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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; Germany ; KINASE ; GENE ; GENE-EXPRESSION ; PROTEIN ; DIFFERENTIATION ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; MESSENGER-RNA ; DOMAIN ; mechanisms ; DOWN-REGULATION ; PHOSPHORYLATION ; PROTEIN-KINASE ; signal transduction ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; SIGNAL-TRANSDUCTION ; CANCER-CELLS ; CARCINOMA-CELLS ; LOCALIZATION ; PROTEIN-KINASE-C ; PHORBOL ESTER ; ESTRADIOL ; SYNTHASE ; TRANSFECTION ; regulation ; ESTROGEN ; estrogen receptor ; GLYCOGEN-SYNTHASE KINASE-3 ; GSK3 ; MCF-7 CELLS ; PKC ; PKC delta
    Abstract: Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKC delta is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKC delta on the regulation of the transcriptional activity of the human ER alpha. By using 12-O-tetradecanoylphorbol- 13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKC delta is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKC delta by TPA resulted in activation and nuclear translocation of ER alpha and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RD delta of PKC delta, which is inhibitory to PKC delta, inhibited the TPA-induced ER alpha activation and translocation. ER alpha was not phosphorylated by PKC delta; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKC delta. The expression of RD delta resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKC delta-related nuclear translocation of ER alpha
    Type of Publication: Journal article published
    PubMed ID: 15824731
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  • 2
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; tumor ; carcinoma ; Germany ; human ; HYBRIDIZATION ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; PATIENT ; FAMILY ; MARKER ; hormone ; IN-SITU ; PROGRESSION ; immunohistochemistry ; PATTERNS ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; BENIGN ; GLYCATION END-PRODUCTS ; RAGE ; CARCINOMAS ; adenocarcinoma ; intraepithelial neoplasia ; NEURITE OUTGROWTH ; KAPPA-B ; CANCER PATIENTS ; HEALTHY ; prostate carcinoma ; OXIDANT STRESS ; SERUM ; in situ hybridization ; ELISA ; RE ; END ; TUMORIGENESIS ; HUMAN PROSTATE ; HYPERPLASIA ; TUMOR TISSUE ; MOLECULAR-GENETICS ; HUMAN-PROSTATE ; S100 PROTEINS ; EXPRESSION PATTERNS ; SERUM-LEVELS ; TUMOR DIFFERENTIATION
    Abstract: Purpose: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S10OA8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. Experimental Design:Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S10OA8, S100A9, and RAGE. In addition, in situ hybridization of S10OA8 and S10OA9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S10OA9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). Results: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S10OA8 and S10OA9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. Conclusion: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH
    Type of Publication: Journal article published
    PubMed ID: 16033829
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; human ; KINASE ; PATHWAY ; PATHWAYS ; PROSTATE ; VITRO ; PROTEIN ; PROTEINS ; cell line ; LINES ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; FAMILY ; BIOLOGY ; CELL-LINES ; PHOSPHORYLATION ; ASSOCIATION ; SIGNAL ; MAP KINASE ; hormone ; prostate cancer ; PROSTATE-CANCER ; CELL-LINE ; LINE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; CANCER-CELLS ; US ; MIGRATION ; LIGANDS ; BENIGN ; EPITHELIAL-CELLS ; INTERMEDIATE-FILAMENTS ; RAGE ; UNITED-STATES ; NEURITE OUTGROWTH ; CALCIUM ; NF-kappa B ; TRANSLOCATION ; pathology ; cell lines ; MAP KINASES ; STATES ; CALCIUM-BINDING PROTEINS ; SUBCELLULAR-LOCALIZATION ; signaling ; PROTEIN TRANSLOCATION ; FEATURES ; ONCOLOGY ; CALCIUM-BINDING PROTEIN ; DISORDERS ; RECOMBINANT ; RE ; FAMILIES ; FUNCTIONAL IMPLICATIONS ; ENHANCED EXPRESSION ; HUMAN PROSTATE ; LEVEL ; HUMAN-PROSTATE ; S100 PROTEINS ; KINASES ; immunofluorescence ; CALCIUM-BINDING ; S100A8 ; S100A9 ; ADVANCED GLYCATION ENDPRODUCTS ; END-PRODUCTS RAGE ; function ; HORMONES ; INTRACELLULAR CALCIUM ; MAP ; PUTATIVE TUMOR-SUPPRESSOR ; S100
