HO-1 INHIBITS PROSTATE TUMOR GROWTH BY DOWNREGULATING METALLOPROTEINASE 9

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

Miami, USA

Congreso; Heme Oxygenases in Biology & Medicine; 2009

Prostate cancer (PCa) is the second leading cause of cancer-associated deathin men. Inflammation has been recognized as a risk factor for this disease.Heme Oxygenase 1 (HO-1), the inducible isoform of the rate-limiting enzymein heme degradation, counteracts oxidative and inflammatory damage. Here weinvestigated the regulated expression of HO-1 and its functionalconsequences in androgen sensitive (MDA PCa 2b and LNCaP) and insensitive(PC3) PCa cell lines. Our results show that HO-1 levels are markedlydecreased in PC3 compared to MDAPCa2b and LNCaP. Hemin treatment increasedHO-1 at both protein and mRNA levels in all cell lines and decreased cellproliferation and invasion. PC3 cells showed a substantially reducedmotility upon hemin treatment. Furthermore, over-expression of HO-1 in PC3resulted in markedly reduced cell proliferation and migration.  Accordingly,siRNA-mediated silencing of HO-1 expression in MDA PCa 2b cells resulted inincreased proliferation and invasion. Using RT-qPCR-generated gene array weobserved a set of inflammatory and angiogenic genes up- or down-regulated inresponse to HO-1 over-expression, identifying MMP9 as a novel downstreamtarget of HO-1. MMP9 production and activity was down-regulated by HO-1over-expression. Furthermore, PC3 cells stable transfected with HO-1(PC3HO-1) and controls were injected into *nu/nu* mice for analysis of *invivo *tumor xenograft phenotype. Tumor growth and MMP9 expression wassignificantly reduced in PC3HO-1 tuors compared to controls xenografts.Takentogether these results implicate HO-1 in PCa migration and proliferationsuggesting its potential role as a therapeutic target in clinical settings.