Journal of Endocrinology and Reproduction

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Membrane Androgen Receptor(S) and their Role in Prostate Cancer:A Review


Affiliations
1 Amity Institute of Biotechnology (AIB), Amity University Gurgaon, Manesar - 122413, Haryana, India
     

   Subscribe/Renew Journal


Androgen, a steroid hormone, typically mediates its action by binding to the cytosolic Androgen Receptor (AR), via the classical or genomic pathway. Androgens can also act through a non-classical or non-genomic pathway interacting with receptors present on the plasma membrane of cells. Although the identity of the nuclear AR is well established, the identity of the membrane AR is still not clear. Through independent studies, three proteins have been identified that are present on plasma membranes of prostate cells and can mediate androgen signalling, viz, GPRC6A, AR8 and ZIP9. Although these proteins can mediate androgen signalling, the membrane receptor which is used most frequently and specifically for mediating androgen action in prostate cells is not confirmed. Recent research has shown that the non-genomic androgen signalling plays a key role in progression of prostate cancer (PCa). In this review, the potential of these three proteins for their ability to act as the membrane AR has been analysed. The use of membrane AR as a novel target for the treatment of PCa has also been discussed.

Keywords

Androgen, Androgen Receptor, Genomic Pathway, Non-Genomic Pathway, Prostate Cancer.
Subscription Login to verify subscription
User
Notifications
Font Size


  • Bagchi G, Wu J, French J, Kim J, Moniri NH, Daaka Y. Androgens transduce the Gαs-mediated activation of protein kinase a in prostate cells. Cancer Res. 2008; 68(9).https://doi.org/10.1158/0008-5472.CAN-07-5026

  • Berg AH, Rice CD, Rahman MS, Dong J, Thomas P. Identification and characterization of membrane androgen receptor in the ZIP9 zinc transporter subfamily: I Discovery in female Atlantic croaker and evidence ZIP9 mediates testosterone induced apoptosis of ovarian follicle cells. Endocrinology.2014; 155(11):4237–49. https://doi.org/10.1210/ en.2014-1198 PMid:25014354 PMCid:PMC4197986

  • Castoria G, Migliaccio A, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. Embo J. 2000; 19(20):5406–54.https://doi.org/10.1093/emboj/19.20.5406 PMid:11032808 PMCid:PMC314017

  • Cheng J, Watkins SC, Walker WH. Testosterone activates mitogen-activated protein kinase via Src kinase and the epidermal growth factor receptor in sertoli cells. Endocrinology.2007; 148(5):2066–20. https://doi.org/10.1210/en.20061465 PMid:17272394

  • Conklin BR, Bourne HR. Homeostatic signals. Marriage of the flytrap and the serpent. Nature. 1994; 367(6458):22 https://doi.org/10.1038/367022a0 PMid:8107768

  • Denmeade SR, Isaacs JT. A history of prostate cancer treatment.Nat Rev Cancer. 2002; 2(5):389–396. https://doi.org/10.1038/nrc801 PMid:12044015 PMCid:PMC4124639

  • Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens. Front Neuroendocrinol. 2008 May; 29(2):169–81. https://doi.org/10.1016/j.yfrne.2007.10.005 PMid:18093638 PMCid:PMC2386261

  • Guo C, Luttrell LM, Price DT. Mitogenic signaling in androgen sensitive and insensitive prostate cancer cell lines.J Urol. 2000 Mar; 163(3):1027–32. https://doi.org/10.1016/ S0022-5347(05)67876-7 PMid:10688043

  • Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung H-J, Brodie AMH, Edwards J, Qiu Y. A novel androgen receptor splice variant is upregulated during prostate cancer progression and promotes androgen-depletion-resistant growth. Cancer Res.2009 Mar 15; 69(6):2305–13. https://doi.org/10.1158/00085472.CAN-08-3795 PMid:19244107 PMCid:PMC2672822

  • John C, Lu LM. Abstract 4287: Intracellular trafficking of androgen receptor splice variant AR8. Molecular and Cellular Biology. 2013; 73(8). https://doi.org/10.1158/15387445.am2013-4287

  • Menachem K, Ido A, Yarden Y. Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta. 2007 Aug; 1773(8):1161–76. https://doi.org/10.1016/j.bbamcr.2007.01.002 PMid:17306385 PMCid: PMC2758354

  • Kuang D, Yao Y, Maclean D, Wang M, Hampson DR, Chang BS. Ancestral reconstruction of the ligand-binding pocket of family C G protein-coupled receptors. Proc Natl Acad Sci USA. 103(38):14050–5. https://doi.org/10.1073/ pnas.0604717103 PMid:16966606 PMCid:PMC1563994

  • Jun L, Changxue L. Decoding the androgen receptor splice variants. Transl Androl Urol. 2013 Sep; 2(3):178–86.

