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01.04.2014 | Original Paper

Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer

verfasst von: Masis Isikbay, Kristen Otto, Steven Kregel, Jacob Kach, Yi Cai, Donald J. Vander Griend, Suzanne D. Conzen, Russell Z. Szmulewitz

Erschienen in: Discover Oncology | Ausgabe 2/2014

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Abstract

Despite new treatments for castrate-resistant prostate cancer (CRPC), the prognosis of patients with CRPC remains bleak due to acquired resistance to androgen receptor (AR)-directed therapy. The glucocorticoid receptor (GR) and AR share several transcriptional targets, including the anti-apoptotic genes serum and g lucocorticoid-regulated kinase 1 (SGK1) and Map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Because GR expression increases in a subset of primary prostate cancer (PC) following androgen deprivation therapy, we sought to determine whether GR activation can contribute to resistance to AR-directed therapy. We studied CWR-22Rv1 and LAPC4 AR/GR-expressing PC cell lines following treatment with combinations of the androgen R1881, AR antagonist MDV3100, GR agonist dexamethasone, GR antagonists mifepristone and CORT 122928, or the SGK1 inhibitor GSK650394. Cell lines stably expressing GR (NR3C1)-targeted shRNA or ectopic SGK1-Flag were also studied in vivo. GR activation diminished the effects of the AR antagonist MDV3100 on tumor cell viability. In addition, GR activation increased prostate-specific antigen (PSA) secretion and induced SGKI and MKP1/DUSP gene expression. Glucocorticoid-mediated cell viability was diminished by a GR antagonist or by co-treatment with the SGK1 inhibitor GSK650394. In vivo, GR depletion delayed castrate-resistant tumor formation, while SGK1-Flag-overexpressing PC xenografts displayed accelerated castrate-resistant tumor initiation, supporting a role for SGK1 in GR-mediated CRPC progression. We studied several PC models before and following treatment with androgen blockade and found that increased GR expression and activity contributed to tumor-promoting PC cell viability. Increased GR-regulated SGK1 expression appears, at least in part, to mediate enhanced PC cell survival. Therefore, GR and/or SGK1 inhibition may be useful adjuncts to AR blockade for treating CRPC.

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Andreu-Vieyra C, Lai J, Berman BP, Frenkel B, Jia L, Jones PA et al (2011) Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells. Mol Cell Biol 31:4648–4662PubMedCentralPubMedCrossRef

Arora Vivek K, Schenkein E, Murali R, Subudhi Sumit K, Wongvipat J, Balbas Minna D et al (2013) Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155:1309–1322PubMedCrossRef

Attardi BJ, Burgenson J, Hild SA, Reel JR (2004) Steroid hormonal regulation of growth, prostate specific antigen secretion, and transcription mediated by the mutated androgen receptor in CWR22Rv1 human prostate carcinoma cells. Mol Cell Endocrinol 222:121–132PubMedCrossRef

Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA et al (2013) Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2:e00499PubMedCentralPubMedCrossRef

Bolton EC, So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR (2007) Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005–2017PubMedCentralPubMedCrossRef

Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S et al (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19:575–586PubMedCentralPubMedCrossRef

Chen Y, Sawyers CL, Scher HI (2008) Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 8:440–448PubMedCentralPubMedCrossRef

Clark RD (2008) Glucocorticoid receptor antagonists. Curr Top Med Chem 8:813–838PubMedCrossRef

Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A et al (2012) ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 72:1494–1503PubMedCentralPubMedCrossRef

10.

Cleutjens CB, Steketee K, van Eekelen CC, van der Korput JA, Brinkmann AO, Trapman J (1997) Both androgen receptor and glucocorticoid receptor are able to induce prostate-specific antigen expression, but differ in their growth-stimulating properties of LNCaP cells. Endocrinology 138:5293–5300PubMed

11.

Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ (2008) Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 68:5469–5477PubMedCentralPubMedCrossRef

12.

Duma D, Jewell CM, Cidlowski JA (2006) Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol 102:11–21PubMedCrossRef

13.

Fakih M, Johnson CS, Trump DL (2002) Glucocorticoids and treatment of prostate cancer: a preclinical and clinical review. Urology 60:553–561PubMedCrossRef

14.

Gabaglia CR, DeLaney A, Gee J, Halder R, Graham FL, Gauldie J et al (2010) Treatment combining RU486 and Ad5IL-12 vector attenuates the growth of experimentally formed prostate tumors and induces changes in the sentinel lymph nodes of mice. J Transl Med 8:98PubMedCentralPubMedCrossRef

15.

Geley S, Fiegl M, Hartmann B, Kofler R (1996) Genes mediating glucocorticoid effects and mechanisms of their regulation. Reviews of physiology biochemistry and pharmacology, vol 128. Springer, Berlin, pp 1–97

16.

Hall BA, Kim TY, Skor MN, Conzen SD (2012) Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression. Breast Cancer Res Treat 135:469–479PubMedCentralPubMedCrossRef

17.

Hammond M, Washburn DG, Hoang HT, Manns S, Frazee JS, Nakamura H et al (2009) Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors. Bioorg Med Chem Lett 19:4441–4445PubMedCrossRef

18.

Huggins C, Stevens RJ, Hodges C (1941) Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 43:209–223CrossRef

19.

Jeanneteau F, Garabedian MJ, Chao MV (2008) Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect. Proc Natl Acad Sci U S A 105:4862–4867PubMedCentralPubMedCrossRef

20.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRef

21.

Kinyamu HK, Archer TK (2003) Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression. Mol Cell Biol 23:5867–5881PubMedCentralPubMedCrossRef

22.

