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Title: Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer
Author: Marin-Aguilera, Mercedes
Codony-Servat, Jordi
Reig, Oscar
Lozano, Juan José
Fernández, Pedro Luis
Pereira, María Verónica
Jimenez, Natalia
Donovan, Michel
Puig, Pere
Mengual Brichs, Lourdes
Bermudo, Raquel
Font, Albert
Gallardo, Enrique
Ribal, María José
Alcaraz Asensio, Antonio
Gascón, Pere
Mellado González, Begoña
Keywords: Càncer de pròstata
Assaigs clínics
Medicaments antineoplàstics
Prostate cancer
Clinical trials
Antineoplastic agents
Issue Date: 21-Mar-2014
Publisher: American Association for Cancer Research
Abstract: Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-k B transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evi-dence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.
Note: Versió postprint del document publicat a:
It is part of: Molecular Cancer Therapeutics, 2014, vol. 13, num. 5, p. 1270-1284
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ISSN: 1535-7163
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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