AR-Signaling in Human Malignancies: Prostate Cancer and Beyond

Abstract

In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types.

Glyoxalase 2 drives tumorigenesis in human prostate cells in a mechanism involving androgen receptor and p53‐p21 axis

“…However, Glo2 silencing could not abrogate the effect of DHT on PSA transcript levels, suggesting that Glo2 might be downstream to PSA in the AR axis or that PSA might not be involved in AR/Glo2 axis‐mediated control of LNCaP growth. Besides, as a transcription factor, AR exerts its actions regulating the expression of a host of target genes , therefore, the participation of other AR target genes cannot be excluded. Finally, silencing of AR in LNCaP cells induced Glo2 down‐regulation compared with siCtr cells (Fig.…”

“…To this aim we treated LNCaP cells, expressing higher levels of AR compared with PNT2 cells (Fig. 7A Besides, as a transcription factor, AR exerts its actions regulating the expression of a host of target genes 41,42 , therefore, the participation of other AR target genes cannot be excluded. Finally, silencing of AR in LNCaP cells induced Glo2 down-regulation compared with siCtr cells (Fig.…”

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

“…However, androgen deprivation therapy (ADT) does not cure PCa, as the disease eventually evolves to castration-resistant PCa (CRPC). At this stage, several molecular mechanisms have been discovered, most of them leading to AR hyperactivation, including AR genomic amplification and mutation (Montgomery et al 2008;Robinson et al 2015;Watson et al 2015;Schweizer and Yu 2017;Ylitalo et al 2017). Consequently, further knowledge of downstream effectors of the AR is necessary to dissect the molecular mechanisms governing PCa progression and develop novel therapeutic approaches.…”

Solvent-driven structural topology involving energetically significant intra- and intermolecular chelate ring contacts and anticancer activities of Cu(ii) phenanthroline complexes involving benzoates: experimental and theoretical studies

“…The involvement of MTORC1, PR, ER-beta and AR signaling pathways are very well connected with cancer cell proliferations and metastasis in multiple cancer type. 88,89 The benzoate moieties in both the complexes are also associated with cyclooxygenase inhibition, antineoplastic, hypoglycemic, contraceptive and anti-inammatory activity and representing properties of multifunctional ligand. Our results together provide further…”