p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells

A J Browne; A Göbel; S Thiele; L C Hofbauer; M Rauner; T D Rachner

doi:10.1038/cddis.2016.32

p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells

Cell Death Dis. 2016 Feb 25;7(2):e2119. doi: 10.1038/cddis.2016.32.

Authors

A J Browne¹, A Göbel¹, S Thiele¹, L C Hofbauer^{1

2}, M Rauner¹, T D Rachner¹

Affiliations

¹ Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
² German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Neutralizing / immunology
Cell Differentiation
Cell Line, Tumor
Down-Regulation / drug effects
Humans
Imidazoles / pharmacology
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / immunology
Intercellular Signaling Peptides and Proteins / metabolism*
Male
Mitogen-Activated Protein Kinase 11 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 11 / genetics
Mitogen-Activated Protein Kinase 11 / metabolism
Mitogen-Activated Protein Kinase 12 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 12 / genetics
Mitogen-Activated Protein Kinase 12 / metabolism
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 / genetics
Mitogen-Activated Protein Kinase 14 / metabolism
Naphthalenes / pharmacology
Prostatic Neoplasms
Pyrazoles / pharmacology
Pyridines / pharmacology
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering
Signal Transduction / drug effects
Wnt3A Protein / genetics
Wnt3A Protein / metabolism
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Antibodies, Neutralizing
DKK1 protein, human
Imidazoles
Intercellular Signaling Peptides and Proteins
Naphthalenes
Pyrazoles
Pyridines
RNA, Messenger
RNA, Small Interfering
Wnt3A Protein
ralimetinib
Mitogen-Activated Protein Kinase 12
Mitogen-Activated Protein Kinase 11
Mitogen-Activated Protein Kinase 14
p38 Mitogen-Activated Protein Kinases
doramapimod
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole