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Involvement of miltefosine‐mediated ERK activation in glioma cell apoptosis through Fas regulation
Author(s) -
Tewari Richa,
Sharma Vivek,
Koul Nitin,
Sen Ellora
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05625.x
Subject(s) - miltefosine , fadd , mapk/erk pathway , apoptosis , death domain , cancer research , kinase , programmed cell death , biology , bcl xl , microbiology and biotechnology , chemistry , immunology , caspase , biochemistry , leishmaniasis , visceral leishmaniasis
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 γH2AX‐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.