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Cancer Cell International
Published in: Cancer Cell International 1/2015

Open Access 01-12-2015 | Review

Overview on the complexity of androgen receptor-targeted therapy for prostate cancer

Authors: Ammad Ahmad Farooqi, Fazlul H Sarkar

Published in: Cancer Cell International | Issue 1/2015

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Abstract

In the past decades, the field of prostate cancer (PCa) biology has developed exponentially and paralleled with that has been the growing interest in translation of laboratory findings into clinical practice. Based on overwhelming evidence of high impact research findings which support the underlying cause of insufficient drug efficacy in patients progressing on standard androgen deprivation therapy (ADT) is due to persistent activation of the androgen receptor (AR) signaling axis. Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents. High-throughput technologies are generating massive and highly dimensional genetic variation data that has helped in developing a better understanding of the dynamic repertoire of AR and AR variants. Full length AR protein and its variants modulate a sophisticated regulatory system to orchestrate cellular responses. We partition this multicomponent review into subsections addressing the underlying mechanisms of resistance to recent therapeutics, positive and negative regulators of AR signaling cascade, and how SUMOylation modulates AR induced transcriptional activity. Experimentally verified findings obtained from cell culture and preclinical studies focusing on the potential of natural agents in inhibiting mRNA/protein levels of AR, nuclear accumulation and enhanced nuclear export of AR are also discussed. We also provide spotlight on molecular basis of enzalutamide resistance with an overview of the strategies opted to overcome such resistance. AR variants are comprehensively described and different mechanisms that regulate AR variant expression are also discussed. Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy. Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients.
Literature
1.
Heidegger I, Massoner P, Eder IE, Pircher A, Pichler R, Aigner F, Bektic J, Horninger W, Klocker H. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer. J Steroid Biochem Mol Biol. 2013; 138: 248–56
2.
Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3(9):1020–9.CrossRefPubMed
3.
Hussain M, Corn PG, Michaelson MD, Hammers HJ, Alumkal JJ, Ryan CJ, et al. Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen. Clin Cancer Res. 2014;20(16):4218–27.CrossRefPubMed
4.
Ahmed A, Ali S, Sarkar FH. Advances in androgen receptor targeted therapy for prostate cancer. J Cell Physiol. 2014;229(3):271–6.CrossRefPubMed
5.
Barboro P, Borzì L, Repaci E, Ferrari N, Balbi C. Androgen receptor activity is affected by both nuclear matrix localization and the phosphorylation status of the heterogeneous nuclear ribonucleoprotein K in anti-androgen-treated LNCaP cells. PLoS One. 2013;8(11):e79212. Biochem Mol Biol. 2013.CrossRefPubMedCentralPubMed
6.
Song X, Wang Y, Du H, Fan Y, Yang X, Wang X, et al. Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer. Prostate. 2014;74(10):1023–33.CrossRefPubMed
7.
An J, Wang C, Deng Y, Yu L, Huang H. Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep. 2014;6(4):657–69.CrossRefPubMed
8.
Köhler A, Demir U, Kickstein E, Krauss S, Aigner J, Aranda-Orgillés B, et al. A hormone-dependent feedback-loop controls androgen receptor levels by limiting MID1, a novel translation enhancer and promoter of oncogenic signaling. Mol Cancer. 2014;13:146.CrossRefPubMedCentralPubMed
9.
Li B, Lu W, Yang Q, Yu X, Matusik RJ, Chen Z. Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt/mTOR pathways in prostate cancer. Prostate. 2014;74(4):421–32.CrossRefPubMedCentralPubMed
10.
Li N, Chen M, Truong S, Yan C, Buttyan R. Determinants of Gli2 co-activation of wildtype and naturally truncated androgen receptors. Prostate. 2014;74(14):1400–10. doi:10.1002/pros.22855.CrossRefPubMed
