1. Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer.
- Author
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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, and Brown M
- Subjects
- Humans, Male, Prostatic Neoplasms therapy, Protein Binding, Protein Interaction Maps, Androgen Receptor Antagonists metabolism, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins metabolism, Prostatic Neoplasms pathology, Receptors, Androgen metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism
- 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.
- Published
- 2017
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