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)

Recently, we have shown that autocrine transforming growth factor-alpha (TGF-alpha) controls the expression of integrin alpha2, cell adhesion to collagen IV and motility in highly progressed HCT116 colon cancer cells (Sawhney, R. S., Zhou, G-H. K., Humphrey, L. E., Ghosh, P., Kreisberg, J. I., and Brattain, M. G. (2002) J. Biol. Chem. 277, 75-86). We now report that expression of basal integrin alpha2 and its biological effects are controlled by constitutive activation of the extracellular signal-regulated/mitogen-activated protein kinase (ERK/MAPK) pathway. Treatment of cells with selective mitogen-activated protein kinase kinase (MEK) inhibitors PD098059 and U0126 showed that integrin alpha2 expression, cell adhesion, and activation of ERK are inhibited in a parallel concentration-dependent fashion. Moreover, autocrine TGF-alpha-mediated epidermal growth factor receptor activation was shown to control the constitutive activation of the ERK/MAPK pathway, since neutralizing antibody to the epidermal growth factor receptor was able to block basal ERK activity. TGF-alpha antisense-transfected cells also showed attenuated activation of ERK. Using a real time electric cell impedance sensing technique, it was shown that ERK-dependent integrin alpha2-mediated cell micromotion signaling is controlled by autocrine TGF-alpha. Thus, this study implicates ERK/MAPK signaling activated by endogenous TGF-alpha as one of the mechanistic features controlling metastatic spread.
 ...
PMID:Integrin alpha2 and extracellular signal-regulated kinase are functionally linked in highly malignant autocrine transforming growth factor-alpha-driven colon cancer cells. 1265 25

Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. VEGF (vascular endothelial growth factor) is known to be the most important proangiogenic factor, necessary for the development of new tumor vessels. Specific inhibitors of the VEGF receptor tyrosine kinases, like PTK787/ZK222584 (PTK/ZK), have shown antitumoral and antiangiogenic activity in several animal models. Ongoing early clinical trials with antiangiogenic compounds reveal the need for diagnostic methods to detect their biological activity. Pro-angiogenic growth factors like VEGF and bFGF (basic fibroblast growth factor), soluble variants of proangiogenic receptors like sFLT-1 and sTIE-2, as well as endothelial activation markers like sE-Selectin, can be measured in the serum and plasma of patients by the ELISA technique. They were detected in various malignant diseases to assess their use as surrogate markers in tumor angiogenesis. In different clinical Phase I trials with antiangiogenic compounds, these soluble markers were used to detect dose levels for biological activity. Soluble markers of tumor angiogenesis can be used as prognostic markers in various malignancies like colon cancer or multiple myeloma. Furthermore, they correlated with disease activity, prognosis and imaging techniques for the detection of vascular changes. In clinical Phase I trials with specific inhibitors of the VEGF receptor tyrosine kinases, VEGF serum levels increased in patients treated with higher doses, indicating increasing tumor hypoxia. Taking results from imaging techniques such as dynamic enhanced MRI into account, optimal doses for biological activity could be concluded. New biological treatment techniques will need new diagnostic methods to assess their specific biological activity in patients. Soluble markers and imaging techniques are useful tools for the detection of hypoxia under antiangiogenic treatment. Nevertheless, these techniques are still experimental. Therefore, further clinical evaluation is necessary.
 ...
PMID:Soluble markers for the detection of hypoxia under antiangiogenic treatment. 1282 Mar 65

In a search for new fungal compounds inducing apoptosis of the colon cancer derived cell line COLO-320, hormonemate (1) was purified from fermentations of an endophytic fungus isolated from living needles of a Pinus species. The producing strain was identified as Hormonema dematioides by microscopy and ITS rDNA sequence analysis. The structure of hormonemate was determined by spectroscopic methods. The compound exhibited cytotoxic effects against the human colon tumor cell lines COLO-320, DLD-1 and HT-29 as well as five other human cell lines (HL-60, JURKAT, HEP-G2, MCF-7, HeLa S3). It also induced apoptosis in COLO-320 cells as detected by a caspase-activity assay and morphological changes, and it triggered morphological and physiological differentiation of HL-60 cells into granulocytes, which subsequently died by apoptosis.
 ...
PMID:Hormonemate, a new cytotoxic and apoptosis-inducing compound from the endophytic fungus Hormonema dematioides. I. Identification of the producing strain, and isolation and biological properties of hormonemate. 1293 42

Hematogenous spread of tumor cells and metastasis formation in the liver are insidious aspects of cancer progression and are not frequently amenable to curative treatment. We examined the effect of Linomide and antibody-targeted therapy against the formation of hepatic metastases in vivo. For this purpose, syngenic B16 melanoma cells transfected with GA733-2 (a human colon cancer cell surface antigen) were injected into a mesenteric vein of C57/Bl6 mice. To test bacterial superantigen (Sag) targeting for immunotherapy of liver metastases, we used genetically fused proteins consisting of SEA and a Fab moiety of a GA733-2 tumor-reactive antibody (C215Fab-SEA). Linomide dose-dependently reduced hepatic metastases, and at 300 mg/kg this reduction was more than 80%. Treatment with C215Fab-SEA decreased metastases formation by 49% and the combination of Linomide and C215Fab-SEA was found to completely abolish liver metastases (>99% reduction). Taken together, our novel data suggest that Linomide and antibody-targeted superantigen therapy individually markedly reduce and together abolish liver metastases. Considering that current therapy of hepatic metastases is mainly limited to surgical resection in a subgroup of patients, these findings indicate that Linomide alone or in combination with antibody-targeted superantigen may provide a novel approach against liver metastases.
 ...
PMID:Linomide and antibody-targeted superantigen therapy abolishes formation of liver metastases in mice. 1459 28

