Abstract
It is well established that some receptor types including G protein-coupled receptors may transduce effects through more than one signaling pathway. This holds also true for A2B adenosine receptors which were shown to trigger an increase in intracellular Ca2+ levels in addition to the canonical stimulation of adenylyl cyclase. We have recently shown that activation of A2B receptors in the breast cancer cell line MBA-MD-231 elicits a reduction in ERK1/2 phosphorylation, an effect that might be exploited in treatment of cancer cell growth and proliferation. In this study, we investigate whether structurally divers agonists show functional selectivity for any of the signaling pathways leading to an increase of intracellular cAMP or Ca2+, or the reduction of ERK1/2 phosphorylation. As agonists, adenosine derivatives were used bearing different substitutions in 2- and 6-position and, in addition, a ligand with a non-nucleoside structure was tested. It was found that all the tested ligands showed similar pharmacological profiles for the three responses investigated in MBA-MD-231 cells. However, the reduction of ERK1/2 phosphorylation occurred with 40–500-fold higher potency compared to stimulation of adenylyl cyclase or increasing intracellular Ca2+ levels. Based on these observations, it seems possible to utilize activation of A2B adenosine receptors expressed in certain cancers to limit cell growth and proliferation due to reduction of MAPK activity without activation of other signaling pathways potentially responsible for side effects.
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01 September 2020
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References
Du X, Ou K, Song T, Zhang W, Cong F, Zhang S, Xiong Y (2015) Adenosine A2B receptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells. Exp Biol Med 240:1472–1479
Feoktistov I, Murray JJ, Biaggioni I (1994) Positive modulation of intracellular Ca2+ levels by adenosine A2b receptors, prostacyclin, and prostaglandin E1 via a cholera toxin-sensitive mechanism in human erythroleukemia cells. Mol Pharmacol 45:1160–1167
Fishman P, Bar-Yehuda S (2003) Pharmacology and therapeutic applications of A3 receptor subtype. Curr Top Med Chem 3:463–469
Fredholm BB, IJzerman AP, Jacobson KA, Klotz K-N, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552
Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Muller CE (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors—an update. Pharmacol Rev 63:1–34
Gao Z-G, Inoue A, Jacobson KA (2018) On the G protein-coupling selectivity of the native A2B adenosine receptor. Biochem Pharmacol 151:201–213
Goldsmith ZG, Dhanasekaran DN (2007) G protein regulation of MAPK networks. Oncogene 26:3122–3142
Graham S, Combes P, Crumiere M, Klotz K-N, Dickenson JM (2001) Regulation of p42/p44 mitogen-activated protein kinase by the human A3 adenosine receptor in transfected CHO cells. Eur J Pharmacol 420:19–26
Gudermann T, Kalkbrenner F, Schultz G (1996) Diversity and selectivity of receptor-G protein interaction. Annu Rev Pharmcol Toxicol 36:429–459
Headrick JP, Peart J (2005) A3 adenosine receptor-mediated protection of the ischemic heart. Vasc Pharmacol 42:271–279
Hodavance SY, Gareri C, Torok RD, Rockman HA (2016) G protein-coupled receptor biased agonism. J Cardiovasc Pharmacol 67:193–202
Kenakin T (2017) Signaling bias in drug discovery. Expert Opin Drug Discov 12:321–333
Klotz K-N, Hessling J, Hegler J, Owman C, Kull B, Fredholm BB, Lohse MJ (1998) Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells. Naunyn Schmiedeberg's Arch Pharmacol 357:1–9
Klotz KN, Camaioni E, Volpini R, Kachler S, Vittori S, Cristalli G (1999) 2-Substituted adenosine derivatives as high affinity agonists at human A3 adenosine receptors. Naunyn Schmiedeberg's Arch Pharmacol 360:103–108
Klotz K-N, Falgner N, Kachler S, Lambertucci C, Vittori S, Volpini R, Cristalli G (2007) [3H]HEMADO—a novel tritiated agonist selective for the human adenosine A3 receptor. Eur J Pharmacol 556:14–18
Kohn EC, Alessandro R, Spoonster J, Wersto RP, Liotta LA (1995) Angiogenesis: role of calcium-mediated signal transduction. Proc Natl Acad Sci U S A 92:1307–1311
Koussémou M, Lorenz K, Klotz K-N (2018) The A2B adenosine receptor in MDA-MB-231 breast cancer cells diminishes ERK1/2 phosphorylation by activation of MAPK-phosphatase-1. PLoS One 13(8):e0202914
Linden J, Thai T, Figler H, Jin X, Robeva AS (1999) Characterization of human A2B adenosine receptors: radioligand binding, Western blotting, and coupling to Gq in human embryonic kidney 293 cells and HMC-1 mast cells. Mol Pharmacol 56:705–713
Marinissen MJ, Gutkind JS (2001) G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 22:368–376
Merighi S, Mirandola P, Varani K, Gessi S, Leung E, Baraldi PG, Tabrizi MA, Borea PA (2003) A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther 100:31–48
Minelli A, Bellezza I, Collodel G, Fredholm BB (2008) Promiscuous coupling and involvement of protein kinase C and extracellular signal-regulated kinase 1/2 in the adenosine A1 receptor signalling in mammalian spermatozoa. Biochem Pharmacol 75:931–941
Moro S, Gao ZG, Jacobson KA, Spalluto G (2006) Progress in the pursuit of therapeutic adenosine receptor antagonists. Med Res Rev 26:131–159
Panjehpour M, Castro M, Klotz K-N (2005) The human breast cell line MDA-MB-231 expresses endogenous A2B adenosine receptors mediating a Ca2+ signal. Br J Pharmacol 155:211–218
Rankovic Z, Brust TF, Bohn LM (2016) Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett 26:241–250
Schulte G, Fredholm BB (2003) Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal 15:813–827
Siuda ER, Carr R 3rd, Rominger DH, Violin JD (2017) Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics. Curr Opin Pharmacol 32:77–84
Acknowledgments
We are grateful for the expert technical assistance by Sonja Kachler. DPA23 was kindly provided by Prof. PG Baraldi, University of Ferrara, Italy; LUF 6210 was kindly contributed by Prof. AP IJzerman, Leiden University, The Netherlands. UK-432097 was a gift from Pfizer Global Research and Development, Kent, England.
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KNK conceived and designed the study; MK conducted all experiments; KNK and MK analyzed and interpreted the data; KNK and MK wrote, read, and approved the manuscript.
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Koussémou, M., Klotz, KN. Agonists activate different A2B adenosine receptor signaling pathways in MBA-MD-231 breast cancer cells with distinct potencies. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1515–1521 (2019). https://doi.org/10.1007/s00210-019-01695-2
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DOI: https://doi.org/10.1007/s00210-019-01695-2