β-Catenin-related Anomalies in Apoptosis-resistant and Hormone-refractory Prostate Cancer Cells
β-Catenin-related Anomalies in Apoptosis-resistant and Hormone-refractory Prostate Cancer Cells
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发表时间：
2003-05
影响因子：
11.5
通讯作者：
A. Taille;M. Rubin;Min‐Wei Chen;F. Vacherot;S. Medina;M. Burchardt;R. Buttyan;D. Chopin
中科院分区：
文献类型：
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作者：
A. Taille;M. Rubin;Min‐Wei Chen;F. Vacherot;S. Medina;M. Burchardt;R. Buttyan;D. Chopin
用途：β-连环蛋白是wnt信号通路的关键末端组分，其响应于细胞间粘附分子调节细胞生长、凋亡和迁移行为。本研究的目的是评估在体外培养的PC细胞和原发性人前列腺癌（PrCa）中获得性前列腺增生抗性模型中β-连环蛋白蛋白表达、亚细胞定位和活性的异常。实验设计：抗凋亡的人前列腺癌细胞系变体通过反复短暂暴露于凋亡刺激物而衍生自亲本LNCaP细胞。使用细胞分级分离和蛋白质印迹法分析衍生细胞和亲本细胞的β-连环蛋白表达和细胞内定位。在用β-连环蛋白敏感报告质粒转染后，还在这些变体中研究了来自TCF/LEF-1应答元件的内源性转录活性。最后，对212例患者的β-连环蛋白表达和细胞内定位进行了评价[122例局部PrCa和90例免疫组化检测的难治性（HRPC）PrCa标本]。结果如下：Western blot分析显示β-catenin在细胞内的分布从亲本细胞的膜部分转移到了耐药细胞系的胞质/核部分。协调，转录活性从TCF/LEF促进报告质粒显着增加，在抗烟草花叶病毒品系。在分析的原发性前列腺肿瘤中，胞质和/或核β-连环蛋白表达与HRPC状态和Gleason评分统计学相关。在局限性PrCa组中，异常β-catenin表达倾向于与较高的Gleason评分和pT 3疾病相关。在HRPC和β-catenin异常表达的患者中未发现突变。结论：这些数据表明，β-连环蛋白表达异常发生在PrCa中，并且这些异常与疾病进展相关，特别是与治疗耐药状态相关。
Purpose: β-Catenin is a critical end component of the wnt signaling pathway that regulates cell growth, apoptosis, and migratory behavior in response to intercellular adhesion molecules. The aim of this study was to evaluate abnormalities of β-catenin protein expression, subcellular localization, and activity in an in vitro model of acquired apoptosis-resistance in cultured PC cells and in primary human prostate cancers (PrCa). Experimental Design: Apoptosis-resistant human prostate cancer cell line variants were derived from parental LNCaP cells by repeated brief exposure to apoptotic stimuli. The derivative and parental cells were analyzed for β-catenin expression and intracellular localization using cell fractionation and Western blotting procedures. Endogenous transcriptional activity from the TCF/LEF-1 response element was also studied in these variants after transfection with a β-catenin sensitive reporter plasmid. Finally, β-catenin protein expression and intracellular localization were evaluated on 212 patients [122 localized PrCa and 90 hormone-refractory (HRPC) PrCa specimens by immunohistochemistry]. Results: Western blot analysis showed that the intracellular partitioning of β-catenin was shifted from the membrane fraction in parental cells to the cytoplasmic/nuclear fractions of the apoptosis-resistant cell lines. Coordinately, transcriptional activity from a TCF/LEF-promoted reporter plasmid was increased significantly in the apoptosis-resistant lines. In the primary prostate tumors analyzed, cytoplasmic and/or nuclear β-catenin expression was correlated statistically with the HRPC status and Gleason score. In the group of localized PrCa, abnormal β-catenin expression tended to be associated with a higher Gleason score and with pT3 disease. No mutation was found in patients with HRPC and abnormal β-catenin expression. Conclusion: These data suggest that anomalies of β-catenin expression occur in PrCa and that these anomalies are associated with disease progression, especially to the therapeutic-resistant state.