PI3K, Erk Signaling in BMP7-Induced Epithelial-Mesenchymal Transition (EMT) of PC-3 Prostate Cancer Cells in 2-and 3-Dimensional Cultures
PI3K, Erk Signaling in BMP7-Induced Epithelial-Mesenchymal Transition (EMT) of PC-3 Prostate Cancer Cells in 2-and 3-Dimensional Cultures
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DOI：
10.1007/s12672-011-0084-4
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发表时间：
2011-10-01
影响因子：
3
通讯作者：
Roy-Burman, Pradip
中科院分区：
文献类型：
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作者：
Lim, Minyoung;Chuong, Cheng-Ming;Roy-Burman, Pradip
我们以前报道过骨形态发生蛋白7（BMP 7）可以诱导PC-3前列腺癌细胞在组织培养板中生长的上皮-间质转化（EMT）。在这项研究中，我们研究了BMP 7诱导的形态和分子表达的变化，这些变化是EMT的特征，使用这些细胞在两个（2D）和三维（3D）培养条件下。当球状体暴露于细胞外BMP 7时，在3D培养物中由PC-3细胞形成的球状体结构的丝状体生长是非常明显的。这种三维形态学变化伴随着E-钙粘蛋白的下调，这是一种重要的粘附分子的上皮表型的完整性。癌细胞的侵袭性在BMP 7处理沿着蛋白酶如MMP 1、MMP 13和尿激酶纤溶酶原激活剂的活化和上调时显著增强。EMT转化的信号转导通过使用某些途径特异性抑制剂来检查。在测试的化学抑制剂中，发现PI 3激酶和Erk的抑制剂在2D和3D条件下都抑制BMP诱导的形态学变化。这些结果表明，除了Smad信号通路，BMP诱导的PI 3 K和Erk的激活有助于PC-3前列腺癌细胞的EMT形态转化。总之，结果支持EMT的复杂性可以在3D细胞培养模型中的空间和时间过程方面更好地评估的概念，所述3D细胞培养模型在生理上比组织培养板中的细胞生长更相关。
We reported previously that bone morphogenetic protein 7 (BMP7) could induce epithelial-mesenchymal transition (EMT) in PC-3 prostate cancer cells grown in tissue culture plates. In this study, we examined BMP7-induced morphological and molecular expression changes that are characteristic of EMT using these cells under both two-(2D) and three-dimensional (3D) culture conditions. Filamentous outgrowths from spheroid structures that were formed from PC-3 cells in 3D cultures were strikingly evident when the spheroids were exposed to extracellular BMP7. This morphological change in 3D was accompanied by down-regulation of E-cadherin, which is an essential adhesion molecule for the integrity of epithelial phenotype. Invasiveness of the cancer cells was significantly enhanced with BMP7 treatment along with activation and up-regulation of proteases such as MMP1, MMP13, and urokinase plasminogen activator. Signal transduction of EMT conversion was examined by the use of certain pathway-specific inhibitors. Of the chemical inhibitors tested, inhibitors of PI3 kinase and Erk were found to suppress BMP-induced morphological changes both in 2D and 3D conditions. These results suggest that, besides the Smad signaling pathways, BMP-induced activation of PI3K and Erk contribute to EMT morphologic conversion of the PC-3 prostate cancer cells. Together, the results support the notion that the complexity of EMT may be better evaluated in terms of both spatial and temporal processes in 3D cell culture models that are physiologically more relevant than the cell growth in tissue culture plates.