Details

Autor(en) / Beteiligte

• Wnorowski, Artur
• Sadowska, Mariola
• Paul, Rajib K.
• Singh, Nagendra S.
• Boguszewska-Czubara, Anna
• Jimenez, Lucita
• Abdelmohsen, Kotb
• Toll, Lawrence
• Jozwiak, Krzysztof
• Bernier, Michel
• Wainer, Irving W.

Titel

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

Ist Teil von

• Cellular signalling, 2015-05, Vol.27 (5), p.997-1007

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• (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. [Display omitted] •β2 adrenergic receptor (β2-AR) is differentially expressed in melanoma cell lines.•(R,R′)-4′-methoxy-1-naphthylfenoterol [(R,R′)-MNF] activates β2-AR in melanoma.•(R,R′)-MNF inhibits migration, invasion, and growth of melanoma cells via β2-AR.•Cyclic AMP (cAMP) is crucial for anti-tumorigenic activities of β2-AR.•β2-AR agonists can be used to restore cAMP signaling in melanomas.