Non-nuclear AR Signaling in Prostate Cancer

Abstract

Despite the key role played by androgen receptor (AR) in tumor cell aggressiveness and prostate cancer (PCa) progression, its function in the tumor microenvironment (TME) is still controversial. Increasing studies highlight the crucial role played by TME modulation in treatment outcome and tumor cell spreading. In this context, targeting specific constituents of the TME could be considered an alternative approach to classic treatments directed against cancer cells. Currently, androgen deprivation therapy (ADT) is a routinely adopted strategy in the management of PCa, with initial success, and consecutive fail. A possible justification to this is the fact that ADT aims to target all the transcription/translation-related activities of AR, which are typical of tumor epithelial cells. Less is still known about side effects of ADT on TME. Cancer Associated Fibroblasts (CAFs), for example, express a classic AR, mostly confined in the extra-nuclear portion of the cell. In CAFs ADT exerts a plethora of non-transcriptional effects, depending by the protein partner linked to AR, leading to cell migration, proliferation, and differentiation. In recent years, substantial progress in the structure-function relationships of AR, identification of its binding partners and function of protein complexes including AR have improved our knowledge of its signaling axis. Important AR non-genomic effects and lots of its cytoplasmatic binding partners have been described, pointing out a fine control of AR non-genomic pathways. Accordingly, new AR inhibitors have been designed and are currently under investigation. Prompt development of new approaches to target AR or block recruitment of its signaling effectors, or co-activators, is urgently needed. The present review takes an in-depth look at current literature, furnishing an exhaustive state-of-the-art overview of the non-genomic role of AR in PCa, with particular emphasis on its involvement in TME biology.

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

“…In addition to regulating gene transcription, AR can also mediate a number of intracellular signaling pathways through direct protein–protein interactions within the cytoplasm (known as non-genomic AR signaling) [ 12 , 281 ]. For instance, AR is reported to activate SRC family kinases, PKC, RAS, ERK, PI3K, and AKT [ 12 , 288 ].…”

Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

“…Another non-receptor tyrosine kinase related to SRC family kinases, protein tyrosine kinase 6 (PTK6), has been found to enhance the epithelial–mesenchymal transition (EMT) by inhibiting E-cadherin expression and inducing expression of the mesenchymal markers vimentin, SLUG, and ZEB1 [ 93 ]. Parallel to Src, the androgen receptor may interact with p85a, the regulatory subunit of PI3K, a recognized oncogenic protein kinase with a key role in malignant transformation, metastasis, and progression of the disease [ 94 , 95 ].…”

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

“…EPI compounds are AR‑antagonists that irreversibly bind to the AR NTD at the transcription activation unit 5 and inhibit AR-mediated transactivation. These compounds inhibit both ligand-activated AR and ligand‑independent activation of AR, including the AR splice variants [ 31 , 32 ]. Therefore, EPI compounds act independently of the AR-LBD deletions or mutations and may be used for the treatment of CRPC dependent on AR-Vs.…”