Abstract 999: Potential role of reactive oxygen species in mediating glioblastoma stem cell differentiation

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of cancer stem cells, which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. In this study, we used several stem-like glioblastoma cell lines (GSC11, GSC23 and GBM3752) derived from patients’ tissues by typical neurosphere culture system, and showed that addition of fetal bovine serum (FBS) to the medium induced an increase of ROS, leading to aberrant differentiation and decreases of stem cell markers such as CD133. We found that exposure of glioblastoma stem cells (GSCs) to serum induces their differentiation through activation of mitochondrial respiration, leading to an increase in superoxide (O2−) generation and a profound reactive oxygen species (ROS) stress response manifested by upregulation of oxidative stress response pathway. This increase in mitochondrial ROS leads to a down-regulation of molecules including SOX2, and Olig2, and Notch1 that are important for stem cell function and an upregulation of mitochondrial superoxide dismutase SOD2 that converts O2− to H2O2. Neutralization of ROS by antioxidant N-acetylcysteine in the serum-treated GSCs suppresses the increase of superoxide and largely rescues the expression of SOX2, Olig2, and Notch1, and prevents the serum-induced differentiation phenotype. Upregulation of ROS by chemical disruption of mitochondrial electron respiration chain induced further decrease of CD133. Our study suggests that mitochondrial function and cellular redox status may profoundly affect the fates of glioblastoma stem cells, and that modulation of ROS generation may be an effective way to impact CSCs, which may provide a new basis for developing novel therapeutic approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 999. doi:1538-7445.AM2012-999