Calcitonin receptor increases invasion of prostate cancer cells by recruiting zonula occludens-1 and promoting PKA-mediated TJ disassembly
Calcitonin receptor increases invasion of prostate cancer cells by recruiting zonula occludens-1 and promoting PKA-mediated TJ disassembly
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DOI：
10.1016/j.cellsig.2017.04.008
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发表时间：
2017-08-01
影响因子：
4.8
通讯作者：
Shah, Girish
中科院分区：
文献类型：
--
作者：
Aljameeli, Ahmed;Thakkar, Arvind;Shah, Girish
几乎所有的原发性前列腺癌（PC）和PC细胞系都表达降钙素（CT）和/或其受体（CTR），并且它们的共表达与它们的侵袭性正相关。非侵袭性LNCaP细胞中CT CTR轴的激活诱导侵袭性表型。相反，CT/CTR表达的沉默在高转移性PC 3 M细胞显着降低其致瘤性和废除其在裸鼠中形成远处转移的能力。我们最近的研究表明CTR通过PDZ相互作用与闭合小带1（ZO-1）相互作用，使紧密连接不稳定并增加PC细胞的侵袭。我们的研究结果表明，CTR激活AKAP 2锚定的cAMP依赖性蛋白激酶A，然后磷酸化紧密连接蛋白ZO-1和claudin 3。此外，PICA介导的紧密连接蛋白的磷酸化需要CTR-ZO-1相互作用，这表明这种相互作用可能使CTR激活的PICA靠近紧密连接蛋白。此外，PICA活性的抑制减弱了CT诱导的TJ功能丧失和侵袭，表明TJ蛋白的磷酸化是TJ分解的原因。最后，我们表明，CTR-ZO-1相互作用的预防消除了CT诱导的侵袭，并可以作为一种新的治疗工具来治疗侵袭性前列腺癌。简而言之，本研究确定了CTR-ZO-1相互作用在前列腺癌进展为其转移形式中的意义。
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, PICA-mediated phosphorylation of tight unction proteins required CTR-ZO-1 interaction, suggesting that the interaction may bring CTR-activated PICA in close proximity of tight junction proteins. Furthermore, inhibition of PICA 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.