Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer.

Jan Kroon,Onno C Meijer,Josbert M Metselaar,Koen A Marijt,Gert Storm,Gabri Van Der Pluijm,Daniëlle M Hemmer,Jeroen T Buijs,Martin Puhr,Stefan Grimm,Motasim Masood,Ming S Hwang,Geertje Van Der Horst,Zoran Culig

doi:10.1530/erc-15-0343

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.

Highlights

Resistance to chemotherapy is a major hurdle in prostate cancer (PCa) treatment
We describe a key role of the glucocorticoid receptor (GR) in PCa docetaxel resistance
We show that the GR is overexpressed in clinical PCa specimens treated with neoadjuvant docetaxel, as well as in docetaxel-resistant PCa cell lines in vitro

Summary

Introduction

Resistance to chemotherapy is a major hurdle in prostate cancer (PCa) treatment. Chemotherapeutic treatments typically display initial benefit, cancer cells frequently acquire novel characteristics that will render these cells unresponsive to current cytotoxic treatments. Docetaxel (Taxotere, Sanofi-Aventis, Paris, France) is a microtubule-stabilizing agent that is clinically approved for a range of malignancies, including castrationresistant PCa (CRPC) for which it is the standard-of-care and prolongs survival of patients (Tannock et al 2004). Tumors inevitably progress due to the acquired docetaxel resistance (O’Neill et al 2011). Docetaxel resistance is often accompanied with a cross-resistance, i.e., dampened efficacy of other antitumor therapeutics and the use of other therapeutic agents, e.g., antiandrogens, appears to be associated with the emergence of resistance to docetaxel (van Soest et al 2014). Identification of the underlying molecular mechanisms of docetaxel resistance is of a pivotal importance to combat docetaxel resistance in clinics (Madan et al 2011)

Objectives

Methods

Results

Conclusion