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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
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An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

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

A J Browne1, A Göbel1, S Thiele1

  • 1Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.

Cell Death & Disease
|February 26, 2016
PubMed

Insights

p38 mitogen-activated protein kinase (MAPK) signaling regulates Dickkopf-1 (DKK-1) expression in prostate cancer cells. This pathway may be a therapeutic target for osteolytic prostate cancers, which are driven by DKK-1 inhibition of bone formation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Dickkopf-1 (DKK-1) is a Wnt inhibitor linked to bone metastases in prostate cancer by suppressing osteoblastogenesis.
  • Dysregulated p38 mitogen-activated protein kinase (MAPK) signaling is observed in advanced prostate cancer.

Purpose of the Study:

  • To investigate the impact of p38 MAPK signaling on DKK-1 expression in prostate cancer.
  • To explore the role of p38 MAPK in the osteolytic phenotype of prostate cancer.

Main Methods:

  • Utilized small molecule inhibitors and siRNA to modulate p38 MAPK activity and its isoforms in PC3 prostate cancer cells.
  • Assessed DKK-1 expression and its effect on Wnt3a-induced osteoblastic differentiation in C2C12 cells.
  • Analyzed p38 MAPK and DKK-1 expression in human prostate cancer tissues.

Main Results:

  • Inhibition of p38 MAPK suppressed DKK-1 expression, while activation increased it.
  • MAPK11 isoform showed a stronger role in DKK-1 regulation compared to MAPK14 and MAPK12.
  • Prostate cancer cells secreted DKK-1, inhibiting osteoblast differentiation, an effect blocked by anti-DKK-1 antibodies or p38 MAPK inhibition.
  • Elevated p38 MAPK and DKK-1 expression was found in tumor tissues versus normal tissues.

Conclusions:

  • p38 MAPK signaling directly regulates DKK-1 expression in prostate cancer.
  • The p38 MAPK/DKK-1 axis represents a potential therapeutic target for osteolytic prostate cancers.

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