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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differentiation-inducing factor-1 (DIF-1) is a chlorinated hexaphenone isolated from Dictyostelium. DIF-1 exhibits antitumor activity in several types of mammalian tumor cells, although the underlying mechanisms remain unknown. On the other hand, recent studies indicate that constitutively activated STAT3 acts as an oncogene and could be a target for antitumor drug. In the present study, we examined the effects of DIF-1 on proliferation of gastric cancer cell lines as well as on its signal transduction pathways, focusing mainly on STAT proteins. DIF-1 inhibited proliferation of gastric cancer cells. Western blot analysis and electrophoretic mobility shift assay showed that DIF-1 inhibited STAT3 activity in an MEK-ERK-dependent manner in gastric cancer cell lines, AGS and MKN28. Moreover, blockade of STAT3 activity by ectopic expression of dominant-negative STAT3 or the Janus kinase inhibitor, tyrphostin AG490, inhibited cell growth of AGS cells. These results suggest that STAT3 activity plays an important role for cell growth in AGS cells, and raises the possibility that inhibition of STAT3 activity is one of the mechanisms responsible for the antitumor effect of DIF-1 in these cells.
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PMID:Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway. 1255 68

In our search for genes associated with gastric cancer progression, we identified macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, as an overexpressed gene in gastric tumor tissues. Expression analysis of MIC-1 in gastric tumor tissues revealed a specific expression in gastric cancer cells, and this expression level was well correlated with invasive potential in various human gastric cancer cell lines. Stable transfection of MIC-1 into SNU-216, a human gastric cancer cell line, significantly increased its invasiveness. The overexpression of MIC-1 into SNU-216 cells significantly increased the activity of urokinase-type plasminogen activator (uPA), and the expressions of uPA and urokinase-type plasminogen activator receptor (uPAR). Similarly, the stimulation of gastric cancer cell lines with purified recombinant MIC-1 dose-dependently increased cell invasiveness, uPA activity, and uPA and uPAR expression. However, MIC-1 did not significantly suppress the proliferation of gastric cancer cell lines. We also found that the stimulation of human gastric cell lines with recombinant MIC-1 strongly induced activation of mitogen-activated protein kinase kinase-1/2 and extracellular signal-regulated kinase-1/2. Additional analysis revealed that PD98059, a selective inhibitor of mitogen-activated protein kinase kinase-1/2, suppressed not only gastric cancer cell invasiveness and uPA activity, but also the mRNA expressions of uPA and uPAR, as induced by recombinant MIC-1. Our results indicate that MIC-1 may contribute to the malignant progression of gastric cancer cells by inducing tumor cell invasion through the up-regulation of the uPA activation system via extracellular signal-regulated kinase-1/2-dependent pathway.
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PMID:Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system. 1290 45

Cyclooxygenase-2 (COX-2) represents the inducible key enzyme of arachidonic acid metabolism and contributes to the pathogenesis of gastroduodenal ulcers and gastric cancer. Helicobacter pylori infection is associated with elevated gastric COX-2 levels, but the mechanisms underlying H. pylori-dependent cox-2 gene expression are unclear. H. pylori stimulated cox-2 mRNA and protein abundance in gastric epithelial cells in vitro and in vivo, and functional analysis of the cox-2 gene promoter mapped its H. pylori-responsive region to a proximal CRE/Ebox element at -56 to -48. Moreover, USF1/-2 and CREB transcription factors binding to this site were identified to transmit H. pylori-dependent cox-2 transcription. Activation of MEK/ERK1/-2 signalling by bacterial virulence factors located outside the H. pylori cag pathogenicity island (cagPAI) was found to mediate bacterial effects on the cox-2 promoter. Our study provides a detailed description of the molecular pathways underlying H. pylori-dependent cox-2 gene expression in gastric epithelial cells, and may thus contribute to a better understanding of mechanisms underlying H. pylori pathogenicity.
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PMID:Helicobacter pylori stimulates host cyclooxygenase-2 gene transcription: critical importance of MEK/ERK-dependent activation of USF1/-2 and CREB transcription factors. 1453 97

