Role of the HSP90-Associated Cochaperone p23 in Enhancing Activity of the Androgen Receptor and Significance for Prostate Cancer

Prostate tumor growth initially depends on androgens, which act via the androgen receptor (AR). Despite androgen ablation therapy, tumors eventually progress to a castrate-resistant stage in which the AR remains active. The mechanisms are poorly understood but it may be that changes in levels or act...

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Published in:	Molecular endocrinology (Baltimore, Md.) Vol. 26; no. 10; pp. 1694 - 1706
Main Authors:	Reebye, Vikash, Querol Cano, Laia, Lavery, Derek N, Brooke, Greg N, Powell, Sue M, Chotai, Deepa, Walker, Marjorie M, Whitaker, Hayley C, Wait, Robin, Hurst, Helen C, Bevan, Charlotte L
Format:	Journal Article
Language:	English
Published:	United States Endocrine Society 01-10-2012 Oxford University Press
Subjects:	Animals Cell Line Cell Nucleus - metabolism Chlorocebus aethiops Enhancer Elements, Genetic Gene Expression HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Humans Intramolecular Oxidoreductases - genetics Intramolecular Oxidoreductases - metabolism Intramolecular Oxidoreductases - physiology Male Original Research Prostaglandin-E Synthases Prostate-Specific Antigen - metabolism Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein Binding Receptors, Androgen - genetics Receptors, Androgen - metabolism Receptors, Androgen - physiology Receptors, Glucocorticoid - metabolism Tissue Array Analysis Transcriptional Activation Two-Hybrid System Techniques AR
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Summary:	Prostate tumor growth initially depends on androgens, which act via the androgen receptor (AR). Despite androgen ablation therapy, tumors eventually progress to a castrate-resistant stage in which the AR remains active. The mechanisms are poorly understood but it may be that changes in levels or activity of AR coregulators affect trafficking and activation of the receptor. A key stage in AR signaling occurs in the cytoplasm, where unliganded receptor is associated with the heat shock protein (HSP)90 foldosome complex. p23, a key component of this complex, is best characterized as a cochaperone for HSP90 but also has HSP90-independent activity and has been reported as having differential effects on the activity of different steroid receptors. Here we report that p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). We show, for the first time, that AR and p23 can interact, perhaps directly, when HSP90 is not present in the same complex. The effects of p23 on AR activity are at least partly HSP90 independent because a mutant form of p23, unable to bind HSP90, nevertheless increases AR activity. In human prostate tumors, nuclear p23 was higher in malignant prostate cells compared with benign/normal cells, supporting the utility of p23 as a therapeutic target in prostate cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 V.R. and L.Q.C. contributed equally to this work.
ISSN:	0888-8809 1944-9917
DOI:	10.1210/me.2012-1056