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DOI: 10.1055/s-0040-1710940
Hif-1α-dependent expression of Adenosine Receptor 2B (ADORA2B) promotes autonomous growth, EMT as well as CSC enrichment in cultures of cells derived from head and neck squamous cell carcinomas
Purpose The adenosinergic system plays an important role in the development of cancer. The present study focused on the regulation of the G-protein coupled receptor (GPCR) adenosine receptor 2B (ADORA2B) expression in head and neck squamous cell carcinoma (HNSCC)-derived tumor cells, and further on the identification of ADORA2B-mediated oncogenic signaling and function. Our data suggest ADORA2B being an important biomarker as well as an interesting therapeutic target for treatment of HNSCC.
Methods HNSCC-derived cell lines were grown under normoxic and hypoxic conditions either as 2D monolayer or spheroid cultures in the absence or presence of the ADORA2B ligands or inhibitors or inhibitors of GPCR-associated signaling molecules. ADORA2B activity was studied by intracellular cAMP level determination. Markers for hypoxia, epithelial-mesenchymal transition (EMT) as well as cancer stem cell (CSC) enrichment were evaluated by Western Blots and qRT-PCR. Moreover, ADORA2B-shRNA approaches as well as in vivo tumor xenografts in CAM assays were applied.
Results We found a HIF-1α-mediated upregulation of ADORA2B in HNSCC-derived cell lines under different culture conditions. Activator and inhibitor studies revealed a constitutive, ligand-independent ADORA2B activity inducing cAMP-dependent (Ga<sub>s</sub>) as well as independent (Ga<sub>q</sub>, Ga<sub>i/0</sub>) signaling in HNSCC, which are essential for processes like EMT and CSC enrichment in vitro. Moreover, in in vivo xenograft experiments, chemical and genetic abrogation of ADORA2B activity impaired tumor initiation and growth associated with decreased tumor vascularization.
Conclusion Our findings characterize ADORA2B as a crucial player in development and maintenance of HNSCC and, therefore, as a potential therapeutic target for HNSCC treatment.
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Publication History
Article published online:
10 June 2020
© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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