糖皮质激素受体拮抗剂可逆转人前列腺癌中的多西他赛耐药性。
Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer.
作者信息
Kroon Jan, Puhr Martin, Buijs Jeroen T, van der Horst Geertje, Hemmer Daniëlle M, Marijt Koen A, Hwang Ming S, Masood Motasim, Grimm Stefan, Storm Gert, Metselaar Josbert M, Meijer Onno C, Culig Zoran, van der Pluijm Gabri
机构信息
Department of UrologyLeiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsDepartment of Targeted TherapeuticsMIRA Institute for Biological Technology and Technical Medicine, University of Twente, Enschede, The NetherlandsDepartment of UrologyMedical University of Innsbruck, Innsbruck, AustriaDepartment of Clinical OncologyLeiden University Medical Center, Leiden, The NetherlandsDivision of Experimental MedicineImperial College London, London, UKDepartment of PharmaceuticsUtrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The NetherlandsDepartment of EndocrinologyLeiden University Medical Center, Leiden, The Netherlands Department of UrologyLeiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsDepartment of Targeted TherapeuticsMIRA Institute for Biological Technology and Technical Medicine, University of Twente, Enschede, The NetherlandsDepartment of UrologyMedical University of Innsbruck, Innsbruck, AustriaDepartment of Clinical OncologyLeiden University Medical Center, Leiden, The NetherlandsDivision of Experimental MedicineImperial College London, London, UKDepartment of PharmaceuticsUtrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The NetherlandsDepartment of EndocrinologyLeiden University Medical Center, Leiden, The Netherlands.
Department of UrologyLeiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsDepartment of Targeted TherapeuticsMIRA Institute for Biological Technology and Technical Medicine, University of Twente, Enschede, The NetherlandsDepartment of UrologyMedical University of Innsbruck, Innsbruck, AustriaDepartment of Clinical OncologyLeiden University Medical Center, Leiden, The NetherlandsDivision of Experimental MedicineImperial College London, London, UKDepartment of PharmaceuticsUtrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The NetherlandsDepartment of EndocrinologyLeiden University Medical Center, Leiden, The Netherlands.
出版信息
Endocr Relat Cancer. 2016 Jan;23(1):35-45. doi: 10.1530/ERC-15-0343. Epub 2015 Oct 19.
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.
对多西他赛的耐药性是晚期前列腺癌（PCa）的一个主要临床问题。尽管糖皮质激素（GCs）经常与多西他赛联合使用，但尚不清楚GCs及其受体糖皮质激素受体（GR）在多大程度上导致化疗耐药。在本研究中，我们旨在阐明GR在多西他赛耐药性PCa中的作用，以改善当前的PCa治疗方法。我们分析了来自未经化疗和接受多西他赛治疗患者的原发性PCa标本组织芯片中的GR表达，以及在获得多西他赛耐药性的培养PCa细胞系（PC3-DR、DU145-DR和22Rv1-DR）中的GR表达。我们发现，接受多西他赛治疗患者的原发性PCa中GR显著过表达，且在培养的多西他赛耐药性人PCa细胞中GR水平升高，表明GR在多西他赛耐药中起关键作用。我们研究了GR拮抗剂（米非司酮和醋酸环丙孕酮）逆转多西他赛耐药性的能力，结果显示多西他赛耐药性PCa细胞对多西他赛治疗有显著的剂量和时间依赖性再敏化，其中雄激素受体（AR）阴性和AR阳性细胞系均实现了多西他赛敏感性的完全恢复。从机制上讲，我们证明了GR拮抗作用后Bcl-xL和Bcl-2的下调，从而确定了潜在的治疗靶点。总之，我们描述了GR参与人类PCa中多西他赛耐药性的获得。对GR进行治疗性靶向可有效使多西他赛耐药性PCa细胞再敏化。这些发现值得进一步研究GR拮抗剂在晚期和多西他赛耐药性PCa患者管理中的临床应用。
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