Journal
ONCOGENE
Volume 25, Issue 26, Pages 3719-3734Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209408
Keywords
RGS2; GPCRs; extracellular signal-regulated; kinases; prostate cancer; androgen receptor; androgen independence
Funding
- NCI NIH HHS [CA88184] Funding Source: Medline
- NCRR NIH HHS [P20 RR018759] Funding Source: Medline
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Hormones acting through G protein-coupled receptors ( GPCRs) can cause androgen-independent activation of androgen receptor ( AR) in prostate cancer cells. Regulators of G-protein signaling ( RGS) proteins, through their GTPase activating protein ( GAP) activities, inhibit GPCR-mediated signaling by inactivating G proteins. Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells. Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgen-independent 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 androgen-sensitive 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.
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