CONICET | Buscador de Institutos y Recursos Humanos

Prostate cancer is one of the leading causes of cancer death in men. Activation of the androgen receptor (AR) is a key step in the development of prostate cancer (PCa). STAT3 signaling has ben identified as one of the mechanisms in AR activation and disruption of STAT3/NFKB activity is associated to cancer progression. HO-1, the rate-limiting enzyme in heme degradation, may play a key role in prostate carcinogenesis that may be independent of its catalytic function. We sought to explore whether HO-1 operates on AR transcriptional activity through the STAT3 and NFKB axis. Our results display that HO-1 induction in PCa cells represses AR activation. Furthermore, HO-1 and STAT3 directly interact as determined by co-immunoprecipitation studies. Forced-expression of HO-1 increases STAT3 cytoplasmic retention. When PCa cells were transfected with a constitutively active STAT3 mutant, AR and STAT3 downstream target genes were abrogated under hemin treatment, a specific inducer of HO-1. Additionally, a significant decrease in pSTAT3 protein levels was detected in the nuclear fraction of these cells. Confocal microscopy images exhibit a decreased rate of AR/STAT3 nuclear co-localization under HO-1 induction. Moreover, the NFKB signaling pathway was significantly impaired together with decreased nuclear translocation of this factor. Strikingly, in vivo studies confirmed STAT3 cytoplasmic retention in PC3 tumors over-expressing HO-1 grown as xenografts in nude mice. These results provide a novel function for HO-1 down-modulating AR transcriptional activity in PCa, interfering with STAT3 and NFKB signaling, unmasking its anti-tumoral role in PCa.