Abstract
Abstract 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 cancer treatments joining the ranks of surgery, chemotherapy and radiotherapy has been a source of renewed hope. Heme oxygenase-1 (HO-1) counteracts oxidative and inflammatory damage. It has become increasingly clear that in addition to its effect on blocking proliferation, invasion and migration, other mechanisms including a direct effect on angiogenic factors 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 present study, 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, KDR and α5β1 integrin. Our results indicated also that HO-1 counteracts oxidative imbalance reducing ROS levels. An in vivo angiogenic assay showed that intradermal inoculation of PC3 cells stable transfected with HO-1 (PC3HO-1) generated tumours less vascularised than controls, with decreased microvessel density and reduced CD34 and MMP9 positive staining. 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 under HO-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 this pathway. Taken together, these data supports an unprecedented role of HO-1, challenging the angiogenic-switch in prostate carcinogenesis outlining a rationale for its development as an anticancer target in PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5290. doi:1538-7445.AM2012-5290
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