Non-Genomic Actions of the Androgen Receptor in Prostate Cancer - PubMed (original) (raw)

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Non-Genomic Actions of the Androgen Receptor in Prostate Cancer

Jacky K Leung et al. Front Endocrinol (Lausanne). 2017.

Abstract

Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens. In the canonical pathway, binding of androgen to AR LBD triggers the release of AR from molecular chaperones which enable conformational changes and protein-protein interactions to facilitate its nuclear translocation where it regulates the expression of target genes. However, preceding AR function in the nucleus, initial binding of androgen to AR LBD in the cytoplasm may already initiate signal transduction pathways to modulate cellular proliferation and migration. In this article, we review the significance of signal transduction pathways activated by rapid, non-genomic signaling of the AR during the progression to metastatic CRPC and put into perspective the implications for current and novel therapies that target different domains of AR.

Keywords: AR antagonists; MAPK/ERK signaling; PI3K/Akt signaling; Src kinase; androgen receptor; non-genomic signaling; prostate cancer.

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Figures

Figure 1

Figure 1

Integration of non-genomic signaling and canonical signaling of androgen receptor (AR). In the presence of low androgen levels (picomolar concentrations), AR interactions with Src kinase and p85α regulatory subunit of phosphoinositide 3-kinase activates mitogen-activated protein kinase (MAPK) and Akt pathways to enhance cell proliferation and survival in a non-genomic fashion. In the presence of high androgen levels (nanomolar concentrations), AR is activated in a canonical pathway to regulate the expression of target genes. Activation of MAPK and Akt by non-genomic signaling also enhances genomic AR signals by phosphorylating the AR or transcriptional coactivators.

Figure 2

Figure 2

Targeting non-genomic actions of androgen receptor (AR). Non-genomic signaling of AR is activated by interactions between the polyproline domain of the AR N-terminal domain (NTD) and Src homology domain 3 of Src. Activated Src can enhance the transactivation of AR directly by phosphorylating AR Y534 or indirectly by stimulating alternate kinase pathways that modulate AR activity. AR NTD inhibitors may prevent non-genomic signals from AR by blocking Src interaction with the AR NTD and can block both ligand-dependent and ligand-independent transactivation of AR.

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