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Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cells via endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation.

Yoon, MJ; Kang, YJ; Kim, IY; Kim, EH; Lee, JA; Lim, JH; Kwon, TK; Choi, KS
Carcinogenesis, 34(8):1918-1928, 2013
Journal Title
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.
MeSH terms
Anti-Bacterial Agents/*pharmacologyAntineoplastic Agents/pharmacologyApoptosis/drug effects/geneticsAstrocytes/drug effects/metabolismCASP8 and FADD-Like Apoptosis Regulating Protein/*genetics/metabolismCell Line, TumorDown-Regulation/drug effectsEndoplasmic Reticulum Stress/*drug effects/geneticsGlioma/*drug therapy/genetics/metabolismHumansMonensin/*pharmacologyProteasome Endopeptidase Complex/drug effects/genetics/metabolismReceptors, TNF-Related Apoptosis-Inducing Ligand/*genetics/metabolismRecombinant Proteins/pharmacologyTNF-Related Apoptosis-Inducing Ligand/*pharmacologyUp-Regulation/drug effects
Appears in Collections:
Journal Papers > Research Organization > Genomic Instability Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
임, 준희최, 경숙
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