Autophagy-induced senescence is regulated by p38α signaling

Abstract

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 p38α. Using an inducible system that specifically activates this pathway, we show that sustained p38α 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 p38α. Moreover, we demonstrate that macroautophagy induction by p38α 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 p38α protects cancer cells from chemotherapy-induced apoptosis by promoting senescence. Our results identify a new mechanism of p38α-regulated basal autophagy that controls the fate of cancer cells in response to stress.

Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy

“…Autophagy is also considered a "first or early responder" to cellular stress (in this case, DNA damage) resulting from the exposure to cancer chemotherapeutics or radiation [34][35][36]. It has been suggested that the regulatory pathways of both processes are intertwined [37][38][39], and it is clear that senescent cells develop abundant acidic vacuoles [40]. However, the relationship of the autophagic response to the induction and the maintenance of senescence does not appear to be consistent across the types of stimuli that promote these responses or the cell lines in which they have been studied [19].…”

Understanding MAPK Signaling Pathways in Apoptosis

“…The role of JNK in autophagy and other types of cell death was also reviewed [38]. Recently, it has been reported that sustained p38α activation induces autophagy but determines that cancer cells preferentially enter senescence instead of apoptosis [39].…”

“…activation induces autophagy but determines that cancer cells preferentially enter senescence instead of apoptosis [39].…”

Pterostilbene Sensitizes Cisplatin-Resistant Human Bladder Cancer Cells with Oncogenic HRAS

“…Recent studies have found that senescence [ 57 ] and autophagy [ 58 ] inhibit cancer progression under certain circumstances, which makes them attractive targets for cancer treatment. However, the relationship between autophagy and senescence and whether autophagy positively regulates senescence are context-dependent and inconclusive [ 59 , 60 , 61 ]. Goehe and colleagues [ 61 ] reported that senescence and autophagy happened collaterally, and inhibition of the latter delayed but not abrogated senescence.…”