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)

Oxidative stress has been associated with neuronal loss in neurodegenerative diseases and during age-associated cognitive decline. Flavonoids have been proposed to play a useful role in protecting the central nervous system against oxidative and excitotoxic stress, although the mechanism of action is unknown. Using oxidized low-density lipoprotein (oxLDL) as the oxidative insult we investigated the mechanism of neurotoxicity and attempted to identify possible sites of action of two of the most potent protective flavonoids, epicatechin and kaempferol, in cultured primary neurons. Using cultured striatal neurons and selective phosphospecific antibodies we addressed the potential role of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). OxLDL stimulated a Ca(2+)-dependent activation of both ERK1/2 and JNK that was strongly inhibited by pre-treatment with low micromolar concentrations of epicatechin. Neurotoxicity induced by oxLDL, however, was neither reduced nor enhanced by inhibiting ERK1/2 activation with mitogen-activated protein kinase kinase (MEK) inhibitors, suggesting that this cascade is unlikely to be involved in either oxLDL toxicity or the protective effects of flavonoids. oxLDL caused a sustained activation of JNK that resulted in the phosphorylation of the transcription factor c-Jun, which was abolished in neurons pre-treated with flavonoids. Furthermore, oxLDL induced the cleavage of procaspase-3 and increased caspase-3-like protease activity in neurons, an effect which was strongly inhibited by pre-exposure to either epicatechin or kaempferol. In addition, a caspase-3 inhibitor reduced oxLDL-induced neuronal death, implicating an apoptotic mechanism. A major in vivo metabolite of epicatechin, 3'-O-methyl-epicatechin was as effective as epicatechin in protecting neurons. Thus dietary flavonoids might have potential as protective agents against neuronal apoptosis through selective actions within stress-activated cellular responses, including protein kinase signalling cascades.
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PMID:Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. 1153 18

A vast variety of naturally occurring substances have been shown to protect against experimental carcinogenesis and an increasing amount of evidence suggests that kaempferol may have cancer chemopreventative properties. However, the precise underlying protective mechanisms are poorly understood. To elucidate these mechanisms, we challenged human lung cancer cell line A549 with kaempferol and investigated its effects upon cellular growth and signal transduction pathways. Treatment of A549 cells with kaempferol resulted in a dose- and time-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 0.9+/-0.5, 5.2+/-1.5, 16.8+/-2.0, 25.4+/-2.6, and 37.8+/-4.5% on treatment with 0, 17.5, 35.0, 52.5, and 70.0 microM kaempferol, respectively. Concomitantly, kaempferol treatments led to a 1.2-, 2.7-, 3.3-, and 3.4-fold increase in Bax. Similar elevations were also observed in Bad which increased 1.2-, 3.3-, 3.7-, and 4.7-fold, respectively, as compared to control. Bcl-2 and Bcl-xL expression were inhibited in a dose-dependent fashion. While the Akt-1 and phosphorylated Akt-1 were inhibited, the mitogen-activated protein kinase (MAPK) was activated upon kaempferol treatment. Kaempferol induced apoptosis was associated with the cleavage of caspase-7 and poly ADP-ribose polymerase (PARP). Inhibition of MEK1/2 but not PI-3 kinase blocked kaempferol-induced cleavage of caspase-7, PARP cleavage, and apoptosis. The results suggest that inactivation of Akt-1 and alteration of Bcl-2 family of proteins are not sufficient for kaempferol to induce apoptosis and activation of MEK-MAPK is a requirement for kaempferol-induced cell death machinery in A549 cells.
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PMID:Kaempferol-induced growth inhibition and apoptosis in A549 lung cancer cells is mediated by activation of MEK-MAPK. 1294 47

[reaction: see text] The synthesis of the naturally occurring kaempferol glycoside SL0101 has been accomplished, as has its biochemical evaluation. SL0101 exhibits selective and potent p90 Rsk inhibitory activity at nanomolar concentrations without inhibiting the function of upstream kinases such as MEK, Raf, or PKC. The synthesis verified the structural assignment of the natural product and has provided access to material sufficient for detailed biological evaluation.
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PMID:Synthesis of a potent and selective inhibitor of p90 Rsk. 1576 Jan 48

