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Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer.
- Source :
-
PloS one [PLoS One] 2011; Vol. 6 (9), pp. e25341. Date of Electronic Publication: 2011 Sep 29. - Publication Year :
- 2011
-
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.
- Subjects :
- Active Transport, Cell Nucleus drug effects
Cell Line, Tumor
Cell Nucleus drug effects
Cell Nucleus metabolism
Cell Proliferation drug effects
Enzyme Activation drug effects
Gene Silencing
Glycogen Synthase Kinase 3 chemistry
Glycogen Synthase Kinase 3 genetics
Glycogen Synthase Kinase 3 metabolism
Glycogen Synthase Kinase 3 beta
Humans
Indoles pharmacology
Karyopherins metabolism
Ligands
Male
Maleimides pharmacology
Phosphorylation drug effects
Prostatic Neoplasms genetics
Prostatic Neoplasms metabolism
Receptors, Cytoplasmic and Nuclear metabolism
Signal Transduction drug effects
Tyrosine metabolism
Up-Regulation drug effects
Exportin 1 Protein
Glycogen Synthase Kinase 3 antagonists & inhibitors
Orchiectomy
Prostatic Neoplasms pathology
Prostatic Neoplasms surgery
Protein Kinase Inhibitors pharmacology
Receptors, Androgen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 6
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 21980429
- Full Text :
- https://doi.org/10.1371/journal.pone.0025341