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Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer

Cato, Laura; Neeb, Antje; Sharp, Adam; Buzón, Victor; Ficarro, Scott B.; Yang, Linxiao; Muhle-Goll, Claudia; Kuznik, Nane C.; Riisnaes, Ruth; Rodrigues, Daniel Nava; Armant, Olivier; Gourain, Victor; Adelmant, Guillaume; Ntim, Emmanuel A.; Westerling, Thomas; Dolling, David; Rescigno, Pasquale; Figueiredo, Ines; Fauser, Friedrich; Wu, Jennifer; ... mehr

Abstract:
Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.


Verlagsausgabe §
DOI: 10.5445/IR/1000073170
Veröffentlicht am 20.11.2017
Originalveröffentlichung
DOI: 10.7554/eLife.27159
Scopus
Zitationen: 17
Dimensions
Zitationen: 21
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biologische Grenzflächen (IBG)
Institut für Organische Chemie (IOC)
Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2017
Sprache Englisch
Identifikator ISSN: 2050-084X
urn:nbn:de:swb:90-731701
KITopen-ID: 1000073170
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in eLife
Verlag eLife Sciences Publications
Band 6
Seiten Art.Nr. e27159
Vorab online veröffentlicht am 10.08.2017
Nachgewiesen in Web of Science
Scopus
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