Abstract
The androgen receptor (AR) is activated in patients with castration resistant prostate cancer (CRPC) despite low circulating levels of androgen, suggesting that intracellular signaling pathways and non-androgenic factors may contribute to AR activation. Many G-protein coupled receptors (GPCR) and their ligands are also activated in these cells indicating that they may play a role in development of Prostate Cancer (PCa) and CRPC. Although a cross talk has been suggested between the two pathways, yet, the identity of GPCRs which may play a role in androgen signaling, is not established yet. By using blast analysis of 826 GPCRs, we identified a GPCR, GPCR 205, which exhibited maximum similarity with the ligand binding domain of the AR. We demonstrate that adhesion GPCR 205, also known as GPR56, can be activated by androgens to stimulate the Rho signaling pathway, a pathway that plays an important role in prostate tumor cell metastasis. Testosterone stimulation of GPR56 also activates the cAMP/ Protein kinase A (PKA) pathway, that is necessary for AR signaling. Knocking down the expression of GPR56 using siRNA, disrupts nuclear translocation of AR and transcription of prototypic AR target genes such as PSA. GPR56 expression is higher in all twenty-five prostate tumor patient's samples tested and cells expressing GPR56 exhibit increased proliferation. These findings provide new insights about androgen signaling and identify GPR56 as a possible therapeutic target in advanced prostate cancer patients.
Highlights
The androgen receptor (AR) plays a central role in the normal growth of prostate as well as its neoplastic transformation into Prostate Cancer (PCa) [1]
Our results provide an alternate mechanism of AR activation in PCa patients, via GPR56 and this may be exploited to aid the hormonal therapies in castration resistant prostate cancer (CRPC) patients
In spite of limitations associated with this approach, in absence of available crystal structures, structures were generated in silico and Activation of GPR56 is necessary for nuclear AR signaling docking studies were performed to evaluate the possible interaction of these G-protein coupled receptors (GPCR) with androgens
Summary
The AR plays a central role in the normal growth of prostate as well as its neoplastic transformation into PCa [1]. The fundamental dependence of prostate tumor on androgen signaling was established when Huggins and Hodges in 1941 demonstrated that orchiectomy in patients could reduce tumor growth [2]. Since endocrine therapies aiming to minimize AR signaling, either by reducing androgen levels by physical or chemical means or by using AR inhibitors, constitute the primary treatment plan for PCa patients [3]. These measures offer only a temporary relief as a more aggressive and androgen-independent form of tumor inevitably reappears, that is untreatable [4].
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