Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis
Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis
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DOI：
10.1158/0008-5472.can-06-0317
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发表时间：
2006-09-15
期刊：
影响因子：
11.2
通讯作者：
McCauley, Laurie K.
中科院分区：
文献类型：
--
作者：
Liao, Jinhui;Schneider, Abraham;McCauley, Laurie K.
前列腺癌几乎完全转移到骨骼部位，表明骨骼为其定位和进展提供了有利的微环境。骨中可能促进肿瘤定位的一个自然但尚未得到充分研究的因素是细胞外钙（[Ca2+]o）升高。本研究发现，升高的[Ca2+]o （2.5 mmol/L）可促进骨骼转移性前列腺细胞系（PC-3和C4-2B）的增殖，但对非骨骼转移性上皮源性前列腺细胞系LNCaP没有作用。升高的[Ca2+]o的增殖作用与钙感应受体（CaSR）的高表达有关，CaSR是一种异三聚体g蛋白偶联受体，是[Ca2+]o的主要细胞表面传感器。通过RNA干扰敲低CaSR可减少体外细胞增殖和体内转移进展。通过测量前列腺素E-2或福斯克林诱导的[Ca2+]o依赖性环AMP积累的升高抑制，评估PC-3细胞中的CaSR信号。升高的[Ca2+]o稳定了细胞周期蛋白D1的表达，这是细胞周期转变所需的蛋白质。此外，升高的[Ca2+]o触发Akt信号通路的激活，增强PC-3细胞的附着。百日咳毒素（一种g蛋白抑制剂）和LY294002（一种Akt信号抑制剂）均可减少细胞附着。这些数据表明，骨重塑增加后的[Ca2+]o升高可以通过CaSR和Akt信号通路促进前列腺癌的转移定位。综上所述，[Ca2+]o是前列腺癌骨转移的候选介质。
Prostate cancer almost exclusively metastasizes to skeletal sites, indicating that the bone provides a favorable microenvironment for its localization and progression. A natural yet understudied factor in bone that could facilitate tumor localization is elevated extracellular calcium ([Ca2+]o). The present study found that elevated [Ca2+]o (2.5 mmol/L) enhanced proliferation of skeletal metastatic prostate cell lines (PC-3 and C4-2B), but not the nonskeletal metastatic, epithelial-derived prostate cell line LNCaP. The proliferative effect of elevated [Ca2+]o was associated with higher expression of the calcium-sensing receptor (CaSR), a heterotrimeric G-protein-coupled receptor that is the predominant cell-surface sensor for [Ca2+]o. Knockdown of the CaSR via RNA interference reduced cell proliferation in vitro and metastatic progression in vivo. CaSR signaling in PC-3 cells was evaluated by measuring the elevated [Ca2+]o-dependent inhibition of cyclic AMP accumulation, induced by either prostaglandin E-2 or forskolin. Elevated [Ca2+]o stabilized expression of cyclin D1, a protein required for cell cycle transition. Furthermore, elevated [Ca2+]o triggered activation of the Akt signaling pathway and enhanced PC-3 cell attachment. Both pertussis toxin (a G-protein inhibitor) and LY294002 (an inhibitor of Akt signaling) reduced cell attachment. These data suggest that elevated [Ca2+]o following increased bone remodeling could facilitate metastatic localization of prostate cancer via the CaSR and the Akt signaling pathway. Taken together, [Ca2+]o is a candidate mediator of prostate cancer bone metastasis.