Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance.
Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance.
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DOI：
10.1038/cddis.2013.407
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发表时间：
2013-10-24
影响因子：
9
通讯作者：
Li, Y.
中科院分区：
文献类型：
--
作者：
Chang, L.;Graham, P. H.;Hao, J.;Ni, J.;Bucci, J.;Cozzi, P. J.;Kearsley, J. H.;Li, Y.
放射抗性是前列腺癌（CaP）放射治疗（RT）的主要挑战。在这项研究中，我们研究了上皮间质转化（EMT），癌症干细胞（CSC）和PI 3 K/Akt/mTOR信号通路在CaP辐射抗性中的作用和关联。我们通过放射治疗开发了三种新型CaP抗辐射（RR）细胞系（PC-3RR、DU 145 RR和LNCaPRR），并使用克隆生存试验证实了它们的抗辐射性。与未处理的CaP对照细胞相比，CaP-RR细胞的集落形成能力、侵袭能力和球体形成能力均增强（P<0.05）。此外，增强EMT/CSC表型和激活的检查点蛋白（Chk 1和Chk 2）和PI 3 K/Akt/mTOR信号通路蛋白也发现在CaP-RR细胞中使用免疫荧光，蛋白质印迹和定量实时PCR（qRT-PCR）。此外，双重PI 3 K/mTOR抑制剂（BEZ 235）与RT的组合有效地增加了CaP-RR细胞的放射敏感性并诱导更多的凋亡，与单独RT相比，这与EMT/CSC标志物和PI 3 K/Akt/mTOR信号通路蛋白的表达降低相关。我们的研究结果表明，CaP辐射抗性与EMT和通过激活PI 3 K/Akt/mTOR信号通路增强CSC表型相关，并且BEZ 235与RT的组合是克服CaP治疗中的辐射抗性的有希望的方式。这种组合方法保证了未来的体内动物研究和临床试验。
Radioresistance is a major challenge in prostate cancer (CaP) radiotherapy (RT). In this study, we investigated the role and association of epithelial–mesenchymal transition (EMT), cancer stem cells (CSCs) and the PI3K/Akt/mTOR signaling pathway in CaP radioresistance. We developed three novel CaP radioresistant (RR) cell lines (PC-3RR, DU145RR and LNCaPRR) by radiation treatment and confirmed their radioresistance using a clonogenic survival assay. Compared with untreated CaP-control cells, the CaP-RR cells had increased colony formation, invasion ability and spheroid formation capability (P<0.05). In addition, enhanced EMT/CSC phenotypes and activation of the checkpoint proteins (Chk1 and Chk2) and the PI3K/Akt/mTOR signaling pathway proteins were also found in CaP-RR cells using immunofluorescence, western blotting and quantitative real-time PCR (qRT-PCR). Furthermore, combination of a dual PI3K/mTOR inhibitor (BEZ235) with RT effectively increased radiosensitivity and induced more apoptosis in CaP-RR cells, concomitantly correlated with the reduced expression of EMT/CSC markers and the PI3K/Akt/mTOR signaling pathway proteins compared with RT alone. Our findings indicate that CaP radioresistance is associated with EMT and enhanced CSC phenotypes via activation of the PI3K/Akt/mTOR signaling pathway, and that the combination of BEZ235 with RT is a promising modality to overcome radioresistance in the treatment of CaP. This combination approach warrants future in vivo animal study and clinical trials.
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影响因子：
9.2
作者：
Sarkar, Fazlul H.;Li, Yiwei;Wang, Zhiwei;Kong, Dejuan
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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