title: Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer.
abstract: In order to generate genomic signals, the androgen receptor (AR) has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC) cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β) induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.
authors: Department of Urology, Ulm University, Ulm, Germany.
authors: Stefanie V
authors: SV
authors: Schütz
authors: Andres J
authors: AJ
authors: Schrader
authors: Friedemann
authors: F
authors: Zengerling
authors: Felicitas
authors: F
authors: Genze
authors: Marcus V
authors: MV
authors: Cronauer
authors: Mark
authors: M
authors: Schrader
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D028884:Karyopherins / Q000378:metabolism; D008024:Ligands; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009919:Orchiectomy; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000097606:Exportin 1 Protein
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles; D028884:Karyopherins; D008024:Ligands; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D014443:Tyrosine; D000097606:Exportin 1 Protein; C417521:SB 216763; C000605506:GSK3B protein, human