Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells

Biochem Pharmacol. 2006 Jun 28;72(1):19-31. doi: 10.1016/j.bcp.2006.03.020. Epub 2006 Mar 29.


Hypoxia appears to induce a program which shifts the cellular phenotype toward an increase in extracellular adenosine. Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. Since in gliomas there is a strong correlation between HIF-1alpha expression, tumor grade and tumor vascularization, the aim of this study was to investigate whether adenosine may regulate HIF-1 in human glioblastoma cell lines. The results indicate that in the human hypoxic A172 and U87MG glioblastoma cell lines adenosine up-regulates HIF-1alpha protein expression via the A(3) receptor subtype. In particular, we investigated the effect of A(3) receptor antagonists on HIF-1 and vascular endothelial growth factor (VEGF) expression. We found that A(3) antagonists inhibit adenosine-induced HIF-1alpha and VEGF protein accumulation in the hypoxic cells. Investigations in the molecular mechanism showed that A(3) receptor stimulation activates p44/p42 and p38 MAPKs that are required for A(3)-induced increase of HIF-1alpha and VEGF. Further studies are required to demonstrate the in vivo relevance of these observations with regard to the proposed role for adenosine as a key element in hypoxia and in tumors.

MeSH terms

  • Adenosine / pharmacology*
  • Adenosine A3 Receptor Antagonists
  • Blotting, Western
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Silencing
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phenylurea Compounds / pharmacology
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptor, Adenosine A3 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triazoles / pharmacology
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adenosine A3 Receptor Antagonists
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MRE 3008-F20
  • Phenylurea Compounds
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptor, Adenosine A3
  • Triazoles
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Adenosine