Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells

Abstract

Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgenindependent LNCaP cells and CWR22Rv1 cells. In LNCaP cells, RGS2 inhibited G q -coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated G q Q209L mutant whereas silencing endogenous RGS2 by siRNA enhanced G q Q209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive G q Q209L/G188S-induced AR activation. Furthermore, extracellular signal-regulated kinase 1/2 (ERK1/2) was found to be involved in RGS2-mediated regulation of androgen-independent AR activity. In addition, RGS2 functioned as a growth suppressor for androgen-independent LNCaP cells whereas androgensensitive LNCaP cells with RGS2 silencing had a growth advantage under steroid-reduced conditions. Finally, RGS2 expression level was significantly decreased in human prostate tumor specimens. Taken together, our results suggest RGS2 as a novel regulator of AR signaling and its repression may be an important step during prostate tumorigenesis and progression.

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

“…As discussed above, RGS2 is one of several RGS proteins that is rapidly degraded through the ubiquitin-proteasomal pathway. Low RGS2 protein levels are associated with hypertension and other cardiovascular pathologies (Heximer et al, 2003;Takimoto et al, 2009;Tsang et al, 2010) and could also be involved in the progression of prostate and breast cancer (Cao et al, 2006;Lyu et al, 2015). In our initial screen, we identified digoxin and other cardiotonic steroids as selective stabilizers of RGS2 protein levels (Sjögren et al, 2012).…”

“…The expression of RGS proteins is not only spatially regulated per cell type and subcellular localization but also temporally regulated by mechanisms that induce or suppress RGS expression in response to specific cues or during pathological conditions. Examples include RGS2 downregulation in androgen-independent prostate cancer (Cao et al, 2006) and hypertension (Semplicini et al, 2006), the down-regulation of RGS10 and RGS17 in models of chemoresistance in ovarian cancer (Hooks et al, 2010), as well as the up-regulation of RGS17 in lung and prostate cancer (James et al, 2009;Bodle et al, 2013). Importantly, RGS transcript and protein levels may be independently regulated.…”

Vasoactive Intestinal Peptide Transactivates the Androgen Receptor through a Protein Kinase A-Dependent Extracellular Signal-Regulated Kinase Pathway in Prostate Cancer LNCaP Cells

“…Upon activation, the ERK-phosphorylated GAL4-Elk1 fusion protein will induce the expression of the luciferase reporter gene (Cao et al, 2006).…”

“…The effect of VIP on the transcriptional activity of AR was then examined using an AR-regulated reporter construct, ARE 3 -tk-LUC (Cao et al, 2006). The transfected cells were cultured in an androgen-depleted medium without or with exogenous VIP or DHT.…”

“…These neuropeptides, acting through their GPCRs, result in androgen-independent AR activation, thus promoting the progression of prostate cancer cells (Shah et al, 1994;Lee et al, 2001). In addition, we reported recently that regulator of G-protein signaling 2, an inhibitor of GPCR function, attenuates androgen-independent AR signaling in prostate cancer cells, thereby inhibiting androgen-independent prostate cancer cell growth (Cao et al, 2006). In fact, inhibition of the excessively activated GPCRs has therapeutic benefits for patients with malignant prostate cancer (Nelson, 2003).…”