Activation of β-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-β-catenin interaction
Activation of β-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-β-catenin interaction
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DOI：
10.1128/mcb.26.3.929-939.2006
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发表时间：
2006-02-01
影响因子：
5.3
通讯作者：
Balk, SP
中科院分区：
文献类型：
--
作者：
Chen, SY;Wulf, G;Balk, SP
雄激素受体 (AR) 与 β-连环蛋白相互作用，可抑制前列腺癌 (PCa) 细胞中 T 细胞因子 4 (Tcf4) 的共激活。 Pin1 是一种肽基脯氨酰顺/反异构酶，通过抑制 P-连环蛋白与腺瘤性息肉病大肠杆菌基因产物的结合以及随后的糖原合酶激酶 3 beta (GSK-3 beta) 依赖性降解来稳定 P-连环蛋白。原发性 PCa 中较高的 Pin1 表达与疾病复发相关，本研究发现转移性 PCa 中 Pin1 表达显着增加。与这一结果一致，转染的 LNCaP PCa 细胞中 Pin1 表达的增加强烈加速了免疫缺陷小鼠体内肿瘤的生长。使用 Tcf4 调节的报告基因评估，LNCaP 细胞中的 Pin1 表达增强了 β-catenin/Tcf4 转录活性，并增加了内源性 Tcf4 和 c-myc 的表达。然而，与具有完整 PTEN 和活性 GSK-3 β 的细胞的结果相反，PTEN 缺陷的 LNCaP PCa 细胞中的 Pin1 表达并没有增加 β-连环蛋白。相反，Pin1 表达显着抑制 β-catenin 与 AR 的相互作用，并且 Pin1 消除了 AR 拮抗 β-catenin/Tcf4 结合和转录活性的能力。这些发现表明，AR 可以抑制 P-连环蛋白信号传导，AR-β-连环蛋白相互作用可以由 Pin1 调节，并且消除这种相互作用可以增强 β-连环蛋白/Tcf4 信号传导并有助于 PCa 中的攻击性生物学行为。
Androgen receptor (AR) interacts with beta-catenin and can suppress its coactivation of T cell factor 4 (Tcf4) in prostate cancer (PCa) cells. Pin1 is a peptidyl-prolyl cis/trans isomerase that stabilizes P-catenin by inhibiting its binding to the adenomatous polyposis coli gene product and subsequent glycogen synthase kinase 3 beta (GSK-3 beta)-dependent degradation. Higher Pin1 expression in primary PCa is correlated with disease recurrence, and this study found that Pin1 expression was markedly increased in metastatic PCa. Consistent with this result, increased expression of Pin1 in transfected LNCaP PCa cells strongly accelerated tumor growth in vivo in immunodeficient mice. Pin1 expression in LNCaP cells enhanced beta-catenin/Tcf4 transcriptional activity, as assessed using Tcf4-regulated reporter genes, and increased expression of endogenous Tcf4 and c-myc. However, in contrast to results in cells with intact PTEN and active GSK-3 beta, Pin1 expression in LNCaP PCa cells, which are PTEN deficient, did not increase beta-catenin. Instead, Pin1 expression markedly inhibited the beta-catenin interaction with AR, and Pin1 abrogated the ability of AR to antagonize beta-catenin/Tcf4 binding and transcriptional activity. These findings demonstrate that AR can suppress P-catenin signaling, that the AR-beta-catenin interaction can be regulated by Pin1, and that abrogation of this interaction can enhance beta-catenin/Tcf4 signaling and contribute to aggressive biological behavior in PCa.