Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

Abstract

Aberrant ligand-independent G protein-coupled receptor constitutive activity has been implicated in the pathophysiology of a number of cancers. The adenosine A 2B receptor (A 2B AR) is dynamically upregulated under pathologic conditions associated with a hypoxic microenvironment, including solid tumors. This, in turn, may amplify ligand-independent A 2B AR signal transduction. The contribution of A 2B AR constitutive activity to disease progression is currently unknown yet of fundamental importance, as the preferred therapeutic modality for drugs designed to reduce A 2B AR constitutive activity would be inverse agonism as opposed to neutral antagonism. The current study investigated A 2B AR constitutive activity in a heterologous expression system and a native 22Rv1 human prostate cancer cell line exposed to hypoxic conditions (2% O 2 ). (4-chlorophenyl)piperazide-1-sulfonyl)phenyl)-1-propylxanthine), mediated a concentration-dependent decrease in baseline cAMP levels in both cellular systems. Proliferation of multiple prostate cancer cell lines was also attenuated in the presence of PSB-603. Importantly, both the decrease in baseline cAMP accumulation and the reduction of proliferation were not influenced by the addition of adenosine deaminase, demonstrating that these effects are not dependent on stimulation of A 2B ARs by the endogenous agonist adenosine. Our study is the first to reveal that wild-type human A 2B ARs have high constitutive activity in both model and native cells. Furthermore, our findings demonstrate that this ligand-independent A 2B AR constitutive activity is sufficient to promote prostate cancer cell proliferation in vitro. More broadly, A 2B AR constitutive activity may have wider, currently unappreciated implications in pathologic conditions associated with a hypoxic microenvironment.

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

“…[113] Moreover, stimulation of A 2B receptor with a non-selective adenosine analog NECA induces apoptosis in ovarian cancer cells. [114] Nonetheless,while a number of studies demonstrate that stimulation of A 2B adenosine receptor in some cancer cell types promotes proliferation, whereby knockdown or pharmacological inhibition of this receptor reduces tumor cell growth and promotes apoptosis, [107][108][109][110][111] opposite results have been also described. [112,113] The discrepancy might likely depend on the cancer cell types, the expression levels of this receptor on tumor cells and the selectivity and/or concentrations of pharmacological tools used in the experimental settings.…”

“…A 2B adenosine receptor is highly expressed in prostate cancer cell lines and selective antagonist of A 2B adenosine receptors or silencing A 2B receptors blocked the proliferative effects induced by a non-selective adenosine analog NECA. [107,108] Other studies indicate that A 2B adenosine receptor is highly expressed also in oral squamous carcinoma cell lines, as well as in human oral carcinoma tissues, where its expression is correlated with those of HIF-1. [109] Studies by Gessi et al [110] demonstrate that in colon cancer cells, although at the mRNA levels A 2B receptor is more expressed than A 1 , A 2A and A 3 , the density of A 3 receptors is the highest among the adenosine receptor subtypes.…”

Adenosine A2B Receptor: From Cell Biology to Human Diseases

“…However, recent advances in pharmacological and molecular tools have allowed researchers to determine that A 2B AR can be coupled to distinct intracellular signaling pathways and play physiological roles that differ from those of A 2A AR (Yang et al, 2006, 2010a; Grenz et al, 2012a; Johnston-Cox et al, 2012; Koupenova et al, 2012; Eckle et al, 2013; Morello and Miele, 2014; Patel et al, 2014; Tak et al, 2014; Eisenstein et al, 2015; Tang et al, 2015; Vecchio et al, 2016). In this review, we discuss our current understanding of the cellular functions of A 2B AR and their implications for the pathogenesis of several human diseases.…”

Adenosine A2B receptor: novel anti-cancer therapeutic implications

“…Pharmacological inhibition or knockdown of A2B decreases proliferation of tumour cells [15][16][17] and a role for A2B in tumour progression and metastasis is supported by multiple studies in bladder, breast, colon, prostate and other cancers [14,15,[18][19][20] .…”

“…Moreover, constitutive activation of the adenosine receptor A2B in response to a hypoxic microenvironment has been associated with increased proliferation of prostate cancer cells in vitro [20] .…”