GLUCOCORTICOID RECEPTOR FUNCTION IS MODULATED BY HO-1 IN PROSTATE CANCER

LEONARDI DAIANA; PAEZ ALEJANDRA; SCHUSTER FEDERICO; ANSELMINO NICOLAS; BRANDANI JAVIER; ABBATE MERCEDES; GUERON GERALDINE; COTIGNOLA JAVIER; VAZQUEZ ELBA

Congreso; The Third South American Symposium in Signal Transduction and Molecular Medicine; 2015

Glucocorticoid receptor (GR) plays an important role in inflammation and cancer progression, GR signaling exhibits tumor suppressor activity in prostate cancer (PCa) cells and dexamethasone (Dex) has been used for the treatment of castration-resistant prostate cancer. However, many authors report that the GR can substitute the androgen receptor (AR) and activate the AR signaling cascade. Given that inflammation is critical for the development and progression of PCa, we first assessed whether heme oxygenase 1 (HO-1), an anti-oxidant and anti-inflammatory protein, could regulate GR. First, we selected the optimum PC3 cells culture conditions (Dex concentration and time exposure) that produced the highest induction of GR at mRNA levels. To study GR transcriptional activity, PC3 cells were transfected with a luciferase expression plasmid containing glucocorticoid response elements (MMTV-luc), and were treated either with hemin (a potent specific inducer of HO-1, 80μM, 24h), Dex (10-8 M, 6h) or both drugs. In all cases cells were cultured in medium with charcoal-dextran treated serum. Hemin significantly reduced (45%; p=0.03) the GR basal activity as well as Dex induced GR activity (35%; p=0.01). GR nuclear translocation was observed under Dex treatment by confocal microscopy, while GR cytoplasmic retention was observed when cells were exposed to hemin+Dex. We showed physical interaction between GR and HO-1 in the nuclear and cytoplasmic compartment of cells by co-immunoprecipitation. All together, this is the first report to show an HO-1/GR association and HO-1 modulation of GR expression and activity in PCa cells, validating HO-1 as a potential target for clinical settings.