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

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyamine depletion with the ornithine decarboxylase inhibitor alpha-difluoromethyl ornithine (DFMO), prevents Rac1 activation causing the formation of a thick actin cortex at the cell periphery and inhibits migration of intestinal epithelial cells. In the present study, we demonstrate that MEK activation by EGF increased Rac1 activation, dissociation of intercellular contacts, and migration in both control and polyamine-depleted cells, while U0126, a specific inhibitor of MEK1, prevented disruption of junctions as well as EGF-induced Rac1 activation. Constitutively active MEK1 (CA-MEK) expression altered cell-cell contacts in control and polyamine depleted cells. The expression of constitutively active Rac1 (CA-Rac1) restored beta-catenin to the cell periphery and prevented the formation of actin cortex and caused the appearance of F-actin stress fibers in polyamine-depleted cells. Inhibition of Rac activation by NSC23766, a specific inhibitor of Tiam1, an upstream guanidine nucleotide exchange factor for Rac1, reproduced the beta-catenin localization and actin structure of polyamine-depleted cells. Tiam1 localized more extensively with beta-catenin at the cell periphery in CA-Rac1 cells compared to vector cells. Polyamine depletion decreased the expression of E-cadherin to a greater extent compared to beta-catenin. Subcellular fractionation further confirmed our immuno-localization and western blotting observations. These data suggest that EGF acting through MEK1/ERK to activate Rac1 regulates cell-cell contacts. Thus, decreased migration in polyamine depleted cells may be due to the inhibition of Tiam1 activation of Rac1 and the subsequent decreased expression of beta-catenin and E-cadherin leading to reduced cell-cell contacts.
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PMID:MEK/ERK regulates adherens junctions and migration through Rac1. 1718 46

Many human breast cancer cell lines have been in culture for several years, serving as model systems for studying aspects of breast cancer biology. Molecular alterations might occur in these cells during cultivation, and it remains unknown to which extent findings in these cell lines can be related to human disease. Hereby, we describe the establishment of a breast cancer cell line, MW1, from malignant pleural effusion. We compare expression patterns of several molecular markers in breast biopsy tissue, in cultivated tumor cells derived from pleural effusion reflecting the metastatic state, and in late passages of a lineage derived from the pleural culture. Our data show that expression of estrogen and progesterone receptors was lost in the cultivated tumor cells derived from pleural effusion as shown by immunohistochemical staining. Cytokeratin expression patterns remained luminal. During cultivation, the growth rate of MW1 cells increased dramatically and the morphology underwent alterations. As shown by Western blotting, E-cadherin expression remained unchanged whereas P-cadherin expression had increased after 4 years of cultivation of the cell line. Integrin beta4 expression was low in early passages of the pleural effusion whereas the cell line exhibited high expression levels of beta4. HGF receptor (c-Met), EGF receptor, VEGF and VEGF receptor-2 (KDR) expression was detectable by semiquantitative RT-PCR and remained unchanged during cultivation. In contrast, VEGF receptor-1 (flt-1) expression showed lower expression after 4 years of cultivation. The cell line migrated towards HGF, but not towards VEGF. This study provides exemplary insight into the molecular metamorphosis tumor cells undergo in vivo or in vitro on their way from the primary tumor via an equivalent of the metastatic state and during the development of a clonal cell line.
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PMID:A novel breast cancer cell line initially established from pleural effusion: evolution towards a more aggressive phenotype. 1727 57

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid, which has been shown to exert beneficial effects against breast carcinogenesis. It has been reported that CLA could modulate cellular proliferation and differentiation through the activation of peroxisome proliferator-activated receptors (PPARs). Among different PPAR isotypes, PPAR gamma is involved in growth inhibition of transformed cells. Ligands of PPAR gamma are considered as potential anticancer drugs, so CLA was tested for its ability to induce PPAR gamma expression in MCF-7 breast cancer cells. The effects of CLA and of a specific synthetic PPAR gamma antagonist were evaluated on cell growth as well as on parameters responsible for cell growth regulation. We demonstrated here that CLA stimulated the expression of PPAR gamma to levels up to control and caused PPAR gamma translocation into the nucleus. Furthermore, the overexpression of PPAR gamma positively correlates with the inhibition of cell proliferation and with the modulation of ERK signaling induced by CLA; in all cases the administration of the antagonist reverted CLA effects. The PPAR-signaling pathway is connected with the beta-catenin/E-cadherin pathway, thus we evaluated CLA effects on the expression and cellular distribution of these proteins, which are involved in cell adhesion and responsible for invasive behavior. The treatment with CLA determined the up-regulation and the redistribution of beta-catenin and E-cadherin and the antagonist reverted only the effect on beta-catenin. These studies indicate that CLA regulates PPAR gamma expression by selectively acting as an agonist and may influence cell-cell adhesion and invasiveness of MCF-7 cells.
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PMID:Involvement of PPAR gamma and E-cadherin/beta-catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF-7 cells. 1735 22

