Involvement of A3 Adenosine Receptor in Neuroblastoma Progression via Modulation of the Hypoxic/Angiogenic Pathway

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The clinical course may range from spontaneous regression towards ganglioneuroblastoma/ganglioneuroma or maturation to a very aggressive form characterized by an extensive hypoxic area. In solid tumors, extracellular microe...

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Bibliographic Details
Published in:Journal of molecular neuroscience 2019-09, Vol.69 (1), p.166-176
Main Authors: Maugeri, Grazia, D’Amico, Agata Grazia, Federico, Concetta, Saccone, Salvatore, Giunta, Salvatore, Cavallaro, Sebastiano, D’Agata, Velia
Format: Article
Language:English
Subjects:
Adenosine
Angiogenesis
Biomedical and Life Sciences
Biomedicine
Cell Biology
Children
Extracellular signal-regulated kinase
Hypoxia
Hypoxia-inducible factors
Kinases
Malignancy
MAP kinase
Modulation
Neuroblastoma
Neurochemistry
Neurology
Neuromodulation
Neurosciences
Protein kinase
Proteomics
Regression analysis
Retinoic acid
Solid tumors
Transcription factors
Tumors
Vascular endothelial growth factor
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Summary:Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The clinical course may range from spontaneous regression towards ganglioneuroblastoma/ganglioneuroma or maturation to a very aggressive form characterized by an extensive hypoxic area. In solid tumors, extracellular microenvironment hypoxia induces the transcription of hypoxia-inducible factors (HIFs) leading to synthesis of pro-angiogenic factor, VEGF; also, it increases extracellular adenosine production from ATP breakdown. To date, the role of this nucleoside in the hypoxic/angiogenic pathway characterizing the core of cancer mass has not been investigated yet. Therefore, the aim of the present study was to analyze the adenosine effect on modulation of the HIF-1α/2α/VEGF pathway mediated through A 3 AR binding. To this end, we have used a selective A 3 AR agonist IB-MECA or antagonist VUF 5574 in an in vitro model of malignant undifferentiated and all-trans retinoic acid (RA)-differentiated SH-SY5Y cells, representing the benign form of NB. Our results have shown that specific A 3 AR stimulation induces HIF and VEGF expression through the activation of mitogen-activated protein kinase/Erk kinase signaling cascade. In conclusion, the data suggest that A 3 AR may represent a marker of NB malignancy as well as a drug target for treatment of this solid tumor. Graphical Abstract
ISSN:0895-8696
1559-1166
DOI:10.1007/s12031-019-01346-4