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)

MKK4, located in close proximity to p53 gene, is thought to be a tumor suppressor and a metastasis suppressor gene. A low-rate MKK4 gene alteration has been found in a few tumor types, including breast and pancreatic. A suppressor activity for prostate and ovarian tumor metastasis has also been suggested. To understand the pathobiologic roles of MKK4 in tumorigenesis, we examined the phenotypic changes in response to perturbation of the MKK4 expression in breast and pancreatic cancer cell lines. Ectopic expression of MKK4 by adenoviral delivery in MKK4-negative cancer lines stimulated the cell proliferation and invasion, whereas knockdown of MKK4 expression by small interference RNA in an MKK4-positive breast cancer cell line, MDA-MB-231, resulted in decreased anchorage-independent growth, suppressed tumor growth in mouse xenograft model, and increased cell susceptibility to apoptosis brought by stress signals such as serum deprivation. These results argue that MKK4 functions as a pro-oncogenic molecule instead of a suppressor in breast and pancreatic tumors.
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PMID:Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors. 1518 66

Pancreatic carcinoma cells exhibit a pronounced tendency to invade along and into intra- and extrapancreatic nerves, even at early stages of the disease. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) has been shown to promote pancreatic cancer cell invasion. Here, we demonstrate that pancreatic carcinoma cell lines, such as PANC-1, expressed the RET and GDNF family receptor alpha receptor components for GDNF and that primary pancreatic tumor samples, derived from carcinomas with regional lymph node metastasis, exhibited marked expression of the mRNA encoding the RET51 isoform. Moreover, GDNF was an efficacious and potent chemoattractant for pancreatic carcinoma cells as examined in in vitro and in vivo model systems. Treatment of PANC-1 cells with GDNF resulted in activation of the monomeric GTPases N-Ras, Rac1, and RhoA, in activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) and in activation of the phosphatidylinositol 3-kinase/Akt pathway. Both inhibition of the Ras-Raf-MEK (mitogen-activated protein/ERK kinase)-ERK cascade by either stable expression of dominant-negative H-Ras(N17) or addition of the MEK1 inhibitor PD98059 as well as inhibition of the phosphatidylinositol 3-kinase pathway by LY294002 prevented GDNF-induced migration and invasion of PANC-1 cells. These results demonstrate that pancreatic tumor cell migration and possibly perineural invasion in response to GDNF is critically controlled by activation of the Ras-Raf-MEK-ERK and the phosphatidylinositol 3-kinase pathway.
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PMID:Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. 1528 35

Pancreatic carcinogenesis is driven by multiple genetic and epigenetic changes. The epidermal growth factor receptor (EGFR) and its downstream signaling pathways, Ras-Raf-MEK-ERK axis, play important roles in pancreatic cancer development. The phosphoinositol 3 kinase (PI3 K)/Akt and the nuclear factor kappaB (NF-kappaB) pathways control both proliferation and resistance to apoptosis of pancreatic cancer. The role of cyclooxygenase (COX) and lipoxygenase (LOX) in the development of pancreatic cancer has been made known recently. The elucidation of these molecular events has led to several distinct therapeutic advances, including therapies that target EGFR, the Ras-Raf-MEK-ERK axis, the COX-2 and LOX pathways, and others. Many novel agents have been developed and are undergoing clinical investigation, such as monoclonal antibodies against EGFR, tyrosine kinase inhibitors (TKIs), farnesyl transferase inhibitors (FTIs), Bay43-9006, CI-1040, CCI-779, celecoxib, and LY293111. This review highlights recent advances in the development of these agents.
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PMID:Molecular targeting therapy for pancreatic cancer. 1531 51

Neurotensin (NT) and epidermal growth factor (EGF) induced rapid extracellular-regulated protein kinase (ERK) activation through different signaling pathways in the K-Ras mutated human pancreatic carcinoma cell lines PANC-1 and MIA PaCa-2. NT stimulated ERK activation via a protein kinase C (PKC)-dependent (but EGF receptor-independent) pathway in PANC-1 and MIA PaCa-2 cells, whereas EGF promoted ERK activation through a PKC-independent pathway in these cells. Concomitant stimulation of these cells with NT and EGF induced a striking increase in the duration of ERK pathway activation as compared with that obtained in cells treated with each agonist alone. Stimulation with NT + EGF promoted synergistic stimulation of DNA synthesis and anchorage-independent growth. Addition of the MEK inhibitor U0126, either prior to stimulation with NT + EGF or 2 h after stimulation with NT + EGF prevented the synergistic increase in DNA synthesis and suppressed the sustained phase of ERK activation. Furthermore, treatment with the selective PKC inhibitor GF-1 converted the sustained ERK activation in response to NT and EGF into a transient signal and also abrogated the synergistic increase in DNA synthesis. Collectively, our results suggest that the sustained phase of ERK signaling mediates the synergistic effects of NT and EGF on DNA synthesis in pancreatic cancer cells.
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PMID:Neurotensin and EGF induce synergistic stimulation of DNA synthesis by increasing the duration of ERK signaling in ductal pancreatic cancer cells. 1538 44

