Autophagy-induced senescence is regulated by p38α signaling

Apoptosis and senescence are two mutually exclusive cell fate programs that can be activated by stress. The factors that instruct cells to enter into senescence or apoptosis are not fully understood, but both programs can be regulated by the stress kinase p38 alpha. Using an inducible system that specifically activates this pathway, we show that sustained p38 alpha activation suffices to trigger massive autophagosome formation and to enhance the basal autophagic flux. This requires the concurrent effect of increased mitochondrial reactive oxygen species production and the phosphorylation of the ULK1 kinase on Ser-555 by p38 alpha. Moreover, we demonstrate that macroautophagy induction by p38 alpha signaling determines that cancer cells preferentially enter senescence instead of undergoing apoptosis. In agreement with these results, we present evidence that the induction of autophagy by p38 alpha protects cancer cells from chemotherapy-induced apoptosis by promoting senescence. Our results identify a new mechanism of p38 alpha-regulated basal autophagy that controls the fate of cancer cells in response to stress.