E-cadherin function leads to the density-dependent contact inhibition of cell growth. Because cadherins control the overall state of cell contact, cytoskeletal organization, and the establishment of many other kinds of cell interactions, it remains unknown whether E-cadherin directly transduces growth inhibitory signals. To address this question, we have selectively formed E-cadherin homophilic bonds at the cell surface of isolated epithelial cells by using functionally active recombinant E-cadherin protein attached to microspheres. We find that E-cadherin ligation alone reduces the frequency of cells entering the S phase, demonstrating that E-cadherin ligation directly transduces growth inhibitory signals. E-cadherin binding to beta-catenin is required for cell growth inhibition, but beta-catenin/T-cell factor transcriptional activity is not involved in growth inhibition resulting from homophilic binding. Neither E-cadherin binding to p120-catenin nor beta-catenin binding to alpha-catenin, and thereby the actin cytoskeleton, is required for growth inhibition. E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a beta-catenin-dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but it inhibits transphosphorylation of Tyr845 and activation of signal transducers and activators of transcription 5. Thus, E-cadherin homophilic binding independent of other cell contacts directly transduces growth inhibition by a beta-catenin-dependent mechanism that inhibits selective signaling functions of growth factor receptors.
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PMID:E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. 1739 17

Intratumoral hypoxia is an independent indicator of poor patient outcome and increasing evidence supports a role for hypoxia in the development of metastatic disease. Studies suggest that the acquisition of the metastatic phenotype is not simply the result of dysregulated signal transduction pathways, but instead is achieved through a stepwise selection process driven by hypoxia. Hypoxia facilitates disruption of tissue integrity through repression of E-cadherin expression, with concomitant gain of N-cadherin expression which allows cells to escape anoikis. Through upregulation of urokinase-type plasminogen activator receptor (uPAR) expression, hypoxia enhances proteolytic activity at the invasive front and alters the interactions between integrins and components of the extracellular matrix, thereby enabling cellular invasion through the basement membrane and the underlying stroma. Cell motility is increased through hypoxia-induced hepatocyte growth factor (HGF)-MET receptor signaling, resulting in cell migration towards the blood or lymphatic microcirculation. Hypoxia-induced vascular endothelial growth factor (VEGF) activity also plays a critical role in the dynamic tumor-stromal interactions required for the subsequent stages of metastasis. VEGF promotes angiogenesis and lymphangiogenesis in the primary tumor, providing the necessary routes for dissemination. VEGF-induced changes in vascular integrity and permeability promote both intravasation and extravasation, while VEGF-induced angiogenesis in the secondary tissue is essential for cell proliferation and establishment of metastatic lesions. Through regulation of these critical molecular targets, hypoxia promotes each step of the metastatic cascade and selects tumor cell populations that are able to escape the unfavorable microenvironment of the primary tumor.
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PMID:Hypoxia-driven selection of the metastatic phenotype. 1745 7

SS18-SSX fusion genes resulting from a chromosomal translocation t(X;18)(p11.2;q11.2) are a genetic hallmark of synovial sarcoma. Although such cytogenetic or molecular aberrations have mostly been detected by fluorescence in situ hybridization or reverse transcription-polymerase chain reaction, the expression of SS18-SSX has been poorly investigated at a cellular or tissue level. In this study, biotinylated tyramide (BT)-based in situ hybridization (ISH) was performed to detect SS18-SSX transcripts using formalin-fixed, paraffin-embedded tissues from 15 synovial sarcomas. Digoxigenin-labeled cRNA probes flanking the fusion points of SS18-SSX1 and SS18-SSX2 were generated by in vitro transcription, and hybridized signals were detected by a streptavidin-biotin complex method after chemical enhancement with BT. The localizations of signals were compared with the immunohistochemical expressions of epithelial or neuroectodermal markers and those of cell adhesion including cytokeratins (CAM5.2, AE1/AE3, CK7), epithelial membrane antigen, E-cadherin, beta-catenin, c-erbB-2 (HER2/neu), CD56, and claudin-1. The ISH signals of the SS18-SSX transcripts were identified in 13 synovial sarcomas, and their fusion types correlated with those determined by reverse transcription-polymerase chain reaction. In biphasic tumors, the ISH signals tended to localize to epithelial areas, whereas spindle-cell areas or monophasic fibrous tumors showed a less intense or focal expression pattern. Notably, the expression patterns of AE1/AE3, CK7, and c-erbB-2 often colocalized with the ISH signals (7 of 11 cases positive for each marker). Our results suggest that BT-based ISH can be used as a molecular technique for the detection of SS18-SSX using formalin-fixed, paraffin-embedded tissues.
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PMID:Molecular detection of SS18-SSX fusion gene transcripts by cRNA in situ hybridization in synovial sarcoma using formalin-fixed, paraffin-embedded tumor tissue specimens. 1747 Nov 53