  • Franck O, Grzegorz S, Olga S, Mathieu F, Haixin C, Charles SE, Louis H. Endocrine regulation of male fertility by the skeleton. Cell. 2011 Mar 4; 144(5):796–809. https://doi.org/10.1016/j.cell.2011.02.004 PMid:21333348 PMCid:PMC3052787

  • Pi M, Quarles LD. GPRC6A regulates prostate cancer progression.The Prostate. 2012 Mar; 72(4):399–409. https:// doi.org/10.1002/pros.21442 PMid:21681779 PMCid:PMC3183291

  • Pi M, Parill AL, Quarles LD. GPRC6A mediates the non-genomic effects of steroids. Jour Bio Chem. 2010 Dec 17; 285(51):39953–64. https://doi.org/10.1074/jbc.m110.158063

  • Pi M, Chen L, Huang ZM, Zhu W, Ringhofer B, Luo J, Christenson L, Li B, Zhang J, Jackson DP, Faber P, Brunden RK, Quarles D. GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE. 2008; 3–12. https://doi.org/10.1371/journal.pone.0003858

  • Thomas.P, Pang Y, Dong J, Berg AH. Identification and characterization of membrane androgen receptor in the ZIP9 zinc transporter subfamily: II-Role of human ZIP9 in testosterone induced prostate and breast cancer cell apoptosis.Endocrinology. 2014 Nov; 155(11):4250–65. https:// doi.org/10.1210/en.2014-1201 PMid:25014355 PMCid:PMC4197988

  • Loomis AK, Thomas P. Effects of estrogens and xenoestrogens on androgen production by Atlantic croaker

  • testes in vitro: evidence for a nongenomic action mediated by an estrogen membrane receptor. Biol Reprod. 2000 Apr; 62(4):995–1004. https://doi.org/10.1095/biolreprod62.4.995 PMid:10727269

  • Sarwar M. The Protein Kinase A (PKA) intracellular pathway and androgen receptor: A novel mechanism underlying the castration-resistant and metastatic prostate cancer. Jour of Can Sci and Therapy. 2012.

  • Li S, Huang S, Peng S-B. Overexpression of G protein-coupled receptors in cancer cells: Involvement in tumor progression.Int J Oncol. 2005 Nov; 27(5):1329–39. https://doi.org/10.3892/ijo.27.5.1329

  • Myers SA. Zinc transporters and zinc signaling: new insights into their role in type 2 diabetes. Inter Jou of Endoc. 2015; 167503-16750. PMid:25983752 PMCid:PMC4423030

  • Thomas P, Braun AM. Androgens inhibit estradiol-17 beta synthesis in Atlantic croaker (Micropogonias undulates) ovaries by a non-genomic mechanism initiated at the cell surface. Biol Reprod. 2003 Nov; 69(5):1642–50. https://doi.org/10.1095/biolreprod.103.015479 PMid:12855603

  • Perrot V. Neuroendocrine differentiation in the progression of prostate cancer: an update on recent developments. Open Journal of Urology 2012; 2:173–82. https://doi.org/10.4236/ oju.2012.223032

  • Whitehead IP, Zohn IE, Der CJ. Rho GTPase-dependent transformation by G protein-coupled receptors. Oncogene.2001; 20(13):1547–55. https://doi.org/10.1038/ sj.onc.1204188 PMid:11313901

  • Wellendorph P, Brauner-Osborne H. Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene. 2004 Jun 23; 335:37–46. https://doi.org/10.1016/j.gene.2004.03.003 PMid:15194188

  • Weber RFA, Smith M, Dohle R. Androgens and male fertility.World J Urol. 2003 Nov; 21(5):341–5. https://doi.org/10.1007/s00345-003-0365-9 PMid:14566423

  • Yang X, Guo Z, Sun F, Li W, Alfano A, Shimelis H, Chen M, Brodie AMH, Chen H, Xiao Z, Veenstra TD, Qiu Y. Novel membrane-associated androgen receptor splice variant potentiates proliferative and survival responses in prostate cancer cells. Journal Bio Chem. 2011 Oct 14; 286(41):36152– 60.https://doi.org/10.1074/jbc.m111.265124


Abstract Views: 435

PDF Views: 1




  • Membrane Androgen Receptor(S) and their Role in Prostate Cancer:A Review

Abstract Views: 435  |  PDF Views: 1

Authors

Julie Pratibha Singh
Amity Institute of Biotechnology (AIB), Amity University Gurgaon, Manesar - 122413, Haryana, India
Gargi Bagchi Bhattacharjee
Amity Institute of Biotechnology (AIB), Amity University Gurgaon, Manesar - 122413, Haryana, India

Abstract


Androgen, a steroid hormone, typically mediates its action by binding to the cytosolic Androgen Receptor (AR), via the classical or genomic pathway. Androgens can also act through a non-classical or non-genomic pathway interacting with receptors present on the plasma membrane of cells. Although the identity of the nuclear AR is well established, the identity of the membrane AR is still not clear. Through independent studies, three proteins have been identified that are present on plasma membranes of prostate cells and can mediate androgen signalling, viz, GPRC6A, AR8 and ZIP9. Although these proteins can mediate androgen signalling, the membrane receptor which is used most frequently and specifically for mediating androgen action in prostate cells is not confirmed. Recent research has shown that the non-genomic androgen signalling plays a key role in progression of prostate cancer (PCa). In this review, the potential of these three proteins for their ability to act as the membrane AR has been analysed. The use of membrane AR as a novel target for the treatment of PCa has also been discussed.

Keywords


Androgen, Androgen Receptor, Genomic Pathway, Non-Genomic Pathway, Prostate Cancer.

References





DOI: https://doi.org/10.18519/jer%2F2016%2Fv20%2F165440