11.
Yao L, Li Y, Du F, Han X, Li X, Niu Y, et al. Histone H4 Lys 20 methyltransferase SET8 promotes androgen receptor-mediated transcription activation in prostate cancer. Biochem Biophys Res Commun. 2014;450(1):692–6.CrossRefPubMed
12.
Jin C, Yang L, Xie M, Lin C, Merkurjev D, Yang JC, et al. Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens. Proc Natl Acad Sci U S A. 2014;111(25):9235–40.CrossRefPubMedCentralPubMed
13.
Jin R, Yamashita H, Yu X, Wang J, Franco OE, Wang Y, Hayward SW, Matusik RJ. Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression. Oncogene. 2014; doi:10.1038/onc.2014.302.
14.
Sutinen P, Malinen M, Heikkinen S, Palvimo JJ. SUMOylation modulates the transcriptional activity of androgen receptor in a target gene and pathway selective manner. Nucleic Acids Res. 2014;42(13):8310–9.CrossRefPubMedCentralPubMed
15.
Sutinen P, Rahkama V, Rytinki M, Palvimo JJ. Nuclear Mobility and Activity of FOXA1 with Androgen Receptor Are Regulated by SUMOylation. Mol Endocrinol. 2014;28(10):1719–28.CrossRefPubMed
16.
Kaikkonen S, Paakinaho V, Sutinen P, Levonen AL, Palvimo JJ. Prostaglandin 15d-PGJ(2) inhibits androgen receptor signaling in prostate cancer cells. Mol Endocrinol. 2013;27(2):212–23. doi:10.1210/me.2012-1313.CrossRefPubMed
17.
Mukherjee S, Cruz-Rodríguez O, Bolton E, Iñiguez-Lluhí JA. The in vivo role of androgen receptor SUMOylation as revealed by androgen insensitivity syndrome and prostate cancer mutations targeting the proline/glycine residues of synergy control motifs. J Biol Chem. 2012;287(37):31195–206.CrossRefPubMedCentralPubMed
18.
Rytinki M, Kaikkonen S, Sutinen P, Paakinaho V, Rahkama V, Palvimo JJ. Dynamic SUMOylation is linked to the activity cycles of androgen receptor in the cell nucleus. Mol Cell Biol. 2012;32(20):4195–205.CrossRefPubMedCentralPubMed
19.
Bawa-Khalfe T, Cheng J, Wang Z, Yeh ET. Induction of the SUMO-specific protease 1 transcription by the androgen receptor in prostate cancer cells. J Biol Chem. 2007;282(52):37341–9.CrossRefPubMed
20.
Huang W, He T, Chai C, Yang Y, Zheng Y, Zhou P, et al. Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression. PLoS One. 2012;7(5):e37693. doi:10.1371/journal.pone.0037693.CrossRefPubMedCentralPubMed
21.
Qiao Z, Wang W, Wang L, Wen D, Zhao Y, Wang Q, et al. Design, synthesis, and biological evaluation of benzodiazepine-based SUMO-specific protease 1 inhibitors. Bioorg Med Chem Lett. 2011;21(21):6389–92.CrossRefPubMed
22.
Chen Y, Wen D, Huang Z, Huang M, Luo Y, Liu B, et al. 2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives, a novel class of SENP1 inhibitors: Virtual screening, synthesis and biological evaluation. Bioorg Med Chem Lett. 2012;22(22):6867–70.CrossRefPubMed
23.
Obakan P, Arisan ED, Coker-Gurkan A, Palavan-Unsal N. Epibrassinolide-induced apoptosis regardless of p53 expression via activating polyamine catabolic machinery, a common target for androgen sensitive and insensitive prostate cancer cells. Prostate. 2014; doi:10.1002/pros.22879.
24.
Sánchez-González C, Ciudad CJ, Noé V, Izquierdo-Pulido M. Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells. Food Funct. 2014;5(11):2922–30.CrossRefPubMed
25.
Zhou DY, Ding N, Du ZY, Cui XX, Wang H, Wei XC, et al. Curcumin analogues with high activity for inhibiting human prostate cancer cell growth and androgen receptor activation. Mol Med Rep. 2014;10(3):1315–22.PubMed
26.
Muniyan S, Chou YW, Ingersoll MA, Devine A, Morris M, Odero-Marah VA, et al. Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells. Cancer Lett. 2014;353(1):59–67.CrossRefPubMed
27.
Hessenkemper W, Roediger J, Bartsch S, Houtsmuller AB, van Royen ME, Petersen I, Grimm MO, Baniahmad A. A Natural androgen receptor antagonist induces cellular senescence in prostate cancer cells. Mol Endocrinol. 2014; 28(11):1831-40.
28.
Yang YC, Meimetis LG, Tien AH, Mawji NR, Carr G, Wang J, et al. Spongian diterpenoids inhibit androgen receptor activity. Mol Cancer Ther. 2013;12(5):621–31.CrossRefPubMedCentralPubMed
