Cis-4-methylsphingosine phosphate induces apoptosis in neuroblastoma cells by opposite effects on p38 and ERK mitogen-activated protein kinases.
Intracellular phosphorylation of cis-4-methylsphingosine was previously shown to result in a metabolically stable compound that accumulates in Swiss 3T3 fibroblasts and mimics the mitogenic effect induced by the short-lived sphingosine metabolite, sphingosine-1-phosphate. In the present study incubation of neuroblastoma B104 cells with cis-4-methylsphingosine (10 microM) also resulted in an intracellular accumulation of its phosphorylated derivative that was, however, associated with the concentration-dependent induction of apoptosis, not observed after treatment with 10 microM of sphingosine-1-phosphate or sphingosine, respectively. In B104 cells, cis-4-methylsphingosine stimulated p38 mitogen-activated protein kinase (p38 MAPK) and simultaneously inhibited extracellular signal-regulated kinase (ERK), whereas sphingosine and sphingosine-1-phosphate only stimulated p38 MAPK without suppression of ERK. Inhibition of cis-4-methylsphingosine phosphorylation reduced both, apoptosis and concurrent regulation of mitogen-activated protein kinases (MAPKs), suggesting that the unusual accumulation of the phosphorylated sphingoid base was responsible for the biological effects. Furthermore, inhibition of p38 MAPK prevented cis-4-methylsphingosine-induced apoptosis, while suppression of the ERK pathway in the presence of sphingosine or sphingosine-1-phosphate resulted in apoptosis, indicating that the simultaneous opposite regulation of the two MAPKs was required for the induction of apoptosis.
Nätzker
Sven
S
Kekulé-lnstitut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany
Heinemann
Thomas
T
Figueroa-Perez
Santiago
S
Schnieders
Barbara
B
Schmidt
Richard R
RR
Sandhoff
Konrad
K
van Echten-Deckert
Gerhild
G
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004591:Electrophoresis, Polyacrylamide Gel; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
C106701:4-methylsphingosine 1-phosphate; D004273:DNA, Neoplasm; D014157:Transcription Factors; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013110:Sphingosine