Abstract
Several evidences indicate that the ubiquitous nucleoside adenosine, acting through A1, A2A, A2B, and A3 receptor (AR) subtypes, plays crucial roles in tumor development. Adenosine has contrasting effects on cell proliferation depending on the engagement of different receptor subtypes in various tumors. The involvement of A2AARs in human A375 melanoma, as well as in human A549 lung and rat MRMT1 breast carcinoma proliferation has been evaluated in view of the availability of a novel A2AAR antagonist, with high affinity and selectivity, named as 2-(2-furanyl)-N5-(2-methoxybenzyl)[1,3]thiazolo[5,4-d]pyrimidine-5,7-diammine (TP455). Specifically, the signaling pathways triggered in the cancer cells of different origin and the antagonist effect of TP455 were investigated. The A2AAR protein expression was evaluated through receptor binding assays. Furthermore, the effect of A2AAR activation on cell proliferation at 24, 48 and 72 hours was studied. The selective A2AAR agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS21680), concentration-dependently induced cell proliferation in A375, A549, and MRMT1 cancer cells and the effect was potently antagonized by the A2AAR antagonist TP455, as well as by the reference A2AAR blocker 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). As for the signaling pathway recruited in this response we demonstrated that, by using the specific inhibitors of signal transduction pathways, the effect of A2AAR stimulation was induced through phospholipase C (PLC) and protein kinase C-delta (PKC-δ). In addition, we evaluated, through the AlphaScreen SureFire phospho(p) protein assay, the kinases enrolled by A2AAR to stimulate cell proliferation and we found the involvement of protein kinase B (AKT), extracellular regulated kinases (ERK1/2), and c-Jun N-terminal kinases (JNKs). Indeed, we demonstrated that the CGS21680 stimulatory effect on kinases was strongly reduced in the presence of the new potent compound TP455, as well as by ZM241385, confirming the role of the A2AAR. In conclusion, the A2AAR activation stimulates proliferation of A375, A549, and MRMT1 cancer cells and importantly TP455 reveals its capability to counteract this effect, suggesting selective A2AAR antagonists as potential new therapeutics.
Highlights
Adenosine, a ubiquitous purine nucleoside, is considered as an important modulator of tissue function, increasing its concentrations under adverse metabolic conditions
U0126, SP600125, and SH5 strongly reduced the effect of CGS21680 on cell proliferation, whilst SB202190 did not. These results suggest the involvement of ERK1/2, Jun-N-terminal kinase 1/2 (JNK1/2) mitogen-activated protein kinases (MAPK) kinases, and AKT in the increase of cell proliferation mediated by A2AAR activation
Adenosine may act as both an anti- or pro-tumoral endogenous nucleoside depending on which adenosine receptor subtype is recruited (Borea et al, 2016, 2017)
Summary
A ubiquitous purine nucleoside, is considered as an important modulator of tissue function, increasing its concentrations under adverse metabolic conditions. An important role of adenosine in human cancerogenesis has been evidenced, as it regulates almost all the phases of cancer development including immunoescaping, cell proliferation, angiogenesis and metastasis, by recruiting different adenosine receptor subtypes (Antonioli et al, 2013a,b; Borea et al, 2017). It is well established the relevance of immune cells in the fight against tumors and adenosine, that increases in hypoxic solid tumors, decreases the recognition of cancer cells by cytolytic T cells (Blay et al, 1997; Merighi et al, 2003; Muller-Haegele et al, 2014). TP455 antagonizes this effect, adding a piece of evidence on the effects of selective A2AAR antagonists on cancer development supporting their role as potential new anticancer drugs
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