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)

Cetuximab, a chimeric monoclonal antibody to epidermal growth factor receptor (EGFR), has been proved to have clinically significant antitumor activity against advanced colorectal cancers, but its therapeutic activity for gastric cancers remains unclear. In the present study, we investigated the antitumor effect and action mechanism of cetuximab using EGFR high-expressing (MKN-28) and EGFR low-expressing (GLM-1) gastric cancer cell lines without gene amplification. Cetuximab showed neither significant growth inhibition nor induction of apoptosis in either cell line in vitro, and only slightly inhibited ligand-induced phosphorylation of protein kinase B and extracellular signal-regulated kinase in MKN-28 cells. In contrast, cetuximab significantly inhibited subcutaneous and intraperitoneal tumor growth of MKN-28 cells, but not GLM-1 cells, in nude mice. This antitumor activity was significantly enhanced and diminished in nude mice by treatment with interleukin-2 (IL-2) and antiasialo GM1 antibody, which can expand and deplete natural killer (NK) cells, respectively. Antibody-dependent cellular cytotoxicity (ADCC) of cetuximab, as measured by (51)Cr release assay, was significantly higher in MKN-28 than in GLM-1 cells. This ADCC activity was enhanced by IL-2 and reduced by heat-aggregate of human immunoglobulin G, an inhibitor for FcR-III of NK cells. These results suggest that cetuximab in combination with IL-2 shows significant antitumor activity against EGFR high-expressing gastric cancer mainly through NK cell-mediated ADCC. Combination therapy with cetuximab and IL-2 would thus offer a new potential therapeutic approach for a subset of EGFR-overexpressing gastric cancers.
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PMID:Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody-dependent cellular cytotoxicity. 1842 55

The effects of combining histone deacetylase (HDAC) inhibitors and proteasome inhibitors were evaluated in both established glioblastoma multiforme (GBM) cell lines and short-term cultures derived from the Mayo Clinic xenograft GBM panel. Coexposure of LBH589 and bortezomib at minimally toxic doses of either drug alone resulted in a striking induction of apoptosis in established U251, U87, and D37 GBM cell lines, as well as in GBM8, GBM10, GBM12, GBM14, and GBM56 short-term cultured cell lines. Synergism of apoptosis induction was also observed in U251 cells when coexposing cells to other HDAC inhibitors, including LAQ824 and trichostatin A, with the proteasome inhibitor MG132, thus demonstrating a class effect. In U251 cells, bortezomib alone or in combination with LBH589 decreased Raf-1 levels and suppressed Akt and Erk activation. LBH589 or bortezomib alone increased expression of the cell cycle regulators p21 and p27. Additionally, the combination, but not the individual agents, markedly enhanced JNK activation. Synergistic induction of apoptosis after exposure to LBH589 and bortezomib was partially mediated by Bax translocation from the cytosol to the mitochondria resulting from Bax conformational changes. Bax translocation precedes cytochrome c release and apoptosis, and selective down-regulation of Bax using siRNA significantly mitigates the cytotoxicity of LBH589 and bortezomib. This combination regimen warrants further preclinical and possible clinical study for glioma patients.
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PMID:Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells. 1844

In human glioblastoma multiforme (GBM), RAS activity is upregulated in the majority of the tumors. Furthermore, the levels of phospho-mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK), a downstream effector of RAS, are also increased. In mice, activated KRas cooperates with the loss of INK4a-ARF locus or with activated Akt to induce gliomas, confirming an important role for this pathway in glioma biology. However, to correctly target therapies against the RAS signaling pathway, it is necessary to identify the effectors that contribute to RAS-mediated gliomagenesis. In this study, we investigated the contribution of RAF signaling in glioma oncogenesis. We find that the levels of RAF-1 and BRAF proteins and RAF kinase activity are increased in human GBM samples. We confirm the importance of this finding by demonstrating a causal role for a constitutively active Raf-1 mutant in glioma formation in mice. Specifically, we find that activated Raf-1 cooperates with Arf loss or Akt activation to generate gliomas similar to activated KRas under the same conditions. Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment.
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PMID:Constitutive activation of Raf-1 induces glioma formation in mice. 1847 67

