title: Arrestin2 modulates androgen receptor activation.
abstract: Androgen receptor (AR) has a pivotal role in the growth and survival of prostate cancer (PCa). Arrestin2 (Arr2) is a ubiquitous scaffolding/adaptor protein first characterized as a regulator of G protein-coupled receptor signaling. In this study, we report that Arr2 additionally functions as a positive regulator of AR expression and function in PCa cells. Expression level of Arr2 correlates with that of AR, and knockdown of Arr2 inhibits the expression of AR and its effectors prostate-specific antigen, transmembrane protease serine 2, FK506-binding protein 51 and fatty acid synthase. Mechanistically, the knockdown of Arr2 attenuates the binding of AR to androgen response elements and consequently decreases transcription of AR-regulated genes. The inhibition of AR by Arr2 knockdown occurs in both androgen-dependent and castration-resistant PCa (CRPC) cells, although the effect is more prominent in CRPC. Arr2 knockdown inhibits the in vitro CRPC cell proliferation, prostasphere growth and invasion, as well as the in vivo prostate tumor formation, local invasion and distant metastasis. These results illustrate a new role for Arr2 in the expression and activation of AR and its potential relevance as a target for therapeutic intervention and monitoring of disease progression.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Purayil
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dey
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Gersey
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Espana-Serrano
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Daaka
mesh_terms: D000818:Animals; D019390:Arrestins / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C410798:AR protein, human; C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D011944:Receptors, Androgen; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
references.citation: Cancer Res. 1995 Jul 15;55(14):3068-72
references.pmid: 7541709
references.citation: Nat Med. 2004 Jan;10(1):33-9
references.pmid: 14702632
references.citation: Cancer Res. 1994 Aug 1;54(15):4096-102
references.pmid: 7518349
references.citation: J Biol Chem. 2003 Mar 28;278(13):11648-53
references.pmid: 12538596
references.citation: PLoS Pathog. 2012;8(3):e1002595
references.pmid: 22438813
references.citation: Clin Cancer Res. 2011 Apr 1;17 (7):1649-57
references.pmid: 21372223
references.citation: J Biol Chem. 2002 Oct 4;277(40):37693-701
references.pmid: 12167659
references.citation: BMC Biol. 2012 Mar 22;10:29
references.pmid: 22439642
references.citation: J Biol Chem. 2012 Mar 16;287(12 ):8932-43
references.pmid: 22267743
references.citation: Oncogene. 2013 Oct 17;32(42):5066-77
references.pmid: 23208497
references.citation: N Engl J Med. 2004 Oct 7;351(15):1488-90
references.pmid: 15470210
references.citation: PLoS One. 2010 May 03;5(5):e10431
references.pmid: 20454659
references.citation: J Transl Med. 2006 Mar 02;4:12
references.pmid: 16509995
references.citation: Cancer Res. 2008 Feb 15;68(4):1128-35
references.pmid: 18281488
references.citation: Adv Cancer Res. 2010;107:137-62
references.pmid: 20399963
references.citation: Mol Cell. 2002 Mar;9(3):601-10
references.pmid: 11931767
references.citation: Curr Opin Pharmacol. 2008 Aug;8(4):440-8
references.pmid: 18674639
references.citation: Br J Cancer. 2001 Aug 17;85(4):590-9
references.pmid: 11506501
references.citation: Cell. 1995 Dec 15;83(6):835-9
references.pmid: 8521507
references.citation: FASEB J. 2008 Feb;22(2):355-64
references.pmid: 17890288
references.citation: Nat Rev Cancer. 2001 Oct;1(1):34-45
references.pmid: 11900250
references.citation: Annu Rev Physiol. 2013;75:201-24
references.pmid: 23157556
references.citation: Science. 2004 Dec 24;306(5705):2264-7
references.pmid: 15618520
references.citation: Cancer Res. 2001 Apr 1;61(7):2892-8
references.pmid: 11306464
references.citation: CA Cancer J Clin. 2013 Jan;63(1):11-30
references.pmid: 23335087
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12011-6
references.pmid: 17620599
references.citation: Clin Cancer Res. 2009 Jan 1;15(1):39-47
references.pmid: 19118031
references.citation: Curr Opin Cell Biol. 2004 Apr;16(2):162-8
references.pmid: 15196559
references.citation: Urology. 2002 Sep;60(3 Suppl 1):132-8; discussion 138-9
references.pmid: 12231070
references.citation: Science. 2003 Sep 5;301(5638):1394-7
references.pmid: 12958365
references.citation: Cell. 2005 Dec 2;123(5):833-47
references.pmid: 16325578
references.citation: Oncogene. 2012 Jan 19;31(3):282-92
references.pmid: 21685944
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1492-7
references.pmid: 16432186
references.citation: Mol Cell. 2008 Sep 5;31(5):695-707
references.pmid: 18775329
references.citation: Endocr Relat Cancer. 2009 Mar;16(1):123-37
references.pmid: 18845648
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23 ):8603-7
references.pmid: 15173580
references.citation: Nat Protoc. 2009;4(3):309-24
references.pmid: 19214182
references.citation: Mol Cell Biol. 2008 Dec;28(23):7096-108
references.pmid: 18794357
references.citation: Science. 2003 Sep 5;301(5638):1391-4
references.pmid: 12958364
references.citation: Clin Chem. 2011 Oct;57(10):1366-75
references.pmid: 21956922
references.citation: J Cell Sci. 2007 Jan 15;120(Pt 2):213-8
references.pmid: 17215450
references.citation: Asian Pac J Cancer Prev. 2012;13(11):5671-5
references.pmid: 23317236
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23 ):9379-84
references.pmid: 19458261