Cadherin Switching and Activation of β-Catenin Signaling Underlie Proinvasive Actions of Calcitonin-Calcitonin Receptor Axis in Prostate Cancer
Calcitonin, a neuroendocrine peptide, and its receptor are localized in the basal epithelium of benign prostate but in the secretory epithelium of malignant prostates. The abundance of calcitonin and calcitonin receptor mRNA displays positive correlation with the Gleason grade of primary prostate ca...
Gespeichert in:
Veröffentlicht in: | The Journal of biological chemistry 2009-01, Vol.284 (2), p.1018 |
---|---|
Hauptverfasser: | , , , , |
Format: | Artikel |
Sprache: | eng |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Calcitonin, a neuroendocrine peptide, and its receptor are localized in the basal epithelium of benign prostate but in the
secretory epithelium of malignant prostates. The abundance of calcitonin and calcitonin receptor mRNA displays positive correlation
with the Gleason grade of primary prostate cancers. Moreover, calcitonin increases tumorigenicity and invasiveness of multiple
prostate cancer cell lines by cyclic AMP-dependent protein kinase-mediated actions. These actions include increased secretion
of matrix metalloproteinases and urokinase-type plasminogen activator and an increase in prostate cancer cell invasion. Activation
of calcitonin-calcitonin receptor autocrine loop in prostate cancer cell lines led to the loss of cell-cell adhesion, destabilization
of tight and adherens junctions, and internalization of key integral membrane proteins. In addition, the activation of calcitonin-calcitonin
receptor axis induced epithelial-mesenchymal transition of prostate cancer cells as characterized by cadherin switch and the
expression of the mesenchymal marker, vimentin. The activated calcitonin receptor phosphorylated glycogen synthase kinase-3,
a key regulator of cytosolic β-catenin degradation within the WNT signaling pathway. This resulted in the accumulation of
intracellular β-catenin, its translocation in the nucleus, and transactivation of β-catenin-responsive genes. These results
for the first time identify actions of calcitonin-calcitonin receptor axis on prostate cancer cells that lead to the destabilization
of cell-cell junctions, epithelial-to-mesenchymal transition, and activation of WNT/β-catenin signaling. The results also
suggest that cyclic AMP-dependent protein kinase plays a key role in calcitonin receptor-induced destabilization of cell-cell
junctions and activation of WNT-β-catenin signaling. |
---|---|
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M807823200 |