Recent studies have suggested that the expression of interleukin-8 (IL-8) directly correlates with the vascularity of human gastric carcinomas. In this study, the effect of IL-1beta on IL-8 expression in human gastric cancer TMK-1 cells and the underlying signal transduction pathways were investigated. IL-1beta induced the IL-8 expression in a time- and concentration-dependent manner. IL-1beta induced the activation of extracellular signal-regulated kinases-1/2 and P38 mitogen-activated protein kinase (MAPK), but not the activation of c-jun amino-terminal kinse and Akt. Specific inhibitors of MEK-1 (PD980590) and P38 MAPK (SB203580) were found to suppress the IL-8 expression and the IL-8 promoter activity. Expression of vectors encoding a mutated-type MEK-1 and P38 MAPK resulted in decrease in the IL-8 promoter activity. IL-1beta also induced the production of reactive oxygen species (ROS). N-acetyl cysteine (NAC) prevented the IL-1beta-induced ROS production and IL-8 expression. In addition, exogenous H2O2 could induce the IL-8 expression. Deletional and site-directed mutagenesis studies on the IL-8 promoter revealed that activator protein-1 (AP-1) and nuclear factor (NF)-kappaB sites were required for the IL-1beta-induced IL-8 transcription. Electrophoretic mobility shift assay confirmed that IL-1beta increased the DNA-binding activity of AP-1 and NF-kappaB. Inhibitor (PD980590, SB203580) and ROS scavenger (NAC) studies revealed that the upstream signalings for the transcription factors AP-1 and NF-kappaB were MAPK and ROS, respectively. Conditioned media from the TMK-1 cells pretreated with IL-1beta could remarkably stimulate the in vitro growth of HUVEC and this effect was partially abrogated by IL-8-neutralizing antibodies. The above results suggest that MAPK-AP-1 and ROS-NF-kappaB signaling pathways are involved in the IL-1beta-induced IL-8 expression and that these paracrine signaling pathways induce endothelial cell proliferation.
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PMID:Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells. 1520 68

Early studies revealed that cigarette smoke promotes gastric cancer growth through the induction of cyclooxygenase-2 (COX-2). Nicotine, one of the active ingredients in cigarette smoke, has detrimental effects in the stomach. To date, there is no direct evidence to validate the effect of nicotine on gastric tumor growth and its carcinogenic mechanism(s). We therefore investigated whether nicotine could promote tumor growth and neovascularization in vivo, and the biological mechanism(s) in connection with the signaling cascade involving COX-2 and extracellular signal-regulated protein kinase (ERK). Athymic nude mice, with gastric cancer cells (AGS) orthotopically implanted into the gastric wall, treated with nicotine (50 or 200 microg/ml) in their drinking water for 3 months developed larger tumor areas than mice in the control group. Nicotine further increased proliferating cellular nuclear antigen (PCNA) staining and microvessel density by 70 and 30%, respectively, with concomitant activation of ERK phosphorylation, COX-2 and vascular endothelial growth factor (VEGF) expression in the tumors. Intraperitoneal administration of a selective COX-2 inhibitor (SC-236, 2 mg/kg) prevented the nicotine-induced tumor growth and neovascularization dose-dependently. Consistent with our animal model, an in vitro study also demonstrated that incubation with nicotine (50-200 microg/ml) for 5 h stimulated cell proliferation dose-dependently and increased COX-2 expression, prostaglandin E(2) (PGE(2)) and VEGF release, as well as activation of ERK phosphorylation. Pre-treatment with specific mitogen-activated protein kinase kinase (MEK) inhibitors (U0126 or PD98059) attenuated COX-2 expression and subsequent PGE(2) release by nicotine. Furthermore, the stimulatory action of nicotine on cancer cell growth and angiogenic factor VEGF production was suppressed by inhibitors of MEK (U0126) and COX-2 (SC-236). These findings reveal a direct promoting action of nicotine on the growth of gastric tumor and neovascularization through sequential activation of the ERK/COX-2/VEGF signaling pathway, which can be targeted for chemoprevention of gastric cancer, particularly in cigarette smokers.
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PMID:Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2. 1531 99

