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

Stefania Merighi; Annalisa Benini; Prisco Mirandola; Stefania Gessi; Katia Varani; Edward Leung; Stephen Maclennan; Pier Andrea Borea

doi:10.1016/j.bcp.2006.03.020

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.

Authors

Stefania Merighi¹, Annalisa Benini, Prisco Mirandola, Stefania Gessi, Katia Varani, Edward Leung, Stephen Maclennan, Pier Andrea Borea

Affiliation

¹ Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, 44100 Ferrara, Italy.

PMID: 16682012
DOI: 10.1016/j.bcp.2006.03.020

Abstract

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

Substances

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