Sphingosine kinase 1 is required for migration and growth of melanoma

ALVAREZ SE; MACEYCKA M; KORDULA T; MILSTIEN S; SPIEGEL S

San Miguel de Tucuman

Congreso; 45th Annual Meeting of the Argentine Society for Biochemsitry and Molecular Biology; 2009

Sphingosine 1-phosphate (S1P) is a lipid mediator that elicitsmultiple cellular processes, including cell migration, survival, andangiogenesis. S1P levels inside the cells are regulated by thebalance between its synthesis by two sphingosine kinases isozymes(SphK1 and SphK2), and degradation by S1P lyase and S1Pphosphatases. Activation of SphK by a variety of agonists increasesS1P levels, which in turn can function intracellularly as a secondmessenger or in an autocrine/paracrine fashion to activate cellsurface S1P receptors.Melanoma is the most aggressive type of skin cancer which causesthe majority of the deaths. Although the mechanisms involved inthe progression of the disease are not fully understood, increasedSphK1 activation has been recognized as a hallmark of manycancers. Here we have identified Filamin A (FlnA) as a SphK1interacting protein, which controls cell migration through theactivation of S1P receptor. SphK1 activation is required for 1heregulin-induced migration, lamellipodia formation, activation ofPAK1, and subsequent FlnA phosphorylation in melanoma cells.Moreover, we also demonstrated that SphK1 has a critical role inthe activation of NF-kB, which in turn is necessary for cellproliferation. Taken together these results suggest a unique role forSphK1 in two main characteristics of melanoma: cell migrationand proliferation.