Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression
| Autor: | Meryem Bektas, Puneet S. Jolly, Jürgen Eberle, Christoph C. Geilen, Carola Müller, Sarah Spiegel |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Programmed cell death Ceramide Sphingosine Sphingosine kinase Down-Regulation Apoptosis Lipid signaling Biology Ceramides Sphingolipid Phosphotransferases (Alcohol Group Acceptor) chemistry.chemical_compound Proto-Oncogene Proteins c-bcl-2 chemistry UVB-induced apoptosis Ceramide kinase Tumor Cells Cultured Genetics Cancer research Humans Extracellular Signal-Regulated MAP Kinases Melanoma neoplasms Molecular Biology |
| Zdroj: | Oncogene. 24:178-187 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1208019 |
| Popis: | While most of the pharmacological therapies for melanoma utilize the apoptotic machinery of the cells, the available therapeutic options are limited due to the ability of melanoma cells to resist programmed cell death. Human melanoma cell lines A-375 and M186 are sensitive to ceramide- and Fas-induced cell death, while Mel-2a and M221 are resistant. We have now found that Mel-2a and M221 cells have a significantly higher ceramide/sphingosine-1-phosphate (S1P) ratio than A-375 and M186 cells. As sphingosine kinase (SphK) type 1 plays a critical role in determining the dynamic balance between the proapoptotic sphingolipid metabolite ceramide and the prosurvival S1P, we examined its role in apoptosis of melanoma cells. Increasing SphK1 expression reduced the sensitivity of A-375 melanoma cells to Fas- and ceramide-mediated apoptosis. Conversely, downregulation of SphK1 with small interfering RNA decreased the resistance of Mel-2a cells to apoptosis. Importantly, overexpression of the prosurvival protein Bcl-2 in A-375 cells markedly stimulated SphK1 expression and activity, while downregulation of Bcl-2 reduced SphK1 expression. This link between Bcl-2 and SphK1 might be an additional clue to chemotherapy resistance of malignant melanoma. |
| Databáze: | OpenAIRE |
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