Rol de esfingosina-1-fosfato en la progresión del melanoma inducida por NF-κB

Abstract

Considering that: a) deregulation of NF-κB signaling pathway is a common feature of many cancer types and modulates inflammation, invasion and angiogenesis, among other tumor characteristics, and b) sphingosine-1-phosphate (S1P) is a bioactive lipid present in the tumor microenvironment that has been extensively associated to chronic inflammation and cancer, we aimed to analyze the role of S1P in melanoma progression triggered by the activation of the nuclear transcription factors NF-κB. To this end we employed a panel of human melanoma cell lines, although most of the experiments were carried out on two melanoma cell lines: M2 (Filamin-A deficient cells or FLNa -) and A7 (Filamin-A expressing cells or FLNa +). This work is organized in two parts: PART I ?Molecular role of S1P?, focused on the study of the molecular mechanism of NF-κB activation induced by extracellular S1P, and PART II ?Biological Role of S1P?, directed to the study of the S1P ability to induce migration, invasion, survival and NF-κB-regulated gene expression. In the first part of this work we established that S1P induced NF-κB activation through the receptors S1PR1-2 only in M2 (FLNa -) melanoma cells. Besides, S1P promoted S1P-kinase (SphK1) and PKCδ phosphorylation, but only PKCδ is necessary for the S1P-induced NF-κB activation. Moreover, high phospho-Akt (pAkt) levels are required for S1P/NF-κB signaling and the PI3K/Akt inhibition impaired the S1P effect. Remarkably, we demonstrated that FLNa regulates negatively the S1P-mediated NF-κB activation through the reduction of pAkt levels. In addition, FLNa downregulation in melanoma cells allowed NF-κB activation mediated by S1P even in the presence of high pAkt levels. In the second part of our work we showed that S1P induces NF-κB-regulated gene expression, cell migration and protected from apoptosis only in M2 (FLNa -) melanoma cells. Furthermore, MMP-9 activity induced by S1P was dependent on NF-κB activation. In summary, our results show a new molecular mechanism by which S1P triggers NF-κB activation and modulates several biological responses related to tumor progression.