29.
Petiwala SM, Berhe S, Li G, Puthenveetil AG, Rahman O, Nonn L, et al. Rosemary (Rosmarinus officinalis) extract modulates CHOP/GADD153 to promote androgen receptor degradation and decreases xenograft tumor growth. PLoS One. 2014;9(3):e89772.CrossRefPubMedCentralPubMed
30.
Reiner T, Parrondo R, de Las PA, Palenzuela D, Perez-Stable C. Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity. PLoS One. 2013;8(2):e56234. doi:10.1371/journal.pone.0056234.CrossRefPubMedCentralPubMed
31.
Loddick SA, Ross SJ, Thomason AG, Robinson DM, Walker GE, Dunkley TP, et al. AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo. Mol Cancer Ther. 2013;12(9):1715–27.CrossRefPubMedCentralPubMed
32.
Jang SY, Jang EH, Jeong SY, Kim JH. Shikonin inhibits the growth of human prostate cancer cells via modulation of the androgen receptor. Int J Oncol. 2014;44(5):1455–60.PubMedCentralPubMed
33.
Liu G, Sprenger C, Sun S, Epilepsia KS, Haugk K, Zhang X, et al. AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer. Neoplasia. 2013;15(9):1009–17.PubMedCentralPubMed
34.
Liu PY, Lin SZ, Sheu JJ, Lin CT, Lin PC, Chou YW, et al. Regulation of androgen receptor expression by Z-isochaihulactone mediated by the JNK signaling pathway and might be related to cytotoxicity in prostate cancer. Prostate. 2013;73(5):531–41.CrossRefPubMed
35.
Mahmoud AM, Zhu T, Parray A, Siddique HR, Yang W, Saleem M, et al. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor. PLoS One. 2013;8(10):e78479.CrossRefPubMedCentralPubMed
36.
Amin KS, Jagadeesh S, Baishya G, Rao PG, Barua NC, Bhattacharya S, et al. A naturally derived small molecule disrupts ligand-dependent and ligand-independent androgen receptor signaling in human prostate cancer cells. Mol Cancer Ther. 2014;13(2):341–52.CrossRefPubMedCentralPubMed
37.
Thiele M, Rabe S, Hessenkemper W, Roell D, Bartsch S, Kraft F, Abraham TE, Houtsmuller AB, van Royen ME, Giannis A, Baniahmad A. Novel Nor-Homo- and Spiro-Oxetan- Steroids Target the Human Androgen Receptor and Act as Antiandrogens. Curr Med Chem. 2014. doi: 0.2174/0929867321666140601164240
38.
Dalal K, Roshan-Moniri M, Sharma A, Li H, Ban F, Hessein M, et al. Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer. J Biol Chem. 2014;289(38):26417–29.CrossRefPubMed
39.
Zhan Y, Cao B, Qi Y, Liu S, Zhang Q, Zhou W, et al. Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer. Int J Cancer. 2013;133(9):2225–33.CrossRefPubMedCentralPubMed
40.
Cao B, Qi Y, Zhang G, Xu D, Zhan Y, Alvarez X, et al. Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget. 2014;5(6):1646–56.PubMed
41.
Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155(6):1309–22.CrossRefPubMedCentralPubMed
42.
Toren P, Kim S, Cordonnier T, Crafter C, Davies BR, Fazli L, Gleave ME, Zoubeidi A. Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models. Eur Urol. 2014; pii: S0302-2838(14)00748-9.
43.
Nguyen HG, Yang JC, Kung HJ, Shi XB, Tilki D, Lara PN, et al. Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. Oncogene. 2014;33(36):4521–30.CrossRefPubMedCentralPubMed
44.
Nadal R, Zhang Z, Rahman H, Schweizer MT, Denmeade SR, Paller CJ, et al. Clinical activity of enzalutamide in Docetaxel-naïve and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer. Prostate. 2014;74(15):1560–8.CrossRefPubMed
45.
Lin TH, Izumi K, Lee SO, Lin WJ, Yeh S, Chang C. Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell Death Dis. 2013;4:e764.CrossRefPubMedCentralPubMed
46.
Hu S, Li L, Yeh S, Cui Y, Li X, Chang HC, Jin J, Chang C. Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling. Mol Oncol. 2014; pii: S1574-7891(14)00168-9.
47.
Ardiani A, Farsaci B, Rogers CJ, Protter A, Guo Z, King TH, et al. Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival in a spontaneous prostate cancer model. Clin Cancer Res. 2013;19(22):6205–18.CrossRefPubMed
48.
Hamid AR, Verhaegh GW, Smit FP, van Rijt-van de Westerlo C, Armandari I, Brandt A, Sweep FC, Sedelaar JP, Schalken JA. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation. J Urol. 2014; pii: S0022-5347(14)04414-0.
