Journal
SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-04009-w
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Funding
- Fay Fuller Foundation
- Australian National Health and Medical Research Council Fellowships [1042589, 1156693]
- RAH Research Fund Florey Fellowship
- Research Training Program Scholarship
- Royal Adelaide Hospital Dawes Top-up scholarship
- National Health and Medical Research Council of Australia [1156693] Funding Source: NHMRC
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The study found that JTE-013 has broad off-target effects on sphingolipid metabolism, increasing cellular levels of ceramides, dihydroceramides, sphingosine, and dihydrosphingosine. Additionally, the study revealed that JTE-013 inhibits the activity of several sphingolipid metabolic enzymes.
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).
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