Twist, a newly found EMT-inducer, has been reported to be up-regulated in those of diffuse-type gastric carcinomas with high N-cadherin level. We show here MKN45, a cell line derived from undifferentiated carcinomas cells, expresses high levels of Twist. Down-regulation of Twist, using an antisense Twist vector in MKN45 cells, inhibits cell migration and invasion, companied with a morphologic changes associated with MET. Suppression of Twist also decreases the expressions of N-cadherin and fibronectin, but not of E-cadherin in MKN45. In contrast, overexpression of Twist in MKN28, a cell line derived from moderate differentiated carcinomas, results in up-regulation of N-cadherin and fibronectin, companied with down-regulation of E-cadherin. Taken together, our results suggest that Twist regulates cell motility and invasion in gastric cancer cell lines, probably through the N-cadherin and fibronectin production.
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PMID:Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. 1751 4

Ovarian carcinomas overexpress endothelin A receptors (ET(A)R) and epidermal growth factor (EGF) receptor (EGFR). In these cells, endothelin-1 (ET-1) triggers mitogenic and invasive signaling pathways that are in part mediated by EGFR transactivation. Combined targeting of ET(A)R, by the specific ET(A)R antagonist ZD4054, and of EGFR by the EGFR inhibitor gefitinib (IRESSA), may offer improvements in ovarian carcinoma treatment. In HEY and OVCA 433 ovarian carcinoma cells, ET-1 or EGF induced rapid activation of EGFR, p42/44 mitogen-activated protein kinase (MAPK), and AKT. ZD4054 was able to reduce the ET-1-induced EGFR transactivation. Gefitinib significantly inhibited EGF- and ET-1-induced EGFR phosphorylation, but incompletely reduced the ET-1-induced activation of downstream targets. ZD4054 plus gefitinib resulted in a greater inhibition of EGFR, MAPK, and AKT phosphorylation, indicating the critical role of these interconnected signaling proteins. ZD4054 effectively inhibited cell proliferation, invasiveness, and vascular endothelial growth factor (VEGF) secretion. Concomitantly, ZD4054 enhanced apoptosis and E-cadherin promoter activity and expression. In both cell lines, the drug combination resulted in a significant decrease in cell proliferation (65%), invasion (52%), and VEGF production (50%), accompanied by a 2-fold increase in apoptosis. The coadministration of ZD4054 enhanced the efficacy of gefitinib leading to partial (82%) or complete tumor regression on HEY ovarian carcinoma xenografts. Antitumor effects were paralleled by biochemical and immunohistologic evidence of decreased vascularization, Ki-67, matrix metalloproteinase-2 (MMP-2), VEGF, MAPK and EGFR, and enhanced E-cadherin expression. The cross-signaling between the EGFR/ET(A)R pathways provides a rationale to combine EGFR inhibitors with ET(A)R antagonists, identifying new effective therapeutic opportunities for ovarian cancer.
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PMID:Combined targeting of endothelin A receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. 1761 94

An 83-year-old woman with long-standing chronic ischemic cardiac and obstructive pulmonary disease, presented with a painless tumor in her right breast. Microscopically the tumor consisted of micropapillary formations and loosely cohesive nests and strands of large, highly pleomorphic cells. Micropapillary formations were surrounded by peritumoral retraction clefting, and the papillae lacked a true fibrovascular core. Multinucleated giant and bizarre tumor cells were also present and numerous. Within the tumor a high-grade intraductal component with the same cell morphology and necrosis and mucin production was found. Micropapillary pattern occupied approximately 60% of the tumor mass, loosely cohesive nests and strands approximately 20% and an intraductal component was noted in approximately 20% of the tumor mass. On immunohistochemistry the tumor cells were positive for pan-cytokeratin, epithelial membrane antigen (EMA), S100 protein and E-cadherin while estrogen and progesterone receptors, HER2-neu and Bcl2 were negative. EMA staining was diffuse and observed in the outer and inner margins of neoplastic nests. The diagnosis of pleomorphic breast carcinoma with predominant micropapillary features was established. In summary, micropapillary carcinoma can be distinguished from other types of breast carcinoma with micropapillary growth pattern on the basis of reverse cell polarity, which is easily confirmed on immunohistochemistry.
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PMID:Pleomorphic ductal carcinoma of the breast with predominant micropapillary features. 1780 59

Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression.
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PMID:Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. 1790 10


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