Kregel S, Kiriluk KJ, Rosen AM, Cai Y, Reyes EE, Otto KB et al (2013) Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer. PLoS One 8:e53701PubMedCentralPubMedCrossRef

23.

Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM (2013) Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 73:483–489PubMedCentralPubMedCrossRef

24.

Ligr M, Li Y, Logan SK, Taneja S, Melamed J, Lepor H et al (2012) Mifepristone inhibits GRbeta coupled prostate cancer cell proliferation. J Urol 188:981–988PubMedCentralPubMedCrossRef

25.

Lin MF, Kawachi MH, Stallcup MR, Grunberg SM, Lin FF (1995) Growth inhibition of androgen-insensitive human prostate carcinoma cells by a 19-norsteroid derivative agent, mifepristone. Prostate 26:194–204PubMedCrossRef

26.

Litvinov IV, Vander Griend DJ, Xu Y, Antony L, Dalrymple SL, Isaacs JT (2006) Low-calcium serum-free defined medium selects for growth of normal prostatic epithelial stem cells. Cancer Res 66:8598–8607PubMedCrossRef

27.

Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD (2001) Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem 276:16649–16654PubMedCrossRef

28.

Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP et al (2013) NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther 12:1629–1637PubMedCentralPubMedCrossRef

29.

Nishimura K, Nonomura N, Satoh E, Harada Y, Nakayama M, Tokizane T et al (2001) Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. J Natl Cancer Inst 93:1739–1746PubMedCrossRef

30.

Pan D, Kocherginsky M, Conzen SD (2011) Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res 71:6360–6370PubMedCentralPubMedCrossRef

31.

Pienta KJ, Abate-Shen C, Agus DB, Attar RM, Chung LW, Greenberg NM et al (2008) The current state of preclinical prostate cancer animal models. Prostate 68:629–639PubMedCentralPubMedCrossRef

32.

Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K et al (2012) Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 72:2176–2182PubMedCrossRef

33.

Sahu B, Laakso M, Pihlajamaa P, Ovaska K, Sinielnikov I, Hautaniemi S et al (2013) FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res 73:1570–1580PubMedCrossRef

34.

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller MD et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187–1197PubMedCrossRef

35.

Scher HI, Sawyers CL (2005) Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 23:8253–8261PubMedCrossRef

36.

Shanmugam I, Cheng G, Terranova PF, Thrasher JB, Thomas CP, Li B (2007) Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival. Cell Death Differ 14:2085–2094PubMedCrossRef

37.

Sherk AB, Frigo DE, Schnackenberg CG, Bray JD, Laping NJ, Trizna W et al (2008) Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic. Cancer Res 68:7475–7483PubMedCentralPubMedCrossRef

38.

Smith RG, Syms AJ, Nag A, Lerner S, Norris JS (1985) Mechanism of the glucocorticoid regulation of growth of the androgen-sensitive prostate-derived R3327H-G8-A1 tumor cell line. J Biol Chem 260:12454–12463PubMed

39.

Song LN, Coghlan M, Gelmann EP (2004) Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor. Mol Endocrinol 18:70–85PubMedCrossRef

40.

Szmulewitz RZ, Chung E, Al-Ahmadie H, Daniel S, Kocherginsky M, Razmaria A et al (2012) Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers. Prostate 72:157–164

41.

Szmulewitz RZ, Clark R, Lotan T, Otto K, Taylor Veneris J, Macleod K et al (2012) MKK4 suppresses metastatic colonization by multiple highly metastatic prostate cancer cell lines through a transient impairment in cell cycle progression. Int J Cancer 130:509–520PubMedCentralPubMedCrossRef

42.

Taplin ME, Manola J, Oh WK, Kantoff PW, Bubley GJ, Smith M et al (2008) A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU Int 101:1084–1089PubMedCrossRef

43.

Tenbaum S, Baniahmad A (1997) Nuclear receptors: structure, function and involvement in disease. Int J Biochem Cell Biol 29:1325–1341PubMedCrossRef

44.

Tieszen CR, Goyeneche AA, Brandhagen BN, Ortbahn CT, Telleria CM (2011) Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression. BMC Cancer 11:207PubMedCentralPubMedCrossRef

45.

Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V et al (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324:787–790PubMedCentralPubMedCrossRef

46.

Vogelzang N (2006) Comprehensive textbook of genitourinary oncology, 3rd edn. Lippincott Williams & Wilkins, Philadelphia

47.

Wu W, Chaudhuri S, Brickley DR, Pang D, Karrison T, Conzen SD (2004) Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer Res 64:1757–1764PubMedCrossRef

48.

Wu W, Pew T, Zou M, Pang D, Conzen SD (2005) Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival. J Biol Chem 280:4117–4124

49.

Yan TZ, Jin FS, Xie LP, Li LC (2008) Relationship between glucocorticoid receptor signal pathway and androgen-independent prostate cancer. Urol Int 81:228–233PubMedCrossRef

50.

Yemelyanov A, Bhalla P, Yang X, Ugolkov A, Iwadate K, Karseladze A et al (2012) Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: a novel therapeutic modality. Cell Cycle 11:395–406PubMedCentralPubMedCrossRef

51.

Zoubeidi A, Zardan A, Beraldi E, Fazli L, Sowery R, Rennie P et al (2007) Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res 67:10455–10465PubMedCrossRef

Titel: Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer
verfasst von: Masis Isikbay
Kristen Otto
Steven Kregel
Jacob Kach
Yi Cai
Donald J. Vander Griend
Suzanne D. Conzen
Russell Z. Szmulewitz
Publikationsdatum: 01.04.2014
Verlag: Springer US
Erschienen in: Discover Oncology / Ausgabe 2/2014
Print ISSN: 1868-8497
Elektronische ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-014-0173-2

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Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer

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