Accumulating evidence suggests an important role for cyclooxygenase-2 (COX-2) in the pathogenesis of a wide range of malignancies. Here we tested the hypothesis that the COX-2 product prostaglandin E(2) (PGE(2)) increases cellular invasive potential by inducing matrix metalloproteinase-2 (MMP-2) expression and activity through an extracellular signal-regulated kinase (ERK)/Ets-1-dependent mechanism in pancreatic cancer. PANC-1 and MIAPaCa-2 pancreatic cancer cells were treated with PGE(2) or rofecoxib, a selective COX-2 inhibitor. MMP-2 expression and activity were assayed using Western blot analysis and zymography, respectively. MMP-2 promoter activity was analyzed with a luciferase-based assay. Ets-1 activity was analyzed using gel shift assay. Ets-1 expression was specifically silenced using RNA interference. Cellular invasive and migratory potentials were determined using a Boyden chamber assay with or without Matrigel, respectively. Exogenous PGE(2) induced MMP-2 expression and activity and increased ERK1/2 phosphorylation, Ets-1 binding activity, and MMP-2 promoter activity. PGE(2) also increased cellular migratory and invasive potentials. The mitogen-activated protein kinase kinase inhibitor PD98059 and Ets-1 silencing each abolished PGE(2)-induced increases in MMP-2 expression. PD98059 and Ets-1 silencing each abrogated the effect of PGE(2) on cellular invasive potential but not on cellular migratory potential. Rofecoxib suppressed MMP-2 expression and activity, Ets-1 binding activity, MMP-2 promoter activity, and cellular migratory and invasive potentials. These results suggest that PGE(2) mediates pancreatic cancer cellular invasiveness through an ERK/Ets-1-dependent induction of MMP-2 expression and activity. They also suggest that COX-2 inhibition may represent a strategy to inhibit invasive potential in pancreatic cancer.
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PMID:Prostaglandin E2 enhances pancreatic cancer invasiveness through an Ets-1-dependent induction of matrix metalloproteinase-2. 1549 68

In our previous investigations, mitogen-activated protein kinase kinase 2 (MEK2)/extracellular signal-regulated kinase 2 (ERK2) signaling pathway was found to be correlated with the cell dissociation induced by dissociation factor (DF) in pancreatic cancer cells. In this study, the expressions of epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and its downstream kinases MEK1/2 and ERK1/2, were analyzed to clarify the regulatory mechanism of cell dissociation in pancreatic cancer cells. Two hamster (PC-1.0 and PC-1) and two human (AsPC-1 and Capan-2) pancreatic cancer cell lines were used. Immunocytochemical study was performed using anti-EGFR, p-EGFR, phosphorylated MEK1/2 (p-MEK1/2), and phosphorylated ERK1/2 (p-ERK1/2) antibodies. DF-treatment markedly induced the expressions of EGFR, p-EGFR, p-MEK1/2, p-ERK1/2, as well as the dissociation of cell colonies in PC-1 and Capan-2 cells. In contrast, AG1478 (an EGFR inhibitor) treatment significantly induced the cell aggregation in PC-1.0 and AsPC-1 cells which usually grew as single cells, but strongly suppressed the expressions of EGFR, p-EGFR, p-MEK1/2, and p-ERK1/2. These observations demonstrate that activation of EGFR is closely involved in cell dissociation in pancreatic cancer through activating MEK/ERK signaling pathway.
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PMID:Relationship between activation of epidermal growth factor receptor and cell dissociation in pancreatic cancer. 1549 19

Mitogen-activated protein kinase kinase 2 (MEK2) was isolated previously as a potential factor related to cancer cell dissociation in highly (PC-1.0) and weakly (PC-1) invasive pancreatic cancer cells. On the other hand, changes of structure and function of tight junction (TJ) are reported to be correlated with carcinogenesis and tumor development. In this study, immunocytochemistry and Western blot analysis were performed in pancreatic cancer cells using anti-claudin-1, MEK2 and phosphorylated MEK1/2 (p-MEK1/2) antibodies to reveal the correlation between TJ and cancer cell dissociation, as well as the involvement of MEK2 in regulation of TJ in cell dissociation of pancreatic cancer. After incubation with conditioned medium of PC-1.0 cells, plasma membrane distribution of claudin-1 was obviously disrupted, and expressions of MEK2 and p-MEK1/2, as well as dissociation of cell colonies, were significantly induced in PC-1 and CAPAN-2 cells. However, U0126 (a MEK1/2 inhibitor) treatment apparently induced the plasma membrane distribution of claudin-1 and aggregation of single cells in PC-1.0 and AsPC-1 cells, synchronously seriously suppressed MEK2 and p-MEK1/2 expression. Arrangement of expression and distribution of claudin-1 is closely related to cell dissociation status in pancreatic cancer cells through MEK2 activation.
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PMID:Arrangement of expression and distribution of tight junction protein claudin-1 in cell dissociation of pancreatic cancer cells. 1554 92

