Sphingosine-1-phosphate-lyase deficiency affects glucose metabolism in a way that abets oncogenesis.

Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival and migration, as well as neovascularization and inflammation. Its critical role in the development and progression of cancer is well documented. The metabolism of S1P, which exerts its effect mainly via five G protein-coupled receptors (S1PR_1-5 ), is tightly regulated. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism and exhibits remarkably decreased enzymatic activity in tumor samples. In this study, we used SGPL1-deficient (Sgpl1^-/- ) mouse embryonic fibroblasts (MEFs) and investigated the impact of S1P on glucose metabolism. Accumulated S1P activates, via its receptors (S1PR_1-3 ), hypoxia-inducible factor 1 and stimulates the expression of proteins involved in glucose uptake and breakdown, indicating that Sgpl1^-/- cells, like cancer cells, prefer to convert glucose to lactate even in the presence of oxygen. Accordingly, their rate of proliferation is significantly increased. Activation of the Akt/mTOR pathway and hence down-regulation of autophagy indicate that these changes do not negatively affect the cellular energy status. In summary, we report on a newly identified role of the S1P/S1PR_1-3 axis in glucose metabolism in SGPL1-deficient MEFs.