    Abstract: S100 proteins, a multigenic family of calcium-binding proteins, have been linked to human pathologies in recent years. Deregulated expression of S100 proteins, including S100A8 and S100A9, was reported in association with neoplastic disorders. In a previous study, we identified enhanced expression of S100A8 and S100A9 in human prostate cancer. To investigate potential functional implications of S100A8 and S100A9 in prostate cancer, we examined the influence of over-expressed and of purified recombinant S100A8 and S100A9 proteins in different prostate epithelial cell lines. S100A8 and S100A9 were secreted by prostate cancer cells, a finding which prompted us to analyze a possible function as extracellular ligands. S100A8/A9 induced the activation of NF-kappa B and an increased phosphorylation of p38 and p44/42 MAP kinases. In addition, extracellular S100A8/A9 stimulated migration of benign prostatic cells in vitro. Furthermore, in immunofluorescence experiments, we found a strong speckled co-localization of intracellular Sl00A8/A9 with RAGE after stimulating cells with recombinant S100A8/A9 protein or by increasing cytosolic Ca2+ levels. In summary, our findings show that S100A8 and S100A9 are linked to the activation of important features of prostate cancer cells. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16297907
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  • 4
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; CELL ; COMBINATION ; Germany ; INHIBITION ; KINASE ; VITRO ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; transcription ; METABOLISM ; ACCUMULATION ; ACTIVATION ; LIGAND ; TRANSCRIPTION FACTOR ; IMPACT ; REDUCTION ; DOWN-REGULATION ; PHOSPHORYLATION ; SIGNAL ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; ELEMENT ; RESPONSE ELEMENT ; TRANSCRIPTION FACTORS ; hormone ; gene expression ; ASSAY ; DECREASE ; CANCER-CELLS ; BETA ; transactivation ; DEGRADATION ; RECEPTORS ; PROTEASOME ; ESTRADIOL ; ESTROGEN-RECEPTOR ; CANCER CELL-LINES ; ENDOCRINE ; RE ; SYNTHASE ; PROTEIN-SYNTHESIS ; regulation ; REPORTER GENE ; SUBSTRATE ; ESTROGEN ; LEVEL ; analysis ; ASSAYS ; NUCLEAR ; estrogen receptor ; MCF-7 CELLS ; USA ; function ; HORMONES ; ANTAGONISTS ; PROTECTS ; progesterone receptor ; in combination ; E2 ; TURNOVER ; MESSENGER-RIBONUCLEIC-ACID
    Abstract: Glycogen synthase kinase- 3 ( GSK- 3) plays a key role in the regulation of transcription factors including steroid receptors. Having identified estrogen receptor-alpha ( ER alpha) as substrate for GSK- 3, the impact of GSK- 3 on ER alpha function and activity upon 17 beta- estradiol ( E2)- dependent activation remains to be clarified. Here we show by using small interfering technology in combination with immunoblot, gene expression analysis, and luciferase reporter assays that silencing of GSK- 3 alpha or GSK- 3 beta results in the reduction of ER alpha levels and transcriptional activity in ER alpha- positive breast cancer cells. Using MCF- 7 cells we demonstrate that reduction of ER alpha levels upon GSK- 3 silencing was due to increased proteasomal degradation of ER alpha rather than inhibition of ER alpha protein synthesis. Indeed, under this condition, ER alpha protein was rescued using the proteasome inhibitor MG132 in presence of the protein synthesis inhibitor cycloheximide. In addition, strong accumulation of ubiquitinated ER alpha was obtained after GSK- 3 silencing in the presence of MG132. We conclude that GSK- 3 protects ER alpha from proteasomal degradation and plays a crucial role in ER alpha protein stabilization and turnover. Furthermore, in vitro kinase assay depicted that GSK- 3 beta phosphorylates ER alpha at Ser- 118. GSK- 3 silencing resulted in decrease of E2- induced nuclear ER alpha phosphorylation at Ser- 118 and E2- induced estrogen response element- dependent luciferase reporter gene expression. Neither Ser- 118 phosphorylation nor luciferase activity was restored by use of MG132. Moreover, the expression of estrogenresponsive genes ( pS2 and progesterone receptor) was decreased upon GSK- 3 silencing. These findings demonstrated that GSK- 3 is required for E2- induced ER alpha phosphorylation at Ser118 and full transcriptional activity of the receptor upon E2 stimulation
    Type of Publication: Journal article published
    PubMed ID: 17609434
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  • 5
    Keywords: proliferation ; PATHWAY ; VIVO ; GENE-EXPRESSION ; FACTOR-I RECEPTOR ; breast cancer ; CARCINOMA CELLS ; ESTRADIOL ; TRANSCRIPTIONAL ACTIVATION ; estrogen receptor ; 17-BETA-ESTRADIOL ; IGF-binding proteins ; Akt/PKB pathway ; IGFBP-5
