Heme oxygenase 1 (HO-1): an auspicious target for state of the art anti-angiogenic therapeutic strategies and new insights in prostate carcinogenesis.

GUERON G; FERRANDO M; ELGUERO B; GIUDICE J; SALLES A; LABANCA E; JAWORSKY F; COLOMBO L; MEISS R; NAVONE; DE SIERVI A ; VAZQUEZ E

Chicago

Congreso; Annual Meeting American Association for Cancer Research AACR; 2012

AACR

Prostate cancer (PCa) is a leading cause of death among males. Angiogenesis is critical during tumor initiation and progression. The arrival of anti-angiogenic agents as cancertreatments joining the ranks of surgery, chemotherapy and radiotherapy has been a source of renewed hope. Heme oxygenase-1 (HO-1) counteracts oxidative and inflammatorydamage. It has become increasingly clear that in addition to its effect on blocking proliferation, invasion and migration, other mechanisms including a direct effect on angiogenicfactors may account for its anti-tumoral role in PCa. To further assess its properties, we investigated its potentiality to modulate PCa associated-angiogenesis. In the presentstudy, we identified in PCa cells a set of inflammatory and pro-angiogenic genes down-regulated in response to HO-1 overexpression, in particular VEGFA, VEGFC, HIF1α, KDRand α5β1 integrin. Our results indicated also that HO-1 counteracts oxidative imbalance reducing ROS levels. An in vivo angiogenic assay showed that intradermal inoculation ofPC3 cells stable transfected with HO-1 (PC3HO-1) generated tumours less vascularised than controls, with decreased microvessel density and reduced CD34 and MMP9 positivestaining. Interestingly, longer term grown PC3HO-1 xenografts displayed reduced neovascularization with the subsequent down-regulation of VEGFR2 expression. Furthermore,using immunofluorescence and structured illumination microscopy we visualized NFκB retention in cytoplasm and demonstrated a higher rate of co-localization with HO-1 underHO-1 over-expression. These observations correlated with repressed nuclear factor κB (NF-κB)-mediated transcription from an NF-κB responsive luciferase reporter construct,induced accumulation of IκB and decreased IKK mRNA levels under HO-1 modulation. These evidences strongly suggest that HO-1 may regulate angiogenesis through thispathway. Taken together, these data supports an unprecedented role of HO-1, challenging the angiogenic-switch in prostate carcinogenesis outlining a rationale for itsdevelopment as an anticancer target in PCa.