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

LEONARDI, DAIANA BEATRIZ; BRANDANI, JAVIER NAHUEL; JAWORSKI, FELIPE MARTIN; PAEZ, ALEJANDRA VERÓNICA; VAZQUEZ, ELBA SUSANA; COTIGNOLA, JAVIER HERNÁN; GUERON, GERALDINE; PECCI, A; NUÑEZ, MYRIAM

Mar del Plata

Congreso; LXI Reunión Científica anual de la Sociedad Argentina de la Investigación Clínica. SAIC; 2016

SAIC

Glucocorticoids are used in the treatment of prostate cancer (PCa) to control disease progression, and to reduce cancer-related pain and side effects of chemo and hormonal therapy. However, they may also have the potential to drive castration-resistant prostate cancer growth via a mutated androgen receptor or glucocorticoid receptor (GR). Given that inflammation is critical for the development and progression of PCa, we first studied whether heme oxygenase 1 (HO-1), an anti-oxidant and anti-inflammatory protein, regulates GR. Dexamethasone (Dex, 10 nM for 6 h) induced GR mRNA levels in PC3 (GR+/AR-) and C4-2B (GR+/AR+). GR transcriptional activity was analysed in PCa cell lines transfected with a reporter plasmid containing glucocorticoid response elements. Cells were treated either with hemin (a potent specific inducer of HO-1, 80 µM for 24 h), Dex or both drugs. In all cases cells were cultured in medium with charcoal-dextran treated serum. Hemin significantly reduced (45%; p=0.03) basal and Dex-induced (35%; p=0.01) GR activity in PC3 cells but not in C4-2B. By confocal microscopy the GR nuclear translocation was detected after Dex treatment, while hemin+Dex co-treatment resulted in a partial GR cytoplasmic retention. Co-immunoprecipitation assays showed physical interaction between GR and HO-1 in nuclear and cytoplasmic compartments. PC3 xenografts were generated in nude mice by s.c. inoculation (3.6x106 cells). Animals received 6 i.p. dosis of Dex (0.2 mg/kg), hemin (25 mg/kg) or both drugs for 12 days. Dex reduced the tumour growth (p