Translation - Non-genomic (rapid) action of Androgen Receptor

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Non-genomic (rapid) action of Androgen Receptor

Androgen is the active metabolic product, 5alpha-Dihydrotestosterone (DHT), which is produced from the transformation of Testosterone catalyzed by the Steroid-5-alpha-reductase, alpha polypeptides 1 and 2 (S5AR1 and S5AR2) [1], [2]. Biological activity of androgens such as Testosterone and DHT is predominantly meditated by its binding to the Androgen receptor, a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor [3], [4].

However, androgens also induce rapid activation of kinase-signaling cascades and modulate intracellular calcium levels. These effects are considered non-genomic, as they occur in cells in the presence of inhibitors of transcription and translation and occur too rapidly to involve transcription [5], [6].

For efficient non-genomic activity, Androgen receptor is recruited to plasma membrane microdomains via interaction with Caveolin 1, caveolae protein, 22kDa (Caveolin-1) [7].

In response to DHT, Androgen receptor interacts with the SH3 domain of tyrosine kinase v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (c-Src) [8].This interaction results in stimulation of two members of the mitogen-activated protein kinase (MAPK) signaling cascade, v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) and Mitogen-activated protein kinase 1 (ERK2(MAPK1)) [6], [9].

Androgen receptor also can activate Phosphoinositide-3-kinase (PI3K)/ V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) kinase pathway through direct interaction with the Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PI3K reg class IA (p85-alpha)) in response to natural androgens [9]. Such androgenic activation of PI3K leads to phosphorylation of AKT(PKB) [9], [10].

Androgens treatment results in higher FK506 binding protein 12-rapamycin associated protein 1 (mTOR) activity mediated by AKT(PKB) protein kinase. AKT(PKB) phosphorylates and inhibits Tuberous sclerosis 2 (Tuberin), this prevents inhibition of mTOR and leads to phosphorylation of the downstream mTOR targets Ribosomal protein S6 kinase, 70kDa, polypeptide 1 (p70 S6 kinase 1), Eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and subsequently activates protein synthesis [11].

Activation of PI3K signaling pathway by Androgen receptor then may lead to various complex regulatory circuits such as positive and negative feedback loops.

Activated AKT(PKB) phosphorylates and stabilizes Mdm2 p53 binding protein homolog (MDM2), which can ubiquitinilate Androgen receptor and target it to degradation via proteasome [12].

Moreover, transcription factor Forkhead box O3 (FOXO3A) can induce Androgen receptor expression [13]. AKT(PKB) phosphorylates FOXO3A thus inactivating its transactivation function. This leads to reducing Androgen receptor expression on mRNA level.

Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB) is an activator of Androgen receptor gene transcription in Sertoli cells and may be an important determinant of androgen activity during spermatogenesis [14].

An interaction between epidermal growth factor receptor Epidermal growth factor receptor (EGFR) and Androgen receptor results in decreasing of EGFR-mediated MAPK signaling and Epidermal growth factor (EGF)-stimulated PI3K activity, mediated through adaptor protein Insulin receptor substrate 1 (IRS-1) [15], [16].

In contrast, stimulation by EGF, Neuregulin 1 and Heparin-binding EGF-like growth factor (HB-EGF) activates downstream signaling of co-receptors EGFR/ v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (ErbB2) including MAPK and PI3K/ AKT(PKB pathways, which stabilizes Androgen receptor protein level and optimizes binding of Androgen receptor to promoter/enhancer regions of androgen-regulated genes [17], [18], [19].

The interaction between phosphatase Phosphatase and tensin homolog (PTEN) and Androgen receptor inhibits Androgen receptor nuclear translocation and promotes its degradation, which results in suppression of Androgen receptor transactivation and induction of apoptosis [20], [21].

Androgen receptor can also inhibit WNT signaling pathway via interaction with beta-catenin. This interaction may lead to inhibition of transactivation function of Catenin (cadherin-associated protein), beta 1 (Beta-catenin) [22], [23]. Glycogen synthase kinase 3 beta (GSK3 beta) is also involved in WNT cascade and can inhibit Androgen receptor via its phosphorylation [21].

