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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine stromal-derived factor-1alpha (SDF-1alpha/CXCL-12) and its receptor, CXCR4, play a crucial role in adhesion and transendothelium migration (TEM) of prostate cancer cells. We tested the hypothesis that enhanced expression of CXCR4 in prostate cancer cells is dependent upon SDF-1alpha-mediated activation of nuclear factor-kappaB (NF-kappaB). SDF-1alpha increased the CXCR4 mRNA and protein expression in PC-3 cells but not in LNCaP cells. Similarly, SDF-1alpha enhanced the NF-kappaB-dependent transcriptional activity in PC-3 cells but not in LNCaP cells. SDF-1alpha increased PC-3 cell adhesion to the human umbilical vein endothelial cell monolayer and enhanced TEM, which was abrogated with anti-CXCR4 monoclonal antibody (mAb). Suppression of NF-kappaB activity in PC-3 cells by a mutant IkappaBalpha super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited adhesion and TEM. Transient overexpression of p65 subunit of NF-kappaB in PC-3 cells up-regulated CXCR4 receptor expression and increased the adhesion and TEM of these cells in response to SDF-1alpha gradient. Treatment of PC-3 cells with SDF-1alpha leads to nuclear translocation of NF-kappaB protein within 15 to 30 minutes, which correlated with IkappaBalpha phosphorylation. A p42/44 mitogen-activated protein kinase [MAPK, extracellular signal regulated kinase-1/2 (ERK-1/2)] biphasic activation pattern was observed in these cells at 15 minutes and 3 hours after SDF-1alpha treatment. Phosphorylation of IkappaB kinase alpha was observed within 30 minutes, which was blocked by PD98059 [MAPK kinase (MEK) inhibitor]. PD98059 cotreatment significantly inhibited SDF-1alpha-induced NF-kappaB reporter activity and CXCR4 receptor expression as shown by flow cytometry. These data suggest that SDF-1alpha-induced expression of CXCR4 in PC-3 cells is dependent on MEK/ERK signaling cascade and NF-kappaB activation.
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PMID:Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. 1626 13

Many isothiocyanates (ITCs) such as sulforaphane (SFN), phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC) are highly effectively in chemoprevention or reduction of the risk of cancer and possess antitumor activities in vitro and in vivo. The activator protein 1 (AP-1) and MAPK signaling pathways are believed to play an important role in cancer chemoprevention and chemotherapy due to their involvement in tumor cell growth, proliferation, apoptosis and survival. In the present study, we determined the effects of SFN, PEITC and AITC on AP-1 activation, and investigated the roles of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways in the regulation of AP-1 activation and cell death elicited by these ITCs in human prostate cancer PC-3 cells. SFN, PEITC and AITC each induced AP-1 activity potently and caused a significant elevation in the phosphorylation of ERK1/2, JNK1/2, Elk-1 and c-Jun. Transfection with ERK2 and upstream kinase DNEE-MEK1 activated AP-1 activity, and transfection with dominant-negative mutant ERK2 (dnERK2) potently decreased AP-1 activation induced by SFN, PEITC and AITC. Transfection with JNK1 and upstream kinase MKK7 activated AP-1 activity, and transfection with dominant-negative mutant JNK1-APF significantly attenuated AP-1 activation induced by SFN, PEITC and AITC. Pretreatment with MEK1-ERK inhibitor U0126 and JNK inhibitor SP600125 substantially attenuated the decrease in cell viability induced by SFN, PEITC and AITC. Transfection with dnERK2 and JNK1-APF significantly reversed the decrease of Bcl-2 expression elicited by these ITCs. Furthermore, transfection with dnERK2 and JNK1-APF blocked the apoptosis induced by these ITCs in PC-3 cells. Taken together, our results indicate that the activation of the ERK and JNK signaling pathways is important for transcriptional activity of AP-1 and is involved in the regulation of cell death elicited by ITCs in PC-3 cells.
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PMID:ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells. 1627 72

