Program of the NCI. Mutation hotspots on the gene were PCR amplified and sequenced, and the trace data were analyzed with software designed to detect mutations. Seven of the cell lines tested have PIK3Ca mutations: two lines derived from breast cancer, two from colon cancer, two from ovarian cancer, and one from lung cancer. BRAF and EGFR genes were normal in the PIK3Ca mutant lines. Two of the cell lines with mutant PIK3Ca also have a mutant version of the KRAS gene. The mutation status was correlated with array-based gene expression that is publicly available for the NCI-60 cell lines. We found increased expression levels for estrogen receptor (ER) and ERBB2 in PIK3Ca mutant lines. The PIK3Ca mutation status was also correlated with compound screening data for the cell lines. PIK3Ca-mutant cell lines were relatively more sensitive than PIK3Ca-normal cell lines to the ER inhibitor tamoxifen and the AKT inhibitor triciribine, among other compounds. The results provide insights into the role of mutant PIK3Ca in oncogenic signaling and allow preliminary identification of novel targets for therapeutic intervention in cancers harboring PIK3Ca mutations.
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PMID:Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. 1637 1

Increased expression of COX-2 appears to play an important role in the development of colorectal cancer. The level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of RTKs. We previously reported that in HT29 human colon cancer cells EGCG, the major biologically active component of green tea, inhibits activation of two members of this family, EGFR and HER2, and multiple downstream signaling pathways. In this study we examined the effects of EGCG on the HER3 RTK and on COX-2 expression in the SW837 human colon cancer cell line that expresses a high level and constitutive activation of HER3 and also expresses a high level of COX-2. Treatment of these cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused, within 6 hours, a decrease in the phosphorylated (i.e. activated) forms of not only EGFR and HER2, but also HER3. At 6 to 12 hours there was a decrease in the phosphorylated forms of the downstream signaling proteins ERK and Akt. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activities of the COX-2, AP-1, and NF-kappaB promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 microg/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of EGFR, HER2, and HER3, a decrease in the levels of COX-2 and Bcl-xL proteins, and apoptosis. These results provide the first evidence that a low concentration of EGCG can inhibit activation of, at least, three members of the EGFR family of RTKs, and also inhibit COX-2 expression in colon cancer cells. These findings extend our previous evidence that EGCG may be useful in the chemoprevention and/or treatment of colorectal cancer.
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PMID:EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells. 1641 3

Higher levels of focal adhesion kinase (FAK) are expressed in colon metastatic carcinomas. However, the signaling pathways and their mechanisms that control cell adhesion and motility, important components of cancer metastasis, are not well understood. We sought to identify the integrin-mediated mechanism of FAK cleavage and downstream signaling as well as its role in motility in human colon cancer GEO cells. Our results demonstrate that phosphorylated FAK (tyrosine 397) is cleaved at distinct sites by integrin signaling when cells attach to collagen IV. Specific blocking antibodies (clone P1E6) to integrin alpha2 inhibited FAK activation and cell motility (micromotion). Ectopic expression of the FAK C-terminal domain FRNK attenuated FAK and ERK phosphorylation and micromotion. Calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal blocked FAK cleavage, cell adhesion, and micromotion. Antisense approaches established an important role for mu-calpain in cell motility. Expression of wild type mu-calpain increased cell micromotion, whereas its point mutant reversed the effect. Further, cytochalasin D inhibited FAK phosphorylation and cleavage, cell adhesion, locomotion, and ERK phosphorylation, thus showing FAK activation downstream of actin assembly. We also found a pivotal role for FAK Tyr(861) phosphorylation in cell motility and ERK activation. Our results reveal a novel functional connection between integrin alpha2 engagement, FAK, ERK, and mu-calpain activation in cell motility and a direct link between FAK cleavage and enhanced cell motility. The data suggest that blocking the integrin alpha2/FAK/ERK/mu-calpain pathway may be an important strategy to reduce cancer progression.
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PMID:Integrin alpha2-mediated ERK and calpain activation play a critical role in cell adhesion and motility via focal adhesion kinase signaling: identification of a novel signaling pathway. 1646 67

