Fig. 7

FOXO3 as a core component in regulating cellular stress: Various cellular stress conditions, including nutrition starvation, hypoxia, oxidative stress, and glucose metabolism, have a reciprocal relationship with FOXO3 in glioma. Nutrition starvation via activating Akt and deactivating FOXO3 causes radioresistance of glioma tumors. The relationship between ROS and FOXO3 is very complicated, and several molecules are involved. In GICs, the production of ROS induces p38-AMPK that, via degradation of Bmi1, activates FOXO3, resulting in differentiation and loss of self-renewal (red arrows). However, the role of ROS was shown to be double-edged in tumor progression in a way that their inhibition following PINK1-induced FOXO3 expression represses cell growth and prevents HIF-1α stabilization (blue lines). On the other hand, the study by He et al. showed that although TMZ, through producing ROS and inducing AIF1 expression, causes cell death followed by DNA double-strand breaks, in this condition, FOXO3 is activated and via upregulating BNIP3 and ATG5 prevents DNA from damage, therefore reverses this process (green lines). In addition, cells undergoing hypoxia in perinecrotic areas express FOXO3 more frequently, inhibiting the transcriptional activity of HIF-1α and p53. Since p53 can repress GLUT1 expression (a glucose transporter), inhibition of p53 by FOXO3 increases glucose consumption by tumor cells (dashed lines)