title: Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-κB Activation in Melanoma Cells by Inhibition of Akt Signaling.
abstract: Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates many processes in inflammation and cancer. S1P is a ligand for five G-protein-coupled receptors, S1PR1 to -5, and also has important intracellular actions. Previously, we showed that intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-κB activation in melanoma cell lines that express filamin A (FLNA). Here, we show that extracellular S1P activates NF-κB only in melanoma cells that lack FLNA. In these cells, S1P, but not TNF, promotes IκB kinase (IKK) and p65 phosphorylation, IκBα degradation, p65 nuclear translocation, and NF-κB reporter activity. NF-κB activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced the phosphorylation of protein kinase Cδ (PKCδ), and its downregulation reduced S1P-induced the phosphorylation of IKK and p65. In addition, silencing of Bcl10 also inhibited S1P-induced IKK phosphorylation. Surprisingly, S1P reduced Akt activation in melanoma cells that express FLNA, whereas in the absence of FLNA, high phosphorylation levels of Akt were maintained, enabling S1P-mediated NF-κB signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation and degradation of IκBα. Hence, these results support a negative role of FLNA in S1P-mediated NF-κB activation in melanoma cells through modulation of Akt.
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biológicas San Luis (IMIBIO-SL) CONICET and Universidad Nacional de San Luis, San Luis, Argentina.
authors.forename: Ludmila S
authors.initials: LS
authors.lastname: Campos
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biológicas San Luis (IMIBIO-SL) CONICET and Universidad Nacional de San Luis, San Luis, Argentina.
authors.forename: Yamila I
authors.initials: YI
authors.lastname: Rodriguez
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Andreia M
authors.initials: AM
authors.lastname: Leopoldino
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.affiliation: Universidad Maimonides, Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lopez Bergami
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biológicas San Luis (IMIBIO-SL) CONICET and Universidad Nacional de San Luis, San Luis, Argentina.
authors.forename: Melina G
authors.initials: MG
authors.lastname: Castro
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biológicas San Luis (IMIBIO-SL) CONICET and Universidad Nacional de San Luis, San Luis, Argentina.
authors.forename: Emilse S
authors.initials: ES
authors.lastname: Sanchez
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Maceyka
authors.affiliation: Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA sspiegel@vcu.edu sealvarez98@gmail.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.affiliation: Instituto Multidisciplinario de Investigaciones Biológicas San Luis (IMIBIO-SL) CONICET and Universidad Nacional de San Luis, San Luis, Argentina sspiegel@vcu.edu sealvarez98@gmail.com.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Alvarez
mesh_terms: D045744:Cell Line, Tumor; D064448:Filamins / Q000276:immunology*; D006801:Humans; D008246:Lysophospholipids / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D051745:Protein Kinase C-delta / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology*; D049349:Receptors, Lysosphingolipid / Q000276:immunology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000276:immunology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: C578663:FLNA protein, human; D064448:Filamins; D008246:Lysophospholipids; D016328:NF-kappa B; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D013110:Sphingosine