Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells.
Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells.
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DOI：
10.3892/or.2014.3200
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发表时间：
2014-07
期刊：
影响因子：
4.2
通讯作者：
K. Shoji;J. Teishima;Tetsutaro Hayashi;S. Ohara;W. Mckeehan;A. Matsubara
中科院分区：
文献类型：
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作者：
K. Shoji;J. Teishima;Tetsutaro Hayashi;S. Ohara;W. Mckeehan;A. Matsubara
成纤维细胞生长因子受体2(FGFR2)被认为是维持正常前列腺组织内环境平衡的重要信号通路。在晚期前列腺癌或前列腺癌细胞系中已经显示出FGFR2的异常，我们先前已经证明了FGFR2IIIb在前列腺癌细胞中的恢复对肿瘤的抑制作用。本研究的目的是确定FGFR2IIIb是否在去势抵抗的前列腺癌细胞的化疗敏感性中发挥作用。将含FGFR2IIIb基因的IRESne2表达载体导入PC-3细胞，建立了表达FGFR2IIIb的PC-3R2IIIb细胞克隆系。用四甲基偶氮唑盐比色法和免疫印迹法检测化疗药物(多西紫杉醇、顺铂、5-氟尿嘧啶和唑来膦酸)对细胞存活率和细胞凋亡率的影响。免疫印迹分析检测上皮细胞向间充质细胞转化的标志分子和化疗敏感性相关蛋白的表达水平。PC-3R2IIIb细胞的存活率明显低于对照组PC-3细胞(PC-3neo)，化疗药物尤其是多西紫杉醇可进一步抑制PC-3R2IIIb细胞的存活率。Caspase-3在PC-3R2IIIb细胞中有明显的诱导表达，经多西紫杉醇处理后进一步增强。N-钙粘蛋白、波形蛋白、Survivin和XIAP在PC-3R2IIIb细胞中的表达低于PC-3neo细胞。而p21在PC-3R2IIIb细胞中的表达高于对照组PC-3neo细胞。这些数据表明，在去势耐受的前列腺癌细胞中修复FGFR2IIIb可能逆转肿瘤细胞的某些上皮间充质细胞特性，并部分诱导间充质细胞向上皮细胞的转变。再加上caspase-3参与的凋亡通路的增强，可能会增强化疗的敏感性，特别是对多西紫杉醇的敏感性，多西紫杉醇被广泛用于治疗去势抵抗的前列腺癌。
Fibroblast growth factor receptor 2 (FGFR2) is thought to mediate an important signaling pathway between prostate epithelial cells and stromal cells for maintenance of homeostasis in normal prostate tissue. Abnormalities of FGFR2 have been shown in advanced prostate cancer or prostate cancer cell lines, and we previously demonstrated the tumor-suppressive effects of the restoration of FGFR2IIIb in prostate cancer cells. The aim of the present study was to determine whether FGFR2IIIb plays a role in the chemosensitivity of castration-resistant prostate cancer cells. A clonal line of PC-3 cells expressing FGFR2IIIb (PC-3R2IIIb) was established by transfection with an IRESneo2-expressing vector bearing FGFR2IIIb cDNA. The effects of chemotherapeutic agents (docetaxel, cisplatin, 5-fluorouracil and zoledronic acid) on cell viability and apoptosis were examined by MTT assay and western blot analysis, respectively. Expression levels of molecules that were markers of epithelial-to-mesenchymal transition and chemosensitivity-related proteins were assessed by western blot analysis. Viability of the PC-3R2IIIb cells was significantly lower than that of the control PC-3 cells transfected with the vector alone (PC-3neo), and viability was further suppressed by treatment with chemotherapeutic agents, particularly docetaxel. Induced expression of caspase-3 was evident in the PC-3R2IIIb cells and was further enhanced by treatment with docetaxel. Expression of N-cadherin, vimentin, survivin and XIAP was lower in the PC-3R2IIIb cells than that in the PC-3neo cells. In contrast, expression of p21 was higher in the PC-3R2IIIb cells than that in the control PC-3neo cells. These data indicate that restoration of FGFR2IIIb in castration-resistant prostate cancer cells may reverse some of the epithelial-to-mesenchymal cell properties characteristic of tumor cells and induce in part mesenchymal-to-epithelial transition properties. This together with enhancement of apoptotic pathways involving caspase-3 may enhance chemosensitivity particularly to docetaxel which is widely used in the treatment of castration-resistant prostate cancer.