CTEN/Tensin 4 Expression Induces Sensitivity to Paclitaxel in Prostate Cancer
CTEN/Tensin 4 Expression Induces Sensitivity to Paclitaxel in Prostate Cancer
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DOI：
10.1002/pros.21037
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发表时间：
2010-01-01
期刊：
影响因子：
2.8
通讯作者：
Namiki, Mikio
中科院分区：
文献类型：
--
作者：
Li, YouQiang;Mizokami, Atsushi;Namiki, Mikio
背景资料。最近，我们建立了耐紫杉醇的前列腺癌细胞系(PC-3-TxR和DU145-TxR)。为了探讨PC-3-TxR细胞对紫杉醇耐药的机制，我们比较了PC-3和PC-3-TxR细胞的基因表达谱。我们的结果表明，在PC-3-TxR细胞中，C末端张力素样蛋白(CTEN，tensin 4)基因的表达下调了10倍。我们研究了CTEN过表达恢复紫杉醇敏感性的可能性。方法通过克隆形成实验和生长抑制实验，研究了雄激素非依赖性细胞系中CTEN过表达和下调对紫杉醇敏感性的影响。为了确定CTEN影响紫杉醇敏感性的机制，我们研究了CTEN与PC-3细胞中F-肌动蛋白或表皮生长因子受体(EGFR)的关系。结果定位于细胞骨架的CTEN表达下调在PC-3-TxR细胞紫杉醇耐药中起重要作用。下调CTEN在PC-3细胞中的表达诱导紫杉醇耐药。在PC-3-TxR和DU145-TxR细胞中过表达CTEN可恢复紫杉醇的敏感性。CTEN的表达与F-肌动蛋白和EGFR的表达呈负相关。在PC-3-TxR细胞中，肌动蛋白和EGFR的表达下调，恢复了对紫杉醇的敏感性，表明CTEN小丑调控通过上调EGFR和肌动蛋白的表达来介导紫杉醇耐药。结论CTEN的表达与PCa的Gleason评分呈负相关，提示CTEN在紫杉醇敏感性中起重要作用，CTEN的表达水平可能是PCa患者预后的预测因素。前列腺70：48-60,2010。(C)2009年Wiley-Lis，Inc.
BACKGROUND. Recently, we established paclitaxel-resistant prostate cancer cell lines (PC-3-TxR and DU145-TxR). To determine the mechanisms of paclitaxel resistance in PC-3-TxR cells, we compared the gene expression profiles between PC-3 and PC-3-TxR cells. Our results indicated that expression of the C-terminal tensin like protein (CTEN, tensin 4) gene was down-regulated by 10-fold in PC-3-TxR cells. We investigated the possibility that CTEN overexpression restores paclitaxel sensitivity.METHODS. We investigated how knockdown and overexpression of CTEN in androgen-independent cell lines affect paclitaxel sensitivity by colony formation assay and growth inhibition assay. To determine the mechanisms by which CTEN affects paclitaxel sensitivity, we investigated the relationships between CTEN and F-actin or epidermal growth factor receptor (EGFR) in PC-3 cells. We also examined the association between expression of CTEN and grade of prostate cancer by immunohistochemistry using tissue microarray analysis.RESULTS. Down-regulation of CTEN, which is located in the cytoskeleton, played an important role in paclitaxel resistance in PC-3-TxR cells. Knockdown of CTEN expression in PC-3 cells induced paclitaxel resistance. Overexpression of CTEN in PC-3-TxR and DU145-TxR cells restored paclitaxel sensitivity. CTEN expression was inversely correlated with F-actin and EGFR expression. Then knockdown of actin and EGFR in PC-3-TxR cells recovered paclitaxel sensitivity, indicating that CTEN clown-regulation mediates paclitaxel resistance through elevation of EGFR and actin expression. Moreover, CTEN expression was inversely correlated with Gleason score.CONCLUSIONS. These results strongly suggested that CTEN plays an important role in paclitaxel sensitivity and that CTEN expression level may be a prognostic predictive factor for PCa patients. Prostate 70: 48-60,2010. (c) 2009 Wiley-Lis, Inc.