    Abstract: Insulin-like growth factor binding proteins (IGFBPs) are modulators of numerous cellular processes including cell proliferation. Although IGFBPs classically act by sequestration of extracellular insulin-like growth factors (IGFs), thereby contributing to the fine-tuning of growth factor signals, IGF-independent actions of IGFBPs have also been described. In the breast, growth factor signaling in association with estradiol (E2)-stimulated estrogen receptor function is organized in a complex cross-talk. The importance of phosphatidylinositol 3-kinase / protein kinase B (Akt/PKB) pathway components for the E2-induced activation of estrogen receptor-alpha (ERalpha) is well accepted. Here we show that in the absence of IGFs, IGFBP-4 or IGFBP-5, either overexpressed in MCF-7 breast cancer cells or added exogenously, decreased the capability of E2 to induce ERalpha transcriptional activity. In addition, overexpression or addition of recombinant IGFBP-4 or IGFBP-5 resulted in reduction of E2-induced phosphorylation of Akt/PKB, GSK-3 and ERalpha in MCF-7 cells. The activation of the Akt/PKB-pathway describes a non-genomic effect of E2, which did not involve activation/ phosphorylation of the IGF-I receptor (IGF-IR). Furthermore, knockdown of the IGF-IR did not affect the inhibition of E2-induced ERalpha phosphorylation by IGFBP-4 and 5. Moreover, IGFBP-4 and IGFBP-5 strongly decreased E2-triggered growth of MCF-7 cells. Our data suggest that IGFBPs interfere with the E2-induced activation of the Akt/PKB-pathway and prevent full hormone-dependent activation of ERalpha and breast cancer cell growth in an IGF- and IGF-IR - independent manner.
    Type of Publication: Journal article published
    PubMed ID: 23499909
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  • 6
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; tumor ; FACTOR RECEPTOR ; Germany ; human ; PATHWAY ; PROSTATE ; SYSTEM ; RISK ; PROTEIN ; PROTEINS ; COMPONENTS ; TISSUE ; TUMORS ; PATIENT ; LIGAND ; MARKER ; ANTIGEN ; BINDING ; hormone ; PROGRESSION ; immunohistochemistry ; UP-REGULATION ; prostate cancer ; PROSTATE-CANCER ; PARAMETERS ; LIGANDS ; BENIGN ; PHENOTYPE ; adenocarcinoma ; ADENOCARCINOMAS ; intraepithelial neoplasia ; PREDICTORS ; BEHAVIOR ; FACTOR-I ; protein expression ; P27(KIP1) ; insulin ; SERUM ; IGF-I ; RE ; FRACTION ; intensity ; development ; BINDING PROTEIN-3 ; RECEPTOR SUBSTRATE-1 ; LEVEL ; insulin-like growth factor ; SERUM-LEVELS ; TUMOR BEHAVIOR ; HIGH-GRADE ; IGF-BINDING PROTEIN-3 ; insulinlike growth factor system
    Abstract: There is an evidence that components of the insulin-like growth factor (IGF)-signaling pathway are involved in the development and progression of prostate cancer. The aim of the present study was to provide a comprehensive analysis of the expression levels of proteins of the IGF axis in prostate cancer. We studied expression of the ligands IGF-I and IGF-II, the inhibitory IGF binding protein-3, the type I IGF receptor (IGF-IR), and the downstream mediator insulin receptor substrate-1 by immunohistochemistry in 56 tissue specimens (28 low-grade and 28 high-grade prostate adenocarcinomas). Protein expression in tumor areas, prostatic intraepithelial neoplasias (PINs), and adjacent benign prostatic tissue were evaluated regarding staining intensity and fraction of positive cells. An immunoreactivity score was established from staining intensity and fraction of positive cells, and correlated with the prognostic clinicopathologic parameters prostate-specific antigen serum levels, Gleason score, and TNM stage. The expression levels of all proteins investigated, except IGF binding protein-3, were up-regulated in PIN and in cancer. IGF-I and IGF-II expression showed a higher expression in high-grade compared with low-grade tumor areas. IGF-I and IGF-II and insulin receptor substrate-1 immunoreactivity was higher in tumors from patients with preoperative prostate-specific antigen serum levels 10 ng/mL or greater, and IGF-II expression was correlated with Gleason score. The data indicate significant alterations in the IGF system as prostate cancer develops. Differential expression of growth-stimulating components of the IGF system may be associated with the malignant phenotype and more aggressive tumor behavior. Expression of IGFs, especially IGF-II, may be predictors of the outcome of prostate cancer. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16260272
