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.
Keywords: Calcitonin receptor-protein kinase A-tight junctions-invasion-prostate cancer.
Copyright © 2017 Elsevier Inc. All rights reserved.