title: 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.affiliation: Department of Chemistry, Medical University of Lublin, 20-093 Lublin, Poland; Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address: artur.wnorowski@gmail.com.
authors.forename: Artur
authors.initials: A
authors.lastname: Wnorowski
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, MD 21201, USA. Electronic address: mariolas349@gmail.com.
authors.forename: Mariola
authors.initials: M
authors.lastname: Sadowska
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address: rajibkpaul@gmail.com.
authors.forename: Rajib K
authors.initials: RK
authors.lastname: Paul
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address: nagendra.singh@nih.gov.
authors.forename: Nagendra S
authors.initials: NS
authors.lastname: Singh
authors.affiliation: Department of Medicinal Chemistry, Medical University of Lublin, 20-093 Lublin, Poland. Electronic address: anna.boguszewska-czubara@am.lublin.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Boguszewska-Czubara
authors.affiliation: SRI International, Menlo Park, CA 94025, USA. Electronic address: lucita.jimenez@sri.com.
authors.forename: Lucita
authors.initials: L
authors.lastname: Jimenez
authors.affiliation: Laboratory of Genetics, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address: abdelmohsenk@grc.nia.nih.gov.
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, USA. Electronic address: ltoll@tpims.org.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Toll
authors.affiliation: Department of Chemistry, Medical University of Lublin, 20-093 Lublin, Poland. Electronic address: krzysztof.jozwiak@umlub.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address: Bernierm@mail.nih.gov.
authors.forename: Michel
authors.initials: M
authors.lastname: Bernier
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address: iwwainer@mitchellwoods.com.
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D005280:Fenoterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000603500:4'-methoxy-1-naphthylfenoterol; D058666:Adrenergic beta-2 Receptor Agonists; D000970:Antineoplastic Agents; D018343:Receptors, Adrenergic, beta-2; D005280:Fenoterol; D000242:Cyclic AMP
keywords: Beta blocker; Beta2 adrenoreceptor selective agonist; Melanocortin 1 receptor; Melanocyte; Metastasis; Migration