title: Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer.
abstract: 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.
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Masaki
authors: M
authors: Shiota
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Momoe
authors: M
authors: Itsumi
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Ario
authors: A
authors: Takeuchi
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Kenjiro
authors: K
authors: Imada
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan yokoa@uro.med.kyushu-u.ac.jp.
authors: Akira
authors: A
authors: Yokomizo
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Hidetoshi
authors: H
authors: Kuruma
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Junichi
authors: J
authors: Inokuchi
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Katsunori
authors: K
authors: Tatsugami
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Takeshi
authors: T
authors: Uchiumi
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Yoshinao
authors: Y
authors: Oda
authors: Departments of UrologyAnatomic PathologyGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDepartment of UrologySchool of Medicine, Jikei University, Tokyo 105-0003, JapanDepartment of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Seiji
authors: S
authors: Naito
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D000728:Androgens; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003131:Combined Modality Therapy; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D009687:Nuclear Proteins / Q000502:physiology*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011897:Random Allocation; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D051879:Twist-Related Protein 1 / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C521813:6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline; D000728:Androgens; D007093:Imidazoles; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011810:Quinoxalines; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C103173:TWIST1 protein, human; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1
keywords: Twist1; androgen receptor; androgen-deprivation therapy; castration resistance; epithelial-mesenchymal transition; prostate cancer