Sphingosine-1-P and its plasma membrane receptors in human glioma cells

Glioblastoma multiforme (GBMs), the most frequent and deadly brain tumors in humans, are characterized by extended invasiveness and cell growth. Different sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), have emerged as active mediators in the complex network of signaling pathways involved in the control of physiological and pathological cell behavior (1). Increasing evidence supports that S1P is implicated in sustaining cell invasiveness. On the other side, various growth factor receptors, such as EGFR, are frequently mutated and/or overexpressed in GBMs (2). Very importantly, S1P is able to regulate EGFR expression in lung adenocarcinoma and rat vascular smooth muscle cells suggesting the existence of a cross-talk between the S1P axis and growth factor signaling pathways induced by EGF in tumors. We investigated the crosstalk between S1P and the EGF/EGFR pathways, focusing on its role in glioma invasiveness. We used U87MG human GBMs cell line overexpressing EGF receptor (EGFR+). EGFR+ cells are characterized by increased levels of extracellular S1P and an higher expression of the active SK-1 form (phosphorylated SK-1). These cells showed increased ability to invade into Matrigel. The high chemioinvasion ability as well as spheroids sprouting were significantly inhibited in EGFR+ cells treated with SK inhibitors, or with S-FTY720-vinylphosphonate, the antagonist of S1P receptors. Moreover, we found that S1P added to the cell medium maintained the ability to drastically increase invasion in EGFR+ cells treated with SK inhibitors. At variance, S1P did not induced invasion over the basal values when glioma cells were treated with FTY720. Altogether our data strongly suggest that increased S1P secretion and signalling associated with EGFR overexpression/iperactivation play an important role in EGFR+ glioblastoma invasiveness by enhancing the invasion potential of GBM. References 1. Giussani et al. (2014) Int. J. Mol. Sci., 15, 4356 2. Zahonero et al (2014) Cell Mol Life Sci. 71, 3465