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The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell

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The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Published OnlineFirst November 20, 2017; DOI: 10.1158/1078-0432.CCR-17-0989 Biology of Human Tumors Clinical Cancer Research The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy Martin Puhr1, Julia Hoefer1, Andrea Eigentler1, Christian Ploner2, Florian Handle1, Georg Schaefer3, Jan Kroon4,5, Angela Leo1, Isabel Heidegger1, Iris Eder1, Zoran Culig1, Gabri Van der Pluijm6, and Helmut Klocker1 Abstract Purpose: The major obstacle in the management of advanced Results: Although GR expression is reduced in primary prostate prostate cancer is the occurrence of resistance to endocrine ther- cancer tissue, it is restored in metastatic lesions. Relapse patients apy. Although the androgen receptor (AR) has been linked to with high GR experience shortened progression-free survival. GR therapy failure, the underlying escape mechanisms have not been is significantly increased upon long-term abiraterone or enzalu- fully clarified. Being closely related to the AR, the glucocorticoid tamide treatment in the majority of preclinical models, thus receptor (GR) has been suggested to play a role in enzalutamide identifying GR upregulation as an underlying mechanism for and docetaxel resistance. Given that glucocorticoids are frequently cells to bypass AR blockade. Importantly, GR inhibition by RNAi applied to prostate cancer patients, it is essential to unravel the or chemical blockade results in impaired proliferation and 3D- exact role of the GR in prostate cancer progression. spheroid formation in all tested cell lines. Experimental Design: Assessment of GR expression and func- Conclusions: GR upregulation seems to be a common mech- tional significance in tissues from 177 prostate cancer patients, anism during antiandrogen treatment and supports the notion including 14 lymph node metastases, as well as in several human that targeting the GR pathway combined with antiandrogen prostate cancer models, including androgen-dependent, andro- medication may further improve prostate cancer therapy. gen-independent, and long-term antiandrogen-treated cell lines. Clin Cancer Res; 24(4); 927–38. Ó2017 AACR. Introduction including AR gene amplification, upregulation of AR variants (8), and AR point mutations (9), can only partially explain drug The development of novel drugs that target androgen recep- insensitivity. This underscores the importance of identifying tor (AR) signaling, such as abiraterone (1, 2) and enzalutamide new molecular events associated with drug resistance to over- (3, 4), has expanded the limited therapeutic options for treat- come therapy failure. ment of prostate cancer. Both drugs are administered to Being closely related to the AR, the glucocorticoid receptor (GR) patients with metastatic castration-resistant prostate cancer is hypothesized to participate in therapy resistance. In the absence (mCRPC) before or after chemotherapy, resulting in prolonged of glucocorticoids (e.g., cortisol, prednisolone, dexamethasone), progression-free and overall survival. However, therapy of such the GR is sequestered in the cytoplasm by chaperone proteins. tumor stages remains palliative and is often limited due to the Ligand binding leads to rapid GR dimerization and nuclear rapid development of drug resistance (5–7).Inthiscontext,the translocation, which subsequently influences target gene expres- AR is known as a prime suspect; however, AR modifications, sion (10, 11). Glucocorticoids are currently being used in the management of several tumor types, including mCRPC, as they suppress the secretion of adrenocorticotrophic hormone, thus 1Department of Urology, Medical University of Innsbruck, Innsbruck, Austria. 2Department of Plastic, Reconstructive and Aesthetic Surgery Innsbruck, Med- resulting in reduced expression of adrenal androgens and conse- ical University of Innsbruck, Innsbruck, Austria. 3Department of Pathology, quently in a decline in PSA and circulating tumor cells (12). In Medical University of Innsbruck, Innsbruck, Austria. 