Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer
Jan Kroon, Martin Puhr, Jeroen T Buijs, Geertje van der Horst, Daniëlle M Hemmer, Koen A Marijt, Ming S Hwang, Motasim Masood, Stefan Grimm, Gert Storm, Josbert M Metselaar, Onno C Meijer, Zoran Culig, Gabri van der Pluijm, Jan Kroon, Martin Puhr, Jeroen T Buijs, Geertje van der Horst, Daniëlle M Hemmer, Koen A Marijt, Ming S Hwang, Motasim Masood, Stefan Grimm, Gert Storm, Josbert M Metselaar, Onno C Meijer, Zoran Culig, Gabri van der Pluijm
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.
Keywords: docetaxel; glucocorticoid receptor; prostate cancer; therapy resistance.
© 2016 The authors.
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References
- Aguilar D, Strom J, Chen QM. Glucocorticoid induced leucine zipper inhibits apoptosis of cardiomyocytes by doxorubicin. Toxicology and Applied Pharmacology. 2014;276:55–62. doi: 10.1016/j.taap.2014.01.013.
- Al-Abd AM, Mahmoud AM, El-Sherbiny GA, El-Moselhy MA, Nofal SM, El-Latif HA, El-Eraky WI, El-Shemy HA. Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro . Cell Proliferation. 2011;44:591–601. doi: 10.1111/j.1365-2184.2011.00783.x.
- Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. New England Journal of Medicine. 2014;371:1028–1038. doi: 10.1056/NEJMoa1315815.
- Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, Nadal R, Paller CJ, Denmeade SR, Carducci MA, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncology. 2015; 1:582–591. doi: 10.1001/jamaoncol.2015.1341.
- Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309–1322. doi: 10.1016/j.cell.2013.11.012.
- de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Jr, Saad F, et al. Abiraterone and increased survival in metastatic prostate cancer. New England Journal of Medicine. 2011;364:1995–2005. doi: 10.1056/NEJMoa1014618.
- Frohlich M, Albermann N, Sauer A, Walter-Sack I, Haefeli WE, Weiss J. In vitro and ex vivo evidence for modulation of P-glycoprotein activity by progestins. Biochemical Pharmacology. 2004;68:2409–2416. doi: 10.1016/j.bcp.2004.08.026.
- Galletti E, Magnani M, Renzulli ML, Botta M. Paclitaxel and docetaxel resistance: molecular mechanisms and development of new generation taxanes. ChemMedChem. 2007;2:920–942. doi: 10.1002/cmdc.200600308.
- Golebiewska A, Brons NH, Bjerkvig R, Niclou SP. Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell. 2011;8:136–147. doi: 10.1016/j.stem.2011.01.007.
- Gruol DJ, Zee MC, Trotter J, Bourgeois S. Reversal of multidrug resistance by RU 486. Cancer Research. 1994;54:3088–3091.
- Hartel A, Didier A, Ulbrich SE, Wierer M, Meyer HH. Characterisation of steroid receptor expression in the human prostate carcinoma cell line 22RV1 and quantification of androgen effects on mRNA regulation of prostate-specific genes. Journal of Steroid Biochemistry and Molecular Biology. 2004;92:187–197. doi: 10.1016/j.jsbmb.2004.07.004.
- Herr I, Ucur E, Herzer K, Okouoyo S, Ridder R, Krammer PH, von Knebel Doeberitz M, Debatin KM. Glucocorticoid cotreatment induces apoptosis resistance toward cancer therapy in carcinomas. Cancer Research. 2003;63:3112–3120.
- Herr I, Gassler N, Friess H, Buchler MW. Regulation of differential pro- and anti-apoptotic signaling by glucocorticoids. Apoptosis. 2007;12:271–291. doi: 10.1007/s10495-006-0624-5.
- Honer C, Nam K, Fink C, Marshall P, Ksander G, Chatelain RE, Cornell W, Steele R, Schweitzer R, Schumacher C. Glucocorticoid receptor antagonism by cyproterone acetate and RU486. Molecular Pharmacology. 2003;63:1012–1020. doi: 10.1124/mol.63.5.1012.
- Isikbay M, Otto K, Kregel S, Kach J, Cai Y, Vander Griend DJ, Conzen SD, Szmulewitz RZ. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Hormones & Cancer. 2014;5:72–89. doi: 10.1007/s12672-014-0173-2.
