Agonists activate different A2B adenosine receptor signaling pathways in MBA-MD-231 breast cancer cells with distinct potencies

被引:6
作者
Koussemou, Marthe [1 ]
Klotz, Karl-Norbert [1 ]
机构
[1] Univ Wurzburg, Inst Pharmakol & Toxikol, Versbacher Str 9, D-97078 Wurzburg, Germany
关键词
Adenosine receptor; A(2B); Agonist; Potency; Signaling bias; INTERNATIONAL UNION; PROTEIN-KINASE; A(3) RECEPTOR; PHARMACOLOGY; CLASSIFICATION; ANGIOGENESIS; NOMENCLATURE;
D O I
10.1007/s00210-019-01695-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 A(2B) 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 A(2B) 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 A(2B) 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.
引用
收藏
页码:1515 / 1521
页数:7
相关论文
共 26 条
[1]   Adenosine A2B receptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells [J].
Du, Xiaolong ;
Ou, Xuehai ;
Song, Tao ;
Zhang, Wentao ;
Cong, Fei ;
Zhang, Shihui ;
Xiong, Yongmin .
EXPERIMENTAL BIOLOGY AND MEDICINE, 2015, 240 (11) :1472-1479
[2]  
FEOKTISTOV I, 1994, MOL PHARMACOL, V45, P1160
[3]   Pharmacology and therapeutic applications of A3 receptor subtype [J].
Fishman, P ;
Bar-Yehuda, S .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2003, 3 (04) :463-469
[4]  
Fredholm BB, 2001, PHARMACOL REV, V53, P527
[5]   International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors-An Update [J].
Fredholm, Bertil B. ;
IJzerman, Adriaan P. ;
Jacobson, Kenneth A. ;
Linden, Joel ;
Mueller, Christa E. .
PHARMACOLOGICAL REVIEWS, 2011, 63 (01) :1-34
[6]   On the G protein-coupling selectivity of the native A2B adenosine receptor [J].
Gao, Zhan-Guo ;
Inoue, Asuka ;
Jacobson, Kenneth A. .
BIOCHEMICAL PHARMACOLOGY, 2018, 151 :201-213
[7]   G protein regulation of MAPK networks [J].
Goldsmith, Z. G. ;
Dhanasekaran, D. N. .
ONCOGENE, 2007, 26 (22) :3122-3142
[8]   Regulation of p42/p44 mitogen-activated protein kinase by the human adenosine A3 receptor in transfected CHO cells [J].
Graham, S ;
Combes, P ;
Crumiere, M ;
Klotz, KN ;
Dickenson, JM .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2001, 420 (01) :19-26
[9]  
Gudermann T, 1996, ANNU REV PHARMACOL, V36, P429
[10]   A3 adenosine receptor-mediated protection of the ischemic heart [J].
Headrick, JP ;
Peart, J .
VASCULAR PHARMACOLOGY, 2005, 42 (5-6) :271-279