Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β-catenin signaling in prostate cancer cells
Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β-catenin signaling in prostate cancer cells
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DOI：
10.1002/ijc.26402
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发表时间：
2012-08-01
影响因子：
6.4
通讯作者：
Ferrari, Nicoletta
中科院分区：
文献类型：
--
作者：
Ciarlo, Monica;Benelli, Roberto;Ferrari, Nicoletta
目前的诊断工具无法预测前列腺癌（PC）患者的临床失败和雄激素非依赖性疾病进展。前列腺细胞的存活信号传导途径在肿瘤向神经内分泌（NE）表型的进展中起核心作用。NE细胞表现出的属性表明，它们是导致去势抵抗性PC的信号级联的组成部分。本研究利用人LNCaP和小鼠TRAMP-C2细胞在雄激素撤除后的体外神经内分泌分化（NED），以及小鼠前列腺转基因腺癌（TRAMP）模型，我们描述了导致NED的一系列分子事件，并鉴定了许多标记物，这些标记物不仅可以在去势抵抗性PC中检测到，而且可以在去势时未接受激素治疗的PC中检测到。初步诊断。我们发现NED与AKT激活相关，AKT激活反过来调节异质核核糖核蛋白K（hnRNP K）、雄激素受体（AR）和β-连环蛋白水平。添加靶向膜结合受体和蛋白激酶的分子阻断LNCaP和TRAMP-C2细胞中的NE分化。AKT磷酸化的程度和hnRNP K，AR和β-连环蛋白水平可能具有潜在的价值，作为区分雄激素反应性细胞和无反应性细胞的预后指标，并可用作分子靶点，以监测基于抗受体药物和/或神经内分泌激素拮抗剂的新治疗方案的抗肿瘤作用。
Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naive PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and beta-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and beta-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.