The ATF6α arm of the Unfolded Protein Response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E 2 intracrine pathway
Open accessAbstract
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 ATF6α, IRE1α and PERK. We found that UPR inducers cause premature senescence through an increase in COX2 expression, and an overproduction of prostaglandin E 2 (PGE 2 ) in wild type fibroblasts but not in ATF6α invalidated ones. In replicative senescent fibroblasts, ATF6α and IRE1α 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 ATF6α. These effects of the ATF6α 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 ATF6α in the establishment and maintenance of cellular senescence in normal human fibroblasts via the up-regulation of a COX2/PGE 2 intracrine pathway.
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Senescent cells have an increased unfolded protein response.
“Accordingly, senescent cells have an increased unfolded protein response 45,54 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [54]
Senescent cells exhibit increased unfolded protein response indicative of endoplasmic reticulum stress.
“Senescent cells exhibit increased unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress [76,77].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [76]
Senescent cells undergo morphological changes: they become larger, flattened and irregular, more prominently in vitro than in vivo, caused by cytoskeletal rearrangements and changes in cell membrane composition.
“Finally, senescent cells also undergo morphological changes. Cells become larger and flattened out and acquire an irregular shape. These alterations are more prominent in vitro than in vivo and appear to be caused by cytoskeletal rearrangements [75,76] and changes in cell membrane composition [77].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [76]
Senescent cells are known to make prostaglandin E2.
“Senescent cells are known to produce prostaglandin E2 (PGE2) (Cormenier et al., 2018; Dagouassat et al., 2013; Kabir et al., 2016; Martien et al., 2013; Yang et al., 2011; Zdanov et al., 2007)”
From Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis (2021) · cites this paper as Cormenier et al., 2018
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- Authors
- Cormenier, J., Martin, N., Deslé, J., Salazar-Cardozo, C., Pourtier, A., Abbadie, C., & Pluquet, O.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Pluquet, Olivier
- Venue
- Mechanisms of Ageing and Development
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 170
- Pages
- 82-91
- ISSN
- 0047-6374 (ISSN-L)
- OpenAlex
- W2742876579
- Cited by
- 64
- References
- 12
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 7 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 9 · 2019: 5 · 2018: 5
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Mechanisms of Ageing and Development (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion, cc-by-nc-nd)
- Funders
- Ligue contre le Cancer (Comité de la Somme, Comité du Nord et Comité du Pas-De-Calais)
- Conseil Régional Nord/Pas-de-Calais
- European Regional Development Fund
- Association pour la Recherche sur le Cancer
- SIRIC OncoLille (INCa-DGOS-Inserm 6041)
- SFR Cancer Lille
- GEFLUC
- University of Lille 2
- Centre National de la Recherche Scientifique (CNRS)
- “Relations Internationales” of the University of Lille 1
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- replicative senescence, unfolded protein response, ATF6α, cyclooxygenase-2, prostaglandin E2, intracrine signaling, human fibroblasts, IRE1α, PERK, endoplasmic reticulum stress, cell size
- MeSH terms
- Fibroblasts, Humans, Dinoprostone, Signal Transduction, Cellular Senescence, Cyclooxygenase 2, Activating Transcription Factor 6, Unfolded Protein Response
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