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Zoran Culig Experimental Urology, Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Isabel Heidegger Department of Urology, Medical University Innsbruck, Innsbruck, Austria

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Zoran Culig Department of Urology, Medical University Innsbruck, Innsbruck, Austria

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Xinyu Wu Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA

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Shiaoching Gong Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA
Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA

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Pradip Roy-Burman Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA

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Peng Lee Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA
Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA
Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA
Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA

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Zoran Culig Department of Pathology, Arthritis and Tissue Degeneration Program, Laboratory of Molecular Biology, Department of Pathology, Department of Urology, NYU Cancer Institute, New York Harbor Healthcare System, Department of Urology, New York University School of Medicine, New York, NY, USA

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Mouse models of prostate cancer (PCa) are critical for understanding the biology of PCa initiation, progression, and treatment modalities. Here, we summarize recent advances in PCa mouse models that led to new insights into specific gene functions in PCa. For example, the study of transgenic mice with TMPRSS2/ERG, an androgen-regulated fusion protein, revealed its role in developing PCa precursor lesions, prostate intraepithelial neoplasia; however, it is not sufficient for PCa development. Double deficiency of Pten and Smad4 leads to a high incidence of metastatic PCa. Targeted deletion of Pten in castration-resistant Nkx3-1-expressing cells results in rapid carcinoma formation after androgen-mediated regeneration, indicating that progenitor cells with luminal characteristics can play a role in initiation of PCa. Transgenic mice with activated oncogenes, growth factors, and steroid hormone receptors or inactivated tumor suppressors continue to provide insights into disease progression from initiation to metastasis. Further development of new PCa models with spatial and temporal regulation of candidate gene expression will probably enhance our understanding of the complex events that lead to PCa initiation and progression, thereby invoking novel strategies to combat this common disease in men.

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Frédéric R Santer Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Kamilla Malinowska Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Zoran Culig Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Ilaria T Cavarretta Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Interleukin-6 (IL-6) is suggested to have a pathogenic role in the progression of prostate cancer (PC), therefore representing an attractive target for new therapies. However, due to the pleiotropy of this cytokine, targeting IL-6 results in different and unpredictable responses. In order to better understand the mechanisms underlying the different responses to the cytokine, we focused our attention on IL-6 receptors (IL-6Rs) that represent the first element in the cascade of cytokine-activated signalling pathways. IL-6 signal transduction may indeed occur through the membrane IL-6R (classical signalling) and/or through the less studied soluble IL-6R (sIL-6R; IL-6 trans-signalling (IL-6TS)). We provide the first evidence how responses to IL-6 may depend on the different content of IL-6Rs in PC. In particular, the studies of 3H-thymidine incorporation and exploitation of different approaches (i.e. activation or inhibition of IL-6TS in sIL-6R-negative and -positive cell lines and transfection of IL-6R siRNA) allowed us to demonstrate that IL-6TS specifically accounts for an anti-proliferative effect of the cytokine in three PC cell lines that are known to respond differently to IL-6. Additionally, by applying migration-, scratch- and adhesion assays, we show that IL-6TS increases motility and migration and decreases adhesion of prostate cells facilitating thereby processes that determine metastasis initiation and spread. Finally, by western analyses, we uncovered an IL-6- and sIL-6R-dependent downregulation of the tumour suppressor maspin. Collectively, these data suggest that selective targeting of IL-6TS might allow to refine the currently available experimental anti-IL-6 therapies against PC.

