ERK1/2 acts as a switch between necrotic and apoptotic cell death in ether phospholipid edelfosine-treated glioblastoma cells.
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-κB 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-xL 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.
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Centre for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.
Sara
S
Melo-Lima
Centre for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000 Coimbra, Portugal.
Maria C
MC
Lopes
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, E-37007 Salamanca, Spain. Electronic address: fmollin@usal.es.
Faustino
F
Mollinedo
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D009336:Necrosis; D009570:Nitriles / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010766:Phosphorylation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000096:biosynthesis
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D010742:Phospholipid Ethers; C113580:U 0126; C026659:edelfosine; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
Alkylphospholipid analog; Apoptosis; ERK1/2; Edelfosine; Glioblastoma; Necroptosis