HO-1 induction interrupts the glucocorticoid receptor signaling in prostate cancer cells

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

Philadelphia, Pennsylvania

Congreso; AACR Annual Meeting 2015; 2015

Although initially treatable, prostate cancer can recur in a hormone refractory form that is not responsive to current available therapies. The mortality rate associated with hormone refractory prostate cancer is high, and there is an urgent need for new therapeutic agents to treat prostate cancer. In order to overcome the toxicity of chemotherapy, glucocorticoids have long been used in the treatment of hormone­resistant prostate cancer. Nevertheless, many authors reported that the glucocorticoid receptor (GR) can substitute the androgen receptor and activate a similar but distinguishable set of genes. A common feature of prostate cancer is the dependence on activated signal transducer and activator of transcription 3 (STAT3), a transcription factor for survival and a coactivator of GR signaling. We have previously demonstrated that the induction of HO1 , an antioxidant and antiinflammatory protein, increases STAT3 cytoplasmic retention, interfering with its signaling and promotes HO1 nuclear localization. Our aim is to study the effect of HO1 induction on GR signaling in prostate cancer. PC3 cells were treated with Dexamethasone (Dex) at different concentrations (1 0­7, 1 0­8 and 1 0­9 M) during 24 h in 1 0% charcoaled­serum media and were exposed to the pharmacological inducer of HO1 (hemin, 80 uM, 24 h). Control cells were treated with vehicles. No significant differences in cell viability were detected by MTT assay. In order to investigate whether HO1 interrupts the GR transcriptional activity, PC3 cells were transfected with a luciferase reporter plamid containing three glucocorticoid response elements. Transfected cells were treated either with hemin (80 uM, 24 h), Dex (1 0­8 M, 6 h) or the combination of both drugs. The GR transcriptional activation was confirmed when cells were treated with the agonist Dex (p