Role and mechanism of arsenic in regulating angiogenesis

PLoS One. 2011;6(6):e20858. doi: 10.1371/journal.pone.0020858. Epub 2011 Jun 8.


Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS) generation, which activates AKT and ERK1/2 signaling pathways and increases the expression of hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF). Inhibition of ROS production suppresses angiogenesis by decreasing AKT and ERK activation and HIF-1 expression. Inhibition of ROS, AKT and ERK1/2 signaling pathways is sufficient to attenuate arsenic-inducing angiogenesis. HIF-1 and VEGF are downstream effectors of AKT and ERK1/2 that are required for arsenic-inducing angiogenesis. These results shed light on the mechanism of arsenic in regulating angiogenesis, and are helpful to develop mechanism-based intervention to prevent arsenic-induced carcinogenesis and angiogenesis in the future.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arsenic / toxicity*
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / prevention & control
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neovascularization, Pathologic / chemically induced*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Time Factors
  • Vascular Endothelial Growth Factor A / genetics


  • Hypoxia-Inducible Factor 1
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Arsenic