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

@article{Cato2017DevelopmentOB,
  title={Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer},
  author={Laura Cato and Antje J. Neeb and Adam Sharp and V{\'i}ctor Buz{\'o}n and Scott B. Ficarro and Linxiao Yang and Claudia Muhle-Goll and Nane C. Kuznik and Ruth Riisnaes and Daniel Nava Rodrigues and Olivier Armant and Victor Gourain and Guillaume Adelmant and Emmanuel Amankwah Ntim and Thomas W. Westerling and David Dolling and Pasquale Rescigno and In{\^e}s Figueiredo and Friedrich Fauser and Jennifer Wu and Jaice T Rottenberg 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 Jarrod A. Marto and Gerd Ulrich Nienhaus and Bissan Al-Lazikani and Xavier Salvatella and Johann S. de Bono and Andrew C B Cato and Myles Brown},
  journal={eLife},
  year={2017},
  volume={6}
}
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… Expand
Bag-1L: a promising therapeutic target for androgen receptor-dependent prostate cancer.
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References

SHOWING 1-10 OF 90 REFERENCES
Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.
TLDR
This work identifies EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. Expand
BAG-1L Protein Enhances Androgen Receptor Function*
TLDR
BAG-1L significantly reduced the concentrations of 5α-dihydrotestosterone required for AR activity but did not induce ligand-independent transactivation, and markedly improved the ability of AR to transactivate reporter genes when cells were cultured with DHT in combination with the anti-androgen cyproterone acetate. Expand
TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer.
TLDR
It is shown that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions, and provides a rationale for therapeutic TRIM 24 targeting in SPOP mutant and CRPC patients. Expand
EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.
TLDR
It is shown, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Expand
Enhanced Inhibition of Prostate Tumor Growth by Dual Targeting the Androgen Receptor and the Regulatory Subunit Type Iα of Protein Kinase A in Vivo
TLDR
The data suggest that dual targeting of the AR and PKARIα is more effective in inhibiting L NCaP and LNCaPabl tumor growth than single treatment and may give a treatment benefit, especially in castration-resistant prostate cancers. Expand
Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif*
TLDR
GARRPR is identified as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR, and a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through theBF-3 pocket. Expand
Molecular Pathways: Targeting Resistance in the Androgen Receptor for Therapeutic Benefit
TLDR
New agents such as enzalutamide, EPI-001, androgen receptor–specific peptidomimetics, novel HSP90 inhibitors, and PARP inhibitors, as well as new approaches to cotargeting the androgens receptor pathway, point to the potential for more complete and durable control of androgen receptors–mediated growth. Expand
Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer.
TLDR
These findings support an adaptive shift toward AR-V-mediated signaling in a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapy. Expand
Different BAG-1 isoforms have distinct functions in modulating chemotherapeutic-induced apoptosis in breast cancer cells
TLDR
Distinct isoforms of BAG-1 have different anti-apoptotic functions in breast cancer cells, and that the B AG-1 p50 isoform can potentiate the role of estrogen in ER-positive breast cancer. Expand
Overexpression and gene amplification of BAG‐1L in hormone‐refractory prostate cancer
TLDR
The data suggest that amplification and overexpression of BAG‐1L may be involved in the progression of prostate cancer, and protein expression was significantly higher in hormone‐refractory tumours than in primary tumours. Expand
...
1
2
3
4
5
...