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  • 7
  • 8
    Keywords: RECEPTOR ; CELLS ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; VITRO ; SITE ; SITES ; GENE-EXPRESSION ; PROTEIN ; transcription ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; MECHANISM ; DOMAIN ; ACTIVATED PROTEIN-KINASE ; BINDING ; PHOSPHORYLATION ; PROTEIN-KINASE ; ALPHA ; hormone ; TRANSCRIPTIONAL ACTIVITY ; ASSAY ; NUMBER ; PROTEIN-KINASES ; beta-catenin ; CONSTITUTIVE ACTIVATION ; TARGETS ; RECEPTORS ; ESTRADIOL ; CELL-GROWTH ; signaling ; RE ; RESIDUES ; SYNTHASE ; KAPPA-B ACTIVATION ; regulation ; MUTATIONAL ANALYSIS ; ESTROGEN ; TRANSCRIPTIONAL ACTIVATION ; ASSAYS ; KINASES ; NUCLEAR RECEPTORS ; estrogen receptor ; GLYCOGEN-SYNTHASE KINASE-3 ; GSK3 ; INTERACT ; CHLORIDE
    Abstract: Like other steroid hormone receptors, estrogen receptor-alpha (ER alpha) is a substrate for protein kinases, and phosphorylation has profound effects on the function and activity of this receptor. A number of different kinases have been implicated in ER alpha regulation. In this report we show by mutational analysis and in vitro kinase assays that ER alpha is a substrate for glycogen synthase kinase-3 (GSK-3) in vitro and is phosphorylated on two sites, the Ser-102, -104, and -106 motif and Ser-118, both located in the N-terminal transcription activation function (AF-1) domain. GSK-3 forms a complex with ER alpha in vivo as demonstrated by co-immunoprecipitation from cell lysates. The GSK-3 inhibitor lithium chloride was used to determine the role of GSK-3 in phosphorylation of Ser-102, -104, and -106 and Ser-118 in vivo and to explore the role of these serines in the regulation of ER alpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of Ser-104 and -106 and Ser-118, which suggests these serine residues as targets for GSK-3 in vivo. Our results further suggest that ER alpha phosphorylation by GSK-3 stabilizes ER alpha under resting conditions and modulates ER alpha transcriptional activity upon ligand binding. Inhibition and constitutive activation of GSK-3, both, resulted in inhibition of ER alpha transcriptional activity, indicating a function of active as well as inactive GSK-3 in ER alpha regulation. These findings uncover a novel mechanism for the regulation of ER alpha-mediated estrogen signaling controlled by a dual action of GSK-3
    Type of Publication: Journal article published
    PubMed ID: 16076840
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  • 9
    Keywords: breast cancer, insulin insulin analogues, signal transduction, cell proliferation
    Abstract: Insulin and insulin analogs stimulate proliferation of human mammary epithelial cells. We identified and analyzed the signaling pathways related to cell proliferation induced by regular insulin and by four insulin analogs presently approved for therapeutical use. Benign and malignant mammary cell lines showing different insulin receptor (IR) and IGF-I receptor (IGF-IR) expression patterns were studied. Cell proliferation was studied by crystal violet staining (BrdU-FACS analysis). Activation of insulin and IGF signaling pathways was studied by analysis of the phosphorylation status of IGF-IR and of key signaling proteins of the phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase pathways, by the use of specific PI3K and MAP kinase inhibitors, and by silencing of IR and IGF-IR. Lantus stimulated the growth of MCF7 cells, which show high IGF-IR/IR ratio, significantly at 0.3 nmol/l, while regular insulin (Actrapid and bovine insulin) and other insulin analogs (Novorapid, Humalog, and Levemir) stimulated cell growth at 1.5-15 nmol/l concentrations. No difference between Lantus and the other insulin analogs was observed regarding growth stimulation of MCF10A cells showing low IGF-IR/IR ratio. Growth stimulation of MCF7 cells by Lantus was mainly due to strong activation of the IGF-IR and the MAP kinase pathway. Regular insulin and other insulin analogs tested activated mainly the IR and the PI3K/Akt pathway. We conclude that unlike regular insulin and other insulin analogs, Lantus strongly activates the IGF-IR and the MAP kinase pathway in MCF7 cells and is a strong mitogen for cells characterized by a high-IGF-IR/IR ratio.
    Type of Publication: Journal article published
    PubMed ID: 19153208
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