eLife (Aug 2017)
Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer
- Laura Cato,
- Antje Neeb,
- Adam Sharp,
- Victor Buzón,
- Scott B Ficarro,
- Linxiao Yang,
- Claudia Muhle-Goll,
- Nane C Kuznik,
- Ruth Riisnaes,
- Daniel Nava Rodrigues,
- Olivier Armant,
- Victor Gourain,
- Guillaume Adelmant,
- Emmanuel A Ntim,
- Thomas Westerling,
- David Dolling,
- Pasquale Rescigno,
- Ines Figueiredo,
- Friedrich Fauser,
- Jennifer Wu,
- Jaice T Rottenberg,
- Liubov Shatkina,
- Claudia Ester,
- Burkhard Luy,
- Holger Puchta,
- Jakob Troppmair,
- Nicole Jung,
- Stefan Bräse,
- Uwe Strähle,
- Jarrod A Marto,
- Gerd Ulrich Nienhaus,
- Bissan Al-Lazikani,
- Xavier Salvatella,
- Johann S de Bono,
- Andrew CB Cato,
- Myles Brown
Affiliations
- Laura Cato
- ORCiD
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
- Antje Neeb
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Adam Sharp
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
- Victor Buzón
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Scott B Ficarro
- The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
- Linxiao Yang
- Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Claudia Muhle-Goll
- Institute for Biological Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Nane C Kuznik
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Ruth Riisnaes
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
- Daniel Nava Rodrigues
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
- Olivier Armant
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institut de Radioprotection et de Sûreté Nucléaire, PRP-ENV/SERIS/LECO, Cadarache, France
- Victor Gourain
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Guillaume Adelmant
- The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
- Emmanuel A Ntim
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Thomas Westerling
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
- David Dolling
- Clinical Trials and Statistics Unit, Institute of Cancer Research, London, United Kingdom
- Pasquale Rescigno
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
- Ines Figueiredo
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
- Friedrich Fauser
- Botanical Institute II, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Jennifer Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
- Jaice T Rottenberg
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
- Liubov Shatkina
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Claudia Ester
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Burkhard Luy
- Institute for Biological Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Holger Puchta
- Botanical Institute II, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Jakob Troppmair
- Daniel-Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
- Nicole Jung
- Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Stefan Bräse
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Uwe Strähle
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Jarrod A Marto
- The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
- Gerd Ulrich Nienhaus
- ORCiD
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Nanotechnology, Karlsruhe Institute of Technology, Karlsruhe, Germany; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, United States
- Bissan Al-Lazikani
- Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
- Xavier Salvatella
- ORCiD
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain; ICREA, Passeig Lluís Companys, Barcelona, Spain
- Johann S de Bono
- Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
- Andrew CB Cato
- ORCiD
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
- Myles Brown
- ORCiD
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
- DOI
- https://doi.org/10.7554/eLife.27159
- Journal volume & issue
-
Vol. 6
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.
Keywords
