Inhibition of glycogen synthase kinase-3beta promotes nuclear export of the androgen receptor through a CRM1-dependent mechanism in prostate cancer cell lines.
The androgen receptor (AR) is a ligand-dependent transcription factor belonging to the steroid hormone receptor superfamily. Under normal conditions, in the absence of a ligand, the AR is localized to the cytoplasm and is actively transported into the nucleus upon binding of androgens. In advanced prostate cancer (PCa) cell lines, an increased sensitivity to dihydrotestosterone (DHT), enabling the cells to proliferate under sub-physiological levels of androgens, has been associated with increased stability and nuclear localization of the AR. There is experimental evidence that the glycogen synthase kinase-3beta (GSK-3beta), a multifunctional serine/threonine kinase is involved in estrogen and AR stability. As demonstrated in the following study by immunoprecipitation analysis, GSK-3beta binds to the AR forming complexes in the cytoplasm and in the nucleus. Furthermore, inhibition of GSK-3beta activity by pharmacological inhibitors like the maleimide SB216761, the chloromethyl-thienyl-ketone GSK-3 inhibitor VI or the aminopyrazol GSK-3 inhibitor XIII in cells grown in the presence of DHT triggered a rapid nuclear export of endogenous AR as well as of green fluorescent AR-EosFP. The nuclear export of AR following GSK-3beta inhibition could be blocked by leptomycin B suggesting a CRM1-dependent export mechanism. This assumption is supported by the localization of a putative CRM1 binding site at the C-terminus of the AR protein. The results suggest that GSK-3beta is an important element not only in AR stability but also significantly alters nuclear translocation of the AR, thereby modulating the androgenic response of human PCa cells.
Schütz
Stefanie V
SV
Institute of General Zoology and Endocrinology, Ulm University, Albert Einstein Allee 11, 89069 Ulm, Germany.
Cronauer
Marcus V
MV
Rinnab
Ludwig
L
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097606:Exportin 1 Protein
D013196:Dihydrotestosterone; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D028884:Karyopherins; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C000605506:GSK3B protein, human; C038753:leptomycin B