Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

    1. Seiji Naito1
    1. 1Departments of Urology
      2Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan
      3Department of Urology, School of Medicine, Jikei University, Tokyo 105‐0003, Japan
      4Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan
    1. Correspondence should be addressed to A Yokomizo; Email: yokoa{at}


    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-β (TGF-β) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer using an in vivo model. This study revealed that an EMT inducer (TGF-β) 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-β 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 EMT and castration resistance, which may play a crucial role in prostate carcinogenesis and progression.

    • Received 24 August 2015
    • Accepted 26 August 2015
    • Made available online as an Accepted Preprint 26 August 2015
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