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Tumor suppressor activity of glucocorticoid receptor in the prostate

Oncogene volume 26, pages 1885–1896 (2007)Cite this article

Abstract

Glucocorticoids are extensively used in combination chemotherapy of advanced prostate cancer (PC). Little is known, however, about the status of the glucocorticoid receptor (GR) in PC. We evaluated over 200 prostate samples and determined that GR expression was strongly decreased or absent in 70–85% of PC. Similar to PC tumors, some PC cell lines, including LNCaP, also lack GR. To understand the role of GR, we reconstituted its expression in LNCaP cells using lentiviral approach. Treatment of LNCaP-GR cells with the glucocorticoids strongly inhibited proliferation in the monolayer cultures and blocked anchorage-independent growth. This was accompanied by upregulation of p21 and p27, down-regulation of cyclin D1 expression and c-Myc phosphorylation. Importantly, the activation of GR resulted in normalized expression of PC markers hepsin, AMACR, and maspin. On the signaling level, GR decreased expression and inhibited activity of the MAP-kinases (MAPKs) including p38, JNK/SAPK, Mek1/2 and Erk1/2. We also found that activation of GR inhibited activity of numerous transcription factors (TF) including AP-1, SRF, NF-κB, p53, ATF-2, CEBPα, Ets-1, Elk-1, STAT1 and others, many of which are regulated via MAPK cascade. The structural analysis of hepsin and AMACR promoters provided the mechanistic rationale for PC marker downregulation by glucocorticoids via inhibition of specific TFs. Our data suggest that GR functions as a tumor suppressor in prostate, and inhibits multiple signaling pathways and transcriptional factors involved in proliferation and transformation.

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Abbreviations

AMACR:

alpha-methylacyl-CoA racemase

AP-1:

activator protein 1

BPH:

benign prostatic hyperplasia

Erk1/2:

extracellular signal-regulated kinase 1 and 2

FA:

fluocinolone acetonide

HGPIN:

high-grade prostatic intraepithelial neoplasia

HRPC:

hormone refractory prostate carcinoma

MAPKs:

mitogen-activated protein kinases

Mek1/2:

dual specificity mitogen-activated protein kinase 1 and 2

NF-κB:

nuclear factor kappa-B

PC:

prostate carcinoma

PIN:

prostatic intraepithelial neoplasia

SAPK/JNK:

stress-activated protein kinase/c-Jun-N-terminal kinase

TF:

transcription factor

YFP:

yellow fluorescent protein

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Acknowledgements

This work was supported by the DOD prostate grant DAMD17-03-1-0522 and the Northwestern University Prostate SPORE Developmental Project (to IB). We thank Drs KR Yamamoto (University of California, San Francisco, CA, USA), WC Greene (Gladstone Institute for Virology and Immunology, University of California, San Francisco, CA, USA), DJ Klumpp, (Northwestern University, Chicago IL, USA), M Beato, (Philipps-Universitat, Marburg, Germany) for their generous gift of plasmids. We are grateful to Drs P Stern, J Pelling and O Volpert (Northwestern University, Chicago, IL, USA) for fruitful discussions of our work.

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Authors and Affiliations

  1. Department of Dermatology, Feinberg Medical School, Northwestern University, Chicago, IL, USA

    A Yemelyanov, J Czwornog, D Chebotaev & I Budunova

  2. Department of Pathology, NN Blokhin Cancer Research Center, RAMS, Moscow, Russia

    A Karseladze & E Kulevitch

  3. Department of Pathology, Feinberg Medical School, Northwestern University, Chicago, IL, USA

    X Yang

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  1. A Yemelyanov
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  2. J Czwornog
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  7. I Budunova
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Correspondence to I Budunova.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Yemelyanov, A., Czwornog, J., Chebotaev, D. et al. Tumor suppressor activity of glucocorticoid receptor in the prostate. Oncogene 26, 1885–1896 (2007). https://doi.org/10.1038/sj.onc.1209991

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