Document Detail


Mifepristone inhibits GRβ coupled prostate cancer cell proliferation.
MedLine Citation:
PMID:  22819113     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The GR gene produces GRα and GRβ isoforms by alternative splicing of a C-terminal exon. GRα binds glucocorticoids, modulates transcription in a glucocorticoid dependent manner and has a growth inhibitory role in prostate cells. Due to this role glucocorticoids are often used to treat androgen independent prostate cancer. In contrast, GRβ has intrinsic transcriptional activity and binds mifepristone (RU486) but not glucocorticoids to control gene expression. To our knowledge the role of GRβ in prostate cell proliferation is unknown.
MATERIALS AND METHODS: We determined GRβ levels in various prostate cancer cell lines by reverse transcriptase-polymerase chain reaction and Western blot. The effect of GRβ on the kinetics of prostate cancer cell growth was determined by cell counting and flow cytometry upon mifepristone and dexamethasone treatment. Cell proliferation was also examined after siRNA mediated knockdown and over expression of GRβ.
RESULTS: GRβ mRNA and protein were up-regulated in LNCaP cells that over expressed the androgen receptor co-factor ARA70β. Treatment of LNCaP-ARA70β with mifepristone or siRNA targeting GRβ inhibited proliferation compared to that of parental LNCaP cells. The immortal but nontumorigenic RC165 prostate cell line and the tumorigenic DU145 prostate cell line with endogenous GRβ also showed partial growth reduction upon GRβ depletion but to a lesser extent than LNCaP-ARA70β cells. The growth stimulatory effect of ARA70β on LNCaP cells was partly GRβ dependent, as was the proliferation of RC165 cells and to a lesser extent of DU145 cells.
CONCLUSIONS: Results suggest that patients with a primary tumor that expresses GRβ and ARA70β may benefit from mifepristone.
Authors:
Martin Ligr; Yirong Li; Susan K Logan; Samir Taneja; Jonathan Melamed; Hebert Lepor; Michael J Garabedian; Peng Lee
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-21
Journal Detail:
Title:  The Journal of urology     Volume:  188     ISSN:  1527-3792     ISO Abbreviation:  J. Urol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-13     Completed Date:  2012-10-29     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0376374     Medline TA:  J Urol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  981-8     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Affiliation:
Department of Pathology, New York University School of Medicine, New York, New York 10010, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Proliferation / drug effects*
Hormone Antagonists / pharmacology*
Humans
Male
Mifepristone / pharmacology*
Prostatic Neoplasms / pathology*
Receptors, Glucocorticoid / antagonists & inhibitors*
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
P30 CA016087/CA/NCI NIH HHS; P30 CA016087/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Hormone Antagonists; 0/Receptors, Glucocorticoid; 0/glucocorticoid receptor beta; 84371-65-3/Mifepristone
Comments/Corrections
Comment In:
J Urol. 2013 May;189(5):1993-4   [PMID:  23201377 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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