Glioblastoma Multiforme (GBM) is almost inevitably a fatal tumor of the brain with most individuals dying within 1 year of diagnosis. It is the most frequent brain tumor in adults. Dose-response studies showed that Cucurbitacin B inhibited 50% growth (ED(50)) of 5 human GBM cell lines in liquid culture at approximately 10(-7) M. Soft-gel assays demonstrated that nearly all of the GBM clonogenic cells were inhibited at 10(-8) M of Cucurbitacin B. FACS analysis found that the compound (10(-7) M, 24 hr) caused G2/M arrest. The GBM cells underwent profound morphologic changes within 15-30 min after exposure to Cucurbitacin B (10(-7) M), rounding up and losing their pseudopodia associated with disruption of actin and microtubules, as observed by immunoflourescence. Cucurbitacin B (10(-7) M) caused prominent multinucleation of the cells after they were pulse-exposed (48 hr) to the drug, washed and cultured in normal medium for an additional 2 days. The drug (10(-7) M, 3-24 hr) increased levels of p-p38, p-JNK and p-JUN in U87 and T98G GBM cell lines as seen by Western blot. Interestingly, alterations in cell morphology caused by Cucurbitacin B (10(-7) M) were blocked by the JNK inhibitor SP600125. In summary, Cucurbitacin B has a prominent anti-proliferative activity on GBM cells; and at least in part, the mode of action is by affecting the cytoskeleton, as well as, the JNK pathway. Clinical trails of this drug should be pursued in GBM.
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PMID:Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme. 1856 12

N-butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either N-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77, were evaluated as well as the effect of N-butylidenephthalide in an in vivo xenograft model. N-butylidenephthalide caused growth inhibition of both the cell lines at 25 microg/ml. Furthermore, N-butylidenephthalide-induced apoptosis seems to be related to Nur77 translocation from nucleus to cytosol, which leads to cytochrome c release and caspase-3-dependent apoptosis. N-butylidenephthalide-related tumor apoptosis was associated with phosphatidylinositol 3-kinase/protein kinase B (AKT)/glycogen synthase kinase-3beta rather than the mitogen-activated protein kinase or protein kinase C pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild-type cAMP-response element-binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of N-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-Butylidenephthalide induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of hepatocellular carcinoma cells.
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PMID:The induction of orphan nuclear receptor Nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy. 1857 87

Macrophage migration inhibitory factor (MIF) has been shown to play a pathogenic role in kidney disease. This article will review the current understanding of the expression of MIF and its functional role in immune-mediated renal injury in both human and animal models of kidney disease. Upregulation of MIF is found in both human and experimental kidney disease including renal allograft rejection and contributes significantly to macrophage and T-cell accumulation and progressive renal injury. It is now clear that MIF is a stress factor, a pro-inflammatory cytokine, a growth factor and a hormone. MIF acts through many mechanisms to mediate renal injury including the innate and adaptive immune systems, the induction of cytokines, chemokines, adhesion molecules as well as interactions with glucocorticoids and the hypothalamic-pituitary-adrenal axis. MIF exerts its biological activities via signaling through its CD74/CD44 receptor complex to activate the downstream ERK1/2 MAP kinase. The functional importance of MIF in kidney disease is demonstrated by the findings that treatment with a neutralizing anti-MIF antibody is able to prevent or reverse renal injury in crescentic anti-GBM glomerulonephritis. In addition, mice null for MIF are protected against immune-mediated lupus nephritis. MIF plays a critical role in kidney diseases and further studies of the functional role and signaling mechanisms of MIF in human kidney diseases are needed.
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PMID:Role of macrophage migration inhibition factor in kidney disease. 1866 34

The anti-neoplastic property of alkyl phospholipids has been tested for the treatment of several malignancies. In this study, we evaluated the efficacy of miltefosine (Hexadecylphosphocholine--an alkyl phospholipids analogue) on glioblastoma multiforme. In this study, we demonstrate that miltefosine-induced apoptosis is accompanied by elevated Fas, Fas-associated death domain (FADD) expression, caspase-8 activity and the increased distribution of Fas and FADD towards lipid raft microdomain to form death inducing signaling complex. Treatment with miltefosine resulted in increase in Ras, extracellular signal-regulated kinase (ERK) and p38MAPK activity. Expression of dominant-negative Ras (Ras N17) attenuated miltefosine-mediated apoptosis. Although inhibition of both ERK and p38MAPK decreased the pro-apoptotic effects of miltefosine, it was the inhibition of ERK and not p38MAPK activation that decreased Fas and FADD expression. An ERK-dependent increase in the expression of gammaH2AX-involved in response to DNA double-stranded breaks was also observed. Taken together, our findings suggest the involvement of ERK activation in miltefosine-induced glioma cell apoptosis.
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PMID:Involvement of miltefosine-mediated ERK activation in glioma cell apoptosis through Fas regulation. 1871 Apr 16