An anti-insect and anti-cancer lectin has been isolated from Arisaema helleborifolium Schott by affinity chromatography using asialofetuin-linked amino activated silica beads. The bound A. helleborifolium lectin (AHL) was eluted with 100mM glycine-HCl buffer, pH 2.5. It gave a single band on SDS-PAGE, pH 8.3, and PAGE, pH 4.5. However, multiple bands were obtained in PAGE at pH 8.3 and isoelectric focusing. The lectin was a homotetramer having subunit molecular mass 13.4kDa while its native molecular mass was 52kDa. It was a glycoprotein with 3.40% carbohydrate and was stable up to 60 degrees C for 30min. It showed anti-insect activity towards second instar larvae of Bactrocera cucurbitae (Coquillett) with LC(50) value of 16.4microg/ml. Larvae fed on artificial diet containing sub-lethal dose of AHL showed a significant decrease in acid phosphatase and alkaline phosphatase activity while esterase activity markedly increased as compared to larvae fed on diet without lectin. AHL was also found to inhibit in vitro proliferation of some well established human cancer cell lines viz HOP-62 (95%), HCT-15 (92%), HEP-2 (66%), HT-29 (68%), PC-3 (39.4%), and A-549 (20.7%).
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PMID:A tuber lectin from Arisaema helleborifolium Schott with anti-insect activity against melon fruit fly, Bactrocera cucurbitae (Coquillett) and anti-cancer effect on human cancer cell lines. 1632 59

Prostate cancer frequently metastasizes to bone resulting in the formation of osteoblastic metastases through unknown mechanisms. Vascular endothelial growth factor (VEGF) has been shown recently to promote osteoblast activity. Accordingly, we tested if VEGF contributes to the ability of prostate cancer to induce osteoblast activity. PC-3, LNCaP, and C4-2B prostate cancer cell lines expressed both VEGF-165 and VEGF-189 mRNA isoforms and VEGF protein. Prostate cancer cells expressed the mRNA for VEGF receptor (VEGFR) neuropilin-1 but not the VEGFRs Flt-1 or KDR. In contrast, mouse pre-osteoblastic cells (MC3T3-E1) expressed Flt-1 and neuropilin-1 mRNA but not KDR. PTK787, a VEGFR tyrosine kinase inhibitor, inhibited the proliferation of human microvascular endothelial cells but not prostate cancer proliferation in vitro. C4-2B conditioned medium induced osteoblast differentiation as measured by production of alkaline phosphatase and osteocalcin and mineralization of MC3T3-E1. PTK787 blocked the C4-2B conditioned medium-induced osteoblastic activity. VEGF directly induced alkaline phosphatase and osteocalcin but not mineralization of MC3T3-E1. These results suggest that VEGF induces initial differentiation of osteoblasts but requires other factors, present in C4-2B, to induce mineralization. To determine if VEGF influences the ability of prostate cancer to develop osteoblastic lesions, we injected C4-2B cells into the tibia of mice and, after the tumors grew for 6 weeks, administered PTK787 for 4 weeks. PTK787 decreased both intratibial tumor burden and C4-2B-induced osteoblastic activity as measured by bone mineral density and serum osteocalcin. These results show that VEGF contributes to prostate cancer-induced osteoblastic activity in vivo.
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PMID:Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. 1632 39

Expression of ErbB4 receptor is correlated with the incidence of non-metastatic types of human cancers, whereas the overexpression of other ErbB receptor families (ErbB1/EGFR, ErbB2 and ErbB3) is correlated to the formation of metastatic tumors. However, the molecular mechanism underlying this phenomenon has been unclear. Earlier, we demonstrated that okadaic acid (OA), an inhibitor of a serine/threonine phosphatase PP2A, stimulated the growth hormone-induced ERK phosphorylation in the wild type Chinese hamster ovary (CHO) cells and the cells expressing ErbB1 receptor, but suppressed ERK activation in CHO cells that express ErbB4 receptor. PP2A had been understood as a negative regulator of the growth hormone-stimulated signal transduction pathways, however, this observation suggested that expression of ErbB4 receptor reversed the regulation of PP2A in the ErbB4 signalling pathway. In this study, we found that OA suppressed phosphorylation of Shc at Tyr317, therefore it down-regulated ERK phosphorylation in the ErbB4 expressing CHO cells. Accordingly, basal PP2A contributed to the phosphorylation of Shc Tyr317 in ErbB4 expressing CHO cells, nevertheless it had been reported that PP2A negatively regulates Shc tyrosine phosphorylation in the EGF- or IGF-I-induced signalling pathways. By testing OA for human cancer cell lines that express different types of ErbB receptors, we found that ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells. Thus, PP2A regulates the ERK activity in a cell-specific manner, and it is speculated that distinct regulation of PP2A in the ErbB4 receptor signalling pathway may cause a difference in progression of cancer phenotypes.
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PMID:Expression of the ErbB4 receptor causes reversal regulation of PP2A in the Shc signal transduction pathway in human cancer cells. 1647 70

