MAPK15 modulates NRF2 activity and the expression of its target genes: a novel mechanism for cellular responses to oxidative stress

Reactive Oxygen Species (ROS) are not deleterious for cells when they are maintained at low level, indeed they fulfill important signaling function. However, a substantial increase in ROS can disrupt redox homeostasis and, consequently, lead to oxidative stress that is correlated to numerous human diseases, including tumors. The nuclear factor erythroid 2–related factor 2 (NRF2) is the master regulator of cellular antioxidant responses, activating the transcription of genes that protect the cell from damage caused by free radicals, toxins, and environmental stressors. This protective role is essential for maintaining genome integrity, thereby acting as a tumor suppressor. However, in many advanced cancers, especially non-small cell lung cancer (NSCLC), NRF2 is chronically hyperactivated and this persistent activation has pro-tumorigenic effects, conferring resistance to oxidative stress and chemotherapeutic drugs, promoting cell proliferation, survival, and tumor progression. Here, we show that endogenous mitogen-activated protein kinase 15 (MAPK15) phosphorylates NRF2, promoting its stabilization at protein level and its nuclear translocation, sustaining, in turn, NRF2 transcriptional activity and the consequent expression of cytoprotective antioxidant genes. On the contrary, when MAPK15 is downregulated, the cell does not properly respond to oxidative insult and ROS and DNA damage increase. This novel MAPK15-dependent mechanism could be an interesting target for pharmacological or genetic therapies against diseases correlated to oxidative stress. Still, for future applicability, the specific mechanism of modulation must be always evaluated based on the biological context, since the upregulation of MAPK15, and the consequent maintenance of the antioxidant response may both protects against ROS and DNA damage, thereby potentially preventing tumorigenesis, but it may also be deleterious in some pathological contexts where NRF2 upregulation supports cancer development and drug resistance.