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.
Highlights
Gliomas account for >50% of all brain tumors and are by far the most common primary brain tumors in adults [1]
Our results revealed that 1 to 7 Amol/L selenite decreased viability in the tested glioma cell lines, whereas the human astrocytes were relatively resistant to the same doses (Fig. 1A), suggesting that selenite is preferentially cytotoxic to malignant glioma cells over normal astrocytes
We examined whether the cytotoxic effect of selenite on glioma cells is associated with induction of apoptosis
Summary
Gliomas account for >50% of all brain tumors and are by far the most common primary brain tumors in adults [1]. Despite the use of conventional treatments, including surgery, g-irradiation, and chemotherapy, the average life expectancy of glioma patients after the initial diagnosis is usually less than 1 year [2]. Caspasemediated apoptosis is the best-defined cell death program counteracting tumor growth, glioma cells are resistant to the conventional proapoptotic cancer therapeutics [3]. Effective treatment of malignant gliomas may rely on the development of novel strategies for inducing nonapoptotic cell death, such as autophagic cell death or cell death through mitotic catastrophe, which has been recently described as alternative death pathways [4]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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