Nuclear factor-kappaB (NF-kappaB) and AP-1 nuclear transcriptional factors regulate expression of multiple genes involved in tumor growth, metastasis and angiogenesis; however, the relative contribution of each factor to cancer initiation and progression has not been established. Prostate carcinogenesis involves transformation of normal zinc-accumulating epithelial cells to malignant cells that do not accumulate zinc. Whereas activation of both NF-kappaB and AP-1 has been implicated in prostate cancer development and growth, we tested the relative effects of zinc supplementation on these important transcriptional factors. Herein, we demonstrate that physiological levels of zinc inhibit NF-kappaB but augment activities of AP-1 in DU-145 and PC-3 human prostate cancer cells. Additionally, we show that chelation of zinc with membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) abolishes this effect. We further propose a potential mechanism for this observation by demonstrating that zinc supplementation induces phosphorylation of the members of three major MAPK subfamilies regulating AP-1 and NF-kappaB activation (ERK 1/2, JNK and p38) while blocking TNF-alpha-mediated degradation of the inhibitory subunit I kappa B alpha and nuclear translocation of RelA in prostate cancer cells. VEGF, IL-6, IL-8 and MMP-9 are major pro-angiogenic and pro-metastatic molecules whose promoter regions contain binding sites for both NF-kappaB and AP-1. These cytokines have been associated with negative prognostic features in prostate cancer. We demonstrate that treatment of human prostate cancer cell lines with zinc reduces expression of VEGF, IL-6, IL-8 and MMP-9. We further show that zinc reduces expression of intercellular adhesion molecule-1 and functionally suppresses tumor cell invasiveness and adhesion. Therefore, the ability of zinc supplementation to inhibit NF-kappaB supercedes zinc-mediated activation of AP-1 family members. Upregulation of intracellular zinc levels may have important implications for inhibiting the angiogenic and metastatic potentials of malignant cells, predominantly through suppression of NF-kappaB signaling.
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PMID:Diverse effects of zinc on NF-kappaB and AP-1 transcription factors: implications for prostate cancer progression. 1660 32

The mechanisms by which a GnRH analogue, leuprorelin acetate (LA), antagonizes the mitogenic effect of dihydrotestosterone (DHT) or epidermal growth factor (EGF) in prostate cancer cells is poorly understood. The mitogen-activated protein kinase system has a central role in growth regulation and, for this reason, we investigated the involvement of the extracellular signal-regulated kinase (ERK1/2) pathway in the response of both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells to LA alone or combined with EGF or DHT. The evaluation of ERK activation was performed by using Western blot analysis and immunocytochemistry. EGF specifically induced ERK1/2 activity in both models and this effect was counteracted by an inhibitor of EGF-receptor phosphorylation. The addition of LA produced an appreciable reduction of ERK phosphorylation promoted by EGF in LNCaP cells, while it generally determined an increase in ERK activity in androgen-unresponsive PC-3 cells. The slight ERK activation induced by DHT in LNCaP cells was counteracted by LA and this effect was evident only by immunocytochemistry. Our findings suggest that the antiproliferative effect of LA in prostate cancer cells stimulated by hormones and growth factors may be, at least in part, mediated by the reduction of ERK1/2 activation in LNCaP cells and linked to the unexpected increase of this activity produced by the analogue in PC-3 cells.
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PMID:Leuprorelin acetate affects ERK1/2 activity in prostate cancer cells. 1677 5

A tuber lectin from Arisaema jacquemontii Blume belonging to family Araceae was purified by employing a single step affinity chromatography using column of asialofetuin-linked amino activated silica beads and the bound lectin was eluted with 100 mM glycine-HCl buffer pH 2.5. The purified A. jacquemontii lectin (AJL) showed a single protein band with an apparent molecular mass of 13.4 kDa when submitted to SDS-polyacrylamide gel electrophoresis under reducing as well as non-reducing conditions. The native molecular mass of AJL determined by gel filtration on a Biogel P-200 column was 52 kDa and its carbohydrate content was estimated to be 3.40%. Thus AJL is a tetrameric glycoprotein. The purified lectin agglutinated erythrocytes from rabbit but not from human. Its activity was not inhibited by any of the mono- and disaccharides tested except N-acetyl-D-lactosamine having minimal inhibitory sugar concentration (MIC) 25 mM. Among the glycoproteins tested only asialofetuin was found to be inhibitory (MIC125 microg/mL). A single band was obtained in native PAGE at pH 4.5 while PAGE at pH 8.3 showed two bands. Isoelectric focusing of AJL gave multiple bands in the pI range of 4.6-5.5. When incorporated in artificial diet AJL significantly affected the development of Bactrocera cucurbitae (Coquillett) larvae indicating the possibility of using this lectin in a biotechnological strategy for insect management of cucurbits. Larvae fed on artificial diet containing sublethal dose of AJL showed a significant decrease in acid phosphatase and alkaline phosphatase activity while esterase activity markedly increased as compared to larvae fed on diet without lectin. Out of various human cancer cell lines employed in sulphorhodamine B (SRB) assay, this lectin was found to have appreciable inhibitory effect on the in vitro proliferation of HCT-15, HOP-62, SW-620, HT-29, IMR-32, SKOV-3, Colo-205, PC-3, HEP-2 and A-549 cancer cell lines by 82, 77, 73, 70, 41, 41, 37, 29, 21 and 21% respectively.
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PMID:A tuber lectin from Arisaema jacquemontii Blume with anti-insect and anti-proliferative properties. 1688 88

