Sense and Sensitivity: FOXO and ROS in Cancer Development and Treatment

Forkhead box O (FOXO) transcription factors are at the center of an emerging paradigm that links longevity, cell fate, and tumor development. Key to these processes is the ability of FOXO to regulate, and be regulated by, oxidative stress. Perturbation of the mechanisms that tightly couple reactive oxygen species (ROS) production, oxidative stress signaling, and FOXO activity to the subsequent cellular response is a pivotal step in cancer development and progression. Consequently, the ROS-FOXO pathway is a major therapeutic target in cancer, not only as it mediates the cellular response to chemotherapy, but also because it underpins drug resistance. As the intimate and reciprocal relation between FOXO and ROS is being unravelled, new opportunities arise to develop more-effective cancer treatments that circumvent resistance to the conventional cytotoxic drugs. Antioxid. Redox Signal. 14, 675-687.