"Immune escape" is a crucial instrument used by carcinoma cells to overcome numerous strategies of immune system to delete transformed cells. Cellular factors that make cancer cells immune to defence mechanisms are incompletely understood while some remain ambiguous. Up to date evidence points to some proteins and/or signaling molecules that might be a basis for unusual behavior of cancer cells. In particular STAT kinases are currently in the main focus of attention since they were both shown to accelerate and/or to inhibit apoptosis. In our studies we observed that human colorectal COLO 205 cancer cells were resistant to TNF-alpha- or cycloheximide-induced cytotoxicity. However, when TNF-alpha (10 ng/ml) has been given along with cycloheximide (5 micro g/ml, CHX) COLO 205 cells died extensively from apoptosis. Apparently, cycloheximide sensitized cells to TNF-alpha-induced programmed cell death. To investigate the role of STAT-1 alpha in CHX-mediated TNF-alpha-induced COLO 205 cell death certain polyphenolic compounds were studied if they modulate STAT-1 alpha phosphorylation status and STAT-1 alpha-protein interaction at the level of TNF-alpha signalosome in the 6(th), 12(th), and 24(th) hour of experiment. Neither of phenolic compound, namely PI-3K inhibitor (LY294002, 20 microM) nor MEK inhibitor (PD98059, 50 microM), nor flavonol quercetin or kaempferol (10, 100 microM) in contrast to apigenin (20 microM) influenced COLO 205 cell viability during individual or combined treatment with TNF-alpha and CHX. We conclude, that some antiapoptotic proteins were involved but not STAT-1 alpha kinase to resist TNF-alpha-dependent cell death promoting activity. Summing up, except apigenin, the above-mentioned polyphenolic compounds were unable to modulate survival signal in COLO 205 cells initially believed to be suppressed by STAT-1 alpha.
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PMID:Position of STAT-1 alpha in cycloheximide-dependent apoptosis triggered by TNF-alpha in human colorectal COLO 205 cancer cell line; role of polyphenolic compounds. 1607 99

In last couple of decades the use of natural compounds like flavonoids as chemopreventive agents has gained much attention. Our current study focuses on identifying chemopreventive flavonoids and their mechanism of action on human prostate cancer cells. Human prostate cancer cells (PC3), stably transfected with activator protein 1 (AP-1) luciferase reporter gene were treated with four main classes of flavonoids namely flavonols, flavones, flavonones, and isoflavones. The maximum AP-1 luciferase induction of about 3 fold over control was observed with 20 microM concentrations of quercetin, chrysin and genistein and 50 microM concentration of kaempferol. At higher concentrations, most of the flavonoids demonstrated inhibition of AP-1 activity. The MTS assay for cell viability at 24 h showed that even at a very high concentration (500 microM), cell death was minimal for most of the flavonoids. To determine the role of MAPK pathway in the induction of AP-1 by flavonoids, Western blot of phospho MAPK proteins was performed. Four out of the eight flavonoids namely kaempferol, apigenin, genistein and naringenin were used for the Western Blot analysis. Induction of phospho-JNK and phospho-ERK activity was observed after two hour incubation of PC3-AP1 cells with flavonoids. However no induction of phospho-p38 activity was observed. Furthermore, pretreating the cells with specific inhibitors of JNK reduced the AP-1 luciferase activity that was induced by genistein while pretreatment with MEK inhibitor reduced the AP-1 luciferase activity induced by kaempferol. The pharmacological inhibitors did not affect the AP-1 luciferase activity induced by apigenin and naringenin. These results suggest the possible involvement of JNK pathway in genistein induced AP-1 activity while the ERK pathway seems to play an important role in kaempferol induced AP-1 activity.
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PMID:Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells. 1696 58

Regular consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases. It is estimated that one third of all cancer deaths in the USA could be avoided through appropriate dietary modification. Several studies have indicated that fruits, vegetables and whole grains contain significant amounts of bioactive phytochemicals that have antiproliferative and antineoplastic properties. The bioactive phytochemicals may help protect cellular systems from oxidative damage as well as reduce the risk of chronic diseases. Quercetin and other related flavonoids have been shown to inhibit carcinogen-induced tumors in rodents. In humans, the total average intake of quercetin and kaempferol is estimated at 20 mg/day and consumption of quercetin from onions and apples was inversely correlated with lung cancer risk. In this study, we report that quercetin-inhibited A549 lung carcinoma cell proliferation was associated with activation of the extracellular signal-regulated kinase (ERK). Inhibition of MEK1/2 but not PI3 kinase, p38 kinase or JNK abolished quercetin-induced apoptosis suggesting MEK-ERK activation was required to trigger apoptosis.
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PMID:Dietary quercetin inhibits proliferation of lung carcinoma cells. 1768 11

Granulocyte-macrophage colony-stimulating factor (GM-CSF) holds immunotherapeutic promise in prostate cancer as it activates the host immune system. Increased production of GM-CSF by cancer cells may facilitate host immunosurveillence by the dendritic cells (DC). Here, we studied the effects of kaempferol (K) and quercetin (Q) on the production of GM-CSF in PC-3 cells. Human cytokine antibody array revealed that treatment with K or Q increased GM-CSF release by PC-3 cells. We further observed by ELISA that K and Q in a concentration-dependent manner increased GM-CSF production without affecting its mRNA levels. Inhibitors of vesicular traffic through the endoplasmic reticulum and Golgi-blocked GM-CSF secretory stimulation. A microtubule-stabilizing agent stimulated GM-CSF release, whereas tubulin and actin depolymerizers suppressed K- or Q-stimulated secretion of GM-CSF. Depletion of extracellular or intracellular calcium ion inhibited the GM-CSF secretion upregulated by both K and Q. Furthermore, we showed that K- and Q-stimulated GM-CSF production involves PLC, PKC, and MEK1/2 activation. Treating human DC with the conditioned medium of K- or Q-incubated PC-3 cells increased chemotaxis of DC, which was significantly attenuated when the conditioned medium was incubated with the neutralizing antibody against GM-CSF. Taken together, our results demonstrate that K and Q activate an immune response in the prostate cancer cells by stimulating GM-CSF production, which in turn could result in the recruitment of DCs to the tumor site.
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PMID:Kaempferol and quercetin stimulate granulocyte-macrophage colony-stimulating factor secretion in human prostate cancer cells. 1834 43

