This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, E. H. Articles by Choi, K. S. Search for Related Content PubMed PubMed Citation Articles by Kim, E. H. Articles by Choi, K. S.

Sodium Selenite Induces Superoxide-Mediated Mitochondrial Damage and Subsequent Autophagic Cell Death in Malignant Glioma Cells

¹ Department of Molecular Science and Technology and ² Lab of Cell Biology, Institute for Medical Sciences and ³ Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea; ⁴ Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada; and ⁵ Laboratory 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. Phone: 82-31-219-4552; Fax: 82-31-219-4401; E-mail: kschoi{at}ajou.ac.kr.

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]

This article has been cited by other articles:

				E. Olm, A. P. Fernandes, C. Hebert, A.-K. Rundlof, E. H. Larsen, O. Danielsson, and M. Bjornstedt Extracellular thiol-assisted selenium uptake dependent on the xc- cystine transporter explains the cancer-specific cytotoxicity of selenite PNAS, July 7, 2009; 106(27): 11400 - 11405. [Abstract] [Full Text] [PDF]

				H.-O. Byun, N.-K. Han, H.-J. Lee, K.-B. Kim, Y.-G. Ko, G. Yoon, Y.-S. Lee, S.-I. Hong, and J.-S. Lee Cathepsin D and Eukaryotic Translation Elongation Factor 1 as Promising Markers of Cellular Senescence Cancer Res., June 1, 2009; 69(11): 4638 - 4647. [Abstract] [Full Text] [PDF]

				W. Zhuang, Z. Qin, and Z. Liang The role of autophagy in sensitizing malignant glioma cells to radiation therapy Acta Biochim Biophys Sin, May 1, 2009; 41(5): 341 - 351. [Abstract] [Full Text] [PDF]

				M. Gao, P. Y. Yeh, Y.-S. Lu, C.-H. Hsu, K.-F. Chen, W.-C. Lee, W.-C. Feng, C.-S. Chen, M.-L. Kuo, and A.-L. Cheng OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species-Related Autophagy in Hepatocellular Carcinoma Cancer Res., November 15, 2008; 68(22): 9348 - 9357. [Abstract] [Full Text] [PDF]

				W.-L. Yen and D. J. Klionsky How to Live Long and Prosper: Autophagy, Mitochondria, and Aging Physiology, October 1, 2008; 23(5): 248 - 262. [Abstract] [Full Text] [PDF]

				K. Singletary and J. Milner Diet, Autophagy, and Cancer: A Review Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1596 - 1610. [Abstract] [Full Text] [PDF]