Abstract
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is preferentially cytotoxic to cancer cells over normal cells. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL. Monensin (a polyether ionophore antibiotic that is widely used in veterinary medicine) and salinomycin (a compound that is structurally related to monensin and shows cancer stem cell-inhibiting activity) are currently recognized as anticancer drug candidates. In this study, we show that monensin effectively sensitizes various glioma cells, but not normal astrocytes, to TRAIL-mediated apoptosis; this occurs at least partly via monensin-induced endoplasmic reticulum (ER) stress, CHOP-mediated DR5 upregulation and proteasome-mediated downregulation of c-FLIP. Interestingly, other polyether antibiotics, such as salinomycin, nigericin, narasin and lasalocid A, also stimulated TRAIL-mediated apoptosis in glioma cells via ER stress, CHOP-mediated DR5 upregulation and c-FLIP downregulation. Taken together, these results suggest that combined treatment of glioma cells with TRAIL and polyether ionophore antibiotics may offer an effective therapeutic strategy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / pharmacology*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Astrocytes / drug effects
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Astrocytes / metabolism
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics*
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Cell Line, Tumor
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Down-Regulation / drug effects
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Endoplasmic Reticulum Stress / drug effects*
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Endoplasmic Reticulum Stress / genetics
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Glioma / drug therapy*
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Glioma / genetics
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Glioma / metabolism
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Humans
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Monensin / pharmacology*
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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Recombinant Proteins / pharmacology
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Up-Regulation / drug effects
Substances
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Anti-Bacterial Agents
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Antineoplastic Agents
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Recombinant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Monensin
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Proteasome Endopeptidase Complex