Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer

Angiogenesis. 2011 Dec;14(4):467-79. doi: 10.1007/s10456-011-9230-4. Epub 2011 Aug 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • DNA Primers / genetics
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Heme Oxygenase-1 / metabolism
  • Heme Oxygenase-1 / pharmacology*
  • Histological Techniques
  • Humans
  • Immunohistochemistry
  • Luciferases
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Plasmids / genetics
  • Prostatic Neoplasms / blood supply*
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor C / metabolism


  • DNA Primers
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Luciferases
  • HMOX1 protein, human
  • Heme Oxygenase-1