Pivotal role for ROS activation of p38 MAPK in the control of differentiation and tumor-initiating capacity of glioma-initiating cells

• The ROS-p38 axis plays a role in the control of stemness of glioma-initiating cells.
• p38-dependent Bmi1 degradation is responsible for ROS-induced loss of self-renewal.
• p38-dependent FoxO3 activation is responsible for ROS-induced differentiation.
• The ROS-p38 axis controls the tumor-initiating capacity of glioma-initiating cells.

Reactive oxygen species (ROS) are involved in various aspects of cancer cell biology, yet their role in cancer stem cells (CSCs) has been poorly understood. In particular, it still remains unclear whether and how ROS control the self-renewal/differentiation process and the tumor-initiating capacity of CSCs. Here we show that ROS-mediated activation of p38 MAPK plays a pivotal role in the control of differentiation and tumor-initiating capacity of glioma-initiating cells (GICs) derived from human glioblastomas. Mechanistically, ROS triggered p38-dependent Bmi1 protein degradation and FoxO3 activation in GICs, which were shown to be responsible for the loss of their self-renewal capacity and differentiation, respectively. Thus, the results suggest that Bmi1 and FoxO3 govern distinct phases of transition from undifferentiated to fully differentiated cells. Furthermore, we also demonstrate in this study that oxidative stress deprives GICs of their tumor-initiating capacity through the activation of the ROS–p38 axis. As such, this is the first study to the best of our knowledge to delineate how ROS control self-renewal/differentiation and the tumor-initiating capacity of stem-like cancer cells. This study also suggests that targeting of the ROS–p38 axis could be a novel approach in the development of therapeutic strategies against gliomas, represented by glioblastoma.

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