摘要 Prostate cancer (PCa) is one of the most lethal cancers in western countries. Androgen receptor (AR) signaling pathway plays a key role in PCa progression. Despite the initial effectiveness of androgen deprivation therapy (ADT)for treatment of patients with advanced PCa, most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer (mCRPC). Constitutively transcriptional activated AR splice variants (AR-Vs) have emerged as critical players in the development and progression of mCRPC. Among AR-Vs identified to date, AR-V7 (a.k.a. AR3) is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues. Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival, growth, differentiation and migration in prostate cells. In this review, we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.
Abstract: Prostate cancer (PCa) is one of the most lethal cancers in western countries. Androgen receptor (AR) signaling pathway plays a key role in PCa progression. Despite the initial effectiveness of androgen deprivation therapy (ADT)for treatment of patients with advanced PCa, most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer (mCRPC). Constitutively transcriptional activated AR splice variants (AR-Vs) have emerged as critical players in the development and progression of mCRPC. Among AR-Vs identified to date, AR-V7 (a.k.a. AR3) is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues. Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival, growth, differentiation and migration in prostate cells. In this review, we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.
Jin Xu, Yun Qiu. Role of androgen receptor splice variants in prostate cancer metastasis[J]. Asian Journal of Urology, 2016, 3(4): 177-184.
Jin Xu, Yun Qiu. Role of androgen receptor splice variants in prostate cancer metastasis. Asian Journal of Urology, 2016, 3(4): 177-184.
American Cancer Society. Cancer facts & figures 2015. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/.
[2]
George D, Moul J. Emerging treatment options for patients with castration resistant prostate cancer. Prostate 2012;72:338-49.
[3]
Gelmann E. Molecular biology of the androgen receptor. J Clin Oncol 2002;20:3001-15.
[4]
Heinlein C, Chang C. Androgen receptor in prostate cancer. Endocr Rev 2004;25:276-308.
[5]
Feldman B, Feldman D. The development of androgenindependent prostate cancer. Nat Rev Cancer 2001;1:34-45.
[6]
Ciccarese C, Santoni M, Brunelli M, Buti S, Modena A, Nabissi M, et al. AR-V7 and prostate cancer:the watershed for treatment selection? Cancer Treat Rev 2016;43:27-35.
[7]
Guo Z, Qiu Y. A new trick of an old molecule:androgen receptor splice variants taking the stage?! Int J Biol Sci 2011;7:815-22.
[8]
Guo Z, Yang X, Sun F, Jiang R, Linn D, Chen H, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletioneresistant growth. Cancer Res 2009;69:2305-13.
[9]
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;286:36152-60.
[10]
Hu R, Dunn T, Wei S, Isharwal S, Veltri R, Humphreys E, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 2009;69:16-22.
[11]
Dehm S, Schmidt L, Heemers H, Vessella R, Tindall D. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 2008;68:5469-77.
[12]
Lu C, Luo J. Decoding the androgen receptor splice variants. Transl Androl Urol 2013;2:178-86.
The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011-25.
[15]
Hörnberg E, Ylitalo E, Crnalic S, Antti H, Stattin P, Widmark A, et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One 2011;6:e19059.
[16]
Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, et al. Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep 2015;5:7654.
[17]
Antonarakis E, Lu C, Wang H, Luber B, Nakazawa M, Roeser J, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028-38.
[18]
Chen C, Welsbie D, Tran C, Baek S, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33-9.
[19]
Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene 2014;33:3140-50.
[20]
Tummala R, Nadiminty N, Lou W, Evans C, Gao A. Lin28 induces resistance to anti androgens via promotion of AR splice variant generation. Prostate 2016;76:445-55.
[21]
Stockley J, Markert E, Zhou Y, Robson C, Elliott D, Lindberg J, et al. The RNA-binding protein Sam68 regulates expression and transcription function of the androgen receptor splice variant AR-V7. Sci Rep 2015;5:13426.
[22]
Shi XB, Ma AH, Xue L, Li M, Nguyen HG, Yang JC, et al. miR-124 and androgen receptor signaling inhibitors repress prostate cancer growth by downregulating androgen receptor splice variants, EZH2, and src. Cancer Res 2015;75:5309-17.