Transcriptional repression of E-cadherin, characteristic of epithelial to mesenchymal transition, is often found also during tumor cell invasion. At metastases, migratory fibroblasts sometimes revert to an epithelial phenotype, by a process involving regulation of the E-cadherin-beta-catenin complex. We investigated the molecular basis of this regulation, using human colon cancer cells with aberrantly activated beta-catenin signaling. Sparse cultures mimicked invasive tumor cells, displaying low levels of E-cadherin due to transcriptional repression of E-cadherin by Slug. Slug was induced by beta-catenin signaling and, independently, by ERK. Dense cultures resembled a differentiated epithelium with high levels of E-cadherin and beta-catenin in adherens junctions. In such cells, beta-catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable. Disruption of E-cadherin-mediated contacts resulted in nuclear localization and signaling by beta-catenin, induction of Slug and inhibition of E-cadherin transcription, without changes in ErbB-1/2 and ERK activation. This autoregulation of E-cadherin by cell-cell adhesion involving Slug, beta-catenin and ERK could be important in tumorigenesis.
 ...
PMID:Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. 1462 71

The AP-1 (activator protein-1) complex, which consists of proteins of the Fos and Jun families, is thought to play an important role in the balance between cell proliferation and apoptosis, the response to genotoxic stress and cell transformation. In cells containing oncogenic Ras, the major components of AP-1 are Fra-1 and c-Jun. Signalling from Ras to AP-1 is through the Raf/MEK[mitogen-activated protein (MAP) kinase kinase]/ERK (extracellular signal-regulated kinase) MAP kinase pathway as sustained activation of Raf1 or Mek1 modifies AP-1 composition and activity. To analyse the potential link between the ERK-MAPK pathway and AP-1 in colon cancer, in which RAS and BRAF mutations are frequent, we have studied the regulation of AP-1 in colon carcinoma cell lines. We show that c-JUN and FRA-1 expression is dependent on ERK activity and that different thresholds of ERK activity control the expression of FRA-1. A basal activity is required to induce transcription of the FRA-1 gene, but additional higher levels of activity stabilize FRA-1 against proteasome-dependent degradation. These results provide a clear-cut example that the magnitude of ERK signalling affects the cellular response. Although we find no contribution of FRA-1 towards cell proliferation of adherent tumour cells, the high levels of FRA-1 in cells where elevated ERK activity leads to protein stabilization provide survival signals for tumour cells removed from the extracellular matrix.
 ...
PMID:Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells. 1462 89

Troglitazone (TGZ) and 15-deoxy-Delta(12,14)-prostaglandin J2 (PGJ2) are peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands that have been shown to possess pro-apoptotic activity in human colon cancer. Although these compounds bind to PPARgamma transcription factors as agonists, emerging evidence suggests that TGZ acts independently of PPARgamma in many functions, including apoptosis. We previously reported that TGZ induces an early growth response transcription factor (EGR-1) by the ERK phosphorylation pathway rather than by the PPARgamma pathway (Baek, S. J., Wilson, L. C., Hsi, L. C., and Eling, T. E. (2003) J. Biol. Chem. 278, 5845-5853). In this report, we show that the expression of the antitumorigenic and/or pro-apoptotic gene NAG-1 (nonsteroidal anti-inflammatory drug-activated gene-1) is induced by TGZ and correlates with EGR-1 induction. In cotransfection and gel shift assays, we show that EGR-1-binding sites are located within region -73 to -51 of the NAG-1 promoter and have an important role in the transactivation of TGZ-induced NAG-1 expression. In contrast, PGJ2 induced NAG-1 protein expression, but PGJ2 may not affect the same region that TGZ does in the NAG-1 promoter. The effect of PGJ2 is probably PPARgamma-dependent because a PPARgamma antagonist inhibited the PGJ2-induced expression of NAG-1. TGZ-induced NAG-1 expression was not inhibited by the PPARgamma antagonist. The fact that TGZ-induced NAG-1 expression was accompanied by the biosynthesis of EGR-1 also suggests that EGR-1 plays a pivotal role in TGZ-induced NAG-1 expression. Our results suggest that EGR-1 induction is a unique property of TGZ, but is independent of PPARgamma activation. The up-regulation of NAG-1 may provide a novel explanation for the antitumorigenic property of TGZ.
 ...
PMID:Expression of NAG-1, a transforming growth factor-beta superfamily member, by troglitazone requires the early growth response gene EGR-1. 1466 74

