Targeting X box-binding protein-1 (XBP1) enhances sensitivity of glioma cells to oxidative stress

Abstract

Reactive oxygen species (ROS) and oxidative stress are tightly linked with cancers including gliomas. We previously reported the protective role of X box-binding protein-1 (XBP1) against oxidative stress in both mouse embryofibroblasts and human Hela cells. This study was to investigate XBP1-mediated protection against oxidative stress in the treatment of gliomas. XBP1 expression levels were knocked down by siRNA transfection in the U251MG cell line. After exposure to hydrogen peroxide (H(2)O(2)) or the ROS inducer arsenic trioxide (As(2)O(3)), cell death, mitochondrial membrane potential (MMP) loss, ROS levels and the expression of several antioxidant molecules were examined. Expression of XBP1 and antioxidant molecules was also detected in surgically excised specimens from 30 patients with glioma, and 10 normal brain control specimens obtained at autopsy. XBP1 knockdown significantly enhanced the cell death fraction, MMP loss and ROS levels in H(2)O(2)- or As(2)O(3)-treated glioma cells, concomitant with a decrease of several antioxidant molecules including catalase. Moreover, the abundant expression of XBP1 and antioxidant molecules was also observed in human glioma specimens, as compared with normal brain tissues. XBP1 confers an important role in protection against oxidative stress in gliomas, potentially via up-regulation of antioxidant molecules such as catalase. Targeting XBP1 may have synergistic effects with ROS inducers on glioma treatment.