In order to determine the effects of a variety of flavonoids, we applied differing amounts of several flavonoids to human breast cancer cells. Kaempferol treatment resulted in significant reduction of cell viability in the MCF-7 cells, although it exerted only minor effect on the cell viability of MDA-MB-231 or mammary epithelial HC-11 cells. Kaempferol was demonstrated to induce sustained ERK activation concomitantly with MEK1 and ELK1 activation, and this kaempferol-induced apoptosis was suppressed by treatment with PD98059, the overexpression of a kinase-inactive ERK mutant, or ERK siRNA. Kaempferol treatment was shown to profoundly induce the generation of fluorescent DCF in the MCF-7 cells, and treatment with N-acetyl cysteine suppressed kaempferol-induced PARP cleavage. Moreover, because breast cancer is associated with increased collagen synthesis and accumulation, we utilized a collagen-based 3D culture method. Under the 3-dimensional culture condition employed herein, kaempferol treatment was shown to result in a significant reduction in cell viability, an effect which occurred in a dose-dependent manner. Compared with what was observed under conventional 2D culture condition, we observed more evident apoptotic cell death and ERK activation as the result of kaempferol treatment in a collagen-based 3D culture environment. Similar to the case of conventional 2D cultured cells, the addition of PD98059 significantly suppressed intracellular ROS production. Collectively, these results show that the sustained activation of the ERK signaling pathway is markedly involved in kaempferol-induced apoptosis of breast cancer MCF-7 cells, and that this effect is more evident under 3D culture condition.
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PMID:Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition. 1844 32

The present study was undertaken to determine the molecular mechanism by which kaempferol induces cell death in human glioma cells. Kaempferol resulted in loss of cell viability and inhibition of proliferation in a dose- and time-dependent manner, which were largely attributed to cell death. Kaempferol caused an increase in reactive oxygen species (ROS) generation and the kaempferol-induced cell death was prevented by antioxidants, suggesting that ROS generation is involved in kaempferol-induced cell death. Kaempferol caused depolarization of mitochondrial membrane potential. Western blot analysis showed that kaempferol treatment caused a rapid reduction in phosphorylation of extracellular signal-regulated kinase (ERK) and Akt. The ERK inhibitor U0126 and the Akt inhibitor LY984002 increased the kaempferol-induced cell death and overexpression of MEK, the upstream kinase of ERK, and Akt prevented the cell death. The expression of anti-apoptotic proteins XIAP and survivin was down-regulated by kaempferol and its effect was prevented by overexpression of MEK and Akt. Kaempferol induced activation of caspase-3 and kaempferol-induced cell death was prevented by caspase inhibitors. Taken together, these findings suggest that kaempferol results in human glioma cell death through caspase-dependent mechanisms involving down-regulation of XIAP and survivin regulating by ERK and Akt.
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PMID:Kaempferol induces cell death through ERK and Akt-dependent down-regulation of XIAP and survivin in human glioma cells. 1894 56

Oxidative stress has been considered as a major cause of cellular injuries in a variety of clinical abnormalities, especially neural diseases. Our aim of research is to investigate the protective effects and mechanisms of kaempferol and rhamnocitrin (kaempferol-7-methyl ether) on oxidative damage in rat pheochromocytoma PC12 cells induced by a limited supply of serum and hydrogen peroxide (H2O2). The current result demonstrated that kaempferol protected PC12 cells from serum deprivation-induced apoptosis. Pretreatment of cells with kaempferol also diminished intracellular generation of reactive oxygen species (ROS) in response to H2O2 and strongly elevated cell viability. RT-Q-PCR and Western blotting revealed that kaempferol and rhamnocitrin significantly induced heme oxygenase (HO)-1 gene expression. Addition of zinc protoporphyrin (Znpp), a HO-1 competitive inhibitor, significantly attenuated their protective effects in H2O2-treated cells, indicating the vital role of HO-1 in cell resistance to oxidative injury. While investigating the signaling pathways responsible for HO-1 induction, we observed that kaempferol induced sustained extracellular signal-regulated protein kinase 1/2 (ERK1/2) in PC12 cells grown in low serum medium; while rhamnocitrin only stimulated transient ERK cascade. Addition of U0126, a highly selective inhibitor of MEK1/2, which is upstream of ERK1/2, had no effect on kaempferol- or rhamnocitrin-induced HO-1 mRNA expression, indicating no direct cross-talk between these two pathways. Furthermore, both kaempferol and rhamnocitrin were able to persistently attenuate p38 phosphorylation. Taking together, the above findings suggest that kaempferol and rhamnocitrin can augment cellular antioxidant defense capacity, at least in part, through regulation of HO-1 expression and MAPK signal transduction.
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PMID:Regulation of heme oxygenase-1 expression and MAPK pathways in response to kaempferol and rhamnocitrin in PC12 cells. 1926 14


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