Allosteric alterations in the androgen receptor and activity in prostate cancer

Abstract

Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen receptor, which displays a diversity of inclusion/exclusion events in its structural motifs as a mechanism of resistance to the most forefront anti-androgen therapies. More than 20 androgen receptor variants that lack various portions of ligand-binding domain have been identified in human prostate cancer (PCa) samples. Most of the variants are inactive on their own, with a few exceptions displaying constitutive activity. The full-length receptor and one or more variants can be co-expressed in the same cell under many circumstances, which raises the question of how these variants physically and functionally interact with the full-length receptor or one another in the course of PCa progression. To address this issue, in this review, we will characterize and discuss androgen receptor variants, including the novel variants discovered in the last couple of years (i) individually, (ii) with respect to their physical and functional interaction with one another and (iii) in clinical relevance. Here, we also introduce the very recent understanding of AR-Vs obtained through successful development of some AR-V-specific antibodies as well as identification of novel AR-Vs by data mining approaches.

Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer

“…AR-V7 is a potent transcriptional activator that does not require androgens for activity, consistent with its frequent upregulation in tumors that have gained resistance to ARSI therapies ( 42 ). Whether AR-V7 signals as a homodimer or as a heterodimer with AR-FL and how this alters the transcriptome is under active investigation ( 43 , 44 , 45 , 46 ).…”

Androgen Receptor Signaling and Metabolic and Cellular Plasticity During Progression to Castration Resistant Prostate Cancer

“…Thus, ADT is the frontline treatment and directed toward disruption of T-DHT-AR axis by suppression of gonadal T by medical or surgical castration ( 26 ). Resistance to gonadal T depletion namely CRPC is associated with AR activity which is achieved by a gain-of-function in AR itself and/or sufficient intratumoral amounts of T and DHT to activate AR ( 25 , 26 , 101 ). Metastatic prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves upregulation of enzymes required for stepwise synthesis from cholesterol to T and DHT ( 93 , 111 ).…”

Efeito do lincRNA >i<PVT1>/i< associado ao potenciador de zeste homólogo 2 (EZH2) e ao receptor de andrógeno (AR) sobre a expressão gênica em larga escala em células LNCaP de câncer de próstata

“…O andrógeno exerce o seu efeito biológico através do receptor de andrógeno (AR). O AR é um membro da superfamília de receptores nucleares do tipo I, que são ativados por um hormônio específico, neste caso, o andrógeno e o seu derivado mais potente, a Dihidrotestosterona (DHT) (Lu, Wardell et al 2006, Uo, Plymate et al 2017. (Uo, Plymate et al 2017).…”

“…Na presença do ligante DHT o motivo FXXFL do AR interage com a região AF-2. Como pode ser observado pela descrição acima, todos esses domínios estruturais permitem uma regulação estrita do receptor de andrógeno pelo hormônio andrógeno (Uo, Plymate et al 2017).…”

“…Mudanças nesses domínios podem tornar o AR constitutivamente ativo e tornar-se independente do hormônio ligante. Mutações no receptor de andrógeno geram domínios não funcionais ou receptores truncados, que levam à ativação do receptor independente de andrógeno, o que leva ao agravamento do câncer de próstata (Feldman and Feldman 2001, Lamont and Tindall 2011, Uo, Plymate et al 2017.…”