Lysosomal sphingomyelinase is not solicited for apoptosis signaling.
Stress-induced activation of an acidic sphingomyelinase leading to generation of ceramide, an important lipid mediator, has been associated with apoptosis; however, the implication of this hydrolase has been questioned. The present study aimed at re-evaluating the role of this lysosomal enzyme in apoptosis initiated by different apoptotic inducers. The sensitivity of a series of acid sphingomyelinase-deficient cell lines derived from Niemann-Pick disease patients to stress-induced apoptosis was investigated. We have now shown that stress stimuli, such as anthracyclines, ionizing radiation, and Fas ligation trigger similar apoptotic hallmarks in normal and acid sphingomyelinase-deficient cell lines. Retrovirus-mediated gene correction of enzyme deficiency in Niemann-Pick cells does not modify response to apoptosis. Ceramide production is comparable in normal and Niemann-Pick cells, and increased activity of neutral sphingomyelinase is observed. Thus, our findings cast serious doubts that lysosomal sphingomyelinase activation is responsible for stress-induced apoptosis of cultured cells.
Bezombes
C
C
INSERM E9910, Institut Claudius Régaud, 20 rue du Pont St Pierre, 31052 Toulouse, France.
Ségui
B
B
Cuvillier
O
O
Bruno
A P
AP
Uro-Coste
E
E
Gouazé
V
V
Andrieu-Abadie
N
N
Carpentier
S
S
Laurent
G
G
Salvayre
R
R
Jaffrézou
J P
JP
Levade
T
T
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002264:Carboxylic Acids / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D003630:Daunorubicin / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037341:Fumonisins; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D008247:Lysosomes / Q000201:enzymology*; D009542:Niemann-Pick Diseases; D010447:Peptide Hydrolases / Q000378:metabolism; D012016:Reference Values; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D019014:fas Receptor / Q000502:physiology
D002264:Carboxylic Acids; D002518:Ceramides; D004791:Enzyme Inhibitors; D037341:Fumonisins; D019014:fas Receptor; C056933:fumonisin B1; D004317:Doxorubicin; D013108:Sphingomyelin Phosphodiesterase; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C108711:DEVDase; D003630:Daunorubicin