Analyzing the Androgen Receptor Interactome in Prostate Cancer: Implications for Therapeutic Intervention

Ujjwal R Dahiya,Hannelore V Heemers

doi:10.3390/cells11060936

Abstract

The androgen receptor (AR) is a member of the ligand-activated nuclear receptor family of transcription factors. AR’s transactivation activity is turned on by the binding of androgens, the male sex steroid hormones. AR is critical for the development and maintenance of the male phenotype but has been recognized to also play an important role in human diseases. Most notably, AR is a major driver of prostate cancer (CaP) progression, which remains the second leading cause of cancer deaths in American men. Androgen deprivation therapies (ADTs) that interfere with interactions between AR and its activating androgen ligands have been the mainstay for treatment of metastatic CaP. Although ADTs are effective and induce remissions, eventually they fail, while the growth of the majority of ADT-resistant CaPs remains under AR’s control. Alternative approaches to inhibit AR activity and bypass resistance to ADT are being sought, such as preventing the interaction between AR and its cofactors and coregulators that is needed to execute AR-dependent transcription. For such strategies to be efficient, the 3D conformation of AR complexes needs to be well-understood and AR-regulator interaction sites resolved. Here, we review current insights into these 3D structures and the protein interaction sites in AR transcriptional complexes. We focus on methods and technological approaches used to identify AR interactors and discuss challenges and limitations that need to be overcome for efficient therapeutic AR complex disruption.

Highlights

Androgen deprivation therapies (ADTs) that interfere with interactions between androgen receptor (AR) and its activating androgen ligands have been the mainstay for treatment of metastatic CaP
We focus on methods and technological approaches used to identify AR interactors and discuss challenges and limitations that need to be overcome for efficient therapeutic AR complex disruption
Its modular structure resembles that of other nuclear receptor (NR) and consists of an N-terminal domain (NTD) which contains a ligand-independent transcriptional function (AF) AF-1, a central DNA binding domain (DBD) and a C-terminal ligand-binding domain (LBD) which harbors the ligand-activated AF-2

Summary

AR Action Drives CaP Progression

As an alternative and sometimes complementary approach for androgen synthesis inhibition, so-called anti-androgens that prevent AR-androgen interaction are administered, with the potency of generation AR inhibitors increasing [18,22,24] Resistance occurs to these novel generation AR inhibiting therapies. The majority of recurrent cases, continue to depend on AR activity that is restored via numerous and ever expanding molecular mechanisms, which broadly encompass diverse ways of AR overexpression or amplification [23,27], mutations that render AR less sensitive to ADT [28], AR gene rearrangements or splicing events that result in loss of functional LBD [9,27] (and a constitutively active AR), or expression of the related NR glucocorticoid receptor that in a subset of cases can take over part of AR’s function in CaP [29,30]

Novel Strategies to Target AR for CaP Treatment

Phage Display Assays

Characterizing the Composition of AR Transcriptional Complexes

Affinity Purification Mass Spectrometry

Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins

Biotin-Based Proximity Ligation Assay