49.
Guerrini A, Tesei A, Ferroni C, Paganelli G, Zamagni A, Carloni S, et al. A New Avenue toward Androgen Receptor Pan-antagonists: C2 Sterically Hindered Substitution of Hydroxy-propanamides. J Med Chem. 2014;57(17):7263–79.CrossRefPubMed
50.
Liu C, Lou W, Zhu Y, Nadiminty N, Schwartz CT, Evans CP, et al. Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res. 2014;20(12):3198–210.CrossRefPubMed
51.
Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 2014;33(24):3140–50.CrossRefPubMed
52.
Ban F, Leblanc E, Li H, Munuganti RS, Frewin K, Rennie PS, et al. Discovery of 1H-indole-2-carboxamides as novel inhibitors of the androgen receptor binding function 3 (BF3). J Med Chem. 2014;57(15):6867–72.CrossRefPubMed
53.
Nyquist MD, Li Y, Hwang TH, Manlove LS, Vessella RL, Silverstein KA, et al. TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer. Proc Natl Acad Sci U S A. 2013;110(43):17492–7.CrossRefPubMedCentralPubMed
54.
Knuuttila M, Yatkin E, Kallio J, Savolainen S, Laajala TD, Aittokallio T, et al. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model. Am J Pathol. 2014;184(8):2163–73.CrossRefPubMed
55.
Yu Z, Chen S, Sowalsky AG, Voznesensky OS, Mostaghel EA, Nelson PS, et al. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res. 2014;20(6):1590–600.CrossRefPubMed
56.
Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A. 2010;107(39):16759–65.CrossRefPubMedCentralPubMed
57.
Yang X, Guo Z, Sun F, Li W, Alfano A, Shimelis H, et al. Novel membrane-associated androgen receptor splice variant potentiates proliferative and survival responses in prostate cancer cells. J Biol Chem. 2011;286(41):36152–60.CrossRefPubMedCentralPubMed
58.
Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 2014;74(8):2270–82.CrossRefPubMed
59.
Krause WC, Shafi AA, Nakka M, Weigel NL. Androgen receptor and its splice variant, AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells. Int J Biochem Cell Biol. 2014;54:49–59.CrossRefPubMed
60.
Lu J, Lonergan PE, Nacusi LP2, Wang L, Schmidt LJ, Sun Z, Van der Steen T, Boorjian SA, Kosari F, Vasmatzis G, Klee GG, Balk SP, Huang H, Wang C, Tindall DJ. The cistrome and gene signature of androgen receptor splice variants in castration-resistant prostate cancer cells. J Urol. 2014; pii: S0022-5347(14)04214-1.
61.
Streicher W, Luedeke M, Azoitei A, Zengerling F, Herweg A, Genze F, et al. Stilbene induced inhibition of androgen receptor dimerization: implications for AR and ARΔLBD-signalling in human prostate cancer cells. PLoS One. 2014;9(6):e98566.CrossRefPubMedCentralPubMed
62.
Sun F, Chen HG, Li W, Yang X, Wang X, Jiang R, et al. Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J Biol Chem. 2014;289(3):1529–39.CrossRefPubMedCentralPubMed
63.
Tsai HC, Boucher DL, Martinez A, Tepper CG, Kung HJ. Modeling truncated AR expression in a natural androgen responsive environment and identification of RHOB as a direct transcriptional target. PLoS One. 2012;7(11):e49887. doi:10.1371/journal.pone.0049887.CrossRefPubMedCentralPubMed
64.
Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP, et al. NF-κB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther. 2013;12(8):1629–37.CrossRefPubMedCentralPubMed
65.
Peacock SO, Fahrenholtz CD, Burnstein KL. Vav3 enhances androgen receptor splice variant activity and is critical for castration-resistant prostate cancer growth and survival. Mol Endocrinol. 2012;26(12):1967–79.CrossRefPubMedCentralPubMed
66.
Mediwala SN, Sun H, Szafran AT, Hartig SM, Sonpavde G, Hayes TG, et al. The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. Prostate. 2013;73(3):267–77.CrossRefPubMedCentralPubMed
Metadata
Title
Overview on the complexity of androgen receptor-targeted therapy for prostate cancer
Authors
Ammad Ahmad Farooqi
Fazlul H Sarkar
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2015
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-014-0153-1

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