Activation of MAP kinases is involved in various cellular processes, including immunoregulation, inflammation, cell growth, cell differentiation, and cell death. To investigate the role of p38 MAP kinase activation in the signaling pathway of TRAIL-mediated apoptosis, we compared TRAIL-mediated MAP kinase activation in TRAIL-susceptible human colon cancer cell line DLD1 and TRAIL-resistant DLD1/TRAIL-R cells. TRAIL-mediated activation of ERK occurred in both cell lines. In contrast, both DLD1 and DLD1/TRAIL-R cells showed no obvious JNK activation after treatment with TRAIL. Interestingly, TRAIL-mediated activation of p38 MAP kinases was observed in DLD1 cells but not in DLD1/TRAIL-R cells. However, activation of p38 MAP kinases was observed in both DLD1 and DLD1/TRAIL-R cells after treatment with anisomycin. Furthermore, inhibiting activated p38 MAP kinases with known inhibitors or with an adenovector expressing dominant negative p38alpha did not block TRAIL-mediated cell death in DLD1 cells. Moreover, activation of p38 MAP kinases by adenovectors expressing constitutive MKK3 or MKK6 (Ad/MKK3bE or Ad/MKK6bE) did not induce cell death in either DLD1 or DLD1/TRAIL-R cell lines. Our results suggest that activation of p38 MAP kinases does not play a major role in TRAIL-mediated apoptosis in DLD1 cells and that lack of TRAIL-mediated p38 MAP kinase activation may not be the mechanism of TRAIL-resistance in DLD1/TRAIL-R cells.
 ...
PMID:Lack of p38 MAP kinase activation in TRAIL-resistant cells is not related to the resistance to TRAIL-mediated cell death. 1510 6

Little information is available as to the potential role of HER-2 as a therapeutic target in colon cancers, which express much fewer HER-2 receptors than breast cancer cells. Treatment of certain human colon cancer cell lines with the HER-2 inhibitory antibody mAb 4D5 demonstrated a role for HER-2 in mediating proliferation, apoptosis and tumorigenicity. However, only the cell lines that were dependent on autocrine EGFR-mediated cell proliferation were susceptible to the antiproliferative and antitumorigenic effects of HER-2 inhibition. The relative levels of HER-2, EGFR, HER-3 and HER-4 were not predictive of responsiveness to mAb 4D5. Treatment with HER-2 antibodies caused a decrease in HER-2 protein levels in all of the colon cancer cell lines and also significantly decreased EGFR levels but only in the EGFR-dependent cell lines. Treatment with mAb 4D5 caused the rapid ubiquitination and ligand-dependent downregulation of the EGFR in an EGFR-dependent colon cancer cell line. Treatment of athymic mice engrafted with EGFR-dependent colon cancer cells with mAb 4D5 caused tumor regression and a decrease in EGFR tyrosine phosphorylation in the tumor cells. EGFR-independent colon cancer cell xenografts were resistant to mAb 4D5 therapy. Combined inhibition of HER-2 and EGFR caused large areas of necrosis in EGFR-dependent colon cancer xenografts, suggesting a benefit of combined HER-2 and EGFR inhibitor therapy. Predicting clinical responsiveness of human colon cancer cells to anti-HER-2 and anti-EGFR therapy may require demonstration of EGFR tyrosine kinase dependency of the cells.
 ...
PMID:Effects of trastuzumab on epidermal growth factor receptor-dependent and -independent human colon cancer cells. 1475 Jan 83

Dok-like adapter molecules represent an expanding family of pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domain-containing tyrosine kinase substrates with negative regulatory functions in hematopoietic cell signaling. In a search for nonhematopoietic counterparts to Dok molecules, we identified and characterized Dok-4, a recently cloned member of the family. dok-4 mRNA was strongly expressed in nonhematopoietic organs, particularly the intestine, kidney, and lung, whereas both mRNA and protein were expressed at high levels in cells of epithelial origin. In Caco-2 human colon cancer cells, endogenous Dok-4 underwent tyrosine phosphorylation in response to pervanadate stimulation. In transfected COS cells, Dok-4 was a substrate for the cytosolic tyrosine kinases Src and Fyn as well as for Jak2. Dok-4 could also be phosphorylated by the receptor tyrosine kinase Ret but not by platelet-derived growth factor receptor-beta or IGF-IR. In both mammalian cells and yeast, Dok-4 was constitutively localized at the membrane in a manner that required both its PH and PTB domains. The PH and PTB domains of Dok-4 were also required for tyrosine phosphorylation of Dok-4 by Fyn and Ret. Finally, wild type Dok-4 strongly inhibited activation of Elk-1 induced by either Ret or Fyn. The attenuation of this inhibitory effect by deletion of the PH domain and its restoration by the addition of a myristoylation signal suggested an important role for constitutive membrane localization of Dok-4. In summary, Dok-4 is a constitutively membrane-localized adapter molecule that may function as an inhibitor of tyrosine kinase signaling in epithelial cells.
 ...
PMID:Pleckstrin homology and phosphotyrosine-binding domain-dependent membrane association and tyrosine phosphorylation of Dok-4, an inhibitory adapter molecule expressed in epithelial cells. 1496 42


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