Role of 1-Deoxysphingolipids in docetaxel neurotoxicity

Katrin A. Becker, Anne Kathrin Uerschels, Laura Goins, Suzanne Doolen, Kristen J. McQuerry, Jacek Bielawski, Ulrich Sure, Erhard Bieberich, Bradley K. Taylor, Erich Gulbins, Stefka D. Spassieva

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

A major dose-limiting side effect of docetaxel chemotherapy is peripheral neuropathy. Patients’ symptoms include pain, numbness, tingling and burning sensations, and motor weakness in the extremities. The molecular mechanism is currently not understood, and there are no treatments available. Previously, we have shown an association between neuropathy symptoms of patients treated with paclitaxel and the plasma levels of neurotoxic sphingolipids, the 1-deoxysphingolipids (1-deoxySL) (Kramer et al, FASEB J, 2015). 1-DeoxySL are produced when the first enzyme of the sphingolipid biosynthetic pathway, serine palmitoyltransferase (SPT), uses L-alanine as a substrate instead of its canonical amino acid substrate, L-serine. In the current investigation, we tested whether 1-deoxySL accumulate in the nervous system following systemic docetaxel treatment in mice. In dorsal root ganglia (DRG), we observed that docetaxel (45 mg/kg cumulative dose) significantly elevated the levels of 1-deoxySL and L-serine-derived ceramides, but not sphingosine-1-phosphate (S1P). S1P is a bioactive sphingolipid and a ligand for specific G-protein-coupled receptors. In the sciatic nerve, docetaxel decreased 1-deoxySL and ceramides. Moreover, we show that in primary DRG cultures, 1-deoxysphingosine produced neurite swellings that could be reversed with S1P. Our results demonstrate that docetaxel chemotherapy up-regulates sphingolipid metabolism in sensory neurons, leading to the accumulation of neurotoxic 1-deoxySL. We suggest that the neurotoxic effects of 1-deoxySL on axons can be reversed with S1P. (Figure presented.).

Original languageEnglish
Pages (from-to)662-672
Number of pages11
JournalJournal of Neurochemistry
Volume154
Issue number6
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Publisher Copyright:
© 2020 International Society for Neurochemistry

Keywords

  • 1-Deoxysphingolipids
  • Ceramide
  • Docetaxel-induced peripheral neuropathy
  • Serine palmitoyltransferase
  • Sphingosine-1-phosphate

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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