Forkhead box O (FOXO) transcription factors induce apoptosis and regulate the production of reactive oxygen species (ROS). In neuronal tumour cells derived from advanced stage neuroblastoma, FOXO3 – the most prevalent FOXO in neuronal cells – is inactivated. Notably, however, chemotherapeutic agents can activate FOXO3 and induce apoptosis in neuronal tumour cells. Judith Hagenbuchner and colleagues (p. ), who have been investigating the molecular events that underlie FOXO3-induced apoptosis, now report that, in two neuroblastoma cell lines, FOXO3 represses mitochondrial respiration and induces cellular ROS in response to chemotherapy. They show that etoposide- and doxorubicin-induced elevation of cellular ROS depends on FOXO3 activation and on induction of its transcriptional target Bim (BCL2L11), a pro-apoptotic protein. Moreover, FOXO3 activation on its own induces two sequential ROS waves and Bim induction is essential for this phenomenon. Other experiments indicate that FOXO3 also activates a ROS rescue pathway by inducing the peroxiredoxin sestrin-3. This dual effect of FOXO3 might be crucial in the control of stress sensitivity and chemotherapy-induced cell death in neuronal tumour cells. Overall, these data identify ROS as important mediators of FOXO3-induced cell death in neuronal cells.