References:

  1. Wilson JD
    The role of 5alpha-reduction in steroid hormone physiology. Reproduction, fertility, and development 2001;13(7-8):673-8
  2. Heinlein CA, Chang C
    Androgen receptor in prostate cancer. Endocrine reviews 2004 Apr;25(2):276-308
  3. Gelmann EP
    Molecular biology of the androgen receptor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002 Jul 1;20(13):3001-15
  4. McEwan IJ
    Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain. Endocrine-related cancer 2004 Jun;11(2):281-93
  5. Heinlein CA, Chang C
    The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Molecular endocrinology (Baltimore, Md.) 2002 Oct;16(10):2181-7
  6. Lange CA, Gioeli D, Hammes SR, Marker PC
    Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annual review of physiology 2007;69:171-99
  7. Lu ML, Schneider MC, Zheng Y, Zhang X, Richie JP
    Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. The Journal of biological chemistry 2001 Apr 20;276(16):13442-51
  8. Migliaccio A, Castoria G, 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. The EMBO journal 2000 Oct 16;19(20):5406-17
  9. Sun M, Yang L, Feldman RI, Sun XM, Bhalla KN, Jove R, Nicosia SV, Cheng JQ
    Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85alpha, androgen receptor, and Src. The Journal of biological chemistry 2003 Oct 31;278(44):42992-3000
  10. Castoria G, Lombardi M, Barone MV, Bilancio A, Di Domenico M, De Falco A, Varricchio L, Bottero D, Nanayakkara M, Migliaccio A, Auricchio F
    Rapid signalling pathway activation by androgens in epithelial and stromal cells. Steroids 2004 Aug;69(8-9):517-22
  11. Xu Y, Chen SY, Ross KN, Balk SP
    Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer research 2006 Aug 1;66(15):7783-92
  12. Gaughan L, Logan IR, Neal DE, Robson CN
    Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation. Nucleic acids research 2005;33(1):13-26
  13. Yang L, Xie S, Jamaluddin MS, Altuwaijri S, Ni J, Kim E, Chen YT, Hu YC, Wang L, Chuang KH, Wu CT, Chang C
    Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells. The Journal of biological chemistry 2005 Sep 30;280(39):33558-65
  14. Zhang L, Charron M, Wright WW, Chatterjee B, Song CS, Roy AK, Brown TR
    Nuclear factor-kappaB activates transcription of the androgen receptor gene in Sertoli cells isolated from testes of adult rats. Endocrinology 2004 Feb;145(2):781-9
  15. Bonaccorsi L, Muratori M, Carloni V, Zecchi S, Formigli L, Forti G, Baldi E
    Androgen receptor and prostate cancer invasion. International journal of andrology 2003 Feb;26(1):21-5
  16. Bonaccorsi L, Muratori M, Carloni V, Marchiani S, Formigli L, Forti G, Baldi E
    The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells. Steroids 2004 Aug;69(8-9):549-52
  17. Adam RM, Kim J, Lin J, Orsola A, Zhuang L, Rice DC, Freeman MR
    Heparin-binding epidermal growth factor-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function. Endocrinology 2002 Dec;143(12):4599-608
  18. Mellinghoff IK, Vivanco I, Kwon A, Tran C, Wongvipat J, Sawyers CL
    HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer cell 2004 Nov;6(5):517-27
  19. Gregory CW, Whang YE, McCall W, Fei X, Liu Y, Ponguta LA, French FS, Wilson EM, Earp HS 3rd
    Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clinical cancer research : an official journal of the American Association for Cancer Research 2005 Mar 1;11(5):1704-12
  20. Lin HK, Hu YC, Lee DK, Chang C
    Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells. Molecular endocrinology (Baltimore, Md.) 2004 Oct;18(10):2409-23
  21. Mulholland DJ, Dedhar S, Wu H, Nelson CC
    PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer. Oncogene 2006 Jan 19;25(3):329-37
  22. Terry S, Yang X, Chen MW, Vacherot F, Buttyan R
    Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer. Journal of cellular biochemistry 2006 Oct 1;99(2):402-10
  23. Chesire DR, Isaacs WB
    Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. Oncogene 2002 Dec 5;21(55):8453-69

