Critical role of endogenous Heme Oxygenase 1 (HO-1) as a tuner of the invasive potential of prostate cancer in vitro and in vivo through MMP9 modulation.

GUERON G; FERRANDO M; SALIERNO M; DE LUCA P; ELGUERO B; MEISS R; DE SIERVI A; NAVONE N; VAZQUEZ ES

Denver, USA

Congreso; American Association for Cancer Research 101st Annual Meeting 2009; 2009

American Association for Cancer Research (AACR)

Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Inflammation has been recognized as a risk factor for this disease. Heme Oxygenase 1 (HO- 1), the inducible isoform of the rate-limiting enzyme in heme degradation, counteracts oxidative and inflammatory damage. Here we investigated the regulated expression of HO-1 and its functional consequences in androgen sensitive (MDA PCa 2b and LNCaP) and insensitive (PC3) PCa cell lines. Our results show that HO-1 levels are markedly decreased in PC3 compared to MDAPCa2b and LNCaP. Hemin treatment increased HO-1 at both protein and mRNA levels in all cell lines and decreased cell proliferation and invasion. PC3 cells showed a substantially reduced motility upon hemin treatment. Furthermore, over-expression of HO-1 in PC3 resulted in markedly reduced cell proliferation and migration. Accordingly, siRNA-mediated silencing of HO-1 expression in MDA PCa 2b cells resulted in increased proliferation and invasion. Using RT-qPCR-generated gene array we observed a set of inflammatory and angiogenic genes up- or down-regulated in response to HO-1 overexpression, identifying MMP9 as a novel downstream target of HO-1. HO-1 over- expression limited the metastatic potential of neoplastic cells by down-regulating MMP9 production and activity. Furthermore, athymic nude mice bearing s.c. human prostate cancer PC3HO-1 xenografts showed significant MMP9 down-regulation (detected by immunohistochemsitry and RT-qPCR) compared to PC3Bgal xenografts. Taken together these results implicate HO-1 for the first time in PCa cell migration, proliferation and invasion, suggesting its potential role as a therapeutic target in clinical settings.