Activation of β2-adrenergic receptor by (R,R')-4'-methoxy-1-naphthylfenoterol inhibits proliferation and motility of melanoma cells.

Abstract

(R,R')-4'-methoxy-1-naphthylfenoterol [(R,R')-MNF] is a highly-selective β2 adrenergic receptor (β2-AR) agonist. Incubation of a panel of human-derived melanoma cell lines with (R,R')-MNF resulted in a dose- and time-dependent inhibition of motility as assessed by in vitro wound healing and xCELLigence migration and invasion assays. Activity of (R,R')-MNF positively correlated with the β2-AR expression levels across tested cell lines. The anti-motility activity of (R,R')-MNF was inhibited by the β2-AR antagonist ICI-118,551 and the protein kinase A inhibitor H-89. The adenylyl cyclase activator forskolin and the phosphodiesterase 4 inhibitor Ro 20-1724 mimicked the ability of (R,R')-MNF to inhibit migration of melanoma cell lines in culture, highlighting the importance of cAMP for this phenomenon. (R,R')-MNF caused significant inhibition of cell growth in β2-AR-expressing cells as monitored by radiolabeled thymidine incorporation and xCELLigence system. The MEK/ERK cascade functions in cellular proliferation, and constitutive phosphorylation of MEK and ERK at their active sites was significantly reduced upon β2-AR activation with (R,R')-MNF. Protein synthesis was inhibited concomitantly both with increased eEF2 phosphorylation and lower expression of tumor cell regulators, EGF receptors, cyclin A and MMP-9. Taken together, these results identified β2-AR as a novel potential target for melanoma management, and (R,R')-MNF as an efficient trigger of anti-tumorigenic cAMP/PKA-dependent signaling in β2-AR-expressing lesions.

• Authors: Artur Wnorowski, Mariola Sadowska, Rajib K Paul, Nagendra S Singh, Anna Boguszewska-Czubara, Lucita Jimenez, Kotb Abdelmohsen, Lawrence Toll, Krzysztof Jozwiak, Michel Bernier, Irving W Wainer
• Journal: Cellular signalling (Cell Signal) Vol. 27 Issue 5 Pg. 997-1007 (May 2015) ISSN: 1873-3913 [Electronic] England
• PMID: 25703025 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• 4'-methoxy-1-naphthylfenoterol
• Adrenergic beta-2 Receptor Agonists
• Antineoplastic Agents
• Receptors, Adrenergic, beta-2
• Fenoterol
• Cyclic AMP

Topics

• Adrenergic beta-2 Receptor Agonists (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cyclic AMP (metabolism)
• Fenoterol (analogs & derivatives, pharmacology)
• Humans
• Melanoma (drug therapy, metabolism, pathology)
• Receptors, Adrenergic, beta-2 (metabolism)
• Signal Transduction (drug effects)