title: p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells.
abstract: The Wnt inhibitor Dickkopf-1 (DKK-1) has been associated with the occurrence of bone metastases in osteotropic prostate cancer by inhibiting osteoblastogenesis. P38 mitogen-activated protein kinase (MAPK) activity is also dysregulated in advanced prostate cancer. However, the impact of p38 MAPK signaling on DKK-1 remains unknown. Inhibition of p38 MAPK signaling in osteolytic PC3 cells by small molecule inhibitors (doramapimod, LY2228820 and SB202190) suppressed DKK-1 expression, whereas activation of p38 MAPK by anisomycin increased DKK-1. Further dissection by targeting individual p38 MAPK isoforms with siRNA revealed a stronger role for MAPK11 than MAPK14 and MAPK12 in the regulation of DKK-1. Moreover, prostate cancer cells with a predominantly osteolytic phenotype produced sufficient amounts of DKK-1 to inhibit Wnt3a-induced osteoblastic differentiation in C2C12 cells. This inhibition was blocked directly by neutralizing DKK-1 using a specific antibody and also indirectly by blocking p38 MAPK. Furthermore, tissue expression in human prostate cancer revealed a correlation between p38 MAPK and DKK-1 expression with higher expression in tumor compared with normal tissues. These results reveal that p38 MAPK regulates DKK-1 in prostate cancer and may present a potential target in osteolytic prostate cancers.
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Browne
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Göbel
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: L C
authors.initials: LC
authors.lastname: Hofbauer
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: T D
authors.initials: TD
authors.lastname: Rachner
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048291:Mitogen-Activated Protein Kinase 12 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D011471:Prostatic Neoplasms; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds
chemical_list: D057134:Antibodies, Neutralizing; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D048290:Mitogen-Activated Protein Kinase 11; D048291:Mitogen-Activated Protein Kinase 12; D048308:Mitogen-Activated Protein Kinase 14; D009281:Naphthalenes; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D060509:Wnt3A Protein; D048051:p38 Mitogen-Activated Protein Kinases; C501126:DKK1 protein, human; C580958:ralimetinib; C452139:doramapimod; D010671:Phenylurea Compounds; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole