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      Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

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          Abstract

          Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.

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          Most cited references 43

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          Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer.

          We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown.
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            Critical appraisal of the side population assay in stem cell and cancer stem cell research.

            The "Side Population" (SP) discrimination assay is a flow cytometry method used to detect stem cells based on the dye efflux properties of ABC transporters. We discuss the SP assay and its applications in stem cell biology, with an emphasis on the technical challenges related to sample preparation, data acquisition, analysis, and interpretation. We highlight the value of multicolor phenotyping, the impact of DNA ploidy, and the importance of distinguishing graft versus host cells for an appropriate SP discrimination. To improve the consistency and reliability of data between laboratories, we propose a set of recommendations for SP assay data reporting. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells.

              Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7-positive patients.
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                Author and article information

                Journal
                Endocr Relat Cancer
                Endocr. Relat. Cancer
                ERC
                Endocrine-Related Cancer
                Bioscientifica Ltd (Bristol )
                1351-0088
                1479-6821
                January 2016
                19 October 2015
                : 23
                : 1
                : 35-45
                Affiliations
                Department of Urology, Leiden University Medical Center , Albinusdreef 22333 ZA, Leiden, The Netherlands
                Department of Targeted Therapeutics, MIRA Institute for Biological Technology and Technical Medicine, University of Twente , Enschede, The Netherlands
                Department of Urology, Medical University of Innsbruck , Innsbruck, Austria
                Department of Clinical Oncology, Leiden University Medical Center , Leiden, The Netherlands
                Division of Experimental Medicine, Imperial College London , London, UK
                Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Utrecht, The Netherlands
                Department of Endocrinology, Leiden University Medical Center , Leiden, The Netherlands
                Author notes
                Correspondence should be addressed to G van der Pluijm G.van_der_Pluijm@ 123456lumc.nl
                Article
                ERC150343
                10.1530/ERC-15-0343
                4657186
                26483423
                © 2016 The authors

                This work is licensed under a Creative Commons Attribution 3.0 Unported License

                Categories
                Research

                Oncology & Radiotherapy

                glucocorticoid receptor, docetaxel, prostate cancer, therapy resistance

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