- Jurado R, Lopez-Flores A, Alvarez A, Garcia-Lopez P. Cisplatin cytotoxicity is increased by mifepristone in cervical carcinoma: an in vitro and in vivo study. Oncology Reports. 2009;22:1237–1245.
- Kettel LM, Murphy AA, Morales AJ, Ulmann A, Baulieu EE, Yen SS. Treatment of endometriosis with the antiprogesterone mifepristone (RU486) Fertility and Sterility. 1996;65:23–28.
- Kroon J, Buijs JT, van der Horst G, Cheung H, van der Mark M, van Bloois L, Rizzo LY, Lammers T, Pelger RC, Storm G, et al. Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth in vivo . Prostate. 2015;75:815–824. doi: 10.1002/pros.22963.
- Laane E, Panaretakis T, Pokrovskaja K, Buentke E, Corcoran M, Soderhall S, Heyman M, Mazur J, Zhivotovsky B, Porwit A, et al. Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members. Haematologia. 2007;92:1460–1469. doi: 10.3324/haematol.10543.
- Lau KM, LaSpina M, Long J, Ho SM. Expression of estrogen receptor (ER)-α and ER-β in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation. Cancer Research. 2000;60:3175–3182.
- Lewis-Tuffin LJ, Cidlowski JA. The physiology of human glucocorticoid receptor β (hGRβ) and glucocorticoid resistance. Annals of the New York Academy of Sciences. 2006;1069:1–9. doi: 10.1196/annals.1351.001.
- Madan RA, Pal SK, Sartor O, Dahut WL. Overcoming chemotherapy resistance in prostate cancer. Clinical Cancer Research. 2011;17:3892–3902. doi: 10.1158/1078-0432.CCR-10-2654.
- Montgomery B, Cheng HH, Drechsler J, Mostaghel EA. Glucocorticoids and prostate cancer treatment: friend or foe? Asian Journal of Andrology. 2014;16:354–358. doi: 10.4103/1008-682X.125392.
- Morgan CJ, Oh WK, Naik G, Galsky MD, Sonpavde G. Impact of prednisone on toxicities and survival in metastatic castration-resistant prostate cancer: a systematic review and meta-analysis of randomized clinical trials. Critical Reviews in Oncology/Hematology. 2014;90:253–261. doi: 10.1016/j.critrevonc.2013.12.001.
- O'Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, Gallagher WM, O'Connor D, O'Connor R, Devery A, Corcoran C, et al. Characterisation and manipulation of docetaxel resistant prostate cancer cell lines. Molecular Cancer. 2011;10:126. doi: 10.1186/1476-4598-10-126.
- Onstenk W, Sieuwerts AM, Kraan J, Van M, Nieuweboer AJ, Mathijssen RH, Hamberg P, Meulenbeld HJ, Laere B, Dirix LY, et al. Efficacy of cabazitaxel in castration-resistant prostate cancer is independent of the presence of AR-V7 in circulating tumor cells. European Urology. 2015;68:939–945. doi: 10.1016/j.eururo.2015.07.007.
- Petrella A, Ercolino SF, Festa M, Gentilella A, Tosco A, Conzen SD, Parente L. Dexamethasone inhibits TRAIL-induced apoptosis of thyroid cancer cells via Bcl-xL induction. European Journal of Cancer. 2006;42:3287–3293. doi: 10.1016/j.ejca.2006.07.018.
- Puhr M, Hoefer J, Schafer G, Erb HH, Oh SJ, Klocker H, Heidegger I, Neuwirt H, Culig Z. Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205. American Journal of Pathology. 2012;181:2188–2201. doi: 10.1016/j.ajpath.2012.08.011.
- Puhr M, Hoefer J, Neuwirt H, Eder IE, Kern J, Schafer G, Geley S, Heidegger I, Klocker H, Culig Z. PIAS1 is a crucial factor for prostate cancer cell survival and a valid target in docetaxel resistant cells. Oncotarget. 2014;5:12043–12056. doi: 10.18632/oncotarget.2658.
- Reeder A, Attar M, Nazario L, Bathula C, Zhang A, Hochbaum D, Roy E, Cooper KL, Oesterreich S, Davidson NE, et al. Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage. British Journal of Cancer. 2015;112:1461–1470. doi: 10.1038/bjc.2015.133.
- Rosewicz S, McDonald AR, Maddux BA, Goldfine ID, Miesfeld RL, Logsdon CD. Mechanism of glucocorticoid receptor down-regulation by glucocorticoids. Journal of Biological Chemistry. 1988;263:2581–2584.
