Abstract
The A1, A2A, A2B and A3 G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A1AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A1AR is mediated via tumor-associated microglial cells. Activation of the A2AAR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition of A2AAR activation by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A2BAR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A2BAR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A3AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-κB, known to act as an A3AR transcription factor. Interestingly, high A3AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A3AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-κB signaling pathways. Taken together, A3ARs that are abundantly expressed in tumor cells may be targeted by specific A3AR agonists, leading to tumor growth inhibition. The unique characteristics of these A3AR agonists make them attractive as drug candidates.
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Abbreviations
- A1AR:
-
A1 adenosine receptor
- A2AAR:
-
A2A adenosine receptor
- A2BAR:
-
A2B adenosine receptor
- A3AR:
-
A3 adenosine receptor
- APCs:
-
Antigen-presenting cells
- AR:
-
Adenosine receptor
- bFGF:
-
Basic fibroblast growth factor
- CCPA:
-
2-Chloro-N 6-cyclopentyladenosine
- CD39:
-
Cluster of differentiation 39
- CD73:
-
Cluster of differentiation 73
- GGAP:
-
Cancer Genome Anatomy Project
- CGS21680:
-
2-p-(2-Carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine 1680
- CHO:
-
Chinese hamster ovary cells
- \(\mathrm{Cl}\! -\!\mathrm{IB} -\mathrm{MECA}\) :
-
2-Chloro-N 6-3-iodobenzyladenosine-5′-N-methyluronamide
- CNS:
-
Central nervous system
- CPA:
-
N 6-Cyclopentyladenosine
- CTLA-4:
-
Cytotoxic T lymphocyte-associated antigen 4
- CTLs:
-
Cytotoxic T lymphocytes
- DPCPX:
-
8-Cyclopentyl-1,3-dipropylxanthine
- EGF:
-
Epidermal growth factor
- Epac:
-
Exchange protein activated by cAMP
- ER:
-
Estrogen receptor
- ERK:
-
Extracellular signal-regulated kinase
- G-CSF:
-
Granulocyte colony stimulating factor
- GPCR:
-
G-protein-coupled receptor
- GSK-3β:
-
Glycogen synthase kinase 3β
- HA:
-
Hyaluronan
- HCC:
-
Hepatocellular carcinoma
- HIF-1:
-
Hypoxia-inducible factor 1
- HMG1b:
-
High mobility group 1b
- HUGO:
-
Human Genome Organization
- \(\mathrm{IB}\rm{\textendash }\mathrm{MECA}\) :
-
Methyl 1-[N 6-(3-iodobenzyl)-adenin-9-yl]-β-d- ribofuronamid
- IKK:
-
IκB kinase
- IL:
-
Interleukin
- Lef/Tcf:
-
Lymphoid enhancer factor/T-cell factor
- MAP:
-
Mitogen-activated protein
- MMP:
-
Metalloproteinase
- MRS1191:
-
3-Ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-( ± )-dihydropyridine-3,5-dicarboxylate
- MTT:
-
1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan thiazolyl
- NECA:
-
Adenosine-5′-N-ethyluronamide
- NF-κB:
-
Nuclear factor kappa B
- NK:
-
Natural killers
- PAMPs:
-
Pathogen-associated molecular patterns
- PARP:
-
Poly(ADP-ribose) polymerase
- PBMCs:
-
Peripheral blood mononuclear cells
- PDTC:
-
Pyrrolidine dithiocarbamate
- PI3K:
-
Phosphoinositide 3-kinase
- PKA:
-
Protein kinase A
- PKB:
-
Protein kinase B
- PKB/Akt:
-
Protein kinase B/Akt
- PLC:
-
Phospholipase C
- PLD:
-
Phospholipase D
- TCR:
-
T-cell receptor
- TGF-β:
-
Transforming growth factor β
- thio-\(\mathrm{Cl}\rm{\textendash }\mathrm{IB}\rm{\textendash }\mathrm{MECA}\) :
-
2-Chloro-N 6-(3-iodobenzyl)-4′-thioadenosine-5′-N-methyluronamide
- TNF-α:
-
Tumor necrosis factor
- VEGF:
-
Vascular endothelial growth factor
- Wt:
-
Wild type
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Fishman, P. et al. (2009). Adenosine Receptors and Cancer. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_14
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