title: Androgen receptor splice variants are resistant to inhibitors of Hsp90 and FKBP52, which alter androgen receptor activity and expression.
abstract: Androgen ablation therapy is the most common treatment for advanced prostate cancer (PCa), but most patients will develop castration-resistant prostate cancer (CRPC), which has no cure. CRPC is androgen-depletion resistant but androgen receptor (AR) dependent. AR is a nuclear receptor whose transcriptional activity is regulated by hormone binding to the ligand-binding domain (LBD). Constitutively active AR splice variants that lack LBDs often are expressed in CRPC. The expression of these variants indicates that methods to inhibit AR activity that do not rely on inactivating the LBD are needed. Heat shock protein 90 (Hsp90), a potential therapeutic target in PCa, is an AR chaperone crucial for proper folding, hormone binding and transcriptional activity of AR. We generated LNCaP cell lines with regulated expression of the AR-V7 variant as well as a cell line expressing artificially truncated AR (termed AR-NTD) to characterize splice variant function. Using an Hsp90 inhibitor, Geldanamycin (GA), and an AR-Hsp90-FKBP52 specific inhibitor, MJC13, we sought to determine if the AR variants also require Hsp90 and associated co-chaperone, FKBP52, for their activity. GA inhibits AR transcriptional activity but has little effect on AR-V7 activity. Moreover, GA decreases the stability of AR protein, with no effect on AR-V7 levels. Full-length AR activity is strongly inhibited by MJC13 while AR-V7 is unaffected. Thus, the variants are resistant to inhibitors of the Hsp90-AR heterocomplex. Although Hsp90 inhibitors will continue to inhibit growth promoting kinases and signaling through activated full-length AR in CRPC, AR signaling through variants will be retained.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, M515, One Baylor Plaza, Houston, TX 77030, USA.
authors: Ayesha A
authors: AA
authors: Shafi
authors: Marc B
authors: MB
authors: Cox
authors: Nancy L
authors: NL
authors: Weigel
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011944:Receptors, Androgen; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; C001277:geldanamycin
references: J Clin Oncol. 2002 Jul 1;20(13):3001-15
references: 12089231
references: Cancer Res. 2009 Jan 1;69(1):16-22
references: 19117982
references: Curr Opin Pharmacol. 2011 Aug;11(4):314-9
references: 21511531
references: Curr Top Med Chem. 2009;9(15):1479-92
references: 19860730
references: Cancer Res. 2009 Mar 15;69(6):2305-13
references: 19244107
references: Mol Endocrinol. 2005 Jun;19(6):1654-66
references: 15831525
references: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11878-83
references: 21730179
references: Cancer Res. 2006 Nov 1;66(21):10594-602
references: 17079484
references: J Clin Oncol. 2010 Mar 20;28(9):1481-8
references: 20159824
references: Cancer Res. 2011 Mar 1;71(5):1978-88
references: 21324924
references: J Cell Biochem. 2006 Oct 1;99(2):362-72
references: 16619264
references: Mol Endocrinol. 2011 Jun;25(6):944-54
references: 21511880
references: Curr Opin Pharmacol. 2008 Aug;8(4):440-8
references: 18674639
references: PLoS One. 2011;6(11):e27970
references: 22114732
references: Trends Endocrinol Metab. 2010 May;21(5):315-24
references: 20138542
references: J Biol Chem. 2007 Feb 16;282(7):5026-5036
references: 17142810
references: Mol Endocrinol. 1990 Jan;4(1):22-8
references: 2325667
references: Cancer Res. 2011 Mar 15;71(6):2108-17
references: 21248069
references: Mol Endocrinol. 2009 Dec;23(12):1963-72
references: 19855091
references: Prostate. 2007 Apr 1;67(5):509-20
references: 17221841
references: J Biol Chem. 2003 Aug 15;278(33):31136-48
references: 12771131
references: PLoS One. 2011 Apr 28;6(4):e19059
references: 21552559
references: Asian J Androl. 2010 Sep;12(5):639-57
references: 20711217
references: Mol Endocrinol. 2002 Dec;16(12):2692-705
references: 12456791
references: Science. 2005 Oct 28;310(5748):644-8
references: 16254181
references: J Clin Invest. 2010 Aug;120(8):2715-30
references: 20644256
references: Cell Stress Chaperones. 2002 Jan;7(1):55-64
references: 11894840
references: J Biol Chem. 1996 Aug 16;271(33):19900-7
references: 8702703