Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKα dependent manner

Oxidative stress induces not only senescence but also autophagy in a variety of mammalian cells. However, the relationship between these two has not been well established and thus, was investigated in the present study using WI38 human diploid fibroblasts (WI38 cells) as a model system. Our results showed that exposure of WI38 cells to H ₂O ₂ induced both senescence and autophagy. Downregulation of autophagy protein 5 (Atg5) with Atg5 siRNA inhibited not only autophagy but also senescence induced by H ₂O ₂. Further studies showed that Atg5 regulates H ₂O ₂-induced senescence primarily by up-regulating the expression of p21 at the level of post-transcription. In addition, we examined the mechanisms by which H ₂O ₂ induces autophagy in WI38 cells. Our results revealed that H ₂O ₂ increases autophagy independent of the mammalian target of rapamycin (mTOR) negative feedback pathway. Instead, the induction of autophagy by H ₂O ₂ depends on the induction of intracellular production of reactive oxygen species (ROS) and activation of the p38 mitogen-activated protein kinase α (p38 MAPKα) pathway.