Overexpression of urokinase plasminogen activator receptor (uPAR) is known to correlate closely with tumor cell invasion and metastasis. In gastric cancer, however, the mechanism for induction of uPAR remains to be elucidated. In this study, to investigate the effect of reactive oxygen species (ROS) on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells, phenazine methosulfate (PMS) and H2O2 were used as ROS generator. PMS and H2O2 induced the uPAR expression in time- and concentration-dependent manner. PMS and H2O2 also induced the activation of extracellular signal-regulated kinases (Erk)-1/2. A specific inhibitor of MEK-1 (PD980590) was found to suppress the PMS-induced uPAR expression and the uPAR promoter activity. Expression of vectors encoding a mutated-type MEK-1 resulted in decreases in the uPAR promoter activity. Electrophoretic mobility shift assay revealed that PMS increased time-dependently the DNA binding activity of AP-1. Transient transfection studies using AP-1 decoy confirmed that the activation of AP-1 is involved in PMS-induced uPAR upregulation. The AGS cells pretreated with PMS showed a remarkably enhanced invasiveness and this effect was partially abrogated by uPAR neutralizing antibodies. The above results suggest that ROS induces uPAR expression via Erk-1/2 and AP-1 signaling pathways and, in turn, stimulates the cell invasiveness in human gastric cancer AGS cells.
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PMID:Extracellular signal-regulated kinase and AP-1 pathways are involved in reactive oxygen species-induced urokinase plasminogen activator receptor expression in human gastric cancer cells. 1587 Aug 84

The gastric pathogen Helicobacter pylori (H. pylori) is suggested to be associated with gastric cancer progression. In this study, we investigated the effect of H. pylori on urokinase plasminogen activator receptor (uPAR) expression which has been known to correlate closely with gastric cancer invasion. H. pylori induced the uPAR expression in a time- and concentration-dependent manner. Specific inhibitors and inactive mutants of MEK-1 and JNK were found to suppress the H. pylori-induced uPAR expression and the uPAR promoter activity. Electrophoretic mobility shift assay and transient transfection study using an AP-1 decoy oligonucleotide confirmed that the activation of AP-1 is involved in the H. pylori-induced uPAR upregulation. The AGS cells treated with H. pylori showed a remarkably enhanced invasiveness, and this effect was partially abrogated by uPAR-neutralizing antibodies. These results suggest that H. pylori induces uPAR expression via Erk-1/2, JNK, and AP-1 signaling pathways and, in turn, stimulates the cell invasiveness in human gastric cancer AGS cells.
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PMID:Urokinase plasminogen activator receptor is upregulated by Helicobacter pylori in human gastric cancer AGS cells via ERK, JNK, and AP-1. 1596 60

Gastric cancers with liver metastasis are fatal diseases with rapid progression and poor patient outcome. To date, however, the molecular basis of their growth and metastasis remains essentially unknown, largely because of the presence of few available gastric cancer cell lines established from liver metastasis. In the present study, we developed two novel cultured cell lines (designated GLM-1 and GLM-2) and one transplantable line in nude mice (designated GLM-3) derived from liver metastasis of gastric cancer patients. These GLM cell lines share unique biological features such as differentiation, growth and metastasis. They form moderately differentiated tumors with CD10 positive and MUC2 negative intestinal absorptive phenotype when injected into nude mice. Their growth is stimulated by EGF and TGF-alpha in vitro like other gastric cancer cell lines. However, GLM cells differ from conventional gastric cancer cell lines in their high apoptotic rate, even in the absence of apoptosis inducing stimuli as revealed by Caspase3/7 assay and the TUNEL method. This apoptosis is further enhanced by phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not by MEK1/2 inhibitor (U0126), indicating the strong dependency of their survival on PI3K/Akt pathway rather than MAPK pathway, the major downstream signaling pathways of EGFR. GLM-1 cells can metastasize to the liver after intrasplenic injection, and GLM-3 cells have spontaneous lung metastatic potential after subcutaneous transplantation, respectively. These results indicate that the GLM series are the first cell lines reflecting the intestinal-type differentiated adenocarcinoma, a major subtype of gastric cancer with liver metastasis. Therefore, they would be excellent models for understanding the mechanism of metastatic growth and the development of a new molecular targeting therapy for gastric cancer with liver metastasis.
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PMID:Establishment and characterization of three novel human gastric cancer cell lines with differentiated intestinal phenotype derived from liver metastasis. 1608 34