The epidermal growth factor has long been known to be strictly correlated with the highly proliferating activities of cancer cells and primary tumors. Moreover, in the nucleus, the epidermal growth factor/epidermal growth factor receptor complex (EGF/EGFR) functions as a transcriptional regulator that activates the cyclin D1 gene. 9-hydroxystearic acid (9-HSA) induces cell proliferation arrest and differentiation in HT29 colon cancer cells by inhibiting histone deacetylase 1 (HDAC1). 9-HSA-treated HT29, when stimulated with EGF, are not responsive and surprisingly undergo a further arrest. In order to understand the mechanisms of this effect, we analyzed the degree of internalization of the EGF/EGFR complex and its interactions with HDAC1. It appears that HDAC1, as modified by 9-HSA, is unable to associate with cyclin D1, interfering with the cell proliferation program, and sequesters the EGF/EGFR complex interrupting the transduction of the mitogenic signal.
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PMID:9-Hydroxystearic acid interferes with EGF signalling in a human colon adenocarcinoma. 1648 28

Cyclooxygenase-2 (COX-2) is an important inducible enzyme in inflammation and is overexpressed in a variety of cancers. Evidence is rapidly accumulating that chronic inflammation may contribute to carcinogenesis through increase of cell proliferation, angiogenesis, and metastasis in a number of neoplasms, including colorectal carcinoma. In the present study, we investigated some mechanistic aspects of DFX-induced hypoxia-driven COX-2 expression. Desferrioxamine (DFX), an iron chelator, is known to upregulate inflammatory mediators. DFX induced the expression of COX-2 and accumulation of HIF-1alpha protein in dose-dependent manners, but hypoxia mimetic agent cobalt chloride (CoCl2) induced accumulation of HIF-1alpha protein but not increase of COX-2 expression. DFX-induced increase of COX-2 expression and HIF-1alpha protein level was attenuated by addition of ferric citrate. This result suggested that the iron chelating function of DFX was important to induce the increase of COX-2 and HIF-1alpha protein. PD98059 significantly inhibited the induction of COX-2 protein and accumulation of HIF-1alpha, suggesting that DFX-induced increase of HIF-1alpha and COX-2 protein was mediated, at least in part, through the ERK signaling pathway. In addition, pretreatment with NS-398 to inhibit COX-2 activity also effectively suppressed DFX-induced HIF-1alpha accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of HIF-1alpha accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization of HIF-1alpha protein by modulating cyclooxygenase-2 signaling pathway.
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PMID:Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway. 1652 54

Oxaliplatin, the first line chemotherapeutic of colon cancer, induces damage to tumors via induction of apoptosis. PUMA (p53 up-regulate modulator of apoptosis) is an important pro-apoptotic member of Bcl-2 family and regulated mainly by p53. Here we investigated the role of PUMA in oxalipaltin-induced apoptosis and the potential mechanism. We showed that oxaliplatin-induced PUMA expression in a time- and dose-dependent manner and suppression of PUMA expression by stable transfecting anti-sense PUMA plasmid decreased oxaliplatin-induced apoptosis in colon cancer cells. By abrogating the function of p53, we further demonstrated that the induction was p53-independent. We also found that oxaliplatin could inactivate ERK and suppression of ERK activity by its specific inhibitor (PD98059), and dominant negative plasmid (DN-MEK1) enhanced the oxaliplatin-induced PUMA expression and apoptosis in a p53-independent manner. Taken together, our data suggest that PUMA plays an important role in oxaliplatin-induced apoptosis and the induction could be both p53-dependent and p53-independent. Moreover, PUMA expression and apoptosis in oxaliplatin-treated colon cancer cells could be regulated partly by ERK inactivation. Identification of the molecular components involved in regulating the cellular sensitivity to oxaliplatin may provide potential targets for development of novel compounds that may be useful in enhancement of oxaliplatin cytotoxicity in p53 deficient colon cancer.
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PMID:The BH3-only protein, PUMA, is involved in oxaliplatin-induced apoptosis in colon cancer cells. 1659 25

Native American medicinal plants are traditionally used to prevent and treat a variety of diseases, including cancer. These herbal preparations are alleged to have many biological activities, such as stimulation or suppression of immune responses and antiproliferative effects on cancer cells. In the present study, we investigated the effects of aqueous and ethanol extracts from two Native American plants, Ligusticum porteri (Osha) and Anemopsis californica (Yerba Manza), on the growth of human MCF-7/AZ breast and HCT8/E11 colon cancer cells. The aqueous and ethanol extracts from A. californica potently inhibited growth of MCF-7/AZ in a concentration-dependent manner, whereas the growth of HCT8/E11 was unaltered. Extracts from L. porteri showed no activity on either cell line. In addition, we observed that the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) activities were markedly decreased when exposed to both extracts from A. californica. These results suggest that the growth inhibitory effect of A. californica in breast cancer cells is ERK-mediated.
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PMID:Effects of extracts from two Native American plants on proliferation of human breast and colon cancer cell lines in vitro. 1659 6


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