Regulation of androgen receptor levels: Implications for prostate cancer progression and therapy

Abstract

Androgen deprivation has been the standard therapy for advanced and metastatic prostate cancer for over half a century, as prostate tumors are initially dependent on androgens for growth and survival. Unfortunately, in most patients undergoing androgen ablation, relapse (recurrent tumor growth) eventually occurs. The actions of the principal androgens, testosterone and dihydrotestosterone (DHT), are mediated via androgen receptors (ARs), ligand-activated transcription factors that belong to the nuclear receptor superfamily. Because of the presence of transcriptionally active ARs in tumors from recurrent or androgen-independent disease, there is a heightened interest in new therapeutic paradigms that target the AR and its regulatory pathways. The regulation of AR levels is highly complex with control exerted by several pathways and in a cell-, tissue-, and developmental-stage specific manner. Androgens are important regulators of AR mRNA and protein through transcriptional and post-transcriptional mechanisms. This article reviews the evidence implicating the AR in recurrent prostate cancer and discusses the multiple mechanisms that regulate AR levels in normal and neoplastic cells. The complexity of AR regulation suggests that there will be an ample array of potential new drug targets for modulating levels of this receptor, a key signaling molecule in prostate cancer.

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

“…Most cancer cells are terminated by these treatments, however, over time, the cancer recurs in a more aggressive and devastating manner termed as hormone refractory disease [2]. The mechanism by which androgens are involved in the progression to this androgenindependent (AI) phenotype remains unclear.…”

“…Based on these studies, androgens are believed to play a significant role in lipogenesis involved in the progression to the AI phenotype but the underlying mechanisms of how this occurs remain to be elucidated. The androgen receptor (AR) is known to be a central mediator in this progression [9,10] as re-ignition of the AR in the AI phenotype has been documented in hormone refractory human tissues [2,11,12]. One contending hypothesis to explain the role of AR in the emergence of the AI phenotype is that it becomes hypersensitive to low circulating levels of androgens following castration [9,10].…”

“…ACAT is an integral membrane protein localized in the endoplasmic reticulum and it is important in catalyzing the transfer of cholesterol to cholesterol esters [2,22]. These cholesterol esters are further stored as lipid droplets within the cell.…”

“…These two genes share high structural homology in their transmembrane domains and phosphorylation sites. Regulation of these two genes is quite diverse in their localization and expression mechanisms [2]. ACAT1 expression is regulated by transcriptional factors such as STAT1a and Sp1 [23] while ACAT2 is regulated by Cdx2 and HNF1a [24].…”

Degradation and beyond: Control of androgen receptor activity by the proteasome system

“…It should be noted that AR is able not only to up-regulate but also to down-regulate gene expression [9], depending on the availability of coactivators and corepressors. As the mechanisms regulating AR expression have been reviewed elsewhere [2,10] only a brief description will be presented here. AR expression is regulated at the transcriptional level by a variety of transcription factors [10], posttranscriptionally by RNA binding proteins [11], and post-translationally; the latter form of regulation includes phosphorylation, sumoylation and acetylation, depending on interaction with coregulatory proteins [12,13].…”