The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism

• Published in: Scientific reports Vol. 12; no. 1; p. 454
• Main Authors: Pitman, Melissa R., Lewis, Alexander C., Davies, Lorena T., Moretti, Paul A. B., Anderson, Dovile, Creek, Darren J., Powell, Jason A., Pitson, Stuart M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45/287; 631/80/86; Acute myeloid leukemia; Desaturase; HEK293 Cells; Humanities and Social Sciences; Humans; Kinetics; Leukemia; Lipid metabolism; Metabolism; multidisciplinary; Oxidoreductases - chemistry; Oxidoreductases - genetics; Oxidoreductases - metabolism; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyridines - chemistry; Pyridines - pharmacology; Science; Science (multidisciplinary); Sphinganine; Sphingolipids - metabolism; Sphingosine 1-phosphate; Sphingosine-1-Phosphate Receptors - antagonists & inhibitors; Sphingosine-1-Phosphate Receptors - genetics; Sphingosine-1-Phosphate Receptors - metabolism; Therapeutic targets
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-04009-w

Sphingosine 1-phosphate (S1P) is a signaling lipid that has broad roles, working either intracellularly through various protein targets, or extracellularly via a family of five G-protein coupled receptors . Agents that selectively and specifically target each of the S1P receptors have been sought as both biological tools and potential therapeutics. JTE-013, a small molecule antagonist of S1P receptors 2 and 4 (S1P 2 and S1P 4 ) has been widely used in defining the roles of these receptors in various biological processes. Indeed, our previous studies showed that JTE-013 had anti-acute myeloid leukaemia (AML) activity, supporting a role for S1P 2 in the biology and therapeutic targeting of AML. Here we examined this further and describe lipidomic analysis of AML cells that revealed JTE-013 caused alterations in sphingolipid metabolism, increasing cellular ceramides, dihydroceramides, sphingosine and dihydrosphingosine. Further examination of the mechanisms behind these observations showed that JTE-013, at concentrations frequently used in the literature to target S1P 2/4 , inhibits several sphingolipid metabolic enzymes, including dihydroceramide desaturase 1 and both sphingosine kinases. Collectively, these findings demonstrate that JTE-013 can have broad off-target effects on sphingolipid metabolism and highlight that caution must be employed in interpreting the use of this reagent in defining the roles of S1P 2/4 .