Calcitonin receptor increases invasion of prostate cancer cells by recruiting zonula occludens-1 and promoting PKA-mediated TJ disassembly
| Autor: | Girish V. Shah, Arvind Thakkar, Ahmed Aljameeli |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Calcitonin
Male 0301 basic medicine medicine.medical_specialty Time Factors Amino Acid Motifs PDZ domain Biology Models Biological Tight Junctions Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Internal medicine LNCaP medicine Claudin-3 Humans Neoplasm Invasiveness Phosphorylation Calcitonin receptor Receptor Claudin Protein kinase A Tight junction Prostatic Neoplasms Cell Biology Receptors Calcitonin Cyclic AMP-Dependent Protein Kinases Endocytosis Kinetics Protein Transport 030104 developmental biology Endocrinology 030220 oncology & carcinogenesis Biocatalysis Zonula Occludens-1 Protein Cancer research Peptides Protein Binding |
| Zdroj: | Cellular Signalling. 36:1-13 |
| ISSN: | 0898-6568 |
| Popis: | Almost all primary prostate cancers (PCs) and PC cell lines express calcitonin (CT) and/or its receptor (CTR), and their co-expression positively correlates with their invasiveness. Activation of the CT–CTR axis in non-invasive LNCaP cells induces an invasive phenotype. In contrast, silencing of CT/CTR expression in highly metastatic PC-3M cells markedly reduces their tumorigenicity and abolishes their ability to form distant metastases in nude mice. Our recent studies suggest that CTR interacts with zonula occludens 1 (ZO-1) through PDZ interaction to destabilize tight junctions and increase invasion of PC cells. Our results show that CTR activates AKAP2-anchored cAMP-dependent protein kinase A, which then phosphorylates tight junction proteins ZO-1 and claudin 3. Moreover, PKA-mediated phosphorylation of tight unction proteins required CTR-ZO-1 interaction, suggesting that the interaction may bring CTR-activated PKA in close proximity of tight junction proteins. Furthermore, inhibition of PKA activity attenuated CT-induced loss of TJ functionality and invasion, suggesting that the phosphorylation of TJ proteins is responsible for TJ disassembly. Finally, we show that the prevention of CTR-ZO-1 interaction abolishes CT-induced invasion, and can serve as a novel therapeutic tool to treat aggressive prostate cancers. In brief, the present study identifies the significance of CTR-ZO-1 interaction in progression of prostate cancer to its metastatic form. |
| Databáze: | OpenAIRE |
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