Androgen receptor is targeted to distinct subcellular compartments in response to different therapeutic antiandrogens.
OBJECTIVE
Antiandrogens are routinely used in the treatment of prostate cancer. Although they are known to prevent activation of the androgen receptor (AR), little is known about the mechanisms involved. This report represents the first study of the localization of wild-type AR following expression at physiologic relevant levels in prostate cells and treatment with androgen and antiandrogens.


METHODS
We have characterized a cellular model for prostate cancer using in situ cellular fractionation, proteomics, and confocal microscopy and investigated the effect of antiandrogens in clinical use on the subcellular localization of the AR.


RESULTS
Different antiandrogens have diverse effects on the subcellular localization of the AR. Treatment with androgen results in translocation from the cytoplasm to the nucleoplasm, whereas the antiandrogens hydroxyflutamide and bicalutamide lead to reversible association with the nuclear matrix. In contrast, treatment with the antiandrogen cyproterone acetate results in AR association with cytoplasmic membranes and irreversible retention within the cytoplasm. In addition, we demonstrate that AR translocation requires ATP and the cytoskeleton, regardless of ligand.


CONCLUSIONS
These results reveal that not all antiandrogens work via the same mechanism and suggest that an informed sequential treatment regime may benefit prostate cancer patients. The observed subnuclear and subcytoplasmic associations of the AR suggest new areas of study to investigate the role of the AR in the response and resistance of prostate cancer to antiandrogen therapy.
Whitaker
Hayley C
HC
Prostate Cancer Research Group, Department of Cancer Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
Hanrahan
Sarah
S
Totty
Nick
N
Gamble
Simon C
SC
Waxman
Jonathan
J
Cato
Andrew C B
AC
Hurst
Helen C
HC
Bevan
Charlotte L
CL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014105:Tosyl Compounds; D014162:Transfection
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C014290:hydroxyflutamide; D005485:Flutamide; D000255:Adenosine Triphosphate; C053541:bicalutamide