title: Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205.
abstract: Docetaxel is a standard chemotherapy for patients with metastatic prostate cancer. However, the response is rather limited and not all of the patients benefit from this treatment. To uncover key mechanisms of docetaxel insensitivity in prostate cancer, we have established docetaxel-resistant sublines. In this study, we report that docetaxel-resistant cells underwent an epithelial-to-mesenchymal transition during the selection process, leading to diminished E-cadherin levels and up-regulation of mesenchymal markers. Screening for key regulators of an epithelial phenotype revealed a significantly reduced expression of microRNA (miR)-200c and miR-205 in docetaxel-resistant cells. Transfection of either microRNA (miRNA) resulted in re-expression of E-cadherin. Functional assays confirmed reduced adhesive and increased invasive and migratory abilities. Furthermore, we detected an increased subpopulation with stem cell-like properties in resistant cells. Tissue microarray analysis revealed a reduced E-cadherin expression in tumors after neoadjuvant chemotherapy. Low E-cadherin levels could be linked to tumor relapse. The present study uncovers epithelial-to-mesenchymal transition as a hallmark of docetaxel resistance. Therefore, we suggest that this mechanism is at least in part responsible for chemotherapy failure, with implications for the development of novel therapeutics.
authors.affiliation: Division of Experimental Urology, Department of Urology, Innsbruck Medical University, Anichstrasse 35,Innsbruck, Austria. martin.puhr@i-med.ac.at
authors.forename: Martin
authors.initials: M
authors.lastname: Puhr
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefer
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.forename: Holger H H
authors.initials: HH
authors.lastname: Erb
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Oh
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.forename: Isabel
authors.initials: I
authors.lastname: Heidegger
authors.forename: Hannes
authors.initials: H
authors.lastname: Neuwirt
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D000077143:Docetaxel; D035683:MicroRNAs; D043823:Taxoids; C533896:MIRN200 microRNA, human; C534425:MIR205, human