P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer
Tilman D Rachner1, Andy Göbel1, Andrew Browne1
1Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
Abstract:
Dickkopf-1 (DKK-1) is an inhibitor of canonical Wnt signalling and has been associated with the progression of osteolytic bone metastases by impairing osteoblast activity. In addition, there is growing evidence supporting a direct anti-tumour effect of DKK-1. The p38 mitogen-activated protein kinase (MAPK) regulates intracellular responses that have been linked to cell cycle, apoptosis and tumorigenesis. P38 inhibitors are currently under clinical evaluation for the treatment of malignancies. However, the influence of p38 on DKK-1 in breast cancer remains elusive. In this work, we show that p38 inhibition using SB202190 or LY2228820 potently suppressed DKK-1 expression by MDA-231 and MCF-7 breast cancer cell lines as well melanoma derived MDA-435 cells. Vice versa, activation of p38 signalling by anisomycin induced DKK-1 expression. Immunohistochemical analysis of DKK-1 expression in 97 breast cancer samples revealed that high expression of p38 was associated with a higher expression of DKK-1 compared to tumours with low p38 expression. In conclusion, these results support a role of p38 in the regulation of DKK-1 in osteolytic tumours and warrant further research on the potential of p38 inhibition for the treatment of malignant bone disease.
Insights
p38 inhibition suppresses Dickkopf-1 (DKK-1) expression in breast cancer cells, suggesting a potential therapeutic target for osteolytic bone metastases. This research highlights the p38 pathway
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Dickkopf-1 (DKK-1) inhibits Wnt signaling and promotes osteolytic bone metastases.
- p38 mitogen-activated protein kinase (MAPK) influences tumorigenesis.
- The relationship between p38 and DKK-1 in breast cancer is not well understood.
Purpose of the Study:
- To investigate the role of p38 in regulating DKK-1 expression in breast cancer.
- To explore the potential of p38 inhibition as a therapeutic strategy for bone metastases.
Main Methods:
- Utilized p38 inhibitors (SB202190, LY2228820) and activator (anisomycin) on breast cancer cell lines (MDA-231, MCF-7) and melanoma cells (MDA-435).
- Assessed DKK-1 expression via cell-based assays.
- Performed immunohistochemical analysis on 97 breast cancer patient samples to correlate p38 and DKK-1 expression.
Main Results:
- p38 inhibition significantly suppressed DKK-1 expression in breast cancer and melanoma cell lines.
- Activation of p38 signaling led to increased DKK-1 expression.
- High p38 expression in patient tumors correlated with higher DKK-1 expression.
Conclusions:
- p38 signaling pathway plays a regulatory role in DKK-1 expression within osteolytic tumors.
- Targeting p38 may offer a novel therapeutic approach for managing malignant bone disease and associated DKK-1 activity.
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