Ceramide launches an acute anti-adhesion pro-migration cell signaling program in response to chemotherapy

Daniel Canals, Silvia Salamone, Bruno Jaime Santacreu, Erika Nemeth, Daniel Aguilar, María José Hernandez-Corbacho, Mohamad Adada, Daniela I. Staquicini, Wadih Arap, Renata Pasqualini, John Haley, Lina M. Obeid, Yusuf A. Hannun

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Chemotherapy has been reported to upregulate sphingomylinases and increase cellular ceramide, often linked to the induction to cell death. In this work, we show that sublethal doses of doxorubicin and vorinostat still increased cellular ceramide, which was located predominantly at the plasma membrane. To interrogate possible functions of this specific pool of ceramide, we used recombinant enzymes to mimic physiological levels of ceramide at the plasma membrane upon chemotherapy treatment. Using mass spectrometry and network analysis, followed by experimental confirmation, the results revealed that this pool of ceramide acutely regulates cell adhesion and cell migration pathways with weak connections to commonly established ceramide functions (eg, cell death). Neutral sphingomyelinase 2 (nSMase2) was identified as responsible for the generation of plasma membrane ceramide upon chemotherapy treatment, and both ceramide at the plasma membrane and nSMase2 were necessary and sufficient to mediate these “side” effects of chemotherapy on cell adhesion and migration. This is the first time a specific pool of ceramide is interrogated for acute signaling functions, and the results define plasma membrane ceramide as an acute signaling effector necessary and sufficient for regulation of cell adhesion and cell migration under chemotherapeutical stress.

Original languageEnglish (US)
Pages (from-to)7610-7630
Number of pages21
JournalFASEB Journal
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2020

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Keywords

  • doxorubicin
  • plasma membrane
  • sphingolipids
  • sphingomyelinase
  • vorinostat

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