HO-1 modulates gene expression in prostate cancer through the regulation of STAT3 signaling pathway.

ELGUERO B; GUERON G; MEISS R; COLLUCCIO-LESKOW F; DE SIERVI A; VAZQUEZ E

Edimburgo

Congreso; 7th INTERNATIONAL MEETING ON HEME OXYGENASE & RELATED ENZYMES; 2012

Chronic inflammation is an important etiologic factor in the development of prostate cancer (PCa). The heme oxygenase-1 (HO-1), a cytoprotective and anti-inflammatory protein, is involved in prostate carcinogenesis. Previously we demonstrated that HO-1 interacts with STAT3, a transcription factor constitutively active in prostate tumors. The aim of this study was to identify the effect of the interaction of STAT3 with HO-1 in PCa gene expression. We transfected cell line LNCaP, androgen-sensitive, with plasmid expressing constitutively active STAT3 and control plasmid, and evaluate the expression of PSA (AR transcriptional target) and Bcl XL (STAT3 target) under treatment with hemin (inducer of HO-1 specific, 80μM, 24h) and / or testosterone (10μM, 24h). The activation of STAT3 induced the expression of PSA (3.79 fold, P <0.05) and Bcl XL (3.8 fold, p <0.05) in the presence of testosterone. However, the combined treatment of testosterone and hemin produced significant repression (0.6 fold in PES, p <0.01 and 0.4 fold in Bcl XL, p <0.01) mRNA levels. By immunofluorescence it was found a differential cellular localization when LNCaP cells were treated with hemin and IL-6 (inducer of STAT3 pathway) compared to controls treated only with IL-6. The immunohistochemical analysis of tumor samples derived from the PC3 line stably transfected with HO-1 (PC3HO-1) grown as xenografts in nude mice, showed cytoplasmic and nuclear localization of STAT3 in tumors PC3HO-1 regarding the predominantly nuclear location in controls tumors. These results show that HO-1 plays a role in co-regulation of STAT3 with gene expression in PCa. Understanding these mechanisms may allow the development of new therapeutic strategies against this disease.