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Cancer Res, July 1, 2007, 67; 6314 | doi: 10.1158/0008-5472.CAN-06-4217 Sodium Selenite Induces Superoxide-Mediated Mitochondrial Damage and Subsequent Autophagic Cell Death in Malignant Glioma Cells

Abstract

Eun Hee Kim¹, Seonghyang Sohn², Hyuk Jae Kwon², Seung U. Kim^3,4, Min-Jung Kim⁵, Su-Jae Lee⁵, and Kyeong Sook Choi^1,3

¹Department of Molecular Science and Technology and ²Lab of Cell Biology, Institute for Medical Sciences and ³Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea; ⁴Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada; and 5Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

Requests for reprints:

Kyeong Sook Choi, Department of Molecular Science and Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea.

Abstract

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.[Cancer Res 2007;67(13):6314-24]

selenite, autophagic cell death, mitochondria, superoxide anion, glioma

논문정보

형식Research article
게재일2007년 07월 (BRIC 등록일 2016-03-14)
연구진국내(교신)+국외 연구진
분야
피인용횟수120회 이상 인용된 논문

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