Back to Search
Start Over
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
- 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.
- Subjects :
- 0301 basic medicine
Male
[SDV]Life Sciences [q-bio]
Druggability
Plasma protein binding
urologic and male genital diseases
Prostate cancer
0302 clinical medicine
androgen receptor
Androgen Receptor Antagonists
Protein Interaction Maps
Biology (General)
Cancer Biology
General Neuroscience
General Medicine
prostate cancer
3. Good health
DNA-Binding Proteins
Receptors, Androgen
030220 oncology & carcinogenesis
ddc:540
Medicine
Protein Binding
Research Article
Human
medicine.medical_specialty
QH301-705.5
Chemistry & allied sciences
Science
DNA-binding protein
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Internal medicine
transcription factors
medicine
Humans
Transcription factor
General Immunology and Microbiology
business.industry
Prostatic Neoplasms
medicine.disease
Androgen receptor
030104 developmental biology
Endocrinology
Bag-1L
Cancer research
Cancer biomarkers
business
Subjects
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⟩