Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis.
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.
Jaffrézou
J P
JP
CJF INSERM 9503, Centre Claudius Régaud, France.
Levade
T
T
Bettaïeb
A
A
Andrieu
N
N
Bezombes
C
C
Maestre
N
N
Vermeersch
S
S
Rousse
A
A
Laurent
G
G
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D055572:Ceramidases; D002518:Ceramides / Q000096:biosynthesis*; D003630:Daunorubicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037341:Fumonisins; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology; D009183:Mycotoxins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013109:Sphingomyelins / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D002518:Ceramides; D004791:Enzyme Inhibitors; D037341:Fumonisins; D009183:Mycotoxins; D013109:Sphingomyelins; C056933:fumonisin B1; D000581:Amidohydrolases; D055572:Ceramidases; D003630:Daunorubicin