Inhibition of glycogen synthase kinase-3beta promotes nuclear export of the androgen receptor through a CRM1-dependent mechanism in prostate cancer cell lines

Journal of Cellular Biochemistry
Stefanie V SchützLudwig Rinnab

Abstract

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 inhibi...Continue Reading

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Oct 9, 2013·The Journal of Steroid Biochemistry and Molecular Biology·Javid A DarZhou Wang
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