Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells.
Malignant gliomas are resistant to various proapoptotic therapies, such as radiotherapy and conventional chemotherapy. In this study, we show that selenite is preferentially cytotoxic to various human glioma cells over normal astrocytes via autophagic cell death. Overexpression of Akt, survivin, XIAP, Bcl-2, or Bcl-xL failed to block selenite-induced cell death, suggesting that selenite treatment may offer a potential therapeutic strategy against malignant gliomas with apoptotic defects. Before selenite-induced cell death in glioma cells, disruption of the mitochondrial cristae, loss of mitochondrial membrane potential, and subsequent entrapment of disorganized mitochondria within autophagosomes or autophagolysosomes along with degradation of mitochondrial proteins were noted, showing that selenite induces autophagy in which mitochondria serve as the main target. At the early phase of selenite treatment, high levels of superoxide anion were generated and overexpression of copper/zinc superoxide dismutase or manganese superoxide dismutase, but not catalase, significantly blocked selenite-induced mitochondrial damage and subsequent autophagic cell death. Furthermore, treatment with diquat, a superoxide generator, induced autophagic cell death in glioma cells. Taken together, our study clearly shows that superoxide anion generated by selenite triggers mitochondrial damage and subsequent mitophagy, leading to irreversible cell death in glioma cells.
Kim
Eun Hee
EH
Department of Molecular Science and Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea.
Sohn
Seonghyang
S
Kwon
Hyuk Jae
HJ
Kim
Seung U
SU
Kim
Min-Jung
MJ
Lee
Su-Jae
SJ
Choi
Kyeong Sook
KS
D017209:Apoptosis; D001343:Autophagy; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D018038:Sodium Selenite / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D051020:bcl-X Protein / Q000378:metabolism
D051020:bcl-X Protein; D013481:Superoxides; D018038:Sodium Selenite