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 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.
Androgen Signaling Laboratory, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
Vikash
V
Reebye
Laia
L
Querol Cano
Derek N
DN
Lavery
Greg N
GN
Brooke
Sue M
SM
Powell
Deepa
D
Chotai
Marjorie M
MM
Walker
Hayley C
HC
Whitaker
Robin
R
Wait
Helen C
HC
Hurst
Charlotte L
CL
Bevan
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D000071876:Prostaglandin-E Synthases; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D046888:Tissue Array Analysis; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D017430:Prostate-Specific Antigen; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases