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)

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
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PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18

In the present study, we examined a role of mitogen-activated protein kinases (MAPKs), extracellular signal-related kinase (ERK), c-Jun N-terminal protein kinase, and p38 MAPK in troglitazone-induced inhibition of cell growth in human pancreatic cancer cells. Among the three kinases, troglitazone specifically inhibited the phosphorylation of ERK1/2 in a dose- and time-dependent manner. Troglitazone also down-regulated the protein expression of mitogen-activated protein kinase kinase (MEK)1/2, an upstream molecule that regulates ERK phosphorylation. Treatment of human pancreatic cancer cells with specific MEK inhibitor, PD98059 or U0126, inhibited ERK1/2 phosphorylation and cell growth. These results suggest for the first time that the inhibition of the MEK1/2-ERK1/2 signaling pathway may be implicated in the growth inhibitory effect by troglitazone in human pancreatic cancer cells.
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PMID:Involvement of MEK-ERK signaling pathway in the inhibition of cell growth by troglitazone in human pancreatic cancer cells. 1589 3

Expression of mutationally activated RAS is a feature common to the vast majority of human pancreatic adenocarcinomas. RAS elicits its effects through numerous signaling pathways including the RAF-->mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase [MEK]-->ERK MAP kinase pathway. To assess the role of this pathway in regulating cell proliferation, we tested the effects of pharmacologic inhibition of MEK on human pancreatic cancer cell lines. In eight cell lines tested, MEK inhibition led to a cessation of cell proliferation accompanied by G0-G1 cell cycle arrest. Concomitant with cell cycle arrest, we observed induced expression of p27Kip1, inhibition of cyclin/cyclin-dependent kinase 2 (cdk2) activity, accumulation of hypophosphorylated pRb, and inhibition of E2F activity. Using both antisense and RNA interference techniques, we assessed the role of p27Kip1 in the observed effects of MEK inhibition on pancreatic cancer cell proliferation. Inhibition of p27Kip1 expression in Mia PaCa-2 cells restored the activity of cyclin/cdk2, phosphorylation of pRb, and E2F activity and partially relieved the effects of U0126 on pancreatic cancer cell cycle arrest. Consistent with the effects of p27Kip1 on cyclin/cdk2 activity, inhibition of CDK2 expression by RNA interference also led to G0-G1 cell cycle arrest. These data suggest that the expression of p27Kip1 is downstream of the RAF-->MEK-->ERK pathway and that the regulated expression of this protein plays an important role in promoting the proliferation of pancreatic cancer cells. Moreover, these data suggest that pharmacologic inhibition of the RAF-->MEK-->ERK signaling pathway alone might tend to have a cytostatic, as opposed to a cytotoxic, effect on pancreatic cancer cells.
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PMID:Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. 1593 Mar 8

We have previously shown the importance of LTB4 in human pancreatic cancer. LTB4 receptor antagonists block growth and induce apoptosis in pancreatic cancer cells both in vitro and in vivo. Therefore, we investigated the effect of LTB4 on proliferation of human pancreatic cancer cells and the mechanisms involved. LTB4 stimulated DNA synthesis and proliferation of both PANC-1 and AsPC-1 human pancreatic cancer cells, as measured by thymidine incorporation and cell number. LTB4 stimulated rapid and transient activation of MEK and ERK1/2 kinases. The MEK inhibitors, PD98059 and U0126, blocked LTB4-stimulated ERK1/2 activation and cell proliferation. LTB4 also stimulated phosphorylation of p38 MAPK; however, the p38 MAPK inhibitor, SB203580, failed to block LTB4-stimulated growth. The activity of JNK/SAPK was not affected by LTB4 treatment. Phosphorylation of Akt was also induced by LTB4 and this effect was blocked by the PI-3 kinase inhibitor wortmannin, which also partially blocked LTB4-stimulated cell proliferation. In conclusion, LTB4 stimulates proliferation of human pancreatic cancer cells through MEK/ERK and PI-3 kinase/Akt pathways, while p38 MPAK and JNK/SAPK are not involved.
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PMID:LTB4 stimulates growth of human pancreatic cancer cells via MAPK and PI-3 kinase pathways. 1610 64

In our previous study, dissociation factor (DF) and mitogen-activated protein kinase kinase 2 (MEK2) were isolated as factors relating to cancer cell dissociation in pancreatic cancer cells. On the other hand, tight junction protein zonula occludens 1 (ZO-1) has been indicated to be involved in carcinogenesis. In this study, the expression of ZO-1 and a downstream kinase of MEK2, extracellular signal-regulated kinase 2 (ERK2), was 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-ZO-1, ERK2, and phosphorylated ERK1/2 (p-ERK1/2) antibodies. DF treatment obviously disrupted ZO-1 expression at the sites of cell-cell contact and markedly induced ERK2 and p-ERK1/2 expression, as well as the dissociation of cell clones in PC-1 and CAPAN-2 cells. In contrast, U0126 (a MEK1/2 inhibitor) treatment significantly induced the peripheral distribution of ZO-1 as well as cell aggregation in PC-1.0 and AsPC-1 cells, which usually grew as single cells, but seriously suppressed ERK2 and p-ERK1/2 expression. We conclude that redistribution of ZO-1 is closely correlated with cell dissociation status in pancreatic cancer cells through activation of ERK2.
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PMID:Zonula occludens-1 (ZO-1) redistribution is involved in the regulation of cell dissociation in pancreatic cancer cells. 1611 Aug 28

The molecular genetic profiles that characterize pancreatic ductal neoplasia have taken shape recently with the help of immunohistochemistry and the establishment of the nomenclature describing pancreatic ductal tumorigenesis. K-ras mutations frequently occur early, changes in the expression and genetic integrity of the p16 gene appear in intermediate lesions, and the inactivation of the p53, DPC4, and BRCA2 genes occur late in the neoplastic progression. Tumor-suppressor genes inactivated in pancreatic cancer such as ALK5, TGFBR2, MKK4, and STK11/LKB1 have been identified, although their roles in tumor progression are not yet well defined. Additional discoveries in this tumor system may be on the horizon, will further refine the molecular genetic profiles for the disease, and should suggest some clinical uses for this fund of knowledge.
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PMID:Molecular genetics of ductal pancreatic neoplasia. 1703 Nov 13

Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the alpha(6)beta(4) integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.
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PMID:Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the beta4 integrin and the PI3k pathway. 1704 57

Connective tissue growth factor (CTGF/CCN2) is thought to play a role in normal wound repair and bone remodeling, but also promotes fibrosis in several disease processes including diabetic nephropathy, sclerodoma and pancreatitis. A contribution to desmoplasia associated with pancreatic cancer progression has also been proposed. CTGF is induced by TGFbeta in diverse cell types, but TGFbeta receptor mediated signaling is impaired in pancreatic cancers and cell lines, usually due to DPC4/Smad4 mutations which arise during the later stages of intraepithelial neoplastic progression. Therefore, in order to define signaling pathways that mediate basal and TGFbeta-induced CTGF expression in normal and transformed cells, we compared CTGF gene regulation in pancreatic cancer cells and fibroblasts by measuring the effects of small molecule inhibitors and dominant negative mutants of signaling proteins on CTGF promoter reporter activity, message, and protein expression. We determined that the previously identified TEF-1 cis element is essential for CTGF promoter reporter activity in pancreatic cancer cell lines. Whereas p38 mediated CTGF induction by TGFbeta in fibroblasts, MEK/ERK signaling mediated TGFbeta-induced CTGF expression in pancreatic cancer cells and was also responsible for basal CTGF expression in pancreatic cancer cell lines with defective Smad signaling. Since activating Ras mutations occur in the earliest stages of pancreatic cancer, CTGF may be induced independent of Smad4 in pancreatic cancer cells.
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PMID:Expression of connective tissue growth factor in pancreatic cancer cell lines. 1778 99

In a study of interactions between the raf-MEK-MAPK (ERK) and JNK-jun pathways, we found previously that JNK can induce phosphorylation of raf but not vice versa. In this study, we investigate the nature of the JNK-induced phosphorylation of raf. In in vitro experiments in which immunobead-bound raf is phosphorylated by activated JNK, we find strong phosphorylation signals at raf-Ser259 and Ser338. The Ser259 phosphorylation is surprising since it is associated with inhibition of migration of raf to the cell membrane where it can interact with ras-p21. We also find that in oocytes induced to mature with oncogenic ras-p21, which induces high levels of phosphorylated JNK and MAPK, the same pattern of phosphorylation of raf occurs. In contrast, in oocytes induced to mature with insulin, which requires activation of wild-type ras-p21, phosphorylation of raf-Ser338 but not raf-Ser259 occurs. In oncogenic ras-transformed human pancreatic cancer MIA-PaCa-2 cells, phosphorylation of both raf serines occurs. Treatment of these cells with the ras peptide, PNC-2 attached to a penetrating sequence that blocks JNK and MAPK phosphorylation and induces tumor cell necrosis, results in a marked decrease in phosphorylation of raf-Ser259, but not that of raf-Ser338. These results suggest that oncogenic ras-p21 induces phosphorylation of both raf-Ser259 and Ser338 and that raf-Ser 259 phosphorylation may be effected by activated JNK.
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PMID:Site-specific phosphorylation of raf in cells containing oncogenic ras-p21 is likely mediated by jun-N-terminal kinase. 1831 82

Imatinib mesylate (imatinib) inhibits the c-Kit-dependent tyrosine kinase activities and highly effective in the treatment of CML and GIST patients. Although pancreatic cancer is reported to express c-Kit, imatinib does not effectively inhibit pancreatic cancer cell growth at physiological concentrations. Therefore, we investigated the mechanism of resistance of pancreatic cancer to imatinib treatment. Imatinib inhibited growth of pancreatic cancer cell lines in concentration and time-dependent fashion regardless of c-Kit expression. However, 5 microM imatinib, which is almost a mean maximal plasma concentration in clinical setting, failed to suppress pancreatic cancer cell growth. Western blot analysis demonstrated that 5 microM imatinib treatment for 1h activated the MEK-MAPK pathway and the activation was independent of Ras activation. Administration of 5 microM imatinib and 1 microM U0126 (MEK inhibitor) significantly suppressed pancreatic cell growth. Our results indicate that a combination therapy of imatinib and MEK inhibitor can be a new therapeutic strategy to suppress the progression of pancreatic cancer.
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PMID:MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth. 1834 44


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