The RAS-activated RAF-->MEK-->extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3'-kinase)-->PDK1-->AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells. To explore the mechanisms that underlie such cooperation, we have derived cells harboring conditionally active, steroid hormone-regulated forms of RAF and AKT. These cells permit the assessment of the biological and biochemical effects of activation of these protein kinases either alone or in combination with one another. Under conditions where activation of neither RAF nor AKT alone promoted S-phase progression, coactivation of both kinases elicited a robust proliferative response. Moreover, under conditions where high-level activation of RAF induced G(1) cell cycle arrest, activation of AKT bypassed the arrest and promoted S-phase progression. At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27(Kip1) expression. Repression of p27(Kip1) was accompanied by a dramatic reduction in KIP1 mRNA and was observed in primary mouse embryo fibroblasts derived from mice either lacking SKP2 or expressing a T187A mutated form of p27(Kip1). Consistent with these observations, pharmacological inhibition of MEK or PI3'-kinase inhibited the effects of activated RAS on the expression of p27(Kip1) in NIH 3T3 fibroblasts and in a panel of bona fide human pancreatic cancer cell lines. Furthermore, we demonstrated that AKT activation led to sustained activation of cyclin/cdk2 complexes that occurred concomitantly with the removal of RAF-induced p21(Cip1) from cyclin E/cdk2 complexes. Cumulatively, these data strongly suggest that the RAF-->MEK-->ERK and PI3'K-->PDK-->AKT signaling pathways can cooperate to promote G(0)-->G(1)-->S-phase cell cycle progression in both normal and cancer cells.
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PMID:Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. 1557 89

Pancreatic adenocarcinoma represents a tumor type with extremely poor prognosis. High apoptosis resistance and a strong invasive and early metastatic potential contribute to its highly malignant phenotype. Here we identified the death receptor adaptor molecule TRAF2 as a key player in pancreatic cancer pathophysiology. Using immunohistochemistry and Western blot analysis we found TRAF2 overexpressed in 34 of 36 pancreatic tumor samples as well as in pancreatic tumor cell lines resistant to CD95-mediated apoptosis. The high TRAF2 protein level was not related to chromosomal changes, as monitored by FISH analysis. Instead, the NF-kappaB- and MEK-signaling pathways were involved. Introduction of a TRAF2 expression vector in CD95-sensitive Colo357 cells resulted in (i) resistance to CD95-induced apoptosis; (ii) increased constitutive NF-kappaB and AP-1 activity; and (iii) higher basal secretion of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (uPA), and IL-8, leading to increased invasiveness. High apoptosis resistance and uPA secretion could be reverted by TRAF2-specific siRNA. Stimulation of TRAF2-overexpressing cells with CD95 ligand led to induction of NF-kappaB and AP-1, enhanced IL-8- and uPA-secretion, and a further increased invasiveness. Thus, TRAF2 overexpression does not only block apoptosis induction by CD95 but also converts this death receptor into a mediator of invasiveness.
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PMID:CD95 and TRAF2 promote invasiveness of pancreatic cancer cells. 1567 Sep 77

Epidermal growth factor receptor (EGFR) mediated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway was isolated as invasion-metastasis related factor in pancreatic cancer in our previous studies. Matrix metalloproteinase-7 (MMP-7) and tight junction (TJ) proteins are indicated to be involved in cancer invasion-metastasis. To clarify the underlying mechanism of involvement of MMP-7 in cancer invasion, western blotting, invasion assay and immunohistochemistry were performed in dissociated (PC-1.0 and AsPC-1) and non-dissociated (PC-1 and Capan-2) pancreatic cancer cells, as well as pancreatic cancer tissues. Intracellular MMP-7 protein presented as pre-proenzyme and its expression was decreased by AG1478 (EGFR inhibitor) or U0126 (MEK inhibitor) treatment in pancreatic cancer cells. Activated MMP-7 protein was only detected in the medium of PC-1.0 and AsPC-1 cells, but not detected in the medium of PC-1 and Capan-2 cells. Moreover, MMP-7 treatment significant induced the dissociation of cell colonies in PC-1 and Capan-2 cells. Synchronously, TJ structure was apparently disrupted and translocation of TJ proteins to cytoplasm or extracellular medium was induced in PC-1 and Capan-2 cells. Furthermore, MMP-7 treatment markedly increased the in vitro invasion of PC-1 and Capan-2 cells. In addition, MMP-7 expression at the invasive front was obviously stronger than that at the center of pancreatic cancer tissues. Activation of MMP-7 protein is closely involved in disruption of TJ structure and consequent induction of cell dissociation as well as invasion in pancreatic cancer. EGFR mediated MEK/ERK signaling pathway is implied to be involved in regulation of MMP-7 expression in pancreatic cancer cells.
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PMID:Involvement of matrix metalloproteinase-7 in invasion-metastasis through induction of cell dissociation in pancreatic cancer. 1580 19


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