Sphingosine kinase and sphingosine-1- phosphate regulate epithelial cell architecture by the modulation of de novo sphingolipid synthesis

BRUNO JAIME SANTACREU; LUCILA GISELE PESCIO; DANIELA JUDITH ROMERO; GERARDO RAUL CORRADI; NORMA STERIN-SPEZIALE; NICOLA´S OCTAVIO FAVALE; NORMA STERIN-SPEZIALE; NICOLAS OCTAVIO FAVALE

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2019

1932-6203

Sphingolipidsregulate several aspects of cell behavior and it has been demonstrated that cellsadjust their sphingolipid metabolism in response to metabolic needs.Particularly, sphingosine-1-phosphate (S1P), a final product of sphingolipidmetabolism, is a potent bioactive lipid involved in the regulation of variouscellular processes, including cell proliferation, cell migration, actincytoskeletal reorganization and cell adhesion. In previous work in rat renalpapillae, we showed that sphingosine kinase (SK) expression and S1P levels are developmentallyregulated and control de novo sphingolipid synthesis. The aim of the present studywas to evaluate the participation of SK/S1P pathway in the triggering of celldifferentiation by external hypertonicity. We found that hypertonicity evoked asharp decrease in SK expression, thus activating the de novo sphingolipidsynthesis pathway. Furthermore, the inhibition of SK activity evoked arelaxation of cell-cell adherens junction (AJ) with accumulation of the AJcomplex (E-cadherin/β-catenin/α-catenin) in the Golgi complex, preventing theacquisition of the differentiated cell phenotype. This phenotype alteration wasa consequence of a sphingolipid misbalance with an increase in ceramide levels.Moreover, we found that SNAI1 and SNAI2 were located in the cell nucleus withimpairment of cell differentiation induced by SK inhibition, a fact that isconsidered a biochemical marker of epithelial to mesenchymal transition. So, wesuggest that the expression and activity of SK1, but not SK2, act as a controlsystem, allowing epithelial cells to synchronize the various branches ofsphingolipid metabolism for an adequate cell differentiation program.