title: Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer.
abstract: Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Once a tumor is established it may attain further characteristics via mutations or hypoxia, which stimulate new blood vessels. Angiogenesis is a hallmark in the pathogenesis of cancer and inflammatory diseases that may predispose to cancer. Heme oxygenase-1 (HO-1) counteracts oxidative and inflammatory damage and was previously reported to play a key role in prostate carcinogenesis. To gain insight into the anti-tumoral properties of HO-1, we investigated its capability to modulate PCa associated-angiogenesis. In the present study, we identified in PC3 cells a set of inflammatory and pro-angiogenic genes down-regulated in response to HO-1 overexpression, in particular VEGFA, VEGFC, HIF1α and α5β1 integrin. Our results indicated 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. Additionally, HO-1 repressed nuclear factor κB (NF-κB)-mediated transcription from an NF-κB responsive luciferase reporter construct, which strongly suggests that HO-1 may regulate angiogenesis through this pathway. Taken together, these data supports a key role of HO-1 as a modulator of the angiogenic switch in prostate carcinogenesis ascertaining it as a logical target for intervention therapy.
authors.affiliation: Department of Biological Chemistry, School of Sciences, CONICET, University of Buenos Aires, Intendente Guiraldes 2160, Ciudad Universitaria, Pabellón II, 2do Piso, 1428, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Ferrando
authors.forename: G
authors.initials: G
authors.lastname: Gueron
authors.forename: B
authors.initials: B
authors.lastname: Elguero
authors.forename: J
authors.initials: J
authors.lastname: Giudice
authors.forename: A
authors.initials: A
authors.lastname: Salles
authors.forename: F Coluccio
authors.initials: FC
authors.lastname: Leskow
authors.forename: E A
authors.initials: EA
authors.lastname: Jares-Erijman
authors.forename: L
authors.initials: L
authors.lastname: Colombo
authors.forename: R
authors.initials: R
authors.lastname: Meiss
authors.forename: N
authors.initials: N
authors.lastname: Navone
authors.forename: A
authors.initials: A
authors.lastname: De Siervi
authors.forename: E
authors.initials: E
authors.lastname: Vazquez
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000378:metabolism / Q000494:pharmacology*; D006652:Histological Techniques; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D011471:Prostatic Neoplasms / Q000098:blood supply*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
chemical_list: D017931:DNA Primers; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D008156:Luciferases; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1