- Sanchez C, Mendoza P, Contreras HR, Vergara J, McCubrey JA, Huidobro C, Castellon EA. Expression of multidrug resistance proteins in prostate cancer is related with cell sensitivity to chemotherapeutic drugs. Prostate. 2009;69:1448–1459. doi: 10.1002/pros.20991.
- Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. New England Journal of Medicine. 2012;367:1187–1197. doi: 10.1056/NEJMoa1207506.
- Shiota M, Yokomizo A, Takeuchi A, Imada K, Kashiwagi E, Song Y, Inokuchi J, Tatsugami K, Uchiumi T, Naito S. Inhibition of protein kinase C/Twist1 signaling augments anticancer effects of androgen deprivation and enzalutamide in prostate cancer. Clinical Cancer Research. 2014;20:951–961. doi: 10.1158/1078-0432.CCR-13-1809.
- Skor MN, Wonder EL, Kocherginsky M, Goyal A, Hall BA, Cai Y, Conzen SD. Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer. Clinical Cancer Research. 2013;19:6163–6172. doi: 10.1158/1078-0432.CCR-12-3826.
- van Soest RJ, de Morree ES, Kweldam CF, de Ridder CM, Wiemer EA, Mathijssen RH, de Wit R, van Weerden WM. Targeting the androgen receptor confers in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in castration-resistant prostate cancer. European Urology. 2014;67:981–985. doi: 10.1016/j.eururo.2014.11.033.
- Szmulewitz RZ, Chung E, Al-Ahmadie H, Daniel S, Kocherginsky M, Razmaria A, Zagaja GP, Brendler CB, Stadler WM, Conzen SD. Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers. Prostate. 2012;72:157–164. doi: 10.1002/pros.21416.
- Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New England Journal of Medicine. 2004;351:1502–1512. doi: 10.1056/NEJMoa040720.
- Taplin ME, Manola J, Oh WK, Kantoff PW, Bubley GJ, Smith M, Barb D, Mantzoros C, Gelmann EP, Balk SP. A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU International. 2008;101:1084–1089. doi: 10.1111/j.1464-410X.2008.07509.x.
- Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, Corey E, Nanus DM, Plymate SR, Giannakakou P. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Research. 2014;74:2270–2282. doi: 10.1158/0008-5472.CAN-13-2876.
- Venkitaraman R, Thomas K, Huddart RA, Horwich A, Dearnaley DP, Parker CC. Efficacy of low-dose dexamethasone in castration-refractory prostate cancer. BJU International. 2008;101:440–443.
- Xie N, Cheng H, Lin D, Liu L, Yang O, Jia L, Fazli L, Gleave ME, Wang Y, Rennie P, et al. The expression of glucocorticoid receptor is negatively regulated by active androgen receptor signaling in prostate tumors. International Journal of Cancer. 2015;136:E27–E38. doi: 10.1002/ijc.29147.
- Yemelyanov A, Czwornog J, Chebotaev D, Karseladze A, Kulevitch E, Yang X, Budunova I. Tumor suppressor activity of glucocorticoid receptor in the prostate. Oncogene. 2007;26:1885–1896. doi: 10.1038/sj.onc.1209991.
- Yemelyanov A, Bhalla P, Yang X, Ugolkov A, Iwadate K, Karseladze A, Budunova I. Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: a novel therapeutic modality. Cell Cycle. 2012;11:395–406. doi: 10.4161/cc.11.2.18945.
- Yoshino T, Shiina H, Urakami S, Kikuno N, Yoneda T, Shigeno K, Igawa M. Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clinical Cancer Research. 2006;12:6116–6124. doi: 10.1158/1078-0432.CCR-06-0147.
- Zhang C, Wenger T, Mattern J, Ilea S, Frey C, Gutwein P, Altevogt P, Bodenmuller W, Gassler N, Schnabel PA, et al. Clinical and mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the majority of solid tumors. Cancer Biology & Therapy. 2007;6:278–287. doi: 10.4161/cbt.6.2.3652.
- Zhang Q, Wang J, He H, Liu H, Yan X, Zou K. Trametenolic acid B reverses multidrug resistance in breast cancer cells through regulating the expression level of P-glycoprotein. Phytotherapy Research. 2014;28:1037–1044. doi: 10.1002/ptr.5089.
- Zhang G, Liu X, Li J, Ledet E, Alvarez X, Qi Y, Fu X, Sartor O, Dong Y, Zhang H. Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents. Oncotarget. 2015; 6:23358–23371. doi: 10.18632/oncotarget.4396.
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