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

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

Authors :
Jakob Troppmair
Jennifer Wu
Jaice T. Rottenberg
Claudia Ester
Olivier Armant
Myles Brown
Claudia Muhle-Goll
Xavier Salvatella
Nane C Kuznik
Johann S. de Bono
Linxiao Yang
Gerd Ulrich Nienhaus
Adam Sharp
Victor Buzon
Scott B. Ficarro
Daniel Nava Rodrigues
Thomas Westerling
Jarrod A. Marto
Ruth Riisnaes
Ines Figueiredo
Guillaume Adelmant
Andrew C.B. Cato
Stefan Bräse
Antje Neeb
Friedrich Fauser
Uwe Strähle
Bissan Al-Lazikani
Victor Gourain
Emmanuel A. Ntim
L. Shatkina
Pasquale Rescigno
Laura Cato
David Dolling
Burkhard Luy
Nicole Jung
Holger Puchta
Laboratoire d'écotoxicologie des radionucléides (PRP-ENV/SERIS/LECO)
Institut de Radioprotection et de Sûreté Nucléaire (IRSN)
Institute of Toxicology and Genetics [Karlsruhe] (ITG)
Karlsruhe Institute of Technology (KIT)
Novartis Deutsche Forschungsgemeinschaft Prostate Cancer Foundation Prostate Cancer UK Deutsche Krebshilfe European Research Council Deutscher Akademischer Austauschdienst Medical Research Council Ministerio de Economía y Competitividad
Source :
eLife, Vol 6 (2017), eLife, eLife, eLife Sciences Publication, 2017, 6, ⟨10.7554/eLife.27159⟩, eLife, 6, Art.Nr. e27159
Publication Year :
2017
Publisher :
eLife Sciences Publications Ltd, 2017.

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.<br />eLife digest Prostate cancer is the second most common cancer in men around the world. The cancer relies on a protein called the androgen receptor in order to develop and grow. Currently, some of the most common treatments for prostate cancer, especially in its advanced stages, are drugs that block the activity of this receptor. However, such treatments are only successful for a limited period of time, and so alternative methods to inhibit this receptor are still needed. The androgen receptor must bind to a number of proteins to carry out its activity. These proteins include one called Bag-1L, which is also important for the development of prostate cancer. Stopping such a protein from binding with the androgen receptor might represent a new way to treat prostate cancer; but first it will be important to understand how this interaction actually regulates the activity of the receptor. Now, Cato et al. have analyzed samples of cancer cells that had been collected from 43 patients with prostate cancer and found that Bag-1L levels increase as the disease progresses. Looking at the patients’ medical records then revealed that therapies targeting the androgen receptor were less effective in people with high levels of Bag-1L. Conversely, altering, removing or inhibiting Bag-1L in prostate cancer cells grown in the laboratory made the receptor less active and made the cells grow slower. Further experiments went on to reveal that Bag-1L interacts with a regulatory region of the androgen receptor. Cato et al. note that this region remains largely unexplored therapeutically, because it has some unique structural properties that restrict how much it can interact with drug molecules. Targeting Bag-1L and stopping it from binding to this region of the androgen receptor would represent a different approach to inhibiting the androgen receptor and treating patients with prostate cancer. Together these new findings should provide pharmaceutical companies with much of the information they would require to immediately start screening for therapies that target Bag-1L. Ultimately, Cato et al. hope that any follow-up findings will benefit prostate cancer patients by improving the currently available treatments.

Details

Language :
English
ISSN :
2050084X
Volume :
6
Database :
OpenAIRE
Journal :
eLife
Accession number :
edsair.doi.dedup.....bb279ceb4922d0c59567631e11647f67
Full Text :
https://doi.org/10.7554/eLife.27159⟩