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 C.B. Cato; Myles Brown

doi:10.7554/eLife.27159

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 WuJaice 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 C.B. Cato, Myles Brown

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English (US)
Article number	e27159
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.27159
State	Published - Aug 10 2017
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.27159

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Cato, L., Neeb, A., Sharp, A., Buzón, V., Ficarro, S. B., Yang, L., Muhle-Goll, C., Kuznik, N. C., Riisnaes, R., Rodrigues, D. N., Armant, O., Gourain, V., Adelmant, G., Ntim, E. A., Westerling, T., Dolling, D., Rescigno, P., Figueiredo, I., Fauser, F., ... Brown, M. (2017). Development of bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer. eLife, 6, Article e27159. https://doi.org/10.7554/eLife.27159

Cato, L, Neeb, A, Sharp, A, Buzón, V, Ficarro, SB, Yang, L, Muhle-Goll, C, Kuznik, NC, Riisnaes, R, Rodrigues, DN, 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, ACB & Brown, M 2017, 'Development of bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer', eLife, vol. 6, e27159. https://doi.org/10.7554/eLife.27159

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title = "Development of bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer",

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.",

author = "Laura Cato and Antje Neeb and Adam Sharp and Victor Buz{\'o}n and Ficarro, {Scott B.} and Linxiao Yang and Claudia Muhle-Goll and Kuznik, {Nane C.} and Ruth Riisnaes and Rodrigues, {Daniel Nava} and Olivier Armant and Victor Gourain and Guillaume Adelmant and Ntim, {Emmanuel A.} and Thomas Westerling and David Dolling and Pasquale Rescigno and Ines Figueiredo and Friedrich Fauser and Jennifer Wu and Rottenberg, {Jaice T.} and Liubov Shatkina and Claudia Ester and Burkhard Luy and Holger Puchta and Jakob Troppmair and Nicole Jung and Stefan Br{\"a}se and Uwe Str{\"a}hle and Marto, {Jarrod A.} and Nienhaus, {Gerd Ulrich} and Bissan Al-Lazikani and Xavier Salvatella and {De Bono}, {Johann S.} and Cato, {Andrew C.B.} and Myles Brown",

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AU - Cato, Laura

AU - Neeb, Antje

AU - Sharp, Adam

AU - Buzón, Victor

AU - Ficarro, Scott B.

AU - Yang, Linxiao

AU - Muhle-Goll, Claudia

AU - Kuznik, Nane C.

AU - Riisnaes, Ruth

AU - Rodrigues, Daniel Nava

AU - Armant, Olivier

AU - Gourain, Victor

AU - Adelmant, Guillaume

AU - Ntim, Emmanuel A.

AU - Westerling, Thomas

AU - Dolling, David

AU - Rescigno, Pasquale

AU - Figueiredo, Ines

AU - Fauser, Friedrich

AU - Wu, Jennifer

AU - Rottenberg, Jaice T.

AU - Shatkina, Liubov

AU - Ester, Claudia

AU - Luy, Burkhard

AU - Puchta, Holger

AU - Troppmair, Jakob

AU - Jung, Nicole

AU - Bräse, Stefan

AU - Strähle, Uwe

AU - Marto, Jarrod A.

AU - Nienhaus, Gerd Ulrich

AU - Al-Lazikani, Bissan

AU - Salvatella, Xavier

AU - De Bono, Johann S.

AU - Cato, Andrew C.B.

AU - Brown, Myles

N1 - Publisher Copyright: © Cato et al. This article is distributed under the terms of the Creative Commons Attribution License.

PY - 2017/8/10

Y1 - 2017/8/10

N2 - 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.

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

Abstract

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