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Research ArticleCellular and Molecular

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

Elizabeth A. Vecchio, Christina Y. R. Tan, Karen J. Gregory, Arthur Christopoulos, Paul J. White and Lauren T. May
Journal of Pharmacology and Experimental Therapeutics April 2016, 357 (1) 36-44; DOI: https://doi.org/10.1124/jpet.115.230003
Elizabeth A. Vecchio
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Christina Y. R. Tan
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Karen J. Gregory
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Arthur Christopoulos
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Paul J. White
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Lauren T. May
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Abstract

Aberrant ligand-independent G protein–coupled receptor constitutive activity has been implicated in the pathophysiology of a number of cancers. The adenosine A2B receptor (A2BAR) is dynamically upregulated under pathologic conditions associated with a hypoxic microenvironment, including solid tumors. This, in turn, may amplify ligand-independent A2BAR signal transduction. The contribution of A2BAR constitutive activity to disease progression is currently unknown yet of fundamental importance, as the preferred therapeutic modality for drugs designed to reduce A2BAR constitutive activity would be inverse agonism as opposed to neutral antagonism. The current study investigated A2BAR constitutive activity in a heterologous expression system and a native 22Rv1 human prostate cancer cell line exposed to hypoxic conditions (2% O2). The A2BAR inverse agonists, ZM241385 [4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol] or PSB-603 (8-(4-(4-(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 A2BARs by the endogenous agonist adenosine. Our study is the first to reveal that wild-type human A2BARs have high constitutive activity in both model and native cells. Furthermore, our findings demonstrate that this ligand-independent A2BAR constitutive activity is sufficient to promote prostate cancer cell proliferation in vitro. More broadly, A2BAR constitutive activity may have wider, currently unappreciated implications in pathologic conditions associated with a hypoxic microenvironment.

Footnotes

    • Received October 13, 2015.
    • Accepted January 19, 2016.
  • This work was supported by the National Health and Medical Research Council (NHMRC) of Australia [1084487] and the Australian Research Council [DE130100117]. L.T.M. is an Australian Research Council (ARC) Discovery Early Career Researcher Award (DECRA) Postdoctoral Research Fellow [DE130100117], K.J.G. is an NHMRC CJ Martin Fellow [1013709], and A.C. is an NHMRC Principal Research Fellow [1041875]. E.A.V. holds an Australian Postgraduate Award and an Australian Cancer Therapeutics scholarship.

  • dx.doi.org/10.1124/jpet.115.230003.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 357 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 357, Issue 1
1 Apr 2016
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Research ArticleCellular and Molecular

Adenosine A2B Receptor Constitutive Activity

Elizabeth A. Vecchio, Christina Y. R. Tan, Karen J. Gregory, Arthur Christopoulos, Paul J. White and Lauren T. May
Journal of Pharmacology and Experimental Therapeutics April 1, 2016, 357 (1) 36-44; DOI: https://doi.org/10.1124/jpet.115.230003

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Research ArticleCellular and Molecular

Adenosine A2B Receptor Constitutive Activity

Elizabeth A. Vecchio, Christina Y. R. Tan, Karen J. Gregory, Arthur Christopoulos, Paul J. White and Lauren T. May
Journal of Pharmacology and Experimental Therapeutics April 1, 2016, 357 (1) 36-44; DOI: https://doi.org/10.1124/jpet.115.230003
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