Helicobacter pylori infection increases the risk of hyperplastic polyps and gastric cancer, but the mechanisms remain to be elucidated. H. pylori was recently shown to transactivate epidermal growth factor receptor (EGFR) through metalloprotease stimulation. The present study was designed to investigate the effect of interleukin-8 (IL-8) induced by H. pylori infection on EGFR transactivation and epithelial cell growth. H. pylori Sydney strain 1 (SS1) having wild-type cag(+)A was used. Phospho-EGFR assay was performed by immunoprecipitation using anti-human EGFR and anti-phosphotyrosine antibodies. DNA synthesis was evaluated by [3H]thymidine uptake using the human gastric cancer cell line, KATO III. H. pylori induced EGFR phosphorylation, and a disintegrin and metalloproteinase (ADAM) inhibitor, KB-R7785, completely suppressed EGFR phosphorylation. IL-8 also induced EGFR phosphorylation, while anti-IL-8 and anti-IL-8 receptor (CXCR1) neutralizing antibodies suppressed EGFR phosphorylation. [(3)H]Thymidine uptake analysis demonstrated that H. pylori increased DNA synthesis in gastric epithelial cells, and tyrosine kinase inhibitor, MEK inhibitor, and ADAM inhibitor suppressed the DNA synthesis induced by H. pylori. H. pylori-stimulated IL-8 accelerates processing of EGFR ligands through ADAM activation, and cleaved EGFR ligands bind and stimulate EGFR in paracrine and autocrine manners to induce cell proliferation. This may be one of the mechanisms of hyperplastic polyp and gastric cancer development in H. pylori-infected gastric mucosa.
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PMID:Helicobacter pylori-stimulated interleukin-8 (IL-8) promotes cell proliferation through transactivation of epidermal growth factor receptor (EGFR) by disintegrin and metalloproteinase (ADAM) activation. 1624 Feb 19

Cyclooxygenase-2 (COX-2) expression is a marker of poor prognosis in gastric cancer patients, and its inhibition suppresses gastric tumorigenesis in experimental animal models. The mechanism that leads to COX-2 overexpression in this tumor type is unknown. We have now shown that inhibition of phosphatidylinositol 3-kinase by LY294002 suppresses both basal and phorbol myristate acetate-induced COX-2 expression in TMK-1 and MKN-28 gastric cancer cells. Furthermore, inhibition of glycogen synthase kinase-3beta (GSK-3beta) by SB415286 induced expression of COX-2 mRNA and protein as well as the enzyme activity in the gastric cancer cells. The effect of SB415286 was confirmed by the use of two additional GSK-3beta inhibitors, lithium chloride and SB216763. SB415286 had a modest 1.6-fold stimulatory effect on a 2-kb COX-2 promoter reporter construct, but more importantly, it was shown to block the decay of COX-2 mRNA. In contrast to modulation of phosphatidylinositol 3-kinase/Akt/GSK-3beta pathway, inhibitors of mitogen-activated protein kinases (MEK 1/2, p38, JNK) or the mammalian target of rapamycin did not alter COX-2 expression in gastric cancer cells. Our data show that inhibition of GSK-3beta stimulates COX-2 expression in gastric cancer cells, which seems to be primarily facilitated via an increase in mRNA stability and to a lesser extent through enhanced transcription.
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PMID:Expression of cyclooxygenase-2 is regulated by glycogen synthase kinase-3beta in gastric cancer cells. 1637 52


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