Involvement of miltefosine-mediated ERK activation in glioma cell apoptosis through Fas regulation.
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.
Tewari
Richa
R
National Brain Research Centre, Manesar, Haryana, India.
Sharma
Vivek
V
Koul
Nitin
N
Sen
Ellora
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005434:Flow Cytometry; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; D010767:Phosphorylcholine; C039128:miltefosine; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins