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.