Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-Methyl-1,6,8-trihydroxyanthraquinone (emodin) is an active component from the rhizome of Rheum palmatum, a widely used traditional Chinese herb. In this study, we found that emodin significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced in vitro invasion of human cancer cells including HSC5 and MDA-MB-231 cells. Matrix metalloproteinases (MMPs) are known to be associated with cancer invasion. Zymographic analysis showed that emodin suppressed TPA-induced MMP-9 activity in a concentration-dependent manner. We further demonstrated that emodin reduced the transcriptional activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), two important nuclear transcription factors involved in MMP-9 expression. Emodin suppressed the phosphorylation of two mitogen-activated protein kinases, extracellular signal-regulated protein kinase and c-Jun N-terminal kinase, but not p38 kinase, leading to reduced c-Jun phosphorylation and AP-1 DNA-binding. Moreover, emodin inhibited TPA-induced degradation of inhibitor of kappaBalpha, nuclear translocation of p65, and NF-kappaB DNA-binding activity. Taken together, these results suggest that emodin inhibits the invasiveness of human cancer cells by suppressing MMP-9 expression through inhibiting AP-1 and NF-kappaB signaling pathways.
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PMID:Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB. 1519 8

Emodin, an inhibitor of protein tyrosine kinase, possesses antiviral, immunosuppressive, anti-inflammatory and anticancer effects. In the present study, we investigated the effect of emodin on the hyaluronic acid (HA)-induced invasion of human glioma cells. Emodin significantly inhibited the HA-induced invasion through a Matrigel coated chamber, secretion of matrix metalloproteinase (MMP)-2, and HA-induced secretion of MMP-9 in glioma cells. To investigate the possible mechanisms involved in these events, we performed Western blot analysis using phospho-specific antibodies, and found that emodin inhibited phosphorylation of focal adhesion kinase (FAK), extracellular regulated protein kinase (ERK) 1/2 and Akt/PKB; emodin also suppressed the transcriptional activity of two transcription factors, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), in glioma cells. In addition, oral administration of emodin suppressed in vivo MMP secretion by glioma tumors in nude mice. Taken together, our results indicate that emodin can effectively inhibit HA-induced MMP secretion and invasion of glioma through inhibition of FAK, ERK1/2 and Akt/PKB activation and partial inhibition of AP-1 and NF-kappaB transcriptional activities. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human glioma.
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PMID:Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. 1607 36

Matrix metalloproteinases (MMPs) are the proteases involved in the degradation of the extracellular matrix. MMP-1 is thought to be one of the key enzymes acting in fibrolysis, a process closely related to tissue remodeling. In this study, we found that emodin, an anthraquinone which has been isolated from the rhizome of Rheum palmatum, significantly inhibited TNF alpha-induced MMP-1 gene expression in a concentration-dependent manner. Therefore, we have attempted to characterize the inhibitory mechanism of emodin in TNF alpha-induced MMP-1 expression. Emodin was determined to inhibit TNF alpha-induced activation of AP-1 promoter, an important nuclear transcription factor in MMP-1 expression. Additionally, we detected that emodin suppressed the TNF alpha-induced phosphorylation of two mitogen-activated protein kinases, extracellular signal-regulated protein kinase and c-Jun N-terminal kinase, but it did not suppress the TNF alpha-induced phosphorylation of p38 kinase. In a consistent result, the TNF alpha-induced MMP-1 expression was inhibited by PD98059 (MEK/ERK inhibitor) and SP600125 (JNK inhibitor), but was not inhibited by SB203580, a p38 MAPK inhibitor. Taken together, these results show that emodin suppresses TNF alpha-induced MMP-1 expression through the inhibition of the AP-1 signaling pathway.
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PMID:Emodin inhibits TNF alpha-induced MMP-1 expression through suppression of activator protein-1 (AP-1). 1695 73

To explore the protection of emodin on renal dysfunction in the streptozotocin-induced diabetic rats with nephropathy and the role of p38 mitogen-activated protein kinase (p38 MAPK) signal transduction pathway in this protection. 30 male Spraque-Dawley rats were randomly divided into control group, model group and emodin group. The rats in the model group and emodin group were administered with streptozotocin (60 mg/kg) to induce diabetes. 40 mg/kg/day of emodin were orally given to the rats in emodin group. The rats in other groups were only given solvent. Biochemical index were analysed by oxidase and oxidase dynamical enzyme method. Glomerular area and volume were determined quantitatively by using Image Analysis System. Western blotting and immunohistochemical staining was used to detect the total p38 MAPK, phosphorylated p38 MAPK, phosphorylated cAMP response element binding protein (CREB) and fibronectin. The average kidney weight/body weight, glomerular area, glomerular volume and all biochemical indexes significantly increased in model group as compared to the control group (P<0.05), while the average body weight decreased. The expressions of phosphorylaed p38 MAPK, phosphorylated CREB and fibronectin increased by 1.98-fold, 1.94-fold and 1.96-fold respectively in model group compared with those in the control group (P<0.05). Emodin markedly decreased the average kidney weight/body weight, glomerular area, glomerular volume and all biochemical indexes (P<0.05), having a weak action on the level of blood glucose. The expressions of phosphorylated p38 MAPK, phosphorylated CREB and fibronectin also significantly downregulated in emodin group compared with those in model group (P<0.05). Emodin was efficient to ameliorate renal dysfunction in diabetic nephropathy rats probably by its inhibition of the activation of p38 MAPK pathway and downregulation of the expression of fibronectin.
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PMID:Inhibition of phosphorylation of p38 MAPK involved in the protection of nephropathy by emodin in diabetic rats. 1707 19

