Involvement of miltefosine-mediated ERK activation in glioma cell apoptosis through Fas regulation
| Autor: | Vivek Sharma, Ellora Sen, Richa Tewari, Nitin Koul |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Fas-Associated Death Domain Protein Phosphorylcholine Blotting Western Antineoplastic Agents Apoptosis Biochemistry p38 Mitogen-Activated Protein Kinases Cellular and Molecular Neuroscience Membrane Microdomains Cell Line Tumor Humans Immunoprecipitation FADD fas Receptor Extracellular Signal-Regulated MAP Kinases Caspase Death domain biology Kinase Glioma Flow Cytometry Enzyme Activation Death-inducing signaling complex Cancer research biology.protein ras Proteins Signal transduction |
| Zdroj: | Journal of neurochemistry. 107(3) |
| ISSN: | 1471-4159 |
| Popis: | The anti-neoplastic property of alkyl phospholipids has been tested for the treatment of several malignancies. In this study, we evaluated the efficacy of miltefosine (Hexadecylphosphocholine--an alkyl phospholipids analogue) on glioblastoma multiforme. In this study, we demonstrate that miltefosine-induced apoptosis is accompanied by elevated Fas, Fas-associated death domain (FADD) expression, caspase-8 activity and the increased distribution of Fas and FADD towards lipid raft microdomain to form death inducing signaling complex. Treatment with miltefosine resulted in increase in Ras, extracellular signal-regulated kinase (ERK) and p38MAPK activity. Expression of dominant-negative Ras (Ras N17) attenuated miltefosine-mediated apoptosis. Although inhibition of both ERK and p38MAPK decreased the pro-apoptotic effects of miltefosine, it was the inhibition of ERK and not p38MAPK activation that decreased Fas and FADD expression. An ERK-dependent increase in the expression of gammaH2AX-involved in response to DNA double-stranded breaks was also observed. Taken together, our findings suggest the involvement of ERK activation in miltefosine-induced glioma cell apoptosis. |
| Databáze: | OpenAIRE |
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