[23]
Watson P, Chen Y, Balbas M, Wongvipat J, Socci N, Viale A, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require fulllength androgen receptor. Proc Natl Acad Sci U S A 2010;107:16759-65.
[24]
Xu D, Zhan Y, Qi Y, Cao B, Bai S, Xu W, et al. Androgen receptor splice variants dimerize to transactivate target genes. Cancer Res 2015;75:3663-71.
[25]
Li Y, Chan S, Brand L, Hwang T, Silverstein K, Dehm S. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 2013;73:483-9.
[26]
Kong D, Sethi S, Li Y, Chen W, Sakr WA, Heath E, et al. Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate 2015;75:161-74.
[27]
Sun F, Chen H, 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;289:1529-39.
[28]
Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009;138:245-56.
[29]
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;5:1646-56.
[30]
Hu R, Lu C, Mostaghel E, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res 2012;72:3457-62.
[31]
Liu G, Sprenger C, Wu PJ, Sun S, Uo T, Haugk K, et al. MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand. Oncotarget 2014;6:288-304.
[32]
Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella R, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res 2014;74:2270-82.
[33]
Reebye V, Querol Cano L, Lavery DN, Brooke GN, Powell SM, Chotai D, et al. Role of the HSP90-associated cochaperone p23 in enhancing activity of the androgen receptor and significance for prostate cancer. Mol Endocrinol 2012;26:1694-706.
[34]
Chan S, Li Y, Dehm S. Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. J Biol Chem 2012;287:19736-49.
[35]
Zhu ML, Horbinski C, Garzotto M, Qian D, Beer T, Kyprianou N. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res 2010;70:7992-8002.
[36]
Thadani-Mulero M, Nanus D, Giannakakou P. Androgen receptor on the move:boarding the microtubule expressway to the nucleus. Cancer Res 2012;72:4611-5.
[37]
Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, et al. Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res 2011;71:6019-29.
[38]
Zhang G, Liu X, Li J, Ledet E, Alvarez X, Qi Y, et al. Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents. Oncotarget 2015;6:23358-71.
[39]
Mediwala S, Sun H, Szafran A, Hartig S, Sonpavde G, Hayes T, et al. The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. Prostate 2013;73:267-77.
[40]
Yang L, Wang L, Lin HK, Kan PY, Xie S, Tsai MY, et al. Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem Biophys Res Commun 2003;305:462-9.
[41]
Carver B, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011;19:575-86.
[42]
Zengerling F, Azoitei A, Herweg A, Jentzmik F, Cronauer M. Inhibition of IGF-1R diminishes transcriptional activity of the androgen receptor and its constitutively active, C-terminally truncated counterparts Q640X and AR-V7. World J Urol 2015; 34:633-9.
[43]
Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans C, et al. NF-kB2/p52 induces resistance to enzalutamide in prostate cancer:role of androgen receptor and its variants. Mol Cancer Ther 2013;12:1629-37.
[44]
Jin R, Yamashita H, Yu X, Wang J, Franco OE, Wang Y, et al. 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 2015;34:3700-10.
[45]
Ritchie CK, Andrews LR, Thomas KG, Tindall DJ, Fitzpatrick LA. The effects of growth factors associated with osteoblasts on prostate carcinoma proliferation and chemotaxis:implications for the development of metastatic disease. Endocrinology 1997; 138:1145-50.
[46]
Christopoulos PF, Msaouel P, Koutsilieris M. The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer 2015;14:43.
[47]
Gennigens C, Menetrier-Caux C, Droz JP. Insulin-like growth factor (IGF) family and prostate cancer. Crit Rev Oncol Hematol 2006;58:124-45.
[48]
Sporn M, Roberts A. Autocrine growth factors and cancer. Nature 1985;313:745-7.
[49]
Cottard F, Asmane I, Erdmann E, Bergerat JP, Kurtz JE, Céraline J. Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells. PLoS One 2013;8:e63466.
[50]
Albany C, Alva AS, Aparicio AM, Singal R, Yellapragada S, Sonpavde G, et al. Epigenetics in prostate cancer. Prostate Cancer 2011;2011:580318.