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Su Jung Oh
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Holger H H Erb
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Alfred Hobisch Division of Experimental Urology, Department of Urology, Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Frédéric R Santer
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Zoran Culig
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Antihormonal and chemotherapy are standard treatments for nonorgan-confined prostate cancer. The effectivity of these therapies is limited and the development of alternative approaches is necessary. In the present study, we report on the use of the multikinase inhibitor sorafenib in a panel of prostate cancer cell lines and their derivatives which mimic endocrine and chemotherapy resistance. 3H-thymidine incorporation assays revealed that sorafenib causes a dose-dependent inhibition of proliferation of all cell lines associated with downregulation of cyclin-dependent kinase 2 and cyclin D1 expression. Apoptosis was induced at 2 μM of sorafenib in androgen-sensitive cells, whereas a higher dose of the drug was needed in castration-resistant cell lines. Sorafenib stimulated apoptosis in prostate cancer cell lines through downregulation of myeloid cell leukemia-1 (MCL-1) expression and Akt phosphorylation. Although concentrations of sorafenib required for the antitumor effect in therapy-resistant sublines were higher than those needed in parental cells, the drug showed efficacy in cells which became resistant to bicalutamide and docetaxel respectively. Most interestingly, we show that sorafenib has an inhibitory effect on androgen receptor (AR) and prostate-specific antigen expression. In cells in which AR expression was downregulated by short interfering RNA, the treatment with sorafenib increased apoptosis in an additive manner. In summary, the results of the present study indicate that there is a potential to use sorafenib in prostate cancers as an adjuvant therapy option to current androgen ablation treatments, but also in progressed prostate cancers that become unresponsive to standard therapies.

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Hannes Neuwirt
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Martin Puhr
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Ilaria T Cavarretta
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Michael Mitterberger
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Alfred Hobisch Department of Urology, General Hospital Feldkirch,, Innsbruck Medical University, Anichtrasse 35, A-6020 Innsbruck, Austria

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Zoran Culig
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Suppressors of cytokine signalling (SOCS) are induced by interleukins (ILs) and various peptide hormones and may prevent sustained activation of signalling pathways. We have previously shown that SOCS-3 antagonizes regulation of cellular events by cAMP and is expressed in human prostate cancer. To investigate possible effects of androgen on SOCS-3 protein expression, two prostate cancer cell lines (PC3-AR and LAPC4) were treated with different concentrations of R1881. Western blot analyses revealed induction of SOCS-3 protein expression in both cell lines by androgen, an effect which can be blocked by the anti-androgen bicalutamide. To further characterize the effects of R1881 on the SOCS-3 gene, promoter–reporter assay and real-time PCR were performed. We found no influence of androgen on promoter activity or SOCS-3 mRNA levels, thus suggesting a post-transcriptional effect of androgen. Concordant with our previous findings, we show a significant increase of SOCS-3 protein after androgen treatment in cells in which transcription was blocked, but not in those with impaired translation. In order to understand implications of SOCS-3 regulation by androgen, we used SOCS-3-negative LNCaP–IL-6 cells and stably transfected them with a tetracycline-responsive SOCS-3 Tet-On plasmid. We report that androgenic effects on cell proliferation and prostate-specific antigen secretion are significantly diminished following up-regulation of SOCS-3. In conclusion, androgen up-regulates SOCS-3 protein via post-transcriptional effects. SOCS-3 inhibits androgen-stimulated proliferation by influencing cell cycle regulation. Taken together with previous findings showing androgen receptor activation by IL-6, our results imply that androgen and cytokine signalling pathways interact at multiple levels in prostate cancer.

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Martin Puhr
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Frédéric R Santer
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Hannes Neuwirt
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Gemma Marcias
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Alfred Hobisch Department of Urology, Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

