CERAMIDE AND SPHINGOSINE-1-PHOSPHATE: CRUCIAL ACTORS IN HUMAN GLIOBLASTOMA CELLS

Glioblastoma multiforme (GBMs), the most frequent and deadly brain tumor in humans, are characterized by extended invasiveness and cell growth. Further elucidation of signaling pathways responsible for the malignant phenotype and resistance to therapy will therefore represent a significant advance in GBM treatment and prognosis. Different sphingolipid metabolites, such as ceramide (Cer), and 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 behaviour in different cancers including glioblastoma. In glial cells, as in other cell types, Cer and S1P have emerged as potent bioactive molecules, which play essential roles in the control of different cell functions such as proliferation, senescence, death, survival, migration and invasiveness. These bioactive sphingolipids exert opposite effects on both normal and tumor glial cell properties. In fact, ceramide mainly induces antiproliferative responses and cell death, being thus considered a tumor suppressor lipid. On the other hand, by acting both intracellularly and as ligand of specific cell surface receptors, sphingosine-1-phosphate can promote cell growth, migration and survival, thus behaving as a tumor promoter lipid. On the other side, various growth factor receptors are frequently mutated and/or overexpressed in GBMs. Most of GBMs overexpress epidermal growth factor receptor (EGFR) and the form EGFRvIII, which possess a ligand-independent constitutive activity, is the most frequent genetic variant. It is known that S1P regulates EGFR expression in different cell types. In glioblastoma cells it has been shown a functional link between S1P-Cer and the EGFRvIII signaling pathways involved in the regulation of cell survival and invasiveness.