[51]
Rubin M, Maher C, Chinnaiyan A. Common gene rearrangements in prostate cancer. J Clin Oncol 2011;29:3659-68.
[52]
Yang Y, Yu J. EZH2, an epigenetic driver of prostate cancer. Protein Cell 2013;4:331-41.
[53]
Xu K, Wu Z, Groner A, He H, Cai C, Lis R, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is polycomb-independent. Science 2012;338:1465-9.
[54]
Ellis L, Ku SY, Lasorsa E, Pili R. Epigenetics in castration resistant prostate cancer. Springer; 2014. http://link.springer.com/chapter/10.1007/978-1-4939-1176-9_20.
[55]
Wissmann M, Yin N, Müller J, Greschik H, Fodor B, Jenuwein T, et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol 2007;9:347-53.
[56]
Yang L, Lin C, Jin C, Yang J, Tanasa B, Li W, et al. lncRNAdependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 2013;500:598-602.
[57]
Cao P, Deng Z, Wan M, Huang W, Cramer S, Xu J, et al. MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1a/HIF-1b. Mol Cancer 2010;9:108.
[58]
Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH, et al. miR-21:an androgen receptoreregulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res 2009;69:7165-9.
[59]
Wang Y, Zhang X, Li H, Yu J, Ren X. The role of miRNA-29 family in cancer. Eur J Cell Biol 2013;92:123-8.
[60]
Gravina G, Marampon F, Piccolella M, Motta M, Ventura L, Pomante R, et al. Hormonal therapy promotes hormoneresistant phenotype by increasing DNMT activity and expression in prostate cancer models. Endocrinology 2011;152:4550-61.
[61]
Scher H, Lu D, Schreiber N, Louw J, Graf R, Vargas H, et al. Association of AR-V7 on circulating tumor cells as a treatmentspecific biomarker with outcomes and survival in castrationresistant prostate cancer. JAMA Oncol 2016. http://dx.doi.org/10.1001/jamaoncol.2016.1828.[Epub ahead of print].
[62]
Tannock IF, de Wit R, Berry WR, Horti J. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12.
[63]
Bono J, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment:a randomised open-label trial. Lancet 2010;376:1147-54.
[64]
Antonarakis E, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castrationresistant prostate cancer. JAMA Oncol 2015;1:582-91.
[65]
Onstenk W, Sieuwerts A, Kraan J, Van M, Nieuweboer A, Mathijssen R, et al. Efficacy of cabazitaxel in castrationresistant prostate cancer is independent of the presence of AR-V7 in circulating tumor cells. Eur Urol 2015;68:939-45.
[66]
Holohan C, Schaeybroeck S, Longley D, Johnston P. Cancer drug resistance:an evolving paradigm. Nat Rev Cancer 2013; 13:714-26.
[67]
Shafi AA, Putluri V, Arnold JM, Tsouko E, Maity S. Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells. Oncotarget 2015;6:31997-2012.
[68]
Boyd L, Mao X, Lu YJ. The complexity of prostate cancer:genomic alterations and heterogeneity. Nat Rev Urol 2012;9:652-64.
[69]
Soest RJ, Royen ME, Morrée ES, Moll JM, Teubel W, Wiemer EAC, et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer 2013;49:3821-30.
[70]
Nadal R, Zhang Z, Rahman H, Schweizer M, Denmeade S, Paller C, et al. Clinical activity of enzalutamide in Docetaxel-naïve and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer. Prostate 2014; 74:1560-8.
[71]
Myung JK, Banuelos C, Fernandez J, Mawji N, Wang J, Tien A, et al. An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest 2013;123:2948-60.
[72]
Kwegyir-Afful AK, Ramalingam S, Purushottamachar P, Ramamurthy VP, Njar VC. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. Oncotarget 2015;6:27440-60.
[73]
Yamashita S, Lai KP, Chuang KL, Xu D, Miyamoto H, Tochigi T, et al. ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors. Neoplasia 2012;14:74-83.
[74]
Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi A, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A 2016;113:7124-9.
Christopher Hartman, Nikhil Gupta, David Leavitt, David Hoenig, Zeph Okeke, Arthur Smith. Advances in percutaneous stone surgery[J]. Asian Journal of Urology, 2015, 2(1): 26
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