fig2

Figure 2. The SASP is sustained by a positive feedback loop constituted by p90RSK-ERK5 S496^[77]. In the cells exposed to chemoradiation, a sustained SASP is maintained for the long term via the positive feedback loop. (1) The chemoradiation induces the production of mitochondrial ROS (mtROS) in the mitochondria, which in turn (2) increases the p90RSK phosphorylation leading to ERK5 S496 phosphorylation, the decreased transcriptional activity of ERK5, and reduced NRF2 transcriptional activity. Consequently, the (3) level of cellular antioxidant is dropped, causing (4) telomeric DNA damage, (5) PARP activation, and leading to NAD⁺ depletion. (6) The NAD⁺ depletion causes mitochondrial dysfunction, along with severe ATP depletion, termed reversible mitochondrial (mt) stunning, which further (7) causes mtROS production and reactivates the same p90RSK-ERK5-NRF2 module, thus constituting a positive feedback loop. This figure was modified from the figure in reference^[77].