  1. Wilson JD
    The role of 5alpha-reduction in steroid hormone physiology. Reproduction, fertility, and development 2001;13(7-8):673-8
  2. Heinlein CA, Chang C
    Androgen receptor in prostate cancer. Endocrine reviews 2004 Apr;25(2):276-308
  3. Gelmann EP
    Molecular biology of the androgen receptor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002 Jul 1;20(13):3001-15
  4. McEwan IJ
    Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain. Endocrine-related cancer 2004 Jun;11(2):281-93
  5. Heinlein CA, Chang C
    The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Molecular endocrinology (Baltimore, Md.) 2002 Oct;16(10):2181-7
  6. Lange CA, Gioeli D, Hammes SR, Marker PC
    Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annual review of physiology 2007;69:171-99
  7. Lu ML, Schneider MC, Zheng Y, Zhang X, Richie JP
    Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. The Journal of biological chemistry 2001 Apr 20;276(16):13442-51
  8. Migliaccio A, Castoria G, 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. The EMBO journal 2000 Oct 16;19(20):5406-17
  9. Sun M, Yang L, Feldman RI, Sun XM, Bhalla KN, Jove R, Nicosia SV, Cheng JQ
    Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85alpha, androgen receptor, and Src. The Journal of biological chemistry 2003 Oct 31;278(44):42992-3000
  10. Castoria G, Lombardi M, Barone MV, Bilancio A, Di Domenico M, De Falco A, Varricchio L, Bottero D, Nanayakkara M, Migliaccio A, Auricchio F
    Rapid signalling pathway activation by androgens in epithelial and stromal cells. Steroids 2004 Aug;69(8-9):517-22
  11. Xu Y, Chen SY, Ross KN, Balk SP
    Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer research 2006 Aug 1;66(15):7783-92
  12. Gaughan L, Logan IR, Neal DE, Robson CN
    Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation. Nucleic acids research 2005;33(1):13-26
  13. Yang L, Xie S, Jamaluddin MS, Altuwaijri S, Ni J, Kim E, Chen YT, Hu YC, Wang L, Chuang KH, Wu CT, Chang C
    Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells. The Journal of biological chemistry 2005 Sep 30;280(39):33558-65
  14. Zhang L, Charron M, Wright WW, Chatterjee B, Song CS, Roy AK, Brown TR
    Nuclear factor-kappaB activates transcription of the androgen receptor gene in Sertoli cells isolated from testes of adult rats. Endocrinology 2004 Feb;145(2):781-9
  15. Bonaccorsi L, Muratori M, Carloni V, Zecchi S, Formigli L, Forti G, Baldi E
    Androgen receptor and prostate cancer invasion. International journal of andrology 2003 Feb;26(1):21-5
  16. Bonaccorsi L, Muratori M, Carloni V, Marchiani S, Formigli L, Forti G, Baldi E
    The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells. Steroids 2004 Aug;69(8-9):549-52
  17. Adam RM, Kim J, Lin J, Orsola A, Zhuang L, Rice DC, Freeman MR
    Heparin-binding epidermal growth factor-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function. Endocrinology 2002 Dec;143(12):4599-608
  18. Mellinghoff IK, Vivanco I, Kwon A, Tran C, Wongvipat J, Sawyers CL
    HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer cell 2004 Nov;6(5):517-27
  19. Gregory CW, Whang YE, McCall W, Fei X, Liu Y, Ponguta LA, French FS, Wilson EM, Earp HS 3rd
    Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clinical cancer research : an official journal of the American Association for Cancer Research 2005 Mar 1;11(5):1704-12
  20. Lin HK, Hu YC, Lee DK, Chang C
    Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells. Molecular endocrinology (Baltimore, Md.) 2004 Oct;18(10):2409-23
  21. Mulholland DJ, Dedhar S, Wu H, Nelson CC
    PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer. Oncogene 2006 Jan 19;25(3):329-37
  22. Terry S, Yang X, Chen MW, Vacherot F, Buttyan R
    Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer. Journal of cellular biochemistry 2006 Oct 1;99(2):402-10
  23. Chesire DR, Isaacs WB
    Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. Oncogene 2002 Dec 5;21(55):8453-69

Target Details

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