title: The role of epithelial-mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel-resistant prostate cancer.
abstract: Docetaxel is the main treatment for advanced castration-resistant prostate cancer; however, resistance eventually occurs. The development of intratumoral drug-resistant subpopulations possessing a cancer stem cell (CSC) morphology is an emerging mechanism of docetaxel resistance, a process driven by epithelial-mesenchymal transition (EMT). This study characterised EMT in docetaxel-resistant sublines through increased invasion, MMP-1 production and ZEB1 and ZEB2 expression. We also present evidence for differential EMT across PC-3 and DU145 in vitro resistance models as characterised by differential migration, cell colony scattering and susceptibility to the CSC inhibitor salinomycin. siRNA manipulation of ZEB1 and ZEB2 in PC-3 and DU145 docetaxel-resistant sublines identified ZEB1, through its transcriptional repression of E-cadherin, to be a driver of both EMT and docetaxel resistance. The clinical relevance of ZEB1 was also determined through immunohistochemical tissue microarray assessment, revealing significantly increased ZEB1 expression in prostate tumours following docetaxel treatment. This study presents evidence for a role of ZEB1, through its transcriptional repression of E-cadherin to be a driver of both EMT and docetaxel resistance in docetaxel-resistant prostate cancer. In addition, this study highlights the heterogeneity of prostate cancer and in turn emphasises the complexity of the clinical management of docetaxel-resistant prostate cancer.
authors.affiliation: UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: Karen
authors.initials: K
authors.lastname: Hanrahan
authors.affiliation: UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: Amanda
authors.initials: A
authors.lastname: O'Neill
authors.affiliation: UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: Maria
authors.initials: M
authors.lastname: Prencipe
authors.affiliation: UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: Jane
authors.initials: J
authors.lastname: Bugler
authors.affiliation: UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Department of Pathology, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Fabre
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Puhr
authors.affiliation: Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
authors.affiliation: UCD School of Mathematical Sciences, University College Dublin, Ireland.
authors.forename: Keefe
authors.initials: K
authors.lastname: Murphy
authors.affiliation: UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: R William
authors.initials: RW
authors.lastname: Watson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008297:Male; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics*; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000032:analysis / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D043823:Taxoids; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000077143:Docetaxel
keywords: ZEB1; ZEB2; docetaxel; epithelial-mesenchymal transition; prostate; resistance