The ATF6α arm of the Unfolded Protein Response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E2 intracrine pathway

Senescence is recognized as a cellular state acquired in response to various stresses. It occurs in correlation with the activation of the Unfolded Protein Response (UPR) pathway. However, the UPR targets which might relay the establishment of the senescent phenotype are not known. Herein, we investigated whether the up-regulation of the COX2 (PTGS2) limiting enzyme in the prostaglandin biosynthesis pathway, known to mediate cellular senescence in normal human fibroblasts, could be controlled by the UPR sensors ATF6 alpha, IRE1 alpha and PERK. We found that UPR inducers cause premature senescence through an increase in COX2 expression, and an over-production of prostaglandin E-2 (PGE(2)) in wild type fibroblasts but not in ATF6 alpha invalidated ones. In replicative senescent fibroblasts, ATF6 alpha and IRE1 alpha silencing abrogated COX2 up-regulation and PGE(2) production. The expanded ER and the large cell size characteristics of senescent fibroblasts were both reduced upon the invalidation of COX2 as well as ATF6 alpha. These effects of the ATF6 alpha invalidation were prevented by favoring the import of PGE(2), but not just by supplying extracellular PGE(2). Taken together, our results support a critical role of ATF6 alpha in the establishment and maintenance of cellular senescence in normal human fibroblasts via the up regulation of a COX2/PGE(2) intracrine pathway.