4Department of Medicine, addition, glucocorticoids exert anti-inflammatory as well as anti- Division of Endocrinology, Leiden University Medical Center, Leiden, the Nether- emetic effects and are therefore frequently given to patients in 5 lands. Einthoven Laboratory of Experimental Vascular Medicine, Leiden Uni- combination with docetaxel, cabazitaxel (13–15), and abirater- 6 versity Medical Center, Leiden, the Netherlands. Department of Urology, Leiden one (16, 17) to suppress severe therapy-related adverse effects. University Medical Center, Leiden, the Netherlands. However, their independent impact on survival is unclear, and Note: Supplementary data for this article are available at Clinical Cancer unfavorable effects, such as osteoporosis and immunosuppres- Research Online (http://clincancerres.aacrjournals.org/). sion, complicate long-term use (12). Recently, elevated GR expres- Corresponding Author: Martin Puhr, Department of Urology, Medical University sion has been associated with resistance to enzalutamide therapy of Innsbruck, Anich Street 35, Innsbruck A-6020, Austria. Phone: 4351-2504- (18, 19). In particular, enhanced GR expression was observed in 24826; Fax: 4351-2504-24817; E-mail: [email protected] enzalutamide-resistant tumors in vivo and in tumor biopsies from doi: 10.1158/1078-0432.CCR-17-0989 enzalutamide-treated prostate cancer patients (18). These find- Ó2017 American Association for Cancer Research. ings might be explained by the fact that AR can directly repress GR www.aacrjournals.org 927 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 20, 2017; DOI: 10.1158/1078-0432.CCR-17-0989 Puhr et al. LAPC4, T47D and MDA-MB231, BPH1, and DUCaP were cul- Translational Relevance tured in RPMI1640 supplemented with 10% FCS (Biowest), 1% Management of advanced prostate cancer is restricted by the penicillin/streptomycin (Szabo Scandic), and 1Â GlutaMAX inevitable occurrence of endocrine therapy resistance, which (Thermo Fisher Scientific). LAPC4 were further supplemented results in rapid disease progression. This study identifies the with 1 nmol/L DHT. VCaP were grown in DMEM supplemented glucocorticoid receptor (GR) as a crucial survival factor for with 10% FCS, 1Â GlutaMAX, and 1.75 g D-glucose. MCF7 and prostate cancer cells and its upregulation as a frequent mech- BT-20 were grown in EMEM medium supplemented with 10% anism to bypass androgen receptor blockade by abiraterone or FCS (Biowest), 1Â GlutaMAX (Thermo Fisher Scientific) and enzalutamide. As glucocorticoids are currently used in the 1% penicillin/streptomycin (Szabo Scandic). For MCF7, 1% management of metastatic castration-resistant prostate cancer nonessential amino acids (Sczabo Scandic) and 0.01 mg/mL in combination with docetaxel, cabazitaxel, and abiraterone, it insulin have been added. Dexamethasone (1 mmol/L; Selleck has to be assumed that this therapeutic strategy might further Chemicals) was used to activate GR signaling in specific experi- promote selection of GRhigh drug-insensitive prostate cancer ments. Before project start, identity of used cell lines was cells and accelerate disease progression. Therefore, the useful- confirmed by short tandem repeat analysis. All cell lines have ness of glucocorticoids in such a therapeutic setting needs to be been used for a maximum of 20 to 30 passages. carefully reevaluated. Moreover, preclinical in vitro data com- bined with GR expression profiles in prostate cancer patient Generation of long-term abiraterone- and enzalutamide- material presented herein provide a strong rationale for the treated cell lines clinical use of GR antagonists in combination with antiandro- LNCaPabl, DUCaP, and LAPC4 cells were cultured in the gens to further optimize treatment of endocrine therapy–na€ve presence of increasing doses of abiraterone (Hycultec) or vehi- and resistant prostate cancer. cle (EtOH). Drug treatment was started using 0.2 mmol/L of abiraterone. Drug-containing medium was changed every third day. Abiraterone concentration was increased when cells started to regrow in the presence of the drug at a growth rate similar to that of control cells until a final concentration of 4 mmol/L for expression in prostate cancer via a negative androgen response DUCaP, 8 mmol/L LAPC4, and 8 mmol/L for LNCaPabl cells. element (ARE) in the GR promoter (20). Therefore, it was The established cell sublines were named DUCaP-Ctrl/-Abi, proposed that GR can functionally replace the AR, when AR LAPC4-Ctrl/-Abi, and LNCaPabl-Ctrl/-Abi. Generation of con- signaling is blocked. Consistently, it has been shown that both trol- or long-term enzalutamide-treated LNCaPabl, DUCaP, receptors not only exhibit a significant overlap in their tran- and LAPC4 (termed LNCaPabl-Ctrl/-Enza, DUCaP-Ctrl/-Enza, scriptome (18), but also share several interacting proteins (21). LAPC4-Ctrl/-Enza) has been described in a previous study (8). In line with these observations, stimulation of GR activity could Long-term enzalutamide-treated LNCaP (LNCaP-Enza) cells rescue cells from enzalutamide-induced cell death (18). In were generated by continuous exposure to 1 mmol/L enzaluta- addition to modulating the efficacy of antiandrogens, dexa- mide until a sustained increase in proliferation was observed. methasone administration undermined the antitumor effects of Subsequently, drug concentration was increased to 5 mmol/L. paclitaxel in vitro and in vivo, thus giving
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