Journal of Molecular Medicine

, 87:1123

Lysosomal ceramide mediates gemcitabine-induced death of glioma cells

  • Claudia A. Dumitru
  • Ibrahim E. Sandalcioglu
  • Marek Wagner
  • Michael Weller
  • Erich Gulbins
Original Article

DOI: 10.1007/s00109-009-0514-8

Cite this article as:
Dumitru, C.A., Sandalcioglu, I.E., Wagner, M. et al. J Mol Med (2009) 87: 1123. doi:10.1007/s00109-009-0514-8

Abstract

Acid sphingomyelinase-induced ceramide release has been shown by many studies to induce apoptosis in response to various stimuli. However, the mechanisms of acid sphingomyelinase/ceramide-mediated death signaling following treatment with chemotherapeutic drugs have not been fully elucidated thus far. The present study demonstrates that treatment of glioma cells with clinically achievable doses of gemcitabine results in acid sphingomyelinase activation, lysosomal accumulation of ceramide, cathepsin D activation, Bax insertion into the mitochondria, and cell death. Pharmacological inhibition or genetic deficiency of acid sphingomyelinase prevented these events while overexpression of the enzyme sensitized cells to gemcitabine. Likewise, inhibitors of lysosomal functions also prevent gemcitabine-induced cell death. Our data indicate a critical role of the acid sphingomyelinase/ceramide system for gemcitabine-induced signaling and suggest that lysosomal ceramide accumulation mediates cell death induced by a chemotherapeutic drug.

Keywords

GliomaCeramideAcid sphingomyelinaseDeathLysosomesApoptosisLipid researchTumor

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Claudia A. Dumitru
    • 1
  • Ibrahim E. Sandalcioglu
    • 2
  • Marek Wagner
    • 1
  • Michael Weller
    • 3
  • Erich Gulbins
    • 1
  1. 1.Department of Molecular BiologyUniversity of Duisburg-EssenEssenGermany
  2. 2.Department of NeurosurgeryUniversity of Duisburg-EssenEssenGermany
  3. 3.Department of NeurologyUniversity Hospital ZurichZurichSwitzerland