The ephrinA1 ligand exerts antioncogenic effects in tumor cells through activation and downregulation of the EphA2 receptor and has been described as a membrane-anchored protein requiring clustering for function. However, while investigating the ephrinA1/EphA2 system in the pathobiology of glioblastoma multiforme (GBM), we uncovered that ephrinA1 is released from GBM and breast adenocarcinoma cells as a soluble, monomeric protein and is a functional form of the ligand in this state. Conditioned media containing a soluble monomer of ephrinA1 caused EphA2 internalization and downregulation, dramatic alteration of cell morphology and suppression of the Ras-MAPK pathway. Moreover, soluble monomeric ephrinA1 was functional in a physiological context, eliciting collapse of embryonic neuronal growth cones. We also found that ephrinA1 is cleaved from the plasma membrane of GBM cells, an event which involves the action of a metalloprotease. Thus, the ephrinA1 ligand can, indeed, function as a soluble monomer and may act in a paracrine manner on the EphA2 receptor without the need for juxtacrine interactions. These findings have important implications for further deciphering the function of these proteins in pathology and physiology, as well as for the design of ephrinA1-based EphA2-targeted antitumor therapeutics.
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PMID:Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. 1879 97

Glioblastoma multiforme is an invasive primary brain tumor, which evades the current standard treatments. The invasion of glioblastoma cells into healthy brain tissue partly depends on the proteolytic and nonproteolytic activities of the plasminogen activator system proteins, including the urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and a receptor for uPA (uPAR). Here we show that sphingosine-1-phosphate (S1P) and the inflammatory mediator interleukin-1 (IL-1) increase the mRNA and protein expression of PAI-1 and uPAR and enhance the invasion of U373 glioblastoma cells. Although IL-1 enhanced the expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, down-regulation of SphK1 had no effect on the IL-1-induced uPAR or PAI-1 mRNA expression, suggesting that these actions of IL-1 are independent of S1P production. Indeed, the S1P-induced mRNA expression of uPAR and PAI-1 was blocked by the S1P(2) receptor antagonist JTE013 and by the down-regulation of S1P(2) using siRNA. Accordingly, the inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and Rho-kinase, two downstream signaling cascades activated by S1P(2), blocked the activation of PAI-1 and uPAR mRNA expression by S1P. More importantly, the attachment of glioblastoma cells was inhibited by the addition of exogenous PAI-1 or siRNA to uPAR, whereas the invasion of glioblastoma cells induced by S1P or IL-1 correlated with their ability to enhance the expression of PAI-1 and uPAR. Collectively, these results indicate that S1P and IL-1 activate distinct pathways leading to the mRNA and protein expression of PAI-1 and uPAR, which are important for glioblastoma invasiveness.
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PMID:Sphingosine-1-phosphate and interleukin-1 independently regulate plasminogen activator inhibitor-1 and urokinase-type plasminogen activator receptor expression in glioblastoma cells: implications for invasiveness. 1881 34

c-Jun N-terminal kinases (JNKs) are part of the mitogen-activated protein kinase (MAPK) family and are important regulators of cell growth, proliferation, and apoptosis. Typically, a sequential series of events are necessary for MAPK activation: phosphorylation, dimerization, and then subsequent translocation to the nucleus. Interestingly, a constitutively active JNK isoform, JNK2alpha2, possesses the ability to autophosphorylate and has been implicated in several human tumors, including glioblastoma multiforme. Because overexpression of JNK2alpha2 enhances several tumorigenic phenotypes, including cell growth and tumor formation in mice, we studied the mechanisms of JNK2alpha2 autophosphorylation and autoactivation. We find that JNK2alpha2 dimerization in vitro and in vivo occurs independently of its autophosphorylation but is dependent on nine amino acids, known as the alpha-region. Alanine scanning mutagenesis of the alpha-region reveals that five specific mutants (L218A, K220A, G221A, I224A, and F225A) prevent JNK2alpha2 dimerization rendering JNK2alpha2 inactive and incapable of stimulating tumor formation. Previous studies coupled with additional mutagenesis of neighboring isoleucines and leucines (I208A, I214A, I231A, and I238A) suggest that a leucine zipper may play an important role in JNK2alpha2 homodimerization. We also show that a kinase-inactive JNK2alpha2 mutant can interact with and inhibit wild type JNK2alpha2 autophosphorylation, suggesting that JNK2alpha2 undergoes trans-autophosphorylation. Together, our results demonstrate that JNK2alpha2 differs from other MAPK proteins in two major ways; its autoactivation/autophosphorylation is dependent on dimerization, and dimerization most likely precedes autophosphorylation. In addition, we show that dimerization is essential for JNK2alpha2 activity and that prevention of dimerization may decrease JNK2alpha2 induced tumorigenic phenotypes.
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PMID:Constitutive activity of JNK2 alpha2 is dependent on a unique mechanism of MAPK activation. 1894 Aug 13


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