Extracellular sphingosine-1-phosphate stimulates NF-κB pathway in cells lacking Filamin-A

CAMPOS LUDMILA ESTEFANÍA; RODRIGUEZ YAMILA ISABEL; CASTRO MELINA GABRIELA; SANCHEZ EMILSE; ALVAREZ SERGIO EDUARDO

Mendoza

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2012

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)

Sphinghosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates several physiological and pathological events, including inflammation and cancer progression. S1P might act as an intracellular second messenger or in an autocrine or paracrine manner through binding to five G-protein-coupled receptors named S1P1-5. Hence, the biological response to extracellular S1P depends on which receptors are expressed in the surface. In many solid tumors, the inflammatory microenvironment stimulates NF-kB activation, converting this pathway in a critical link between inflammation and cancer. We have previously demonstrated the importance of intracellular S1P in NF-κB activation triggered by tumor necrosis factor (TNF) in melanoma cell lines that express Filamin A (FlnA), an actin-binding protein. Here, we show that extracellular S1P induces the activation of NF-kB only in cells lacking FlnA. To examine NF-kB activation, we analyzed IKK phosphorylation and IkBa degradation. Moreover, by using inhibitors and siRNA, our preliminary data suggest that PKCδ might be involved in the pathway. To definitely address the role of FlnA, we downregulated the protein in FlnA-expressing A7 cells and we are currently analyzing both TNF and S1P induced NF-kB activation. Also, further investigations are necessary to determine which S1PR is involved in the proposed mechanism.