Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Mercedes Marin-Aguilera; Jordi Codony-Servat; Oscar Reig; Juan Jose Lozano; Pedro Luis Fernandez; Maria Veronica Pereira; Natalia Jimenez; Michael Donovan; Pere Puig; Lourdes Mengual; Raquel Bermudo; Albert Font; Enrique Gallardo; Maria Jose Ribal; Antonio Alcaraz; Pere Gascon; Begona Mellado

doi:10.1158/1535-7163.MCT-13-0775

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Mercedes Marin-Aguilera, Jordi Codony-Servat, Oscar Reig, Juan Jose Lozano, Pedro Luis Fernandez, Maria Veronica Pereira, Natalia Jimenez, Michael Donovan, Pere Puig, Lourdes Mengual, Raquel Bermudo, Albert Font, Enrique Gallardo, Maria Jose Ribal, Antonio Alcaraz, Pere Gascon, Begona Mellado^*

^*Corresponding author for this work

Department of Morphological Sciences

Hosp Clin Barcelona, University of Barcelona, Hospital Clinic de Barcelona, Dept Med Oncol
Hosp Clin Barcelona, CIBER - Centro de Investigacion Biomedica en Red, CIBEREHD, University of Barcelona, Hospital Clinic de Barcelona, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Bioinformat Platform Dept
Althia
Univ Barcelona, University of Barcelona, Hospital Clinic de Barcelona, IDIBAPS, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Lab & Dept Urol, Hosp Clin
Hosp Clin IDIBAPS Biobank, University of Barcelona, Hospital Clinic de Barcelona, IDIBAPS, Tumor Bank
Hosp Badalona Germans Trias & Pujol, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Dept Med Oncol, Catalan Inst Oncol
Hosp Parc Tauli, Autonomous University of Barcelona, Parc Tauli Hospital Universitari, Dept Med Oncol
Univ Barcelona, University of Barcelona, Hospital Clinic de Barcelona, IDIBAPS, IDIBAPS, Inst Invest Biomed August Pi & Sunyer
Univ Barcelona, University of Barcelona, Hospital Clinic de Barcelona, Hosp Clin, Dept Anat Pathol

Research output: Contribution to journal › Article › Research › peer-review

139 Citations (Scopus)

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 + 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-kappa 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(+) subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44(+) 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 evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. (C) 2014 AACR.

Original language	English
Pages (from-to)	1270-1284
Number of pages	15
Journal	Molecular Cancer Therapeutics
Volume	13
Issue number	5
DOIs	https://doi.org/10.1158/1535-7163.MCT-13-0775
Publication status	Published - May 2014

Keywords

FACTOR-KAPPA-B
ANDROGEN RECEPTOR
NEOADJUVANT DOCETAXEL
SIGNALING PATHWAYS
EXPRESSION
SUPPRESSION
INHIBITION
CELLS
CHEMORESISTANCE
IDENTIFICATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1535-7163.MCT-13-0775

Cite this

Marin-Aguilera, M., Codony-Servat, J., Reig, O., Jose Lozano, J., Luis Fernandez, P., Veronica Pereira, M., Jimenez, N., Donovan, M., Puig, P., Mengual, L., Bermudo, R., Font, A., Gallardo, E., Jose Ribal, M., Alcaraz, A., Gascon, P., & Mellado, B. (2014). Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer. Molecular Cancer Therapeutics, 13(5), 1270-1284. https://doi.org/10.1158/1535-7163.MCT-13-0775

@article{5cd6538bb15e47b58cdbbfd6fc8edd16,

title = "Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer",

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 + 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-kappa 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(+) subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44(+) 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 evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. (C) 2014 AACR.",

keywords = "FACTOR-KAPPA-B, ANDROGEN RECEPTOR, NEOADJUVANT DOCETAXEL, SIGNALING PATHWAYS, EXPRESSION, SUPPRESSION, INHIBITION, CELLS, CHEMORESISTANCE, IDENTIFICATION",

author = "Mercedes Marin-Aguilera and Jordi Codony-Servat and Oscar Reig and {Jose Lozano}, Juan and {Luis Fernandez}, Pedro and {Veronica Pereira}, Maria and Natalia Jimenez and Michael Donovan and Pere Puig and Lourdes Mengual and Raquel Bermudo and Albert Font and Enrique Gallardo and {Jose Ribal}, Maria and Antonio Alcaraz and Pere Gascon and Begona Mellado",

year = "2014",

month = may,

doi = "10.1158/1535-7163.MCT-13-0775",

language = "English",

volume = "13",

pages = "1270--1284",

journal = "Molecular Cancer Therapeutics",

issn = "1535-7163",

publisher = "American Association for Cancer Research Inc.",

number = "5",

}

Marin-Aguilera, M, Codony-Servat, J, Reig, O, Jose Lozano, J, Luis Fernandez, P, Veronica Pereira, M, Jimenez, N, Donovan, M, Puig, P, Mengual, L, Bermudo, R, Font, A, Gallardo, E, Jose Ribal, M, Alcaraz, A, Gascon, P & Mellado, B 2014, 'Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer', Molecular Cancer Therapeutics, vol. 13, no. 5, pp. 1270-1284. https://doi.org/10.1158/1535-7163.MCT-13-0775

TY - JOUR

T1 - Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

AU - Marin-Aguilera, Mercedes

AU - Codony-Servat, Jordi

AU - Reig, Oscar

AU - Jose Lozano, Juan

AU - Luis Fernandez, Pedro

AU - Veronica Pereira, Maria

AU - Jimenez, Natalia

AU - Donovan, Michael

AU - Puig, Pere

AU - Mengual, Lourdes

AU - Bermudo, Raquel

AU - Font, Albert

AU - Gallardo, Enrique

AU - Jose Ribal, Maria

AU - Alcaraz, Antonio

AU - Gascon, Pere

AU - Mellado, Begona

PY - 2014/5

Y1 - 2014/5

N2 - 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 + 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-kappa 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(+) subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44(+) 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 evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. (C) 2014 AACR.

AB - 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 + 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-kappa 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(+) subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44(+) 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 evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. (C) 2014 AACR.

KW - FACTOR-KAPPA-B

KW - ANDROGEN RECEPTOR

KW - NEOADJUVANT DOCETAXEL

KW - SIGNALING PATHWAYS

KW - EXPRESSION

KW - SUPPRESSION

KW - INHIBITION

KW - CELLS

KW - CHEMORESISTANCE

KW - IDENTIFICATION

U2 - 10.1158/1535-7163.MCT-13-0775

DO - 10.1158/1535-7163.MCT-13-0775

M3 - Article

SN - 1535-7163

VL - 13

SP - 1270

EP - 1284

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 5

ER -

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Abstract

Keywords

UN SDGs

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