Journal
PHARMACOLOGICAL RESEARCH
Volume 95-96, Issue -, Pages 2-11Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2015.02.007
Keywords
ERK1/2; Apoptosis; Necroptosis; Alkylphospholipid analog; Edelfosine; Glioblastoma
Categories
Funding
- Spanish Ministerio de Ciencia e Innovacion [SAF2011-30518]
- Spanish Ministerio de Economia y Competitividad
- Junta de Castilla y Leon [CSI052A11-2, CSI221Al2-2]
- Red Tematica de Investigacion Cooperativa en Cancer, Instituto de Salud Carlos III [RD12/10036/0065]
- Fondo Europeo de Desarrollo Regional of the European Union
- Fundacao para a Ciencia e Tecnologia [SFRH/BD/46330/2008]
- Portuguese Ministerio da Ciencia, Tecnologia e Ensino Superior
- European Community [HEALTH-F2-2011-256986]
- Fundacao para a Ciencia e Tecnologia (Ministerio da Ciencia, Tecnologia e Ensino Superior of Portugal)
- Fundação para a Ciência e a Tecnologia [SFRH/BD/46330/2008] Funding Source: FCT
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Glioblastoma is characterized by constitutive apoptosis resistance and survival signaling expression, but paradoxically is a necrosis-prone neoplasm. Incubation of human U118 glioblastoma cells with the antitumor alkylphospholipid analog edelfosine induced a potent necrotic cell death, whereas apoptosis was scarce. Preincubation of U118 cells with the selective MEK1/2 inhibitor U0126, which inhibits MEK1/2 mediated activation of ERK1/2, led to a switch from necrosis to caspase-dependent apoptosis following edelfosine treatment. Combined treatment of U0126 and edelfosine totally inhibited ERK1/2 phosphorylation, and led to RIPK1 and RelA/NF-kappa B degradation, together with a strong activation of caspase-3 and -8. This apoptotic response was accompanied by the activation of the intrinsic apoptotic pathway with mitochondrial transmembrane potential loss, Bcl-x(L) degradation and caspase-9 activation. Inhibition of ERK phosphorylation also led to a dramatic increase in edelfosine-induced apoptosis when the alkylphospholipid analog was used at a low micromolar range, suggesting that ERK phosphorylation acts as a potent regulator of apoptotic cell death in edelfosine-treated U118 cells. These data show that inhibition of MEK1/2-ERK1/2 signaling pathway highly potentiates edelfosine-induced apoptosis in glioblastoma U118 cells and switches the type of edelfosine-induced cell death from necrosis to apoptosis. (C) 2015 Elsevier Ltd. All rights reserved.
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