Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis

Justin M. Snider, Magali Trayssac, Christopher J. Clarke, Nicholas Schwartz, Ashley J. Snider, Lina M. Obeid, Chiara Luberto, Yusuf A. Hannun

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Sphingolipids (SLs) have been implicated in numerous important cellular biologies; however, their study has been hindered by the complexities of SL metabolism. Furthermore, enzymes of SL metabolism represent a dynamic and interconnected network in which one metabolite can be transformed into other bioactive SLs through further metabolism, resulting in diverse cellular responses. Here we explore the effects of both lethal and sublethal doses of doxorubicin (Dox) in MCF-7 cells. The two concentrations of Dox resulted in the regulation of SLs, including accumulations in sphingosine, sphingosine-1-phosphate, dihydroceramide, and ceramide, as well as reduced levels of hexosylceramide. To further define the effects of Dox on SLs, metabolic flux experiments utilizing a d17 dihydrosphingosine probe were conducted. Results indicated the regulation of ceramidases and sphingomyelin synthase components specifically in response to the cytostatic dose. The results also unexpectedly demonstrated dose-dependent inhibition of dihydroceramide desaturase and glucosylceramide synthase in response to Dox. Taken together, this study uncovers novel targets in the SL network for the action of Dox, and the results reveal the significant complexity of SL response to even a single agent. This approach helps to define the role of specific SL enzymes, their metabolic products, and the resulting biologies in response to chemotherapeutics and other stimuli.

Original languageEnglish (US)
Pages (from-to)819-831
Number of pages13
JournalJournal of Lipid Research
Volume60
Issue number4
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Chemotherapeutic
  • High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry
  • Metabolism

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis'. Together they form a unique fingerprint.

Cite this