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Zoran Culig
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Fibroblast growth factor-2 (FGF-2) is highly expressed in prostate cancer. It promotes tumour progression through multiple pathways including those of signal transducers and activators of transcription factor 3 (STAT3), mitogen-activated protein kinases (MAPKs) and Akt. In previous studies, we have reported that STAT3 phosphorylation inversely correlates with suppressor of cytokine signalling-3 (SOCS-3) expression in prostate cancer cells. Recently, it has become evident that SOCS-3-negative regulation is not only limited to the interleukin-6 (IL-6) receptor. We hypothesised that SOCS-3 interferes with FGF signalling, thus influencing the outcome of its action in prostate cancer cells. For this purpose, we treated DU-145 and LNCaP-IL-6+ cells with increasing concentrations of FGF-2, and verified protein phosphorylation. In the presence of FGF-2, neither STAT3, STAT1, nor Akt could be phosphorylated. Solely the p44/p42 MAPK pathway was activated after FGF-2 stimulation. We show for the first time that SOCS-3 interferes with the FGF-2 signalling pathway by modulating p44 and p42 phosphorylation in prostate cancer cells. Decreased SOCS-3 protein expression results in increased MAPK phosphorylation, whereas SOCS-3 overexpression leads to a decreased cellular proliferation and migration. On the basis of the present results, we propose that SOCS-3 is a novel modulator of FGF-2-regulated cellular events in prostate cancer.

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Birgit Luef Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

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Florian Handle Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

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Gvantsa Kharaishvili Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

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Martina Hager Department of Pathology, Paracelsus Medical University, Salzburg, Austria

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Johannes Rainer Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

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Günter Janetschek Department of Urology, Paracelsus Medical University, Salzburg, Austria

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Stephan Hruby Department of Urology, Paracelsus Medical University, Salzburg, Austria

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Christine Englberger Department of Urology, Paracelsus Medical University, Salzburg, Austria

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Jan Bouchal Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

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Frédéric R Santer Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

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Zoran Culig Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

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Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [3H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line’s AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

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Kamilla Malinowska Division of Biological Chemistry, Department of Urology, Department of Urology

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Hannes Neuwirt Division of Biological Chemistry, Department of Urology, Department of Urology

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Ilaria T Cavarretta Division of Biological Chemistry, Department of Urology, Department of Urology

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Jasmin Bektic Division of Biological Chemistry, Department of Urology, Department of Urology

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Hannes Steiner Division of Biological Chemistry, Department of Urology, Department of Urology

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Hermann Dietrich Division of Biological Chemistry, Department of Urology, Department of Urology

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Patrizia L Moser Division of Biological Chemistry, Department of Urology, Department of Urology

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Dietmar Fuchs Division of Biological Chemistry, Department of Urology, Department of Urology

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Alfred Hobisch Division of Biological Chemistry, Department of Urology, Department of Urology

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Zoran Culig Division of Biological Chemistry, Department of Urology, Department of Urology

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It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.

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Holger H H Erb Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Regina V Langlechner Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Patrizia L Moser Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Florian Handle Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Tineke Casneuf Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Karin Verstraeten Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Bettina Schlick Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Georg Schäfer Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Brett Hall Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Kate Sasser Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Zoran Culig Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Frédéric R Santer Division of Experimental Urology, Department of Pathology, Oncology Biomarkers, Oncotyrol, Oncology Biomarkers, Department of Urology

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Development and progression of prostate cancer (PCa) are associated with chronic inflammation. The cytokine interleukin 6 (IL6) can influence progression, differentiation, survival, and angiogenesis of PCa. To identify novel pathways that are triggered by IL6, we performed a gene expression profiling of two PCa cell lines, LNCaP and MDA PCa 2b, treated with 5 ng/ml IL6. Interferon (IFN) regulatory factor 9 (IRF9) was identified as one of the most prevalent IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN signaling and acts together with STAT1 and 2 to activate transcription of IFN-responsive genes. The IL6 regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab. Three PCa cell lines, PC3, Du-145, and LNCaP-IL6+, with an autocrine IL6 loop displayed high expression of IRF9. A tissue microarray with 36 PCa tissues showed that IRF9 protein expression is moderately elevated in malignant areas and positively correlates with the tissue expression of IL6. Downregulation and overexpression of IRF9 provided evidence for an IFN-independent role of IRF9 in cellular proliferation of different PCa cell lines. Furthermore, expression of IRF9 was essential to mediate the antiproliferative effects of IFNα2. We concluded that IL6 is an inducer of IRF9 expression in PCa and a sensitizer for the antiproliferative effects of IFNα2.

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