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

CAMPOS,L; RODRIGUEZ, Y; MACHADO LEOPOLDINO, A; HAIT, N; LOPEZ BERGAMI, P; CASTRO, MG; SANCHEZ, ES; MACEYKA, M; SPIEGEL S; ALVAREZ, SE

MOLECULAR AND CELLULAR BIOLOGY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2015

0270-7306

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates many processes in inflammation and cancer. S1P is aligand for five G-protein-coupled receptors, S1PR1 to -5, and also has important intracellular actions. Previously, we showedthat intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-B activation in melanoma cell lines thatexpress filamin A (FLNA). Here, we show that extracellular S1P activates NF-B only in melanoma cells that lack FLNA. In thesecells, S1P, but not TNF, promotes IB kinase (IKK) and p65 phosphorylation, IB degradation, p65 nuclear translocation, andNF-B reporter activity. NF-B activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced thephosphorylation of protein kinase C (PKC), and its downregulation reduced S1P-induced the phosphorylation of IKK andp65. In addition, silencing of Bcl10 also inhibited S1P-induced IKK phosphorylation. Surprisingly, S1P reduced Akt activation inmelanoma cells that express FLNA, whereas in the absence of FLNA, high phosphorylation levels of Akt were maintained, enablingS1P-mediated NF-B signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation anddegradation of IB. Hence, these results support a negative role of FLNA in S1P-mediated NF-B activation in melanoma cellsthrough modulation of Akt.Sphingosi