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

SANTACREU, BRUNO JAIME; CORRADI, GERARDO RAÚL; SANTACREU, BRUNO JAIME; CORRADI, GERARDO RAÚL; PESCIO, LUCILA GISELE; STERIN-SPEZIALE, NORMA; PESCIO, LUCILA GISELE; STERIN-SPEZIALE, NORMA; ROMERO, DANIELA JUDITH; FAVALE, NICOLÁS OCTAVIO; ROMERO, DANIELA JUDITH; FAVALE, NICOLÁS OCTAVIO

PLOS ONE

PUBLIC LIBRARY SCIENCE

Año: 2019 vol. 14

1932-6203

Sphingolipids regulate several aspects of cell behavior and it has been demonstrated that cells adjust their sphingolipid metabolism in response to metabolic needs. Particularly, sphingosine-1-phosphate (S1P), a final product of sphingolipid metabolism, is a potent bio- active lipid involved in the regulation of various cellular processes, including cell prolifera- tion, cell migration, actin cytoskeletal reorganization and cell adhesion. In previous work in rat renal papillae, we showed that sphingosine kinase (SK) expression and S1P levels are developmentally regulated and control denovo sphingolipid synthesis. The aim of the pres- ent study was to evaluate the participation of SK/S1P pathway in the triggering of cell differ- entiation by external hypertonicity. We found that hypertonicity evoked a sharp decrease in SK expression, thus activating the denovo sphingolipid synthesis pathway.Furthermore, the inhibition of SK activity evoked a relaxation of cell-cell adherens junction (AJ) with accu- mulation of the AJ complex (E-cadherin/β-catenin/α-catenin) in the Golgi complex, prevent- ing the acquisition of the differentiated cell phenotype. This phenotype alteration was a consequence of a sphingolipid misbalance with an increase in ceramide levels. Moreover, we found that SNAI1 and SNAI2 were located in the cell nucleus with impairment of cell dif- ferentiation induced by SK inhibition, a fact that is considered a biochemical marker of epi- thelial to mesenchymal transition. So, we suggest that the expression and activity of SK1, but not SK2, act as a control system, allowing epithelial cells to synchronize the various branches of sphingolipid metabolism for an adequate cell differentiation program.