Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells

K. Kimura, M. Markowski, L. C. Edsall, S. Spiegel, E. P. Gelmann

Research output: Contribution to journalArticle

Abstract

The sphingomyelin metabolites ceramide and sphingosine are mediators of cell death induced by γ-irradiation. We studied the production of ceramide and the effects of exogenous ceramide on apoptosis in LNCaP prostate cancer cells that are highly resistant to γ-irradiation-induced cell death. LNCaP cells can be sensitized to γ-irradiation by tumor necrosis factor α (TNF-α) and, to a lesser degree, by the agonistic FAS antibody CH-11. TNF-α activated intrinsic and extrinsic apoptosis pathways and increased ceramide and sphingosine levels in irradiated LNCaP cells. CH-11 activated only the extrinsic apoptosis pathways and had a negligible effect on ceramide and sphingosine levels in irradiated LNCaP cells. Exogenous ceramide and bacterial sphingo-myelinase sensitized LNCaP cells to radiation-induced apoptosis and had a synergistic effect on cell death after irradiation with TNF-α, but not with CH-11. Cell death effects after exposure to ceramide and irradiation were blocked by the serine protease inhibitor TLCK (Na-p-tosyl-L-lysine-chloromethylketone), but not by the caspase inhibitor z-VAD (2-val-Ala-Asp(oMe)-CH2F). During LNCaP cell apoptosis induced by exogenous ceramide, we observed activation of caspase-9, but not caspases-8, -3, or -7. The effect of ceramide occurred largely via the intrinsic mitochondrial apoptosis pathway and enhanced TNF-α, but not CH-11 effects on irradiated cells. The data show that ceramide enhanced activation of the intrinsic apoptotic pathway and enhanced cell death induced by TNF-α with or without γ-irradiation. TNF-α and γ-irradiation elevated levels of endogenous ceramide and activated the intrinsic cell death pathway.

Original languageEnglish (US)
Pages (from-to)240-248
Number of pages9
JournalCell death and differentiation
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2003
Externally publishedYes

Keywords

  • Caspase
  • Ceramide
  • Prostate cancer
  • Radiation
  • Serine protease
  • TNF-α

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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