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

X. Cao, J. Qin, Y. Xie, O. Khan, F. Dowd, M. Scofield, Ming-Fong Lin, Y. Tu

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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 Gq-coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated GqQ209L mutant whereas silencing endogenous RGS2 by siRNA enhanced GqQ209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive GqQ209L/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.

Original languageEnglish (US)
Pages (from-to)3719-3734
Number of pages16
JournalOncogene
Volume25
Issue number26
DOIs
StatePublished - Jun 22 2006

Fingerprint

GTP-Binding Protein Regulators
Androgen Receptors
Androgens
Prostatic Neoplasms
G-Protein-Coupled Receptors
RGS Proteins
GTPase-Activating Proteins
Prostate
Gq-G11 GTP-Binding Protein alpha Subunits
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Growth
GTP-Binding Proteins
Small Interfering RNA

Keywords

  • Androgen independence
  • Androgen receptor
  • Extracellular signal-regulated kinases
  • GPCRs
  • Prostate cancer
  • RGS2

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. / Cao, X.; Qin, J.; Xie, Y.; Khan, O.; Dowd, F.; Scofield, M.; Lin, Ming-Fong; Tu, Y.

In: Oncogene, Vol. 25, No. 26, 22.06.2006, p. 3719-3734.

Research output: Contribution to journalArticle

Cao, X. ; Qin, J. ; Xie, Y. ; Khan, O. ; Dowd, F. ; Scofield, M. ; Lin, Ming-Fong ; Tu, Y. / Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. In: Oncogene. 2006 ; Vol. 25, No. 26. pp. 3719-3734.
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AU - Khan, O.

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AB - 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 Gq-coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated GqQ209L mutant whereas silencing endogenous RGS2 by siRNA enhanced GqQ209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive GqQ209L/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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