Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. |
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| Authors: | J P Jaffrzou T Levade A Bettaïeb N Andrieu C Bezombes N Maestre S Vermeersch A Rousse and G Laurent |
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| Affiliation: | J P Jaffrézou, T Levade, A Bettaïeb, N Andrieu, C Bezombes, N Maestre, S Vermeersch, A Rousse, and G Laurent |
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| Abstract: | The nature of the signaling pathway(s) which initiate drug-triggered apoptosis remains largely unknown and is of fundamental importance in understanding cell death induced by chemotherapeutic agents. Here we show that in the leukemic cell lines U937 and HL-60, daunorubicin, at concentrations which trigger apoptosis, stimulated two distinct cycles of sphingomyelin hydrolysis (approximately 20% decrease at 1 microM) within 4-10 min and 60-75 min with concomitant ceramide generation. We demonstrate that the increase in ceramide levels, which precedes apoptosis, is mediated by a neutral sphingomyelinase and not by ceramide synthase. Indeed, potent ceramide synthase inhibitors such as fumonisin B1 did not affect daunorubicin-triggered sphingomyelin hydrolysis, ceramide generation or apoptosis. In conclusion, we provide evidence that daunorubicin-triggered apoptosis is mediated by a signaling pathway which is initiated by an early sphingomyelin-derived ceramide production. |
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