Emodin inhibited expression of both transforming growth factor beta1 (TGFbeta1)- and phorbol ester (PMA)-induced tissue inhibitors of metalloproteinase-1 (TIMP-1) in an immortalized rat hepatic stellate cell line, HSC-T6, by Western blot and reverse transcription polymerase chain reaction. Reporter gene assays showed that emodin reduced both basal and PMA-induced activated protein-1 (AP-1) promoter activities. Electrophoretic mobility shift assay revealed that emodin reduced AP-1 DNA binding activities in HSC-T6 cells. AP-1 components analysis showed that emodin also attenuated JunD mRNA expression. Furthermore, emodin markedly inhibited TGFbeta1-induced p42/p44 mitogen-activated protein kinase phosphorylation but did not alter PMA induction. We conclude that emodin effectively inhibits PMA- and TGFbeta1-stimulated TIMP-1 expression in hepatic stellate cells by suppressing the AP-1 signaling pathway and extracellular signal-regulated kinase activation, respectively. These data provide new insight into the cellular and molecular mechanisms of emodin against liver fibrosis.
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PMID:Inhibitory effect of emodin on tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in rat hepatic stellate cells. 1716 Apr 80

Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a moderately potent and poorly selective inhibitor of protein kinase CK2, one of the most pleiotropic serine/threonine protein kinases, implicated in neoplasia and in other global diseases. By virtual screening of the MMS (Molecular Modeling Section) database, we have now identified quinalizarin (1,2,5,8-tetrahydroxyanthraquinone) as an inhibitor of CK2 that is more potent and selective than emodin. CK2 inhibition by quinalizarin is competitive with respect to ATP, with a Ki value of approx. 50 nM. Tested at 1 microM concentration on a panel of 75 protein kinases, quinalizarin drastically inhibits only CK2, with a promiscuity score (11.1), which is the lowest ever reported so far for a CK2 inhibitor. Especially remarkable is the ability of quinalizarin to discriminate between CK2 and a number of kinases, notably DYRK1a (dual-specificity tyrosine-phosphorylated and -regulated kinase), PIM (provirus integration site for Moloney murine leukaemia virus) 1, 2 and 3, HIPK2 (homeodomain-interacting protein kinase-2), MNK1 [MAPK (mitogen-activated protein kinase)-interacting kinase 1], ERK8 (extracellular-signal-regulated kinase 8) and PKD1 (protein kinase D 1), which conversely tend to be inhibited as drastically as CK2 by commercially available CK2 inhibitors. The determination of the crystal structure of a complex between quinalizarin and CK2alpha subunit highlights the relevance of polar interactions in stabilizing the binding, an unusual characteristic for a CK2 inhibitor, and disclose other structural features which may account for the narrow selectivity of this compound. Tested on Jurkat cells, quinalizarin proved able to inhibit endogenous CK2 and to induce apoptosis more efficiently than the commonly used CK2 inhibitors TBB (4,5,6,7-tetrabromo-1H-benzotriazole) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole).
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PMID:Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2. 1943 57

Early stage diabetic nephropathy is characterized by elevated glomerular filtration. Recent studies have identified high-glucose induced p38 MAPK (p38) over-activation in mesangial cells. Mesangial hypocontractility is the major underlying mechanism, however, no ameliorating agents are currently available. We investigated the protective effects of emodin on high-glucose induced mesangial cell hypocontractility. Mesangial cells were cultured under normal (5.6 mM) and high glucose (30 mM) conditions. Emodin was administrated at doses of 50 mg/l and 100 mg/l. Angiotension II stimulated cell surface reductions were measured to evaluate cell contractility. p38 activity was detected using Western blotting. To further explore the possible mechanism of emodin, expression of the peroxisome proliferator- activated receptorgamma (PPARgamma) was measured and its specific inhibitor, gw9662, was administrated. Our results showed: (1) high-glucose resulted in a 280% increase in p38 activity associated with significant impairment of mesangial contractility; (2) emodin treatment dose-dependently inhibited high-glucose induced p38 over-activation (a 40% decrease for 50 mg/l emodin and a 73% decrease for 100 mg/l emodin), and mesangial hypocontractility was ameriolated by emodin; (3) both the PPARgamma mRNA and protein levels were elevated after emodin treatment; (4) inhibition of PPARgamma using gw9662 effectively blocked the ameliorating effects of emodin on high-glucose induced p38 over-activation and mesangial hypocontractility. Emodin effectively ameliorated p38 over-activation and hypocontractility in high-glucose induced mesangial cells, possibly via activation of PPARgamma.
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PMID:Emodin ameliorates high-glucose induced mesangial p38 over-activation and hypocontractility via activation of PPARgamma. 1947 55

Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It reportedly exhibits an anticancer effect on lung cancer. Gefitinib (Iressa) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for human non-small cell lung cancer (NSCLC). However, the molecular mechanism of how emodin combined with gefitinib decreases NSCLC cell viability is unclear. The recombinase protein Rad51 is essential for homologous recombination repair, and Rad51 overexpression is resistant to DNA double-strand break-inducing cancer therapies. In this study, we found that emodin enhanced the cytotoxicity induced by gefitinib in two NSCLC cells lines, A549 and H1650. Emodin at low doses of 2-10 microM did not affect ERK1/2 activation, mRNA, and Rad51 protein levels; however, it enhanced a gefitinib-induced decrease in phospho-ERK1/2 and Rad51 protein levels by enhancing Rad51 protein instability. Expression of constitutively active MKK1/2 vectors (MKK1/2-CA) significantly rescued the reduced phospho-ERK1/2 and Rad51 protein levels as well as cell viability on gefitinib and emodin cotreatment. Blocking of ERK1/2 activation by U0126 (an MKK1/2 inhibitor) lowered Rad51 protein levels and cell viability in emodin-treated H1650 and A549 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA enhanced emodin cytotoxicity. In contrast, Rad51 overexpression protected the cells from the cytotoxic effects induced by emodin and gefitinib. Consequently, emodin-gefitinib cotreatment may serve as the basis for a novel and better therapeutic modality in the management of advanced lung cancer.
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PMID:Emodin enhances gefitinib-induced cytotoxicity via Rad51 downregulation and ERK1/2 inactivation. 1950 57

1,3,8-Trihydroxy-6-methylanthaquinone (emodin) is recognized as an antiproliferative compound. In the present study, however, we show that emodin has both toxic and survival effects in glioma cells and that the survival effects involve Mdr1a. Emodin inhibited the proliferation and induced apoptosis of C6 cells in a 12-h treatment, but C6 cells survived a 72-h drug treatment, indicating resistance to emodin. Emodin-induced apoptosis was reduced by inhibition of the expression and activation of apoptosis-associated proteins including p53, Bax, Bcl-2, Fas, and caspase-3. C6 cells could express antioxidant proteins (superoxide dismutase and catalase) to decrease reactive oxygen species-induced cytotoxicity of emodin and overexpress multidrug resistance genes (Mdr1a, MRP2, MRP3, and MRP6) to decrease the intracellular accumulation of emodin. Electrophoretic mobility shift analysis showed that emodin decreased nuclear factor kappaB (NF-kappaB) expression in 24 h of treatment, but in 48 h, emodin increased NF-kappaB activity. A confocal microscope showed that emodin induced NF-kappaB translocation from cytoplasm to nuclei. C6 cells would activate the mitogen-activated protein kinase survival pathway and express the DNA repair gene (MGMT) and associated proteins (PARP and XRCC1) to recover the cell activity. C6 cells also expressed GRP78 to decrease emodin-induced endoplasmic reticulum (ER) stress that would cause apoptosis in C6 cells, and GRP78 inhibited the expression of GADD153 to enhance the expression of Bcl-2 that could balance the ER- and mitochondria-induced apoptosis of C6 cells.
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PMID:Emodin has cytotoxic and protective effects in rat C6 glioma cells: roles of Mdr1a and nuclear factor kappaB in cell survival. 1954 30

Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. Emodin exhibits anticancer effects against a variety of cancer cells, including lung cancer cells. ERCC1 and Rad51 proteins are essential for nucleotide excision repair and homologous recombination, respectively. Furthermore, ERCC1 and Rad51 overexpression induces resistance to DNA-damaging agents that promote DNA double-strand breaks. Accordingly, the aim of this study was to determine the role of ERCC1 and Rad51 in emodin-mediated cytotoxicity in human non-small cell lung cancer (NSCLC) cells. Both ERCC1 and Rad51 protein levels as well as mRNA levels were decreased in four different NSCLC cell lines after exposure to emodin. These decreases correlated with the inactivation of the MKK1/2-ERK1/2 pathway. Moreover, cellular ERCC1 and Rad51 protein and mRNA levels were specifically inhibited by U0126, a MKK1/2 inhibitor. We found that transient transfection of human NSCLC cells with si-ERCC1 or si-Rad51 RNA and cotreatment with U0126 could enhance emodin-induced cytotoxicity. In contrast, overexpression of constitutively active MKK1/2 vectors (MKK1/2-CA) was shown to significantly recover reduced phospho-ERK1/2, ERCC1, and Rad51 protein levels and to rescue cell viability upon emodin treatment. These results demonstrate that activation of the MKK1/2-ERK1/2 pathway is the upstream signal regulating the expressions of ERCC1 and Rad51, which are suppressed by emodin to induce cytotoxicity in NSCLC cells.
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PMID:Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells. 1979 75


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