Abstract
Abstract Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. The metastatic spread of PCa cells and the ability to survive when reaching the metastatic nitch is affected by growth factors, chemokines, angiogenic factors and hormones. Heme oxygenase-1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, counteracts oxidative and inflammatory damage. Here we investigated its nuclear translocation in androgen sensitive (MDAPCa2b and LNCaP) and insensitive (PC3) PCa cell lines. Our results show that endogenous levels of HO-1 are markedly lower in PC3 compared to MDAPCa2b and LNCaP. Hemin treatment, a potent and specific inducer of HO-1, increased protein levels with a resulting nuclear translocation in PCa cell lines. Stable transfection of HO-1 in PC3 (PC3HO-1) also showed a significant nuclear translocation. Furthermore, human prostate cancer PC3HO-1 cells growing subcutaneously in athymic nude mice showed significant HO-1 nuclear staining (detected by immunohistochemsitry and immunofluorescence) compared to PC3pcDNA3 xenografts. 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 VEGFA as a novel downstream target of HO-1. HO-1 modulation limited the metastatic potential of neoplastic cells by down-regulating VEGFA production. An in vivo angiogenic assay also demonstrated that PC3HO-1 tumors presented less neovascularization than tumors derived from control cells, giving further evidence to support HO-1 anti-angiogenic function. These results implicate for the first time HO-1 in the regulation of key proinflammatory factors, involved in PCa progression. Taken together our results suggest that HO-1 may be a potential target for therapeutic interventions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-245.
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