Activation of GPR56, a novel adhesion GPCR, is necessary for nuclear androgen receptor signaling in prostate cells

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 a role for these in 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. 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 prostate tumor 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.

Complex roles of cAMP–PKA–CREB signaling in cancer

“…Androgen receptor (AR) signaling is critical for prostate carcinogenesis. Testosterone directly stimulates GPR56 and then activates the cAMP/PKA pathway, which promotes AR signaling [ 90 ]. PKA also phosphorylates the Thr 89 residue in HSP90, leading to the release of AR from HSP90 and the binding of AR to HSP27, which transfers AR into the nucleus to transactivate its targets [ 91 ].…”

Functions of G protein‐coupled receptor 56 in health and disease

“…Human prostate cancer tissues express abundant GPR56, which are transactivated by androgens and promote prostate cancer cell metastasis by stimulating the Rho signaling pathway 150 . Interference of the expression of GPR56 reduces LNCaP and PC3 cell proliferation, the nuclear translocation of AR, and prostate‐specific antigen target gene transcription in LNCaP cells 150 . Likewise, high levels of GPR56 have been detected in ovarian serous carcinoma tissue from epithelial ovarian cancer (EOC) patients.…”

“…150 Interference of the expression of GPR56 reduces LNCaP and PC3 cell proliferation, the nuclear translocation of AR, and prostate-specific antigen target gene transcription in LNCaP cells. 150 Likewise, high levels of GPR56 have been detected in ovarian serous carcinoma tissue from epithelial ovarian cancer (EOC) patients. Its expression is positively correlated with the advanced FIGO stage, which is a classification for ovarian cancer, and lymph node invasion.…”

Androgen Plays a Potential Novel Hormonal Therapeutic Role in Th17 Cells Predominant Neutrophilic Severe Asthma by Attenuating BECs Regulated Th17 Cells Differentiation via MBD2 Expression

“…Magnetic bead separation (130-049-201, Miltenyi Biotec, Germany) isolated mice splenic CD4+ T cells. The asthma model transfected BECs were pretreated with 10 nM of DHT [41], 1 nM of E2 [42], and 10 : 1 nM of DHT:E2 (see subsection 4.2.3) in severe asthma + DHT, severe asthma +E2, and severe asthma +DHT/E2 groups, respectively, for 24 h, cocultured with CD4+ T cells at a ratio of 10 : 1 (TCs: BECs) for 24 h in complete RPMI 1640 culture medium (Gibco, Australia) supplemented with 10% FBS, 1% penicillin and streptomycin, soluble anti-CD28 (1.0 μg/ml, eBioscience), soluble anti-cd3e (0.5 μg/ml, eBioscience), and IL-2 (20 ng/ ml, eBioscience). To analyze T cell subsets, cells were collected after 24 h, and flow cytometry determined the concentration of IL-4 and IL-17A to obtain the ratio of Th2 to Th17 cells.…”

“…Oxidative Medicine and Cellular Longevity 45], 2.5 μg/mice of E2 [35,45], 3.6 μg/g body wt. of DHT:2.5 μg of DHT/E2 in the allocated groups of experimental mice, and 10 nM of DHT in BECs severe asthma model [41,42]. However, we need more extensive and elaborative studies on various multiple doses of androgen.…”