Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer
Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer
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DOI：
10.1530/erc-15-0225
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发表时间：
2015-12-01
影响因子：
3.9
通讯作者：
Naito, Seiji
中科院分区：
文献类型：
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作者：
Shiota, Masaki;Itsumi, Momoe;Naito, Seiji
尽管通过上皮-间质转化（EMT）的侵袭性和转移性进展以及获得去势抗性都是前列腺癌的关键步骤，但这种相互作用的分子机制尚不清楚。在这项研究中，我们旨在阐明去势抵抗与EMT之间的信号相互作用，并将这些信息应用于利用转化生长因子- β (tgf - β)抑制剂SB525334联合雄激素剥夺治疗前列腺癌的新治疗概念。本研究发现，一种em诱导剂（tgf - β）可诱导全长雄激素受体（AR）及其变异表达。此外，高侵袭性克隆扩增了AR全长和AR变体表达，并获得了去势抗性。相反，全长AR和AR以及Twist1和间充质分子变异表达在抗去势LNCaP异种移植物中上调。最后，tgf - β抑制剂抑制Twist1和AR表达以及前列腺癌合并去势的生长。综上所述，这些结果表明，Twist1/AR信号在去势抗性和间质表型前列腺癌中被增强，提示emt与去势抗性之间相互和功能性串扰的分子机制，可能在前列腺癌的发生和发展中发挥重要作用。
Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-beta (TGF-beta) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer usinganin vivomodel. This study revealedthat anEMTinducer (TGF-beta) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-beta inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMTand castration resistance, which may play a crucial role in prostate carcinogenesis and progression.