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

Oncogene volume 25, pages 3719–3734 (2006)Cite this article

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.

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Acknowledgements

We thank Dr David Siderovski, University of North Carolina at Chapel Hill for providing anti-RGS2 antibody, Dr Paul C Sternweis (UT Southwestern Medical Center) for the polyclonal rabbit Gq antibody and Dr Melanin Cobb (UT Southwestern Medical Center) for providing dominant-negative MEK1 and ERK2 mutants. We also thank Dr Zafar Nawaz for critical reading of the manuscript. This work was supported in part by NIH Grant number P20 RR018759 from the National Center for Research Resource (YT and MFL), CA88184 (MFL), Creighton Health Future Foundation (YT), Nebraska State LB692 (YT) and National Scientist Development Grant from American Heart Association (YT).

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  1. X Cao and J Qin: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA

    X Cao, J Qin, Y Xie, O Khan, F Dowd, M Scofield & Y Tu

  2. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    M-F Lin

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Cao, X., Qin, J., Xie, Y. et al. Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene 25, 3719–3734 (2006). https://doi.org/10.1038/sj.onc.1209408

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