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.

Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

“…Despite initial robust responses to androgen deprivation therapy (ADT), nearly all patients with advanced disease progress to fatal castration resistant PC (CRPC). There is increasing evidence of persistent AR signaling as patients progress to CRPC with rising prostate specific antigen (PSA), increasing steroidogenesis, overexpression of AR co-regulators and the development of AR aberrations (6)(7)(8). The discovery of second generation anti-androgen therapies, such as abiraterone and enzalutamide, that effectively target AR signaling in patients with hormone sensitive disease and CRPC has improved patient outcome (9)(10)(11)(12)(13).…”

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

“…The residues in the AR tau 5 most affected by the BAG1L BAG domain interaction correspond to a region previously identified as partially folded in the intrinsically disordered AR N-terminus (De Mol et al 2016). Moderate decreases in resonance Knapp et al (2012) intensity were also observed in AR tau 1 (100-360 amino acids), in a region centered around residue 275, which has the propensity to adopt an extended conformation (Cato et al 2017). This describes a protein structure defined by crystallographic, isotopic labeling NMR and transferred nuclear overhauser effect studies as an important element of secondary structure at the binding site of many peptide/protein complexes (Siligardi & Drake 1995).…”

“…Contrasting reports were made by Shatkina and colleagues who demonstrated that BAG1L bound and enhanced AR transactivation through the interaction of the BAG domain with the AR N-terminal tau 5 region (360-528 amino acids) (Shatkina et al 2003). Solution NMR experiments showed that this interaction resulted in the reduction of resonance intensities within the C-terminal part of AR AF1, indicating that the interaction is transient (Cato et al 2017). The residues in the AR tau 5 most affected by the BAG1L BAG domain interaction correspond to a region previously identified as partially folded in the intrinsically disordered AR N-terminus (De Mol et al 2016).…”

“…showed that the BAG1 proteins have a role in proteome homeostasis and in protein folding (Cato et al 2017). The LUMIER studies further showed association of BAG3 with heat shock proteins Hsp22/HSPB8, Hsp27/HAPB1, and with the master regulator of the heat shock response, HSF1 (Taipale et al 2014).…”

Tandem Affinity Purification and Mass Spectrometry (TAP‐MS) for the Analysis of Protein Complexes

“…Researchers seeking to test hypotheses in a specific cellular context may opt for a focused analysis of individual protein complexes rather than the “representative” biochemical networks provided by large‐scale studies. In such cases, tandem affinity purification remains the method of choice to provide insights into protein function and to address mechanistic gaps in our interpretation of genotype‐phenotype relationships (Adelmant et al., ; Cato et al., ; Chen et al., ; Doherty, Adelmant, Cecchetelli, Marto, & Cram, ; Duarte et al., ; Durzynska et al., ; Ferry et al., ; Fine et al., ; Goudreault et al., ; Hill et al., ; Hwang et al., ; Jager et al., ; Kim et al., ; Koleva et al., ; Lee et al., ; Mathias et al., ; Meijer et al., ; Miotto et al., ; Pathania et al., ; Pichlmair et al., ; Quan et al., ; Rozenblatt‐Rosen et al., ; Sand‐Dejmek et al., ; Simarro et al., ; Uljon et al., ; Wang et al., ; Watanabe et al., ; Wei, Chiang, Sumpter, Mishra, & Levine, ; Zhang et al., ; Zhang et al., ; Zhou et al., ).…”