The impact of human chorionic gonadotropin (hCG) on prostate carcinoma viability was investigated. Treatment of LNCaP and PC-3 cells with hCG modestly reduced cell viability within 96 h. Treatment of cells with hCG followed by exposure to ionizing radiation enhanced radiosensitivity. Exposure of LNCaP cells to hCG promoted activation of epidermal growth factor receptor (ERBB1) via a Galpha(i)-, mitogen-activated protein kinase kinase (MEK)1/2-, and metalloprotease-dependent paracrine mechanism, effects that were further enhanced after radiation exposure, and that were causal in prolonged intense activation of poly(ADP-ribose) polymerase (PARP). Inhibition of ERBB1, MEK1, or PARP1 function suppressed the radiosensitizing properties of hCG. Radiosensitization was also, in part, dependent upon c-Jun NH2-terminal kinase 1/2 signaling. PARP1-dependent radiosensitization was suppressed by a pan-caspase inhibitor and by knockdown of apoptosis-inducing factor expression. Inhibition of phosphatidylinositol 3-kinase, expression of dominant-negative AKT, or treatment with the HMG CoA reductase inhibitor lovastatin suppressed AKT phosphorylation and enhanced the cytotoxic effects of hCG. The enhancing effect of lovastatin was reproduced by incubation with a geranylgeranyl transferase inhibitor and blocked by coexposure to geranylgeranyl pyrophosphate. Treatment with hCG and lovastatin decreased expression of BCL-(XL) and XIAP, and increased expression of IkappaB. The cytotoxic effects of hCG were enhanced by expression of dominant-negative IkappaB, and they were abolished by coexpression of activated AKT. Expression of activated AKT maintained BCL-(XL) levels in cells expressing dominant-negative IkappaB. The promotion of hCG lethality by lovastatin was abolished by overexpression of BCL-(XL), and was dependent upon activation of caspase-9. Thus, hCG, in combination with radiation and lovastatin, may represent a novel approach to kill prostate cancer cells.
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PMID:Human chorionic gonadotropin modulates prostate cancer cell survival after irradiation or HMG CoA reductase inhibitor treatment. 2741 95

Insulin-like growth factor 1 receptor (IGF-1R) activation is required for prostate cell proliferation. Prostate cancer is one of the most commonly diagnosed malignant tumors in Western countries. Overexpression of IGF-1R in prostate cancer is associated with tumor growth. These suggest that IGF-1R inhibitory agents may be of preventive and/or therapeutic value. With evidence accumulating for a chemopreventive role of flavonoids, the effects of luteolin, a bioactive flavonoid, on IGF-1R signaling in prostate cancer cells were examined. Luteolin inhibited insulin-like growth factor 1 (IGF-1) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells. Inhibition of AKT by luteolin resulted in decreased phosphorylation of its downstream targets, including p70S6K1, GSK-3beta and FKHR/FKHRL1. Luteolin also inhibited the IGF-1-induced activation of EGFR and MAPK/ERK signaling. Luteolin inhibited expression of cyclin D1 and increased expression of p21. As a result, luteolin suppressed proliferation and induced apoptosis of prostate cancer cells. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of prostate cancer cells. Results of in vivo tumor growth assay indicated that luteolin inhibited PC-3 tumor growth. Immunoblotting of the extracts of tumor tissues showed that luteolin inhibited IGF-1R/AKT signaling. Our results provide a new insight into the mechanisms that luteolin is against cancer cells.
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PMID:Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells. 1706


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