Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer.
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Date
2017-08-10ICR Author
Author
Cato, L
Neeb, A
Sharp, A
Buzón, V
Ficarro, SB
Yang, L
Muhle-Goll, C
Kuznik, NC
Riisnaes, R
Nava Rodrigues, D
Armant, O
Gourain, V
Adelmant, G
Ntim, EA
Westerling, T
Dolling, D
Rescigno, P
Figueiredo, I
Fauser, F
Wu, J
Rottenberg, JT
Shatkina, L
Ester, C
Luy, B
Puchta, H
Troppmair, J
Jung, N
Bräse, S
Strähle, U
Marto, JA
Nienhaus, GU
Al-Lazikani, B
Salvatella, X
de Bono, JS
Cato, AC
Brown, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Humans
Prostatic Neoplasms
DNA-Binding Proteins
Receptors, Androgen
Transcription Factors
Protein Binding
Male
Androgen Receptor Antagonists
Protein Interaction Maps
Research team
Computational Biology and Chemogenomics
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Language
eng
Date accepted
2017-08-07
License start date
2017-08-10
Citation
eLife, 2017, 6
Publisher
ELIFE SCIENCES PUBLICATIONS LTD