Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-kB Activation in Melanoma Cells by Inhibition of Akt Signaling

CAMPOS L; RODRIGUEZ Y; MACHADO LEOPOLDINO A; HAIT NC; LOPEZ BERGAMI P; CASTRO M; SANCHEZ ES; MACEYCKA M; SPIEGEL S; ALVAREZ SE

MOLECULAR AND CELLULAR BIOLOGY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2015 vol. 36 p. 320 - 329

0270-7306

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, S1PR1-5, and also has important intracellular actions. Previously we have shown that intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-kB activation in melanoma cell lines that express filamin A (FLNA). Here, we show that extracellular S1P activates NF-kB only in melanoma cells that lack FLNA. In these cells S1P, but not TNF, promotes IKK and p65 phosphorylation, IkBa degradation, p65 nuclear translocation and NF-kB reporter activity. NF-kB activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced phosphorylation of PKCδ and its downregulation reduced S1P-induced 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-kB signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation and degradation of IkBa. Hence, these results support a negative role of FLNA in S1P-mediated NF-kB activation in melanoma cells through modulation of Akt.