Fig. 2.

Therapy-induced senescence through the redox lens. (A) Cancer therapy induces high ROS levels and high oxidative stress in cells, causing the formation of telomeric 8-oxoguanine and telomeric oxidative damage. The telomeric lesion is sensed by DNA damage-sensing proteins, causing activation of p53/p21 pathways, resulting in senescence. (B) Genotoxic chemotherapy causes inhibition of DNA replication and the cell cycle, which induces global DNA damage. Double-stranded and single-stranded breaks are sensed by ATM and ATR respectively, inducing a p53 response that results in activation of the senescence program. The p53/p21 response may in turn induce production of ROS via mitochondrial dysfunction, causing increased oxidative DNA damage and persistent DNA damage response signaling. (C) SASP induces paracrine DNA damage as well as increased ROS production via upregulation of NADPH oxidase (NOX). In the absence of genotoxic drugs, ROS-induced DNA damage may play a more prominent role in driving p53 activation, resulting in paracrine senescence. (D) Senescent cells may accumulate at the invasive front of cancers and create high ROS levels, high oxidative stress, and a pro-inflammatory environment via the SASP. Pro-Inflammatory SASP factors then facilitate aggressive and invasive behavior, while the high ROS microenvironment creates an immunosuppresive, tumorigenic-permissive millieu. (E) A small subpopulation of therapy-induced senescent cells may re-enter the cell cycle via upregulation of Cdk1. These “senescence-escaped” cells are phenotypically different to their non-senescent counterparts prior to escape, and are characterized by high self-renewal capacity via upregulation of stemness-related genes. Upon escape from senescence, these cells possess a low ROS, high antioxidant phenotype, in contrast to the senescence-associated pro-oxidant environment. This suggests a redox-rewiring event associated with senescence escape with implications for tumor recurrence.